Sublobar Resection, Stereotactic Body Radiation Therapy, and Percutaneous Ablation Provide Comparable Outcomes for Lung Metastasis-Directed Therapy.

BACKGROUND: Prolonged survival of patients with metastatic disease has furthered interest in metastasis-directed therapy (MDT). RESEARCH QUESTION: There is a paucity of data comparing lung MDT modalities. Do outcomes among sublobar resection (SLR), stereotactic body radiation therapy (SBRT), and percutaneous ablation (PA) for lung metastases vary in terms of local control and survival? STUDY DESIGN AND METHODS: Medical records of patients undergoing lung MDT at a single cancer center between January 2015 and December 2020 were reviewed. Overall survival, local progression, and toxicity outcomes were collected. Patient and lesion characteristics were used to generate multivariable models with propensity weighted analysis. RESULTS: Lung MDT courses (644 total: 243 SLR, 274 SBRT, 127 PA) delivered to 511 patients were included with a median follow-up of 22 months. There were 47 local progression events in 45 patients, and 159 patients died. Two-year overall survival and local progression were 80.3% and 63.3%, 83.8% and 9.6%, and 4.1% and 11.7% for SLR, SBRT, and PA, respectively. Lesion size per 1 cm was associated with worse overall survival (hazard ratio, 1.24; P = .003) and LP (hazard ratio, 1.50; P < .001). There was no difference in overall survival by modality. Relative to SLR, there was no difference in risk of local progression with PA; however, SBRT was associated with a decreased risk (hazard ratio, 0.26; P = .023). Rates of severe toxicity were low (2.1%-2.6%) and not different among groups. INTERPRETATION: This study performs a propensity weighted analysis of SLR, SBRT, and PA and shows no impact of lung MDT modality on overall survival. Given excellent local control across MDT options, a multidisciplinary approach is beneficial for patient triage and longitudinal management.

Development and validation of a unifying pre-treatment decision tool for intracranial and extracranial metastasis-directed radiotherapy.

Background: Though metastasis-directed therapy (MDT) has the potential to improve overall survival (OS), appropriate patient selection remains challenging. We aimed to develop a model predictive of OS to refine patient selection for clinical trials and MDT. Patients and methods: We assembled a multi-institutional cohort of patients treated with MDT (stereotactic body radiation therapy, radiosurgery, and whole brain radiation therapy). Candidate variables for recursive partitioning analysis were selected per prior studies: ECOG performance status, time from primary diagnosis, number of additional non-target organ systems involved (NOS), and intracranial metastases. Results: A database of 1,362 patients was assembled with 424 intracranial, 352 lung, and 607 spinal treatments (n=1,383). Treatments were split into training (TC) (70%, n=968) and internal validation (IVC) (30%, n=415) cohorts. The TC had median ECOG of 0 (interquartile range [IQR]: 0-1), NOS of 1 (IQR: 0-1), and OS of 18 months (IQR: 7-35). The resulting model components and weights were: ECOG = 0, 1, and > 1 (0, 1, and 2); 0, 1, and > 1 NOS (0, 1, and 2); and intracranial target (2), with lower scores indicating more favorable OS. The model demonstrated high concordance in the TC (0.72) and IVC (0.72). The score also demonstrated high concordance for each target site (spine, brain, and lung). Conclusion: This pre-treatment decision tool represents a unifying model for both intracranial and extracranial disease and identifies patients with the longest survival after MDT who may benefit most from aggressive local therapy. Carefully selected patients may benefit from MDT even in the presence of intracranial disease, and this model may help guide patient selection for MDT.

New School Technology Meets Old School Technique: Intensity Modulated Proton Therapy and Laparoscopic Pelvic Sling Facilitate Safe and Efficacious Treatment of Pelvic Sarcoma.

Purpose: Small bowel tolerance may be dose-limiting in the management of some pelvic and abdominal malignancies with curative-intent radiation therapy. Multiple techniques previously have been attempted to exclude the small bowel from the radiation field, including the surgical insertion of an absorbable mesh to serve as a temporary pelvic sling. This case highlights a clinically meaningful application of this technique with modern radiation therapy. Methods and Materials: A patient with locally invasive, unresectable high-grade sarcoma of the right pelvic vasculature was evaluated for definitive radiation therapy. The tumor immediately abutted the small bowel. The patient underwent laparoscopic placement of a mesh sling to retract the abutting small bowel and subsequently completed intensity modulated proton therapy. Results: The patient tolerated the mesh insertion procedure and radiation therapy well with no significant toxic effects. The combination approach achieved excellent dose metrics, and the patient has no evidence of progression 14 months out from treatment. Conclusions: The combination of mesh as a pelvic sling and proton radiation therapy enabled the application of a curative dose of radiation therapy and should be considered for patients in need of curative-intent radiation when the bowel is in close proximity to the target.

Cardiac Magnetic Resonance Imaging and Blood Biomarkers for Evaluation of Radiation-Induced Cardiotoxicity in Patients With Breast Cancer: Results of a Phase 2 Clinical Trial.

PURPOSE: Radiation therapy (RT) can increase the risk of cardiac events in patients with breast cancer (BC), but biomarkers predicting risk for developing RT-induced cardiac disease are currently lacking. We report results from a prospective clinical trial evaluating early magnetic resonance imaging (MRI) and serum biomarker changes as predictors of cardiac injury and risk of subsequent cardiac events after RT for left-sided disease. METHODS: Women with node-negative and node-positive (N-/+) left-sided BC were enrolled on 2 institutional review board (IRB)-approved protocols at 2 institutions. MRI was conducted pretreatment (within 1 week of starting radiation), at the end of treatment (last day of treatment ±1 week), and 3 months after the last day of treatment (±2 weeks) to quantify left and right ventricular volumes and function, myocardial fibrosis, and edema. Perfusion changes during regadenoson stress perfusion were also assessed on a subset of patients (n = 28). Serum was collected at the same time points. Whole heart and cardiac substructures were contoured using CT and MRI. Models were constructed using baseline cardiac and clinical risk factors. Associations between MRI-measured changes and dose were evaluated. RESULTS: Among 51 women enrolled, mean heart dose ranged from 0.80 to 4.7 Gy and mean left ventricular (LV) dose from 1.1 to 8.2 Gy, with mean heart dose 2.0 Gy. T1 time, a marker of fibrosis, and right ventricular (RV) ejection fraction (EF) significantly changed with treatment; these were not dose dependent. T2 (marker of edema) and LV EF did not significantly change. No risk factors were associated with baseline global perfusion. Prior receipt of doxorubicin was marginally associated with decreased myocardial perfusion after RT (P = .059), and mean MHD was not associated with perfusion changes. A significant correlation between baseline IL-6 and mean heart dose (MHD) at the end of RT (ρ 0.44, P = .007) and a strong trend between troponin I and MHD at 3 months post-treatment (ρ 0.33, P = .07) were observed. No other significant correlations were identified. CONCLUSIONS: In this prospective study of women with left-sided breast cancer treated with contemporary treatment planning, cardiac radiation doses were very low relative to historical doses reported by Darby et al. Although we observed significant changes in T1 and RV EF shortly after RT, these changes were not correlated with whole heart or substructure doses. Serum biomarker analysis of cardiac injury demonstrates an interesting trend between markers and MHD that warrants further investigation.

Intact SMAD-4 is a predictor of increased locoregional recurrence in upfront resected pancreas cancer receiving adjuvant therapy.

BACKGROUND: Previous reports suggest that intact SMAD4 expression is associated with a locally aggressive pancreas cancer phenotype. The objectives of this work were to determine the frequency of intact SMAD4 and its association with patterns of recurrence in patients with upfront resected pancreas cancer receiving adjuvant therapy. METHODS: A tissue microarray was constructed using resected specimens from patients who underwent upfront surgery and adjuvant gemcitabine with no neoadjuvant treatment for pancreas cancer. SMAD4 expression was determined by immunohistochemical staining. Associations of SMAD4 expression and clinicopathologic parameters with clinical outcomes were evaluated using Cox proportional hazard models. RESULTS: One hundred twenty-seven patients were included with a median follow up of 5.7 years. Most patients had stage ≥ pT3 tumors (75%) and pN1 (68%). All patients received adjuvant gemcitabine, and 79% of patients received adjuvant chemoradiotherapy. Ten (8%) patients had intact SMAD4 expression. Grade was the only clinicopathologic parameter statistically associated with SMAD4 expression (P=0.05). Median overall survival was 2.1 years. On univariate analysis, SMAD4 expression was associated with increased locoregional recurrence (hazard ratio 7.0, P<0.01, 95% confidence interval: 2.8-18.0) but not distant recurrence (P=0.06) or overall survival (P=0.73). On multivariable analysis, SMAD4 expression (hazard ratio 9.6, P<0.01, 95% confidence interval: 3.7-24.8) and adjuvant chemoradiotherapy (hazard ratio 0.3, P=0.01, 95% confidence interval: 0.1-0.8) were associated with higher and lower locoregional recurrence, respectively. CONCLUSIONS: In patients with upfront resected pancreas cancer, SMAD4 expression was associated with an increased risk of locoregional recurrence. Prospective evaluation of the frequency of SMAD4 expression and validation of its predictive utility is warranted.

Predicting Adverse Pathologic Features and Clinical Outcomes of Resectable Pancreas Cancer With Preoperative CA 19-9.

BACKGROUND: We evaluated preoperative CA 19-9 levels in patients with resected pancreatic cancer to analyze whether they were predictive of clinical outcomes and could help select patients for additional therapy. We hypothesized that elevated CA 19-9 would be associated with worse pathologic findings and oncologic outcomes. METHODS: This study assessed 509 patients with non-metastatic pancreatic adenocarcinoma who underwent resection at our institution from 1995-2011 and had preoperative CA 19-9 recorded. No patients received neoadjuvant therapy. CA 19-9 level was analyzed as a continuous and a dichotomized (> vs. ≤ 55 U/mL) variable using logistic and Cox models. RESULTS: Median follow-up was 7.8 years, and the median age was 66 years (33-90). 64% of patients had elevated preoperative CA 19-9 (median: 141 U/mL), that did not correlate with bilirubin level or tumor size. Most patients had ≥ T3 tumors (72%) and positive lymph nodes (62%). The rate of incomplete (R1 or R2) resection was 19%. Increasing preoperative CA 19-9 was associated with extra-pancreatic extension (p=0.0005), lymphovascular space invasion (p=0.0072), incomplete resection [HR (95% CI) 2.0 (1.2-3.5)], and lower OS [HR = 1.6 (1.3-2.0)]. Each doubling in preoperative CA 19-9 value was associated with an 8.3% increased risk of death [HR = 1.08 (1.02-1.15)] and a 10.0% increased risk of distant recurrence [HR = 1.10 (1.02-1.19)]. Patients classified as non-secretors had comparable outcomes to patients with normal CA 19-9. CONCLUSIONS: Elevated preoperative CA 19-9 level was associated with adverse pathologic features, incomplete resection, and inferior clinical outcomes. Neither tumor size nor bilirubin confound an elevated CA 19-9 level. Preoperative CA 19-9 level may help select patients for additional therapy.

Medulloblastoma therapy generates risk of a poorly-prognostic H3 wild-type subgroup of diffuse intrinsic pontine glioma: a report from the International DIPG Registry.

With improved survivorship in medulloblastoma, there has been an increasing incidence of late complications. To date, no studies have specifically addressed the risk of radiation-associated diffuse intrinsic pontine glioma (DIPG) in medulloblastoma survivors. Query of the International DIPG Registry identified six cases of DIPG with a history of medulloblastoma treated with radiotherapy. All patients underwent central radiologic review that confirmed a diagnosis of DIPG. Six additional cases were identified in reports from recent cooperative group medulloblastoma trials (total n = 12; ages 7 to 21 years). From these cases, molecular subgrouping of primary medulloblastomas with available tissue (n = 5) revealed only non-WNT, non-SHH subgroups (group 3 or 4). The estimated cumulative incidence of DIPG after post-treatment medulloblastoma ranged from 0.3-3.9%. Posterior fossa radiation exposure (including brainstem) was greater than 53.0 Gy in all cases with available details. Tumor/germline exome sequencing of three radiation-associated DIPGs revealed an H3 wild-type status and mutational signature distinct from primary DIPG with evidence of radiation-induced DNA damage. Mutations identified in the radiation-associated DIPGs had significant molecular overlap with recurrent drivers of adult glioblastoma (e.g. NRAS, EGFR, and PTEN), as opposed to epigenetic dysregulation in H3-driven primary DIPGs. Patients with radiation-associated DIPG had a significantly worse median overall survival (median 8 months; range 4-17 months) compared to patients with primary DIPG. Here, it is demonstrated that DIPG occurs as a not infrequent complication of radiation therapy in survivors of pediatric medulloblastoma and that radiation-associated DIPGs may present as a poorly-prognostic distinct molecular subgroup of H3 wild-type DIPG. Given the abysmal survival of these cases, these findings provide a compelling argument for efforts to reduce exposure of the brainstem in the treatment of medulloblastoma. Additionally, patients with radiation-associated DIPG may benefit from future therapies targeted to the molecular features of adult glioblastoma rather than primary DIPG.

No microstructural white matter alterations in chronic and episodic migraineurs: a case-control diffusion tensor magnetic resonance imaging study.

BACKGROUND: In patients with episodic migraine (EM), diffusion tensor imaging (DTI) revealed microstructural white matter alterations in various brain regions related to pain processing. Some of these changes were correlated with migraine duration and attack frequency, suggesting that migraine is a progressive disease with proceeding structural alterations of the brain. This study aimed to identify possible microstructural white matter alterations in patients with chronic migraine (CM) using DTI. We hypothesized that alterations in DTI are more pronounced in patients with CM compared with EM. METHODS: Individually, age- and sex-matched subjects with CM without aura, EM without aura, and healthy controls (n = 21 per group) underwent conventional head magnetic resonance imaging and DTI imaging in a 3T MRI scanner and were included in analysis. DTI data were analyzed using a tract-based spatial statistics approach. Fractional anisotropy (FA), mean diffusivity, radial diffusivity, and axial diffusivity were compared between subjects with CM and EM, CM and controls, EM and controls, as well as between all subjects with migraine (EM + CM) and controls. RESULTS: In chronic migraineurs (mean age 49 ± 7.5 years), we did not find any statistically significant difference (P < .05, threshold-free cluster enhancement corrected for multiple comparison) in DTI-derived parameters in comparison with episodic migraineurs (FA: P > .245) and healthy controls (FA: P > .099). In contrast to previous DTI studies, we did not find alterations in DTI-derived indices in subjects with EM compared with healthy controls (FA: P > .486). CONCLUSIONS: No microstructural white matter changes could be observed in middle-aged chronic and episodic migraineurs using DTI. CM does not seem to be a risk factor for progressive microstructural changes in DTI.

High yielding allylation of a chiral secondary alcohol containing base sensitive functional groups.

Inhibitors of neuronal nitric oxide synthase, based on a chiral pyrrolidine scaffold, show promise for the treatment of certain neurodegenerative diseases. We recently reported the synthesis of a series of selective inhibitors, but the method was limited at a key step of formingan allyl ether intermediate. Yields for this step were very inconsistent, and the presence of base sensitive functional groups limited the range of available methods for forming this ether bond. This work describes a novel application of palladium catalyzed decarboxylativeallylation, consistently resulting in 90% isolated yields, which is crucial for the synthesis of the critical allyl ether late stage intermediate. We also report a new quantitative yielding and straightforward synthesis of the allyl-t-butylcarbonate precursor.