Cone beam CT-based adaptive intensity modulated proton therapy assessment using automated planning for head-and-neck cancer.

BACKGROUND: To assess the feasibility of CBCT-based adaptive intensity modulated proton therapy (IMPT) using automated planning for treatment of head and neck (HN) cancers. METHODS: Twenty HN cancer patients who received radiotherapy and had pretreatment CBCTs were included in this study. Initial IMPT plans were created using automated planning software for all patients. Synthetic CTs (sCT) were then created by deforming the planning CT (pCT) to the pretreatment CBCTs. To assess dose calculation accuracy on sCTs, repeat CTs (rCTs) were deformed to the pretreatment CBCT obtained on the same day to create deformed rCT (rCTdef), serving as gold standard. The dose recalculated on sCT and on rCTdef were compared by using Gamma analysis. The accuracy of DIR generated contours was also assessed. To explore the potential benefits of adaptive IMPT, two sets of plans were created for each patient, a non-adapted IMPT plan and an adapted IMPT plan calculated on weekly sCT images. The weekly doses for non-adaptive and adaptive IMPT plans were accumulated on the pCT, and the accumulated dosimetric parameters of two sets were compared. RESULTS: Gamma analysis of the dose recalculated on sCT and rCTdef resulted in a passing rate of 97.9% ± 1.7% using 3 mm/3% criteria. With the physician-corrected contours on the sCT, the dose deviation range of using sCT to estimate mean dose for the most organ at risk (OARs) can be reduced to (- 2.37%, 2.19%) as compared to rCTdef, while for V95 of primary or secondary CTVs, the deviation can be controlled within (- 1.09%, 0.29%). Comparison of the accumulated doses from the adaptive planning against the non-adaptive plans reduced mean dose to constrictors (- 1.42 Gy ± 2.79 Gy) and larynx (- 2.58 Gy ± 3.09 Gy). The reductions result in statistically significant reductions in the normal tissue complication probability (NTCP) of larynx edema by 7.52% ± 13.59%. 4.5% of primary CTVs, 4.1% of secondary CTVs, and 26.8% tertiary CTVs didn't meet the V95 > 95% constraint on non-adapted IMPT plans. All adaptive plans were able to meet the coverage constraint. CONCLUSION: sCTs can be a useful tool for accurate proton dose calculation. Adaptive IMPT resulted in better CTV coverage, OAR sparing and lower NTCP for some OARs as compared with non-adaptive IMPT.

Effects of model size and composition on quality of head-and-neck knowledge-based plans.

PURPOSE: Knowledge-based planning (KBP) aims to automate and standardize treatment planning. New KBP users are faced with many questions: How much does model size matter, and are multiple models needed to accommodate specific physician preferences? In this study, six head-and-neck KBP models were trained to address these questions. METHODS: The six models differed in training size and plan composition: The KBPFull (n = 203 plans), KBP101 (n = 101), KBP50 (n = 50), and KBP25 (n = 25) were trained with plans from two head-and-neck physicians. KBPA and KBPB each contained n = 101 plans from only one physician, respectively. An independent set of 39 patients treated to 6000-7000 cGy by a third physician was re-planned with all KBP models for validation. Standard head-and-neck dosimetric parameters were used to compare resulting plans. KBPFull plans were compared to the clinical plans to evaluate overall model quality. Additionally, clinical and KBPFull plans were presented to another physician for blind review. Dosimetric comparison of KBPFull against KBP101 , KBP50 , and KBP25 investigated the effect of model size. Finally, KBPA versus KBPB tested whether training KBP models on plans from one physician only influences the resulting output. Dosimetric differences were tested for significance using a paired t-test (p < 0.05). RESULTS: Compared to manual plans, KBPFull significantly increased PTV Low D95% and left parotid mean dose but decreased dose cochlea, constrictors, and larynx. The physician preferred the KBPFull plan over the manual plan in 20/39 cases. Dosimetric differences between KBPFull , KBP101 , KBP50 , and KBP25 plans did not exceed 187 cGy on aggregate, except for the cochlea. Further, average differences between KBPA and KBPB were below 110 cGy. CONCLUSIONS: Overall, all models were shown to produce high-quality plans. Differences between model outputs were small compared to the prescription. This indicates only small improvements when increasing model size and minimal influence of the physician when choosing treatment plans for training head-and-neck KBP models.

CivaSheet® use for soft tissue sarcoma: A single institution experience.

OBJECTIVE: CivaSheet is a palladium-103, implantable, intraoperative radiation therapy device which emits unidirectional radiation that enables boost doses in patients who have otherwise received the maximum radiation dose. Here, we present our initial clinical experience with the first 10 cases using this new technology. METHODS AND MATERIALS: A retrospective chart review of all patients with STS treated with surgical resection and CivaSheet placement at the University of Miami Hospital, a tertiary care center, from January 2018 to December 2019, was performed. Adjuvant radiation was administered by a palladium-103 implant, which delivered an average of 47 Gy (35-55) to a depth of 5 mm. RESULTS: Nine patients underwent CivaSheet placement from January 2018 until December 2019 for a total of 10 CivaSheets placed (1 patient had 2 CivaSheets inserted) and followed for a mean of 27 months (4-45 months). Four tumors were located in the retroperitoneum, two in the chest, two in the groin, and two within the lower extremity. At the time of tumor resection and CivaSheet placement, tumor sizes ranged from 2.5 cm to 13.8 cm with an average of 7.6 cm. Four patients necessitated musculocutaneous tissue flaps for closure and reconstruction. All patients with Grade 4 complications had flap reconstruction and prior radiation. Four patients' tumors recurred locally for a local recurrence rate of 40%. Three patients had modified accordion Grade 4 complications necessitating additional surgery for CivaSheet removal. Extremity tumors unanimously developed modified accordion Grade 4 adverse events. CONCLUSIONS: CivaSheet may be an acceptable alternative treatment modality compared to prior brachytherapy methods.

Delineation of recurrent glioblastoma by whole brain spectroscopic magnetic resonance imaging.

BACKGROUND: Glioblastoma (GBM) cellularity correlates with whole brain spectroscopic MRI (sMRI) generated relative choline to N-Acetyl-Aspartate ratio (rChoNAA) mapping. In recurrent GBM (rGBM), tumor volume (TV) delineation is challenging and rChoNAA maps may assist with re-RT targeting. METHODS: Fourteen rGBM patients underwent sMRI in a prospective study. Whole brain sMRI was performed to generate rChoNAA maps. TVs were delineated by the union of rChoNAA ratio over 2 (rChoNAA > 2) on sMRI and T1PC. rChoNAA > 2 volumes were compared with multiparametric MRI sequences including T1PC, T2/FLAIR, diffusion-restriction on apparent diffusion coefficient (ADC) maps, and perfusion relative cerebral blood volume (rCBV). RESULTS: rChoNAA > 2 (mean 27.6 cc, range 6.6-79.1 cc) was different from other imaging modalities (P ≤ 0.05). Mean T1PC volumes were 10.7 cc (range 1.2-31.4 cc). The mean non-overlapping volume of rChoNAA > 2 and T1PC was 29.2 cm3. rChoNAA > 2 was 287% larger (range 23% smaller-873% larger) than T1PC. T2/FLAIR volumes (mean 111.7 cc, range 19.0-232.7 cc) were much larger than other modalities. rCBV volumes (mean 6.2 cc, range 0.2-19.1 cc) and ADC volumes were tiny (mean 0.8 cc, range 0-3.7 cc). Eight in-field failures were observed. Three patients failed outside T1PC but within rChoNAA > 2. No grade 3 toxicities attributable to re-RT were observed. Median progression-free and overall survival for re-RT patients were 6.5 and 7.1 months, respectively. CONCLUSIONS: Treatment of rGBM may be optimized by sMRI, and failure patterns suggest benefit for dose-escalation within sMRI-delineated volumes. Dose-escalation and radiologic-pathologic studies are underway to confirm the utility of sMRI in rGBM.

Chromosome 8q arm overexpression is associated with worse prostate cancer prognosis.

OBJECTIVE: Chromosome 8q arm (chr8q) is the most amplified chromosomal segment in advanced metastatic castration-resistant prostate cancer after chXq12. These regions harbor important oncogenes driving prostate cancer progression, including MYC that plays a role in various hallmarks of cancer, including cell cycle progression and immune surveillance. Herein we characterize the co-expression patterns of chr8q genes and their clinical utility in more than 7,000 radical prostatectomy samples. MATERIALS AND METHODS: Copy Number alterations of 336 genes on chr8q21 to chr8q24 were extracted from 2 primary prostate cancer cohorts (TCGA, n = 492; MSK-primary, n = 856) and 3 metastatic prostate cancer cohorts (MSK-met, N = 432; MSK-mCSPC, N = 424; SU2CPNAS, n = 444) from cBioPortal. Expression data for the 336 genes was extracted from 6,135 radical prostatectomy samples from Decipher GRID registry. For survival analysis, patients were grouped into top 10% and top 25% by band expression and were compared with the remaining cohort. Hazard ratios were calculated using Cox proportional hazards models. RESULTS: Genes on chr8q were highly co-amplified and co-expressed. Copy number alterations and overexpression of chr8q genes in primary disease were associated with higher Gleason scores, increased risk of metastases, and increased prostate cancer specific mortality. Additionally, our data demonstrated high expression of MYC alone was not associated with differences in metastases free survival while high expression of other chr8q bands was associated with decreased metastases free survival. By combining chr8q data with an established genomic classifier like Decipher, we were able to develop a new model that was better at predicting metastases than Decipher alone. CONCLUSIONS: Our findings highlight the clinical utility of chr8q data, which can be used to improve prognostication and risk prediction in localized prostate cancer.

Clinical characteristics and postoperative complications as predictors of radiation toxicity after treatment with I125 Eye Plaque Brachytherapy for Uveal Melanomas.

PURPOSE: I125 Eye Plaque brachytherapy is the standard treatment for medium-sized uveal melanomas (UM). Patients develop radiation toxicities (RTT), including radiation maculopathy (RM), radiation neovascular glaucoma/iris neovascularization (RNGI) and radiation optic neuropathy (RON). We aim to investigate demographics, pretreatment tumor characteristics and posttreatment complications as predictors of RTT. METHODS AND MATERIALS: An IRB-approved single-institution retrospective chart review was performed from 2011 to 2019 for patients with posterior UM treated with brachytherapy. We collected demographics, pretreatment tumor characteristics and posttreatment complications. Univariate analysis (UVA) and multivariate analysis (MVA) were performed using logistic regression model. Hazard ratios (HR) and corresponding p-values were reported. All tests were two-sided; statistical significance was considered when p<0.05. RESULTS: Two hundred and fifty eight patients were evaluated. Median follow-up was 33.50 months (range 3.02-97.31). 178 patients (69.0%) had RTT. 131 patients (50.8%) developed RM. Fifty-six patients (21.7%) developed RON. Nineteen patients (7.4%) developed RNGI. UVA found shorter distance to fovea (DF) (p = 0.04), posttreatment exudative retinal detachment (PERD) (p = 0.001) and posttreatment vitreous hemorrhage (PVH) (p = 0.001) are associated with RTT. MVA found shorter DF (HR=1.03, p = 0.04), PERD (HR=2.52, p = 0.01) and PVH (HR=3.34, p = 0.006) are associated with RTT. MVA found female sex (HR=1.731, p = 0.031) and tumor height (HR=1.13, p = 0.013) are associated with RM and pretreatment retinal detachment (HR=3.41, p<0.001) is associated with RON. CONCLUSIONS: Shorter DF, PERD and PVH are associated with RTT; female sex and tumor height are associated with RM and tumor height is associated with RON. These findings serve as prognostic tools to counsel patients and promote early intervention in management of RTT.

Predictive Value of Delta-Radiomics Texture Features in 0.35 Tesla Magnetic Resonance Setup Images Acquired During Stereotactic Ablative Radiotherapy of Pancreatic Cancer.

Purpose: The purpose of this work is to explore delta-radiomics texture features for predicting response using setup images of pancreatic cancer patients treated with magnetic resonance image guided (MRI-guided) stereotactic ablative radiotherapy (SBRT). Methods: The total biological effective dose (BED) was calculated for 30 patients treated with MRI-guided SBRT that delivered physical doses of 30-60 Gy in three to five fractions. Texture features were then binned into groups based upon BED per fraction by dividing BED by the number of fractions. Delta-radiomics texture features were calculated after delivery of 20 Gy BED (BED20 features) and 40 Gy BED (BED40 features). A random forest (RF) model was constructed using BED20 and then BED40 features to predict binary outcome. During model training, the Gini Index, a measure of a variable's importance for accurate prediction, was calculated for all features, and the two features that ranked the highest were selected for internal validation. The two features selected from each bin were used in a bootstrapped logistic regression model to predict response and performance quantified using the area under the receiver operating characteristic curve (AUC). This process was an internal validation analysis. Results: After RF model training, the Gini Index was highest for gray-level co-occurrence matrix-based (GLCM) sum average, and neighborhood gray tone difference matrix-based (NGTDM) busyness for BED20 features and gray-level size zone matrix-based (GLSZM) large zones low gray-level emphasis and gray-level run length matrix-based (GLRLM) run percentage was selected from the BED40-based features. The mean AUC obtained using the two BED20 features was AUC = 0.845 with the 2.5 percentile and 97.5 percentile values ranging from 0.794 to 0.856. Internal validation of the BED40 delta-radiomics features resulted in a mean AUC = 0.567 with a 2.5 and 97.5 percentile range of 0.502-0.675. Conclusion: Early changes in treatment quantified with the BED20 delta-radiomics texture features in low field images acquired during MRI-guided SBRT demonstrated better performance in internal validation than features calculated later in treatment. Further analysis of delta-radiomics texture analysis in low field MRI is warranted.

A Single Axial Slice of the Sternocleidomastoids and Paravertebral Muscles Associated with Worse Local Progression-Free Survival and Severe Toxicity in Sarcopenic Head and Neck Cancer Patients Undergoing Radiotherapy.

Objective The objective of this study is to contrast the predictive ability of targeted muscle groups as radiographic proxies of sarcopenia on computerized tomography (CT) with body mass index (BMI) in head and neck cancer patients (H&NCP) undergoing radiation at a safety net hospital, and to evaluate sarcopenia with survival, local progression, toxicities and treatment delays. Methods A retrospective review included 52 H&NCP treated between 2017-2019. The posterior neck muscles (PN), sternocleidomastoids (SCM), and their summed volume (AM) were contoured at C3 on patients' pre-treatment CT scans, then normalized to obtain skeletal muscle index (MI) values. Pre-treatment BMI was also evaluated. Cutoffs for sarcopenia were determined by receiver operating characteristic curves. Overall survival and local recurrence-free survival were evaluated by Kaplan-Meier. Acute grade 3 or higher toxicities were evaluated by binomial logistic regression. Results Using all neck muscles (AM-MI) produced the best model for predicting outcomes, outperforming individual muscle groups and BMI. Local progression-free survival was worse in sarcopenic patients at 25.81 months versus 35.40 months (p=0.026). Acute grade 3 or higher toxicities were associated with sarcopenia (p=0.005). Conclusions In this small, retrospective single-institution experience at a safety net hospital, a single axial slice of the combined sternocleidomastoids and paravertebral muscles at C3 performed better than either muscle group alone or pre-treatment BMI at predicting oncologic outcomes.

Predictors of Local Recurrence and Progression-Free Survival in Iodine-125 Brachytherapy-Treated Uveal Melanomas: A Modern Institutional Study.

Introduction: Iodine-125 brachytherapy is an effective eye-sparing treatment for uveal melanoma. Previous work has shown that uveal melanomas cluster into distinct molecular classes based on gene expression profiles - discriminating low-grade from high-grade tumors. Our objective was to identify clinical and molecular predictors of local recurrence (LR) and progression-free survival (PFS). Methods: We constructed a retrospective database of uveal melanoma patients from the University of Miami's electronic medical records that were treated between January 8, 2012, and January 5, 2019, with either COMS-style or Eye Physics plaque. Data on tumor characteristics, pretreatment retinal complications, post-plaque treatments, LR, and PFS were collected. Univariate and multivariate Cox models for cumulative incidence of LR and PFS were conducted using SAS version 9.4. Results: We identified 262 patients, with a median follow-up time of 33.5 months. Nineteen patients (7.3%) had LR, and 56 patients (21.4%) were classified as PFS. We found that ocular melanocytosis (hazard ratio = 5.55, p < 0.001) had the greatest impact on PFS. Genetic expression profile did not predict LR outcomes (hazard ratio = 0.51, p = 0.297). Conclusion: These findings help physicians identify predictors for short-term brachytherapy outcomes, allowing better shared decision making with patients preoperatively when deciding between brachytherapy versus enucleation. Patients stratified to higher risk groups based on preoperative characteristics such as ocular melanocytosis should be monitored more closely. Future studies must validate these findings using a prospective cohort study.

Radiomics Predicts for Distant Metastasis in Locally Advanced Human Papillomavirus-Positive Oropharyngeal Squamous Cell Carcinoma.

(1) Background and purpose: clinical trials have unsuccessfully tried to de-escalate treatment in locally advanced human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) with the goal of reducing treatment toxicity. The aim of this study was to explore the role of radiomics for risk stratification in this patient population to guide treatment. (2) Methods: the study population consisted of 225 patients with locally advanced HPV+ OPSCC treated with curative-intent radiation or chemoradiation therapy. Appearance of distant metastasis was used as the endpoint event. Radiomics data were extracted from the gross tumor volumes (GTVs) identified on the planning CT, with gray level being discretized using three different bin widths (8, 16, and 32). The data extracted for the groups with and without distant metastasis were subsequently balanced using three different algorithms including synthetic minority over-sampling technique (SMOTE), adaptive synthetic sampling (ADASYN), and borderline SMOTE. From these different combinations, a total of nine radiomics datasets were derived. Top features that minimized redundancy while maximizing relevance to the endpoint were selected individually and collectively for the nine radiomics datasets to build support vector machine (SVM) based predictive classifiers. Performance of the developed classifiers was evaluated by receiver operating characteristic (ROC) curve analysis. (3) Results: of the 225 locally advanced HPV+ OPSCC patients being studied, 9.3% had developed distant metastases at last follow-up. SVM classifiers built for the nine radiomics dataset using either their own respective top features or the top consensus ones were all able to differentiate the two cohorts at a level of excellence or beyond, with ROC area under curve (AUC) ranging from 0.84 to 0.95 (median = 0.90). ROC comparisons further revealed that the majority of the built classifiers did not distinguish the two cohorts significantly better than each other. (4) Conclusions: radiomics demonstrated discriminative ability in distinguishing patients with locally advanced HPV+ OPSCC who went on to develop distant metastasis after completion of definitive chemoradiation or radiation alone and may serve to risk stratify this patient population with the purpose of guiding the appropriate therapy.

Inhibiting Focal Adhesion Kinase Ameliorates Cyst Development in Polycystin-1-Deficient Polycystic Kidney Disease in Animal Model.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by numerous cysts originating from renal tubules and is associated with significant tubular epithelial cell proliferation. Focal adhesion kinase (FAK) promotes tumor growth by regulating multiple proliferative pathways. METHODS: We established the forskolin (FSK)-induced three-dimensional (3D) Madin-Darby Canine Kidney cystogenesis model and 8-bromoadenosine-3`,5`-cyclic monophosphate-stimulated cyst formation in ex vivo embryonic kidney culture. Cultured human renal cyst-lining cells (OX-161) and normal tubular epithelial cells were treated with FAK inhibitors or transfected with green fluorescent protein-tagged FAK mutant plasmids for proliferation study. Furthermore, we examined the role of FAK in two transgenic ADPKD animal models, the kidney-specific Pkd1 knockout and the collecting duct-specific Pkd1 knockout mouse models. RESULTS: FAK activity was significantly elevated in OX-161 cells and in two ADPKD mouse models. Inhibiting FAK activity reduced cell proliferation in OX-161 cells and prevented cyst growth in ex vivo and 3D cyst models. In tissue-specific Pkd1 knockout mouse models, FAK inhibitors retarded cyst development and mitigated renal function decline. Mechanically, FSK stimulated FAK activation in tubular epithelial cells, which was blocked by a protein kinase A (PKA) inhibitor. Inhibition of FAK activation by inhibitors or transfected cells with mutant FAK constructs interrupted FSK-mediated Src activation and upregulation of ERK and mTOR pathways. CONCLUSIONS: Our study demonstrates the critical involvement of FAK in renal cyst development, suggests that FAK is a potential therapeutic target in treating patients with ADPKD, and highlights the role of FAK in cAMP-PKA-regulated proliferation.

Isocitrate dehydrogenase 1 mutant glioblastomas demonstrate a decreased rate of pseudoprogression: a multi-institutional experience.

BACKGROUND: Pseudoprogression (psPD) represents false radiologic evidence of tumor progression and is observed in some glioblastoma (GBM) patients after postoperative chemoradiation (CRT) with temozolomide (TMZ). The ambiguity of the psPD diagnosis confounds identification of true progression and may lead to unnecessary interventions. The association between psPD and isocitrate dehydrogenase 1 (IDH1) mutational (mut) status is understudied, and its incidence may alter clinical decision making. METHODS: We retrospectively evaluated 120 patients with IDH1-mut (n = 60) and IDH1-wild-type (IDH-WT; [n = 60]) GBMs who received postoperative CRT with TMZ at 4 academic institutions. Response Assessment in Neuro-Oncology criteria were used to identify psPD rates in routine brain MRIs performed up to 90 days after CRT completion. RESULTS: Within 90 days of completing CRT, 9 GBM patients (1 [1.7%] IDH1-mut and 8 [13.3%] IDH1-WTs) demonstrated true progression, whereas 17 patients (3 [5%] IDH1-muts and 14 [23.3%] IDH1-WTs) demonstrated psPD (P = .004). IDH1-mut GBMs had a lower probability of psPD (hazard ratio: 0.173, 95% CI, 0.047-0.638, P = .008). Among the patients with radiologic signs suggestive of progression (n = 26), psPD was found to be the cause in 3 of 4 (75.0%) of the IDH1-mut GBMs and 14 of 22 (63.6%) of the IDH1-WT GBMs (P = .496). Median overall survival for IDH1-mut and IDH1-WT GBM patients was 40.3 and 23.0 months, respectively (P < .001). CONCLUSIONS: IDH1-mut GBM patients demonstrate lower absolute rates of psPD expression. Irrespective of GBM subtype, psPD expression was more likely than true progression within 90 days of completing CRT. Continuing adjuvant treatment for IDH1-mut GBMs is suggested if radiologic progression is suspected during this time interval.

Cardamonin retards progression of autosomal dominant polycystic kidney disease via inhibiting renal cyst growth and interstitial fibrosis.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenetic inherited kidney disease characterized by renal progressive fluid-filled cysts and interstitial fibrosis. Inhibiting renal cyst development and interstitial fibrosis has been proven effective in delaying the progression of ADPKD. The purpose of this study was to discover effective drugs from natural products for preventing and treating ADPKD. Candidate compounds were screened from a natural product library by virtual screening. The Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model, and orthologous mouse model of ADPKD were utilized to determine the pharmacological activities of the candidate compounds. Western blot and morphological analysis were used to investigate underlying mechanisms. The experimental results showed that 0.625, 2.5, and 10 µM cardamonin dose-dependently reduced formation and enlargement in MDCK cyst model. Cardamonin also significantly attenuated renal cyst enlargement in ex vivo mouse embryonic kidneys and PKD mouse kidneys. We found that cardamonin inhibited renal cyst development and interstitial fibrosis by downregulating the MAPK, Wnt, mTOR, and transforming growth factor-ß/Smad2/3 signaling pathways. Cardamonin significantly inhibits renal cyst development and interstitial fibrosis, suggesting that cardamonin shows promise as a potential therapeutic drug for preventing and treating ADPKD.

Using the Albumin-Bilirubin (ALBI) grade as a prognostic marker for radioembolization of hepatocellular carcinoma.

BACKGROUND: The Child-Pugh (CP) class is a commonly used scoring system to measure liver function in patients with hepatocellular carcinoma (HCC). We correlate the Albumin-Bilirubin (ALBI) grading system and CP to overall survival in our HCC patients receiving radioembolization. METHODS: We retrospectively evaluated patients who received radioembolization for HCC between the years 2009-2014. We evaluated the albumin and bilirubin levels in our patients prior to receiving their first (n=124) radioembolization. The ALBI grades were calculated from these data with the formula (log10 bilirubin ×0.66) + (albumin × -0.085) and correlated to outcomes using Mantel-Cox Log analysis. These statistical comparisons were duplicated with CP classes. RESULTS: Median survival differences between CP class A and B and between ALBI grade 1 and 2 were 4.7 and 9.9 months, respectively. A subset of ALBI grades 1 and 2 were identified within our CP class A patients with a median survival difference of 9.9 months. CONCLUSIONS: ALBI is a more sensitive marker of liver function than CP in the setting of mild dysfunction. Using ALBI, we identified a subset of patients that have significantly better outcomes from Y-90 radioembolization than previously identified with CP.

Adjuvant radiation provides survival benefit for resected pancreatic adenocarcinomas of the tail.

BACKGROUND: The appropriate adjuvant treatment for resected pancreatic cancer remains a controversy. We sought to determine the effect of adjuvant treatment on overall survival (OS) in patients with pancreatic tail adenocarcinoma. METHODS: Retrospective review of patients with upfront surgically resected pancreatic tail cancer treated at our institution between 2000-2012 was performed to determine outcomes of patients treated with and without adjuvant radiation therapy (RT). Survival curves were calculated according to the Kaplan-Meier method. Univariate analysis (UVA) and multivariate analysis (MVA) were performed using the Cox proportional hazards model. RESULTS: Thirty-four patients met inclusion criteria. 79% received adjuvant chemotherapy, either concurrent with RT or alone. The groups were well matched, with the only significant difference being patient sex. On both UVA and MVA there was significantly worse survival in patients with a post-op CA19-9 >90 [hazard ratio (HR) 5.55; 95% confidence interval (CI): 1.20-25.7, P=0.03] and improved survival in patients treated with adjuvant RT (HR 0.15; 95% CI: 0.04-0.58, P=0.006). The median and 2-year OS were 21.6 months and 47% for patients treated with adjuvant RT compared with 11.3 months and 21% for those treated without RT. CONCLUSIONS: Although few in patient numbers, this data suggests integration of adjuvant RT in resected pancreatic tail adenocarcinoma may improve OS.

Impact of sarcopenia in borderline resectable and locally advanced pancreatic cancer patients receiving stereotactic body radiation therapy.

BACKGROUND: Total psoas area (TPA), a marker of sarcopenia, has been used as an independent predictor of clinical outcomes in gastrointestinal (GI) cancers as a proxy for frailty and nutritional status. Our study aimed to evaluate whether TPA, in contrast to traditional measurements of nutrition like body mass index (BMI) and body surface area (BSA), was predictive of outcomes in borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) patients receiving stereotactic body radiation therapy (SBRT). METHODS: Retrospective analysis of an institutional review board approved database of 222 BRPC and LAPC treated with SBRT from 2009-2016 yielded 183 patients that met our selection criteria of pre-SBRT computed tomography (CT) imaging with an identifiable L4 vertebra. Once the L4 vertebral level was identified, the bilateral psoas muscles were manually contoured. This area was normalized by patient height, with units described in mm2/m2. Receiver operating characteristic (ROC) curves were generated for TPA, BMI, and BSA to elicit clinically relevant cutoffs. Regression and Kaplan-Meier analyses were used to correlate toxicity with survival functions. RESULTS: Low TPA (OR =1.903, P=0.036) was predictive of acute toxicities, and only TPA was predictive of Grade 3 or higher acute toxicities (OR =10.24, P=0.007). Both findings were independent of tumor resectability. Pain (P=0.003), fatigue (P=0.040), and nausea (P=0.039) were significantly associated with low TPA. No association was identified between any measurement of nutritional status and the development of late toxicities, overall survival, local progression or local recurrence. However, BRPC patients survived longer (median =21.98 months) than their LAPC (median =16.2 months) counterparts (P=0.002), independent of nutritional status. CONCLUSIONS: TPA measurement is readily available and more specific than BMI or BSA as a predictor of acute radiotoxic complications following SBRT in BRPC/LAPC patients. A TPA of <500 mm2/m2 is a clinically relevant cutoff that can direct physicians to address expected complications of pain, fatigue, and nausea. However, tumor resectability remains as the only predictor of overall survival in this cohort.

Recurrence patterns and associated factors of locoregional failure following neoadjuvant chemoradiation and surgery for esophageal cancer.

BACKGROUND: Despite neoadjuvant chemoradiation (nCRT) followed by esophagectomy for locally advanced esophageal cancer, locoregional recurrence (LRR) is common and factors associated with LRR have not been clearly identified. METHODS: Patients were identified from a single institution, prospectively maintained database (1996-2013). Patterns of recurrence were described and associated factors of LRR were analyzed using competing risks regression models. RESULTS: Of the 456 patients treated with nCRT and surgery, 167 patients developed recurrence. Locoregional and distant recurrences were observed in 69 (15.1%) and 140 (30.9%) patients, respectively. Time to recurrence (13.6 vs 10.4 months, P = 0.20) and median overall survival (29.3 vs 19.1 months, P = 0.12) were no different among the 27 patients (6%) who developed a solitary LRR compared to patients who developed distant recurrence. Univariable analysis identified lymphovascular invasion (HR 1.46, P = 0.07), lymph node ratio >0.5 (HR 2.16, P = 0.02), positive margin (HR 1.95, P = 0.05), lack of response to neoadjuvant therapy (HR 1.99, P < 0.01), clinical T stage (HR 2.62, P < 0.01) and final T3/4 stage (HR 2.06, P < 0.01) as factors significantly associated with LRR. Clinical T stage and response to neoadjuvant treatment were independently associated with LRR on multivariable analysis. CONCLUSIONS: Although aggressive tumor biology plays a significant role in LRR, optimizing neoadjuvant treatments to obtain a complete pathologic response may lead to improved locoregional control.

Impact of sarcopenia on outcomes of locally advanced esophageal cancer patients treated with neoadjuvant chemoradiation followed by surgery.

BACKGROUND: Sarcopenia is an independent predictor of clinical outcomes in multiple gastrointestinal cancers. Total psoas area (TPA), as measured on a single cross-sectional CT image at the L4 vertebral body level, has been correlated with sarcopenia. We sought to evaluate whether TPA was predictive of acute grade ≥3 toxicity, pathologic response, and overall survival in patients with locally advanced esophageal cancer receiving tri-modality therapy. METHODS: An institutional database of esophageal cancer patients treated with neoadjuvant chemoradiation followed by surgery was queried. Of 77 patients treated from 2008 to 2012 with intensity modulated radiation therapy (IMRT) and image guided radiation therapy (IGRT), 56 patients were eligible based on having CT imaging that included the L4 vertebral body. The L4 vertebra was identified on axial CT and the psoas muscle was manually contoured bilaterally to determine the skeletal muscle index. Sarcopenia was defined by the presence of the psoas area less than the median of the cohort. Acute toxicity was defined as within 3 months of radiotherapy based on Common Terminology Criteria for Adverse Events. ROC curve, logistic regression, and Kaplan Meier estimates were used when appropriate. RESULTS: Sarcopenia was associated with increased acute grade ≥3 toxicity from chemoradiation by ROC analysis using a cut off of 841.5 mm2/m2 (P=0.003, AUC 0.709, sensitivity 60.9%, specificity 78.8%) and logistic regression (P=0.002). Patients with TPA <841.5 mm2/m2 were 5.78 times more likely to develop grade 3 or higher toxicity (P=0.004). Sarcopenia did not predict a difference in overall survival (P=0.217) and was not significant for pathologic complete response or favorable pathologic response (TRG 0/1). CONCLUSIONS: In our cohort of patients, sarcopenia was associated with a significant increase in acute grade ≥3 toxicity with chemoradiation, suggesting a potential role for neoadjuvant patient selection strategies. There was no difference in pathologic response or overall survival.

Ezrin directly interacts with AQP2 and promotes its endocytosis.

The water channel aquaporin-2 (AQP2) is a major regulator of water homeostasis in response to vasopressin (VP). Dynamic trafficking of AQP2 relies on its close interaction with trafficking machinery proteins and the actin cytoskeleton. Here, we report the identification of ezrin, an actin-binding protein from the ezrin/radixin/moesin (ERM) family as an AQP2-interacting protein. Ezrin was first detected in a co-immunoprecipitation (co-IP) complex using an anti-AQP2 antibody in a proteomic analysis. Immunofluorescence staining revealed the co-expression of ezrin and AQP2 in collecting duct principal cells, and VP treatment caused redistribution of both proteins to the apical membrane. The ezrin-AQP2 interaction was confirmed by co-IP experiments with an anti-ezrin antibody, and by pulldown assays using purified full-length and FERM domain-containing recombinant ezrin. By using purified recombinant proteins, we showed that ezrin directly interacts with AQP2 C-terminus through its N-terminal FERM domain. Knocking down ezrin expression with shRNA resulted in increased membrane accumulation of AQP2 and reduced AQP2 endocytosis. Therefore, through direct interaction with AQP2, ezrin facilitates AQP2 endocytosis, thus linking the dynamic actin cytoskeleton network with AQP2 trafficking.