Volumetric and actuarial analysis of brain necrosis in proton therapy using a novel mixture cure model.

BACKGROUND AND PURPOSE: High-dose fractionated radiotherapy is often necessary to achieve long-term tumor control in several types of tumors involving or within close proximity to the brain. There is limited data to guide on optimal constraints to the adjacent nontarget brain. This investigation explored the significance of the three-dimensional (3D) dose distribution of passive scattering proton therapy to the brain with other clinicopathological factors on the development of symptomatic radiation necrosis. MATERIALS AND METHODS: All patients with head and neck, skull base, or intracranial tumors who underwent proton therapy (minimum prescription dose of 59.4 Gy(RBE)) with collateral moderate to high dose radiation exposure to the nontarget brain were retrospectively reviewed. A mixture cure model with respect to necrosis-free survival was used to derive estimates for the normal tissue complication probability (NTCP) model while adjusting for potential confounding factors. RESULTS: Of 179 identified patients, 83 patients had intracranial tumors and 96 patients had primary extracranial tumors. The optimal dose measure obtained to describe the occurrence of radiation necrosis was the equivalent uniform dose (EUD) with parameter a = 9. The best-fit parameters of logistic NTCP models revealed D50 = 57.7 Gy for intracranial tumors, D50 = 39.5 Gy for extracranial tumors, and γ50 = 2.5 for both tumor locations. Multivariable analysis revealed EUD and primary tumor location to be the strongest predictors of brain radiation necrosis. CONCLUSION: In the current clinical volumetric data analyses with multivariable modelling, EUD was identified as an independent and strong predictor for brain radiation necrosis from proton therapy.

Seeking Consensus on the Terminology of Value-Based Transformation Through use of a Delphi Process.

Collaboration among diverse stakeholders involved in the value transformation of health care requires consistent use of terminology. The objective of this study was to reach consensus definitions for the terms value-based care, value-based payment, and population health. A modified Delphi process was conducted from February 2017 to July 2017. An in-person panel meeting was followed by 3 rounds of surveys. Panelists anonymously rated individual components of definitions and full definitions on a 9-point Likert scale. Definitions were modified in an iterative process based on results of each survey round. Participants were a panel of 18 national leaders representing population health, health care delivery, academic medicine, payers, patient advocacy, and health care foundations. Main measures were survey ratings of definition components and definitions. At the conclusion of round 3, consensus was reached on the following definition for value-based payment, with 13 of 18 panelists (72.2%) assigning a high rating (7- 9) and 1 of 18 (5.6%) assigning a low rating (1-3): "Value-based payment aligns reimbursement with achievement of value-based care (health outcomes/cost) in a defined population with providers held accountable for achieving financial goals and health outcomes. Value-based payment encourages optimal care delivery, including coordination across healthcare disciplines and between the health care system and community resources, to improve health outcomes, for both individuals and populations." The iterative process elucidated specific areas of agreement and disagreement for value-based care and population health but did not reach consensus. Policy makers cannot assume uniform interpretation of other concepts underlying health care reform efforts.

Development and validation of NTCP models for acute side-effects resulting from proton beam therapy of brain tumours.

BACKGROUND: The limited availability of proton beam therapy (PBT) requires individual treatment selection strategies, such as based on normal tissue complication probability (NTCP). We developed and externally validated NTCP models for common acute side-effects following PBT in brain tumour patients in effort to provide guidance on optimising patient quality of life. METHODS: An exploration cohort including 113 adult brain tumour patients who underwent PBT was investigated for the following endpoints: alopecia, scalp erythema, headache, fatigue and nausea. Dose-volume parameters of associated normal tissues were used for logistic regression modelling. Statistically significant parameters showing high area under the receiver operating characteristic curve (AUC) values in internal cross-validation were externally validated on two cohorts of 71 and 96 patients, respectively. RESULTS: Statistically significant correlations of dose-volume parameters of the skin for erythema and alopecia were found. In internal cross-validation, the following prognostic parameters were selected: V35Gy (absolute volume receiving 35 Gy) for erythema grade ≥1, D2% (dose to 2% of the volume) for alopecia grade ≥1 and D5% for alopecia grade ≥2. Validation was successful for both cohorts with AUC >0.75. A bivariable model for fatigue grade ≥1 could not be validated externally. No correlations of dose-volume parameters of the brain were seen for headache or nausea. CONCLUSION: We developed and successfully validated NTCP models for scalp erythema and alopecia in primary brain tumour patients treated with PBT.

The role of proton beam therapy in central neurocytoma: A single-institution experience.

PURPOSE: Central neurocytomas (CNs) are rare World Health Organization grade II tumors managed with surgery and radiation therapy. We report our experience in managing CN with proton beam therapy (PBT) when radiation therapy was used. METHODS AND MATERIALS: We identified 61 patients with pathologically diagnosed CN treated at our institution between 1996 and 2016, of which 24 met inclusion criteria. Patient, tumor, and treatment characteristics are reported in context of progression-free survival and treatment-related adverse events. RESULTS: Of 24 patients identified, median age at diagnosis was 21 years (range, 14-60). Median maximal tumor diameter was 4.5 cm (range, 1.4-6.8). Eighteen (75%) patients underwent upfront surgery alone. Sixteen (67%) patients received adjuvant or salvage PBT at a median dose of 54 Gy (relative biological effectiveness). Median follow-up was 56 months. Median progression-free survival (PFS) was 61 months. Eleven patients had disease progression with median time to progression of 22 months. Of the 5 patients with gross total resection, 4 experienced local recurrence and had MIB-1 >4% (range, 4.5-30). There was improved PFS with addition of PBT to definitive surgery (log-rank, P = .06); there was no disease progression to date. In patients who experienced disease recurrence/progression, MIB-1 <4% was associated with improved PFS (log-rank, P = .007). All patients tolerated PBT well with toxicities typical for cranial irradiation and with no grade 3+ toxicities. CONCLUSION: In our cohort, CN with elevated MIB-1 index were at increased risk for disease progression. However, adjuvant radiation therapy appears to effectively prevent failure. PBT toxicities appear to be comparable to if not less than published photon experiences.

Improved Overall Survival and Locoregional Disease Control With Concurrent PD-1 Pathway Inhibitors and Stereotactic Radiosurgery for Lung Cancer Patients With Brain Metastases.

PURPOSE: Despite the emerging role of programmed cell death-1 (PD-1) pathway inhibitors for patients with advanced lung cancer, a paucity of data are available on the activity of these agents among patients with brain metastases. We investigated the outcomes of PD-1 pathway inhibitors and stereotactic radiosurgery (SRS) for the treatment of patients with brain metastases from lung cancer. METHODS AND MATERIALS: We retrospectively reviewed the medical records of non-small-cell lung cancer patients with brain metastases consecutively treated with PD-1 pathway inhibitors and SRS at our institution from 2012 to 2017. Overall survival (OS), distant brain failure (DBF), and local control (LC) were assessed using Kaplan-Meier estimates and Cox regression models. RESULTS: We identified 37 patients treated with SRS to 85 lesions (90.6% intact and 9.4% resected) and a median total of 7 doses of PD-1 pathway inhibitors (83.8% nivolumab, 10.8% atezolizumab, 5.4% pembrolizumab). Most lesions were treated with 18 Gy in a single fraction (n = 61; 71.8%). Patients treated with concurrent SRS and PD-1 pathway inhibitors had longer OS and reduced rates of DBF compared with patients treated with SRS before or after PD-1 pathway inhibitor therapy (1-year OS, 87.3% vs 70.0% vs 0%, P = .008; 1-year DBF, 38.5% vs 65.8% vs 100%, P = .042). LC was favorable among lesions treated with SRS concurrent with or after PD-1 pathway inhibitor therapy compared with before PD-1 pathway inhibitor therapy (1-year LC, 100% vs 72.3%, P = .016). Three lesions transiently enlarged after SRS and then had partially or completely resolved on follow-up imaging. Four patients required steroids for SRS-associated toxicity. No patient experienced grade ≥ 4 toxicity. CONCLUSIONS: Concurrent treatment with SRS and PD-1 pathway inhibitors was associated with favorable OS and locoregional disease control. This combination of therapy was well tolerated and merits further evaluation in larger cohorts in a prospective setting.

Safety of Combined PD-1 Pathway Inhibition and Intracranial Radiation Therapy in Non-Small Cell Lung Cancer.

INTRODUCTION: Intracranial metastases are a common cause of morbidity and mortality in patients with advanced NSCLC, and are frequently managed with radiation therapy (RT). The safety of cranial RT in the setting of treatment with immune checkpoint inhibitors (ICIs) has not been established. METHODS: We identified patients with advanced NSCLC with brain metastases who received cranial RT and were treated with or without programmed cell death 1/programmed death ligand 1 inhibitors between August 2013 and September 2016. RT-related adverse events (AEs) were retrospectively evaluated and analyzed according to ICI treatment status, cranial RT type, and timing of RT with respect to ICI. RESULTS: Of 163 patients, 50 (31%) received ICIs, whereas 113 (69%) were ICI naive. Overall, 94 (58%), 28 (17%), and 101 (62%) patients received stereotactic radiosurgery, partial brain irradiation, and/or whole brain RT, respectively. Fifty percent of patients received more than one radiation course. We observed no significant difference in rates of all-grade AEs and grade 3 or higher AEs between the ICI-naive and ICI-treated patients across different cranial RT types (grade ≥3 AEs in 8% of ICI-naive patients versus in 9% of ICI-treated patients for stereotactic radiosurgery [p = 1.00] and in 8% of ICI-naive patients versus in 10% of ICI-treated patients for whole brain RT [p = 0.71]). Additionally, there was no difference in AE rates on the basis of timing of ICI administration with respect to RT. CONCLUSIONS: Treatment with an ICI and cranial RT was not associated with a significant increase in RT-related AEs, suggesting that use of programmed cell death 1/programmed death ligand 1 inhibitors in patients receiving cranial RT may have an acceptable safety profile. Nonetheless, additional studies are needed to validate this approach.

Keeping it in the family: the impact of marital status and next of kin on cancer treatment and survival.

BACKGROUND: This study examines the impact of marriage and next of kin identity on timing of diagnosis, treatment, and survival in cancer patients. METHODS: Retrospective review of patients with 5 solid tumor types treated at an academic medical center from 2002 to 2012. Exposures of interest were marriage status at time of diagnosis and familial relationship with next of kin (NOK). Association with overall survival determined via Cox regressions and with early diagnosis (stage I to II) and receipt of surgery via logistic regressions. RESULTS: Marriage was not associated with early diagnosis for any cancer type. After adjustment, being married was associated with significantly higher odds of receiving surgery only for pancreatic cancer and with improved survival for breast and lung cancers. Having a nuclear relationship with NOK was not associated with any outcomes. CONCLUSIONS: Marriage status was associated with improved outcomes for certain cancers whereas familial relationship with NOK was not.

IQGAP1 and IQGAP3 Serve Individually Essential Roles in Normal Epidermal Homeostasis and Tumor Progression.

IQ motif-containing GTPase-activating protein (IQGAP) scaffolding proteins regulate many essential cellular processes including growth factor receptor signaling, cytoskeletal rearrangement, adhesion, and proliferation and are highly expressed in many cancers. Using genetically engineered human skin tissue in vivo, we demonstrate that diminished, sub-physiologic expression of IQGAP1 or IQGAP3 is sufficient to maintain normal epidermal homeostasis, whereas significantly higher levels are required to support tumorigenesis. To target this tumor-specific IQGAP requirement in vivo, we engineered epidermal keratinocytes to express individual IQGAP protein domains designed to compete with endogenous IQGAPs for effector protein binding. Expression of the IQGAP1-IQ motif decoy domain in epidermal tissue in vivo inhibits oncogenic Ras-driven mitogen-activated protein kinase signaling and antagonizes tumorigenesis, without disrupting normal epidermal proliferation or differentiation. These findings define essential non-redundant roles for IQGAP1 and IQGAP3 in the epidermis and demonstrate the potential of IQGAP antagonism for cancer therapy.

Systematic review of early surgery for chronic pancreatitis: impact on pain, pancreatic function, and re-intervention.

BACKGROUND: Surgical intervention has traditionally been reserved as the last management option for pain in chronic pancreatitis. Recently, there has been a call for surgery to be offered earlier in the disease process. The objectives of this review were to evaluate the effect of early surgery on postoperative pain, pancreatic function, and re-intervention rates in chronic pancreatitis. METHODS: A systematic literature search through EMBASE, Cochrane Review, and PubMed from January 1950 to January 2014 was conducted. Citations found in relevant papers are hand-searched. Data which could be pooled were analyzed using Revman (v5.2). Risk of bias analysis was conducted. RESULTS: Of the 2,886 potentially eligible studies identified, 11 studies met the inclusion criteria. There was large heterogeneity in the study designs, and studies were conducted over a lengthy time span. Seven studies examined pain, three studies examined pancreatic function, and three studies examined rates of re-intervention. Meta-analysis of the three studies with comparative raw data regarding complete pain relief showed that early surgery was associated with an increased likelihood of complete postoperative pain relief (RR = 1.67, 95% CI 1.09-2.56, p = 0.02). Early surgery was also associated with reduced risk of pancreatic insufficiency and low re-intervention rates. CONCLUSIONS: Data from this study supports considering early surgery for pain management in patients with chronic pancreatitis, with the potential of a reduced risk of pancreatic insufficiency and the need for further intervention. Further prospective randomized studies are warranted comparing early surgery against conservative step-up approaches.