Phase I study of taselisib in Japanese patients with advanced solid tumors or hormone receptor-positive advanced breast cancer

Summary

Taselisib is a potent and selective phosphatidylinositide 3-kinase (PI3K) inhibitor. This paper reports the first study of taselisib administration in Japanese patients. The aim of this two-stage, phase I, multicenter, open-label, dose-escalation study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of taselisib as monotherapy in Japanese patients with advanced solid tumors (Stage 1), and as part of combination therapy in Japanese patients with hormone receptor (HR)-positive locally advanced or recurrent breast cancer (Stage 2). In Stage 1, oral taselisib tablets 2, 4, and 6 mg/day were administered in 28-day cycles. In Stage 2, successive cohorts of patients received oral taselisib tablets (2 or 4 mg/day) with intramuscular fulvestrant 500 mg. Nine and six patients were enrolled in Stage 1 and Stage 2, respectively. Taselisib was well tolerated. No dose-limiting toxicities were experienced in any cohort of patients and no deaths were observed. The most common treatment-related adverse events in Stage 1 and Stage 2 were rash (55.6%, 66.7%), diarrhea (44.4%, 66.7%), stomatitis (44.4%, 66.7%). Taselisib was rapidly absorbed after administration; its half-life was 12.9–32.0 hours in Stage 1 and 16.1–26.5 hours in Stage 2. Two patients achieved partial response (PR) and five patients had stable disease (SD) in Stage 1, and one patient had PR and five patients had SD in Stage 2. All patients with PR were positive for PIK3CA gene mutations. These preliminary data suggest that taselisib may be effective in patients with PIK3CA-mutated solid tumors or HR-positive advanced breast cancer.

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Phase I study of taselisib in Japanese patients with advanced solid tumors or hormone receptor-positive advanced breast cancer

Summary

Taselisib is a potent and selective phosphatidylinositide 3-kinase (PI3K) inhibitor. This paper reports the first study of taselisib administration in Japanese patients. The aim of this two-stage, phase I, multicenter, open-label, dose-escalation study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of taselisib as monotherapy in Japanese patients with advanced solid tumors (Stage 1), and as part of combination therapy in Japanese patients with hormone receptor (HR)-positive locally advanced or recurrent breast cancer (Stage 2). In Stage 1, oral taselisib tablets 2, 4, and 6 mg/day were administered in 28-day cycles. In Stage 2, successive cohorts of patients received oral taselisib tablets (2 or 4 mg/day) with intramuscular fulvestrant 500 mg. Nine and six patients were enrolled in Stage 1 and Stage 2, respectively. Taselisib was well tolerated. No dose-limiting toxicities were experienced in any cohort of patients and no deaths were observed. The most common treatment-related adverse events in Stage 1 and Stage 2 were rash (55.6%, 66.7%), diarrhea (44.4%, 66.7%), stomatitis (44.4%, 66.7%). Taselisib was rapidly absorbed after administration; its half-life was 12.9–32.0 hours in Stage 1 and 16.1–26.5 hours in Stage 2. Two patients achieved partial response (PR) and five patients had stable disease (SD) in Stage 1, and one patient had PR and five patients had SD in Stage 2. All patients with PR were positive for PIK3CA gene mutations. These preliminary data suggest that taselisib may be effective in patients with PIK3CA-mutated solid tumors or HR-positive advanced breast cancer.

This article is protected by copyright. All rights reserved.

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Synthesis and Evaluation of 2-[18F]Fluoroethyltriazolesuberohydroxamine Acid for Histone Deacetylase in a Tumor Model as a Positron Emission Tomography Radiotracer

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Taxane use in breast cancer and risk of brain metastases

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Taxane use in breast cancer and risk of brain metastases

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ASP2215 in the treatment of relapsed/refractory acute myeloid leukemia with FLT3 mutation: background and design of the ADMIRAL trial

Future Oncology, Ahead of Print.


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ASP2215 in the treatment of relapsed/refractory acute myeloid leukemia with FLT3 mutation: background and design of the ADMIRAL trial

Future Oncology, Ahead of Print.


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Low Incidence of esophageal toxicity following Lung SBRT: Are current esophageal dose constraints too conservative?

Publication date: Available online 2 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Vivian Yau, Patricia Lindsay, Lisa Le, Anthea Lau, Olive Wong, Daniel Glick, Andrea Bezjak, B.C.John Cho, Andrew Hope, Alex Sun, Meredith Giuliani
IntroductionTumours in close proximity to the esophagus present a challenge for lung SBRT, as potential esophageal toxicity must be balanced with the goal of tumour control. The purpose of this study was to explore and quantify the relationship between esophageal dose and toxicity.MethodsWe conducted this analysis based on a prospective study of patients treated with SBRT at our institution from October 2004 to December 2015. Most patients were treated with 54Gy/3, 48Gy/4 alternate days, or 60Gy/8 daily. Toxicity was prospectively graded using CTCAE v3.0. Logistic regression was used to estimate the risk of esophageal toxicity as a function of radiotherapy dose, in 2-Gy-equivalent dose (EQD2), using an alpha-beta ratio of 3 Gy in the linear-quadratic model.Results632 patients were analyzed. The median follow up was 20.8 months. Median overall survival was 35.3 months. The rate of late or acute, grade 1 or greater esophageal toxicity, including dysphagia, odynophagia, and esophagitis, was 3.3% (n=21). The median (range) esophageal doses were 11.8Gy (0.2-48.2Gy), 10.34Gy (0.17- 44.5Gy), and 9.63Gy (0.08- 43Gy) for Dmax, D1cc and D2cc, respectively. A 15% risk of esophageal toxicity was associated with EQD2 of Dmax 141.6Gy, D1cc 123.61, and D2cc 117.6Gy. Of the 21 patients who experienced esophageal toxicity, only 1 patient had grade 3 toxicity and the remainder had grade 2 or lower toxicity.Discussion: The observed rate of toxicity was low, despite some patients receiving relatively high doses to the esophagus. A prospective study in a targeted population, for example patients with ultracentral tumours, may provide more accurate dose-toxicity parameters.



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Multimodal Imaging of Pathologic Response to Chemoradiation in Esophageal Cancer

Publication date: Available online 2 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Penny Fang, Benjamin C. Musall, Jong Bum Son, Amy C. Moreno, Brian P. Hobbs, Brett W. Carter, Bryan M. Fellman, Osama Mawlawi, Jingfei Ma, Steven H. Lin
PurposeTo examine the value of early changes in quantitative diffusion-weighted imaging (DWI) and ¹⁸F-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for discriminating complete pathologic response (pCR) to chemoradiation (CRT) in esophageal cancer.MethodsTwenty esophageal cancer patients treated with chemoradiation followed by surgery were prospectively enrolled. Patients underwent MRI and FDG-PET/CT scans at baseline (BL), interim (IM, 2 weeks after CRT start), and first follow-up (FU). Based on pathologic findings at surgery, patients were categorized into tumor regression groups (TRG1, TRG2, and TRG3+). Distributions of summary statistics in apparent diffusion coefficient (ADC) and FDG-PET at BL and relative change at IM and FU scans were compared between pCR/TRG1 and non-pCR/TRG2+ groups and across readers. Receiver operating characteristics (ROCs) were evaluated for summary measures to characterize discrimination of pCR from non-pCR.ResultsRelative changes in tumor volume ADC (ΔADC) mean, 25^th and 10^th percentiles were able to completely discriminate (AUC=1, p<0.0011) between pCR and non-pCR (thresholds = 27.7%, 29.2%, and 32.1%, respectively) and were found to have high inter-reader reliability (95% limits of agreement of 1.001, 0.944 and 0.940, respectively). Relative change in total lesion glycolysis (TLG) from BL to IM was significantly different among pCR and non-pCR groups (p=0.0117) and yielded AUC of 0.947 (95% CI: 0.8505-1.043). An optimal threshold of 59% decrease in TLG provided optimal sensitivity (specificity) of 1.000 (0.867). Changes in ADC summary measures were negatively correlated with that of TLG (Spearman, -0.495, p=0.027).ConclusionQuantitative volume ΔADC and TLG during treatment may serve as early imaging biomarkers for discriminating pathologic response to chemoradiation in esophageal cancer. Validation of this data in larger prospective multicenter studies is essential.



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A Phase II Study of Stereotactic Body Radiotherapy and Stereotactic Body Proton Therapy for High-Risk Medically Inoperable Early-Stage Non-Small Cell Lung Cancer

Publication date: Available online 2 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Chonnipa Nantavithya, Daniel R. Gomez, Xiong Wei, Ritsuko Komaki, Zhongxing Liao, Steven H. Lin, Melenda Jeter, Quynh-Nhu Nguyen, Heng Li, Xiaodong Zhang, Falk Poenisch, X Ronald Zhu, Peter A. Balter, Lei Feng, Noah C. Choi, Radhe Mohan, Joe Y. Chang
PurposeTo report the feasibility of conducting a randomized study to compare the toxicity and efficacy of stereotactic body radiotherapy (SBRT) versus stereotactic body proton therapy (SBPT) for high-risk medically inoperable early-stage non-small cell lung cancer (NSCLC).Methods and MaterialsWe randomly assigned patients with medically inoperable NSCLC with high-risk features (centrally located or <5 cm-T3 tumor or isolated lung parenchymal recurrences) to SBRT or SBPT. Radiation dose was 50 Gy(RBE) in four 12.5-Gy(RBE) fractions prescribed to the planning target volume. SBRT was given using 3-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT), and SBPT was given using passive scattering. Consistency in patient setup was ensured with on-board cone-beam computed tomography for the SBRT group and with orthogonal X-rays for the SBPT group.ResultsThe study closed early owing to poor accrual, largely because of insurance coverage, and lack of volumetric imaging in the SBPT group. Ultimately, 21 patients were enrolled, and 19 patients who received 50 Gy in 4 fractions were included for analysis (9 SBRT, 10 SBPT). At a median follow-up time of 32 months, median overall survival (OS) time was 28 months in the SBRT group and not reached in the SBPT group. Three-years OS was 27.8% and 90%, 3-year local control (LC) was 87.5% (8/9) and 90.0% (9/10) and 3-years regional control (RC) was 47.6% (5/9) and 90% (9/10) in SBRT and SBPT respectively. One patient in the SBPT group developed grade 3 skin fibrosis. No patients experienced grade 4/5 toxicity.ConclusionPoor accrual, due to lack of volumetric image and insurance coverage for proton therapy led to early closure of the trial and precluded accurate assessment of efficacy and toxicity. Comparable maturity of two radiotherapy modalities, particularly on-board image, and better insurance coverage for SBPT should be considered for the future studies.

Teaser

A phase II randomized study to compare SBRT vs. SBPT was terminated early due to poor accrual; treatment outcomes after SBPT appeared no worse than those after SBRT numerically with low treatment related toxicity in both groups. Lack of volumetric imaging and insurance coverage for patients treated with SBPT were the major barriers to accrual. In addition to financial issues, similar maturity of treatment planning and imaged-guided delivery are essential for future comparison studies between proton and photon therapy.


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Correlation Between Tumor Metabolism and Semiquantitative Perfusion MRI Metrics in Non-small Cell Lung Cancer

Publication date: Available online 2 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sang Ho Lee, Andreas Rimner, Emily Gelb, Joseph O. Deasy, Margie A. Hunt, John L. Humm, Neelam Tyagi
PurposeTo correlate semiquantitative parameters derived from dynamic contrast-enhanced MRI (DCE-MRI) and ¹⁸F-FDG-PET for non-small cell lung cancer (NSCLC).MethodsTwenty-four NSCLC patients who underwent pretreatment ¹⁸F-FDG-PET and DCE-MRI were analyzed. The maximum standardized uptake value (SUVmax) was measured from ¹⁸F-FDG-PET. DCE-MRI was obtained on 3T MRI scanner using four-dimensional T1-weighted high-resolution imaging with volume excitation sequence. DCE-MRI parameters consisting of mean, median, standard deviation (SD), and median absolute deviation (MAD) of peak enhancement, time-to-peak (TTP), time-to-half-peak (TTHP), wash-in slope (WIS), wash-out slope (WOS), initial gradient, wash-out gradient, signal enhancement ratio, and initial area under the relative signal enhancement curve taken up to 30, 60, 90, 120, 150, and 180 s, TTP, and TTHP (IAUCtthp) were calculated for each lesion. Univariate analysis (UVA) was performed using Spearman correlation. A linear regression model to predict SUVmax from DCE-MRI parameters was developed by multivariate analysis (MVA) using least absolute shrinkage selection operator in combination with leave-one-out cross-validation (LOOCV).ResultsIn UVA, mean(WOS) (ρ = -0.456, p = 0.025), mean(IAUCtthp) (ρ = -0.439, p = 0.032), median(IAUCtthp) (ρ = -0.543, p = 0.006), and MAD(IAUCtthp) (ρ = -0.557, p = 0.005) were statistically significant; all these parameters were negatively correlated with SUVmax. In MVA, a linear combination of SD(WIS), SD(TTP), MAD(TTHP), and MAD(IAUCtthp) was statistically significant for predicting SUVmax (LOOCV-based adjusted R² = 0.298, p = 0.0006). A decrease in SD(WIS), MAD(TTHP), and MAD(IAUCtthp) and an increase in SD(TTP) were associated with a significant increase in SUVmax.ConclusionAssociation was found between SUVmax, the SD, and MAD of DCE-MRI metrics derived during contrast uptake in NSCLC, reflecting that intratumoral heterogeneity in wash-in contrast kinetics is associated with tumor metabolism. Although MAD(IAUCtthp) was a significant feature in both UVA and MVA, the LASSO-based multivariate regression model yielded better predictability of SUVmax than a univariate regression model using MAD(IAUCtthp). This study will facilitate understanding of the complex relationship between tumor vascularization and metabolism, and eventually help in guiding targeted therapy.

Teaser

Balance between vascularity and glucose metabolism in tumor could prove to be an important indicator of its biological status and resistance to treatment. This study evaluates the use of semiquantitative dynamic contrast-enhanced MRI parameters for predicting the ¹⁸F-FDG-PET maximum standardized uptake value in non-small cell lung cancer (NSCLC). It was found that intratumoral heterogeneity in wash-in contrast kinetics is associated with tumor metabolism. Investigating vascular-metabolic relationship will help in guiding personalized targeted therapy in NSCLC.


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Measurement of Tumor Hypoxia in Patients with Locally Advanced Cervical Cancer using Positron Emission Tomography (PET) with 18F-Fluoroazomyin Arabinoside (18F-FAZA)

Publication date: Available online 2 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Kathy Han, Tina Shek, Douglass Vines, Brandon Driscoll, Anthony Fyles, David Jaffray, Harald Keller, Ur Metser, Melania Pintilie, Jason Xie, Ivan Yeung, Michael Milosevic
PurposePoor tumor oxygenation (hypoxia) is associated with inferior survival in cervical cancer and resistance to radiotherapy. Positron emission tomography (PET) imaging of tumor hypoxia is minimally invasive and allows evaluation of the entire tumor, but has not been widely studied in cervical cancer. This study assesses cervical tumor hypoxia using hypoxia tracer ¹⁸F-fluoroazomycin arabinoside (¹⁸F-FAZA), and compares different reference tissues and thresholds for quantifying tumor hypoxia.Methods and MaterialsTwenty-seven patients with cervical cancer were studied prospectively by PET imaging with ¹⁸F-FAZA before starting standard chemoradiation. The hypoxic volume (HV) was defined as all voxels within a tumor (T) with standardized uptake values (SUVs) greater than 3 standard deviations from the mean gluteus maximus muscle SUV value (M), or SUVs greater than 1–1.4 times the mean SUV value of the left ventricle, a blood (B) surrogate. The hypoxic fraction (HF) was defined as the ratio of the number of hypoxic voxels to the total number of tumor voxels.ResultsA ¹⁸F-FAZA PET HV could be identified in the majority of cervical tumors (89% when using T/M or T/B >1.2 as threshold) on the 2-hour static scan. The HF ranged from 0-99% (median 31%) when defined using the T/M threshold, and 0-78% (median 32%) with the T/B >1.2 threshold. HVs derived from the different thresholds were highly correlated (Spearman's correlation coefficient ρ between T/M and T/B >1–1.4 were 0.82-0.91), as were HFs (0.75-0.85). Compartmental analysis of the dynamic scans showed k3, the FAZA accumulation constant, to be strongly correlated with HF defined using the T/M (Spearman's ρ=0.72) and T/B >1.2 thresholds (0.76).ConclusionsHypoxia was detected in the majority of cervical tumors on ¹⁸F-FAZA-PET imaging. The extent of hypoxia varied markedly between tumors, but not significantly with different reference tissues/thresholds.



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Using Big Data Analytics to Advance Precision Radiation Oncology

Publication date: Available online 2 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Todd R. McNutt, Stanley H. Benedict, Daniel A. Low, Kevin Moore, Ilya Shpitser, Wei Jiang, Pranav Lakshminarayanan, Zhi Cheng, Peijin Han, Xuan Hui, Minoru Nakatsugawa, Junghoon Lee, Joseph A. Moore, Scott P. Robertson, Veeraj Shah, Russ Taylor, Harry Quon, John Wong, Theodore DeWeese
Big Clinical Data Analytics as a primary component of precision medicine is discussed, ] identifying where these emerging tools fit in the spectrum of genomic and radiomic research. A learning health system (LHS) is conceptualized that utilizes clinically acquired data with machine learning to advance the initiatives of precision medicine. The LHS is comprehensive and can be used for clinical decision support, discovery, and hypothesis derivation. These developing uses can positively impact the ultimate management and therapeutic course for patients. The conceptual model for each use of clinical data, is however different, and an overview of the implications is discussed. With advancement in technologies and culture to improve the efficiency, accuracy and breadth of measurements of the patient condition, the concept of a LHS may be realized in precision radiotherapy.



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Demonstration of safety and feasibility of hydrogel marking of the pancreas-duodenum interface for image-guided radiation therapy (IGRT) in a porcine model: Implications in IGRT for pancreatic cancer patients

Publication date: Available online 2 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Avani D. Rao, Eun Ji Shin, Sarah E. Beck, Caroline Garrett, Seong-Hun Kim, Nam Ju Lee, Eleni Liapi, John Wong, Joseph Herman, Amol Narang, Kai Ding
PurposeLimitations in cone beam computed tomography (CBCT) soft-tissue contrast prohibit clinicians from clearly identifying the dose-limiting proximal duodenum in unresectable pancreatic cancer patients treated with radiation therapy (RT). This study tests the feasibility and safety of injecting a high-contrast hydrogel marker at the head of the pancreas (HOP) and duodenum interface and assesses the marker visibility on CBCT to localize this important boundary during image-guided RT in a porcine model.Methods and MaterialsThis was a two-stage study. The feasibility/visibility stage evaluated the ability to place the hydrogel using endoscopic ultrasound-guidance on 8 swine (4 euthanized at post-injection day 8, 4 euthanized at post-injection day 22) and assessed the quality of visibility of the marked location on CBCT in the longer-surviving group. The risk assessment stage evaluated the toxicity of targeted intrapancreatic injections (3 swine) and intramural duodenal wall injections (3 swine) to assess toxicity of a misplaced hydrogel injection. All swine underwent post-mortem examination and histopathological studies.ResultsThe HOP-duodenum interface was successfully marked using hydrogel in 6 of the 8 swine. Histopathologic examination of the 6 successful hydrogel injections showed mild/minimal (4 cases) or moderate (2 cases) reactive inflammation isolated to the injection site. Of the 4 swine survived to 22 days, 3 demonstrated successful hydrogel placement at the HOP-duodenum interface, and this marked location was clearly visible for positional guidance on CBCT. There was no evidence of pancreatitis or duodenal toxicity in the swine undergoing targeted intrapancreatic or intramural duodenum injections for the risk assessment stage.ConclusionsWe demonstrate the feasibility and safety of injecting a hydrogel marker to highlight the HOP-duodenum interface that has acceptable visibility on CBCT. This technique, translated to humans, enables on-board visualization of this important boundary between the radiation target and dose-limiting, radiosensitive duodenum, facilitating efforts to safely deliver dose-escalated RT.

Teaser

This study presents the feasibility and safety of marking the pancreas and duodenum interface with a high-contrast hydrogel and demonstrates acceptable visibility of the marked location on cone beam computed tomography using a porcine model. Translation of this technique to the radiotherapy treatment of pancreatic cancer patients would enable on-board visualization of this important boundary between the radiation target and the dose-limiting duodenum, facilitating future efforts towards safe dose-escalation.


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Using Big Data Analytics to Advance Precision Radiation Oncology

Publication date: Available online 2 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Todd R. McNutt, Stanley H. Benedict, Daniel A. Low, Kevin Moore, Ilya Shpitser, Wei Jiang, Pranav Lakshminarayanan, Zhi Cheng, Peijin Han, Xuan Hui, Minoru Nakatsugawa, Junghoon Lee, Joseph A. Moore, Scott P. Robertson, Veeraj Shah, Russ Taylor, Harry Quon, John Wong, Theodore DeWeese
Big Clinical Data Analytics as a primary component of precision medicine is discussed, ] identifying where these emerging tools fit in the spectrum of genomic and radiomic research. A learning health system (LHS) is conceptualized that utilizes clinically acquired data with machine learning to advance the initiatives of precision medicine. The LHS is comprehensive and can be used for clinical decision support, discovery, and hypothesis derivation. These developing uses can positively impact the ultimate management and therapeutic course for patients. The conceptual model for each use of clinical data, is however different, and an overview of the implications is discussed. With advancement in technologies and culture to improve the efficiency, accuracy and breadth of measurements of the patient condition, the concept of a LHS may be realized in precision radiotherapy.



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Low Incidence of esophageal toxicity following Lung SBRT: Are current esophageal dose constraints too conservative?

Publication date: Available online 2 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Vivian Yau, Patricia Lindsay, Lisa Le, Anthea Lau, Olive Wong, Daniel Glick, Andrea Bezjak, B.C.John Cho, Andrew Hope, Alex Sun, Meredith Giuliani
IntroductionTumours in close proximity to the esophagus present a challenge for lung SBRT, as potential esophageal toxicity must be balanced with the goal of tumour control. The purpose of this study was to explore and quantify the relationship between esophageal dose and toxicity.MethodsWe conducted this analysis based on a prospective study of patients treated with SBRT at our institution from October 2004 to December 2015. Most patients were treated with 54Gy/3, 48Gy/4 alternate days, or 60Gy/8 daily. Toxicity was prospectively graded using CTCAE v3.0. Logistic regression was used to estimate the risk of esophageal toxicity as a function of radiotherapy dose, in 2-Gy-equivalent dose (EQD2), using an alpha-beta ratio of 3 Gy in the linear-quadratic model.Results632 patients were analyzed. The median follow up was 20.8 months. Median overall survival was 35.3 months. The rate of late or acute, grade 1 or greater esophageal toxicity, including dysphagia, odynophagia, and esophagitis, was 3.3% (n=21). The median (range) esophageal doses were 11.8Gy (0.2-48.2Gy), 10.34Gy (0.17- 44.5Gy), and 9.63Gy (0.08- 43Gy) for Dmax, D1cc and D2cc, respectively. A 15% risk of esophageal toxicity was associated with EQD2 of Dmax 141.6Gy, D1cc 123.61, and D2cc 117.6Gy. Of the 21 patients who experienced esophageal toxicity, only 1 patient had grade 3 toxicity and the remainder had grade 2 or lower toxicity.Discussion: The observed rate of toxicity was low, despite some patients receiving relatively high doses to the esophagus. A prospective study in a targeted population, for example patients with ultracentral tumours, may provide more accurate dose-toxicity parameters.



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Multimodal Imaging of Pathologic Response to Chemoradiation in Esophageal Cancer

Publication date: Available online 2 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Penny Fang, Benjamin C. Musall, Jong Bum Son, Amy C. Moreno, Brian P. Hobbs, Brett W. Carter, Bryan M. Fellman, Osama Mawlawi, Jingfei Ma, Steven H. Lin
PurposeTo examine the value of early changes in quantitative diffusion-weighted imaging (DWI) and ¹⁸F-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for discriminating complete pathologic response (pCR) to chemoradiation (CRT) in esophageal cancer.MethodsTwenty esophageal cancer patients treated with chemoradiation followed by surgery were prospectively enrolled. Patients underwent MRI and FDG-PET/CT scans at baseline (BL), interim (IM, 2 weeks after CRT start), and first follow-up (FU). Based on pathologic findings at surgery, patients were categorized into tumor regression groups (TRG1, TRG2, and TRG3+). Distributions of summary statistics in apparent diffusion coefficient (ADC) and FDG-PET at BL and relative change at IM and FU scans were compared between pCR/TRG1 and non-pCR/TRG2+ groups and across readers. Receiver operating characteristics (ROCs) were evaluated for summary measures to characterize discrimination of pCR from non-pCR.ResultsRelative changes in tumor volume ADC (ΔADC) mean, 25^th and 10^th percentiles were able to completely discriminate (AUC=1, p<0.0011) between pCR and non-pCR (thresholds = 27.7%, 29.2%, and 32.1%, respectively) and were found to have high inter-reader reliability (95% limits of agreement of 1.001, 0.944 and 0.940, respectively). Relative change in total lesion glycolysis (TLG) from BL to IM was significantly different among pCR and non-pCR groups (p=0.0117) and yielded AUC of 0.947 (95% CI: 0.8505-1.043). An optimal threshold of 59% decrease in TLG provided optimal sensitivity (specificity) of 1.000 (0.867). Changes in ADC summary measures were negatively correlated with that of TLG (Spearman, -0.495, p=0.027).ConclusionQuantitative volume ΔADC and TLG during treatment may serve as early imaging biomarkers for discriminating pathologic response to chemoradiation in esophageal cancer. Validation of this data in larger prospective multicenter studies is essential.



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A Phase II Study of Stereotactic Body Radiotherapy and Stereotactic Body Proton Therapy for High-Risk Medically Inoperable Early-Stage Non-Small Cell Lung Cancer

Publication date: Available online 2 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Chonnipa Nantavithya, Daniel R. Gomez, Xiong Wei, Ritsuko Komaki, Zhongxing Liao, Steven H. Lin, Melenda Jeter, Quynh-Nhu Nguyen, Heng Li, Xiaodong Zhang, Falk Poenisch, X Ronald Zhu, Peter A. Balter, Lei Feng, Noah C. Choi, Radhe Mohan, Joe Y. Chang
PurposeTo report the feasibility of conducting a randomized study to compare the toxicity and efficacy of stereotactic body radiotherapy (SBRT) versus stereotactic body proton therapy (SBPT) for high-risk medically inoperable early-stage non-small cell lung cancer (NSCLC).Methods and MaterialsWe randomly assigned patients with medically inoperable NSCLC with high-risk features (centrally located or <5 cm-T3 tumor or isolated lung parenchymal recurrences) to SBRT or SBPT. Radiation dose was 50 Gy(RBE) in four 12.5-Gy(RBE) fractions prescribed to the planning target volume. SBRT was given using 3-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT), and SBPT was given using passive scattering. Consistency in patient setup was ensured with on-board cone-beam computed tomography for the SBRT group and with orthogonal X-rays for the SBPT group.ResultsThe study closed early owing to poor accrual, largely because of insurance coverage, and lack of volumetric imaging in the SBPT group. Ultimately, 21 patients were enrolled, and 19 patients who received 50 Gy in 4 fractions were included for analysis (9 SBRT, 10 SBPT). At a median follow-up time of 32 months, median overall survival (OS) time was 28 months in the SBRT group and not reached in the SBPT group. Three-years OS was 27.8% and 90%, 3-year local control (LC) was 87.5% (8/9) and 90.0% (9/10) and 3-years regional control (RC) was 47.6% (5/9) and 90% (9/10) in SBRT and SBPT respectively. One patient in the SBPT group developed grade 3 skin fibrosis. No patients experienced grade 4/5 toxicity.ConclusionPoor accrual, due to lack of volumetric image and insurance coverage for proton therapy led to early closure of the trial and precluded accurate assessment of efficacy and toxicity. Comparable maturity of two radiotherapy modalities, particularly on-board image, and better insurance coverage for SBPT should be considered for the future studies.

Teaser

A phase II randomized study to compare SBRT vs. SBPT was terminated early due to poor accrual; treatment outcomes after SBPT appeared no worse than those after SBRT numerically with low treatment related toxicity in both groups. Lack of volumetric imaging and insurance coverage for patients treated with SBPT were the major barriers to accrual. In addition to financial issues, similar maturity of treatment planning and imaged-guided delivery are essential for future comparison studies between proton and photon therapy.


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Correlation Between Tumor Metabolism and Semiquantitative Perfusion MRI Metrics in Non-small Cell Lung Cancer

Publication date: Available online 2 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sang Ho Lee, Andreas Rimner, Emily Gelb, Joseph O. Deasy, Margie A. Hunt, John L. Humm, Neelam Tyagi
PurposeTo correlate semiquantitative parameters derived from dynamic contrast-enhanced MRI (DCE-MRI) and ¹⁸F-FDG-PET for non-small cell lung cancer (NSCLC).MethodsTwenty-four NSCLC patients who underwent pretreatment ¹⁸F-FDG-PET and DCE-MRI were analyzed. The maximum standardized uptake value (SUVmax) was measured from ¹⁸F-FDG-PET. DCE-MRI was obtained on 3T MRI scanner using four-dimensional T1-weighted high-resolution imaging with volume excitation sequence. DCE-MRI parameters consisting of mean, median, standard deviation (SD), and median absolute deviation (MAD) of peak enhancement, time-to-peak (TTP), time-to-half-peak (TTHP), wash-in slope (WIS), wash-out slope (WOS), initial gradient, wash-out gradient, signal enhancement ratio, and initial area under the relative signal enhancement curve taken up to 30, 60, 90, 120, 150, and 180 s, TTP, and TTHP (IAUCtthp) were calculated for each lesion. Univariate analysis (UVA) was performed using Spearman correlation. A linear regression model to predict SUVmax from DCE-MRI parameters was developed by multivariate analysis (MVA) using least absolute shrinkage selection operator in combination with leave-one-out cross-validation (LOOCV).ResultsIn UVA, mean(WOS) (ρ = -0.456, p = 0.025), mean(IAUCtthp) (ρ = -0.439, p = 0.032), median(IAUCtthp) (ρ = -0.543, p = 0.006), and MAD(IAUCtthp) (ρ = -0.557, p = 0.005) were statistically significant; all these parameters were negatively correlated with SUVmax. In MVA, a linear combination of SD(WIS), SD(TTP), MAD(TTHP), and MAD(IAUCtthp) was statistically significant for predicting SUVmax (LOOCV-based adjusted R² = 0.298, p = 0.0006). A decrease in SD(WIS), MAD(TTHP), and MAD(IAUCtthp) and an increase in SD(TTP) were associated with a significant increase in SUVmax.ConclusionAssociation was found between SUVmax, the SD, and MAD of DCE-MRI metrics derived during contrast uptake in NSCLC, reflecting that intratumoral heterogeneity in wash-in contrast kinetics is associated with tumor metabolism. Although MAD(IAUCtthp) was a significant feature in both UVA and MVA, the LASSO-based multivariate regression model yielded better predictability of SUVmax than a univariate regression model using MAD(IAUCtthp). This study will facilitate understanding of the complex relationship between tumor vascularization and metabolism, and eventually help in guiding targeted therapy.

Teaser

Balance between vascularity and glucose metabolism in tumor could prove to be an important indicator of its biological status and resistance to treatment. This study evaluates the use of semiquantitative dynamic contrast-enhanced MRI parameters for predicting the ¹⁸F-FDG-PET maximum standardized uptake value in non-small cell lung cancer (NSCLC). It was found that intratumoral heterogeneity in wash-in contrast kinetics is associated with tumor metabolism. Investigating vascular-metabolic relationship will help in guiding personalized targeted therapy in NSCLC.


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Measurement of Tumor Hypoxia in Patients with Locally Advanced Cervical Cancer using Positron Emission Tomography (PET) with 18F-Fluoroazomyin Arabinoside (18F-FAZA)

Publication date: Available online 2 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Kathy Han, Tina Shek, Douglass Vines, Brandon Driscoll, Anthony Fyles, David Jaffray, Harald Keller, Ur Metser, Melania Pintilie, Jason Xie, Ivan Yeung, Michael Milosevic
PurposePoor tumor oxygenation (hypoxia) is associated with inferior survival in cervical cancer and resistance to radiotherapy. Positron emission tomography (PET) imaging of tumor hypoxia is minimally invasive and allows evaluation of the entire tumor, but has not been widely studied in cervical cancer. This study assesses cervical tumor hypoxia using hypoxia tracer ¹⁸F-fluoroazomycin arabinoside (¹⁸F-FAZA), and compares different reference tissues and thresholds for quantifying tumor hypoxia.Methods and MaterialsTwenty-seven patients with cervical cancer were studied prospectively by PET imaging with ¹⁸F-FAZA before starting standard chemoradiation. The hypoxic volume (HV) was defined as all voxels within a tumor (T) with standardized uptake values (SUVs) greater than 3 standard deviations from the mean gluteus maximus muscle SUV value (M), or SUVs greater than 1–1.4 times the mean SUV value of the left ventricle, a blood (B) surrogate. The hypoxic fraction (HF) was defined as the ratio of the number of hypoxic voxels to the total number of tumor voxels.ResultsA ¹⁸F-FAZA PET HV could be identified in the majority of cervical tumors (89% when using T/M or T/B >1.2 as threshold) on the 2-hour static scan. The HF ranged from 0-99% (median 31%) when defined using the T/M threshold, and 0-78% (median 32%) with the T/B >1.2 threshold. HVs derived from the different thresholds were highly correlated (Spearman's correlation coefficient ρ between T/M and T/B >1–1.4 were 0.82-0.91), as were HFs (0.75-0.85). Compartmental analysis of the dynamic scans showed k3, the FAZA accumulation constant, to be strongly correlated with HF defined using the T/M (Spearman's ρ=0.72) and T/B >1.2 thresholds (0.76).ConclusionsHypoxia was detected in the majority of cervical tumors on ¹⁸F-FAZA-PET imaging. The extent of hypoxia varied markedly between tumors, but not significantly with different reference tissues/thresholds.



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Demonstration of safety and feasibility of hydrogel marking of the pancreas-duodenum interface for image-guided radiation therapy (IGRT) in a porcine model: Implications in IGRT for pancreatic cancer patients

Publication date: Available online 2 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Avani D. Rao, Eun Ji Shin, Sarah E. Beck, Caroline Garrett, Seong-Hun Kim, Nam Ju Lee, Eleni Liapi, John Wong, Joseph Herman, Amol Narang, Kai Ding
PurposeLimitations in cone beam computed tomography (CBCT) soft-tissue contrast prohibit clinicians from clearly identifying the dose-limiting proximal duodenum in unresectable pancreatic cancer patients treated with radiation therapy (RT). This study tests the feasibility and safety of injecting a high-contrast hydrogel marker at the head of the pancreas (HOP) and duodenum interface and assesses the marker visibility on CBCT to localize this important boundary during image-guided RT in a porcine model.Methods and MaterialsThis was a two-stage study. The feasibility/visibility stage evaluated the ability to place the hydrogel using endoscopic ultrasound-guidance on 8 swine (4 euthanized at post-injection day 8, 4 euthanized at post-injection day 22) and assessed the quality of visibility of the marked location on CBCT in the longer-surviving group. The risk assessment stage evaluated the toxicity of targeted intrapancreatic injections (3 swine) and intramural duodenal wall injections (3 swine) to assess toxicity of a misplaced hydrogel injection. All swine underwent post-mortem examination and histopathological studies.ResultsThe HOP-duodenum interface was successfully marked using hydrogel in 6 of the 8 swine. Histopathologic examination of the 6 successful hydrogel injections showed mild/minimal (4 cases) or moderate (2 cases) reactive inflammation isolated to the injection site. Of the 4 swine survived to 22 days, 3 demonstrated successful hydrogel placement at the HOP-duodenum interface, and this marked location was clearly visible for positional guidance on CBCT. There was no evidence of pancreatitis or duodenal toxicity in the swine undergoing targeted intrapancreatic or intramural duodenum injections for the risk assessment stage.ConclusionsWe demonstrate the feasibility and safety of injecting a hydrogel marker to highlight the HOP-duodenum interface that has acceptable visibility on CBCT. This technique, translated to humans, enables on-board visualization of this important boundary between the radiation target and dose-limiting, radiosensitive duodenum, facilitating efforts to safely deliver dose-escalated RT.

Teaser

This study presents the feasibility and safety of marking the pancreas and duodenum interface with a high-contrast hydrogel and demonstrates acceptable visibility of the marked location on cone beam computed tomography using a porcine model. Translation of this technique to the radiotherapy treatment of pancreatic cancer patients would enable on-board visualization of this important boundary between the radiation target and the dose-limiting duodenum, facilitating future efforts towards safe dose-escalation.


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Repeat stereotactic radiosurgery for Cushing’s disease: outcomes of an international, multicenter study

Abstract

Stereotactic radiosurgery (SRS) is frequently used for Cushing's disease (CD) after failed pituitary surgery. Management of patients with persistent CD after failed SRS is complex, as the alternative therapeutic options harbor significant risks. The outcomes of repeat pituitary radiosurgery, however, have not been described. We sought to determine the outcomes of repeat SRS in patients with CD. We pooled data from five institutions participating in the International Gamma Knife Research Foundation for patients with recurrent or persistent CD ≥ 12 months after initial SRS. Patients were included in the study if they had ≥ 6 months endocrine follow-up after repeat SRS. Twenty patients were included in the study. Repeat single-session SRS was performed 1.3–9.7 years after initial SRS. Median endocrine follow-up was 6.6 years (1.4–19.1 years). Median margin dose was 20 Gy (range 10.8–35 Gy). Endocrine remission after second SRS was noted in 12 patients (60%), with a median time to remission of 6 months (range 2–64 months). Biochemical recurrence occurred in two patients (17%) after initial remission. Overall, the cumulative rates of durable endocrine remission at 5 and 10 years were 47 and 53%, respectively. Two patients (10%) experienced adverse radiation effects, including transient visual loss and permanent diplopia. Repeat SRS achieves lasting biochemical remission in approximately half of patients with CD refractory to both prior microsurgery and SRS. Because of the morbidity of refractory or recurrent CD, repeat SRS should be considered for carefully selected patients with hypercortisolism confirmed one or more years after initial SRS.

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Repeat stereotactic radiosurgery for Cushing’s disease: outcomes of an international, multicenter study

Abstract

Stereotactic radiosurgery (SRS) is frequently used for Cushing's disease (CD) after failed pituitary surgery. Management of patients with persistent CD after failed SRS is complex, as the alternative therapeutic options harbor significant risks. The outcomes of repeat pituitary radiosurgery, however, have not been described. We sought to determine the outcomes of repeat SRS in patients with CD. We pooled data from five institutions participating in the International Gamma Knife Research Foundation for patients with recurrent or persistent CD ≥ 12 months after initial SRS. Patients were included in the study if they had ≥ 6 months endocrine follow-up after repeat SRS. Twenty patients were included in the study. Repeat single-session SRS was performed 1.3–9.7 years after initial SRS. Median endocrine follow-up was 6.6 years (1.4–19.1 years). Median margin dose was 20 Gy (range 10.8–35 Gy). Endocrine remission after second SRS was noted in 12 patients (60%), with a median time to remission of 6 months (range 2–64 months). Biochemical recurrence occurred in two patients (17%) after initial remission. Overall, the cumulative rates of durable endocrine remission at 5 and 10 years were 47 and 53%, respectively. Two patients (10%) experienced adverse radiation effects, including transient visual loss and permanent diplopia. Repeat SRS achieves lasting biochemical remission in approximately half of patients with CD refractory to both prior microsurgery and SRS. Because of the morbidity of refractory or recurrent CD, repeat SRS should be considered for carefully selected patients with hypercortisolism confirmed one or more years after initial SRS.

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Chemotherapy induces breast cancer stemness in association with dysregulated monocytosis

Purpose: Preoperative or neoadjuvant therapy (NT) is increasingly used in patients with locally advanced or inflammatory breast cancer (BC) to allow optimal surgery and aim for pathological response. However, many BCs are resistant or relapse after treatment. Here, we investigated conjunctive chemotherapy-triggered events occurring systemically and locally, potentially promoting a cancer stem-like cell (CSC) phenotype and contributing to tumor relapse. Experimental Design: We started by comparing the effect of paired pre- and post-NT patient sera on the CSC properties of BC cells. Using cell lines, patient-derived xenograft models and primary tumors, we investigated the regulation of CSCs and tumor progression by chemotherapy-induced factors. Results: In human patients and mice, we detected a therapy-induced CSC-stimulatory activity in serum, which was attributed to therapy-associated monocytosis leading to systemic elevation of monocyte chemoattractant proteins (MCPs). The post-NT hematopoietic regeneration in the bone marrow highlighted both altered monocyte-macrophage differentiation and biased commitment of stimulated hematopoietic stem cells towards monocytosis. Chemotherapeutic agents also induce monocyte expression of MCPs through a JNK-dependent mechanism. Genetic and pharmacological inhibitions of the MCP-CCR2 pathway blocked chemotherapy's adverse effect on CSCs. Levels of nuclear Notch and ALDH1 were significantly elevated in primary BCs following NT, whereas higher levels of CCR2 in pre-NT tumors were associated with a poor response to NT. Conclusions: Our data establish a mechanism of chemotherapy-induced cancer stemness by linking the cellular events in the bone marrow and tumors, and suggest pharmacological inhibition of CCR2 as a potential co-treatment during conventional chemotherapy in neoadjuvant and adjuvant settings.

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IDO1 inhibition synergizes with radiation and PD-1 blockade to durably increase survival against advanced glioblastoma

Purpose: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults with a median survival of 15-20 months. Numerous approaches and novel therapeutics for treating GBM have been investigated in the setting of phase III clinical trials, including a recent analysis of the immune checkpoint inhibitor, Nivolumab (anti-PD-1), which failed to improve recurrent GBM patient survival. However, rather than abandoning immune checkpoint inhibitor treatment for GBM, which has shown promise in other types of cancer, ongoing studies are currently evaluating this therapeutic class when combined with other agents. Experimental Design: Here, we investigated immunocompetent orthotopic mouse models of GBM treated with the potent CNS-penetrating IDO1 enzyme inhibitor, BGB-5777, combined with anti-PD1 mAb, as well as radiation therapy (RT), based on our recent observation that tumor-infiltrating T cells directly increase immunosuppressive IDO1 levels in human GBM, the previously-described enhancement of immune cell functions after PD-1 blockade, as well as the pro-inflammatory effects of radiation. Results: Our results demonstrate a durable survival benefit from this novel three-agent treatment, but not for any single- or dual-agent combination. Unexpectedly, treatment efficacy required IDO1 enzyme inhibition in non-GBM cells, rather than tumor cells. Timing of effector T cell infiltration, animal subject age and usage of systemic chemotherapy, all directly impacted therapy-mediated survival benefit. Conclusions: These data highlight a novel and clinically-relevant immunotherapeutic approach with associated mechanistic considerations that have formed the basis of a newly-initiated phase I/II trial for GBM patients.

http://ift.tt/2F7LjEA

Sequencing pancreatic juice: squeezing the most out of surveillance

Next-generation sequencing of pancreatic juice can detect and quantify tumor-promoting mutations, supporting imaging and cytology findings to predict the degree of dysplasia in patients at high risk for pancreatic cancer. Future studies are needed to optimize this approach and determine how it best fits into clinical practice.

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A Phase 1 Clinical Trial of Guadecitabine and Carboplatin In Platinum-Resistant, Recurrent Ovarian Cancer: Clinical, Pharmacokinetic And Pharmacodynamic Analyses

Purpose: Epigenetic changes are implicated in acquired resistance to platinum. Guadecitabine is a next-generation hypomethylating agent (HMA). Here we report the clinical results, along with pharmacokinetic (PK) and pharmacodynamic analyses of the phase 1 study of guadecitabine and carboplatin (G+C) in patients with recurrent, platinum resistant high-grade serous ovarian cancer (OC), primary peritoneal carcinoma (PPC), or fallopian tube cancer (FTC). Experimental Design: Guadecitabine was administered once daily on Days 1-5 followed by carboplatin IV on Day 8 of a 28-day cycle. Patients had either measurable or detectable disease. Safety assessments used CTCAE v4. Results: Twenty patients were enrolled and treated. Median age was 56 years (38-72). Median number of prior regimens was 7 (1-14). In the first cohort (N=6), the starting doses were guadecitabine 45 mg/m² and carboplatin AUC5. Four patients experienced dose-limiting toxicity (DLT; neutropenia and thrombocytopenia) leading to dose de-escalation of guadecitabine to 30 mg/m² and of carboplatin to AUC4. No DLTS were observed in the subsequent 14 patients. Grade ≥3AEs ≥10% were neutropenia, leukopenia, anemia, nausea, vomiting, ascites, constipation, hypokalemia, pulmonary embolism, small intestinal obstruction, and thrombocytopenia. Three patients had a partial response (PR) and six patients had stable disease (SD) >3 months, for an overall response rate (ORR) and clinical benefit rate of 15% and 45%, respectively. LINE-1 demethylation in PBMCs and promoter demethylation/gene re-expression in paired tumor biopsies/ascites were recorded. Conclusions: G+C was tolerated and induced clinical responses in a heavily pretreated platinum resistant OC population, supporting a subsequent randomized phase 2 trial.

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Metabolomics profiles of hepatocellular carcinoma in a Korean prospective cohort: the Korean Cancer Prevention Study-II

In the prospective Korean Cancer Prevention Study-II (KCPS-II), we investigated the application of metabolomics to differentiate subjects with incident hepatocellular carcinoma (HCC group) from subjects who remained free of cancer (control group) during a mean follow-up period of 7 years with the aim of identifying valuable metabolic biomarkers for HCC. We used baseline serum samples from 75 subjects with incident HCC and 134 age- and gender-matched cancer-free subjects. Serum metabolic profiles associated with HCC incidence were investigated via metabolomics analysis. Compared to the control group, the HCC group showed significantly higher serum levels of aspartate aminotransferase (AST), alanine aminotransferase, and gamma-glutamyl transpeptidase. At baseline, compared to the control group, the HCC group showed significantly higher levels of 9 metabolites, including leucine, 5-hydroxyhexanoic acid, phenylalanine, tyrosine, arachidonic acid, and tauroursodeoxycholic acid (TUDCA), but lower levels of 28 metabolites, including oleamide, androsterone sulfate, L-palmitoylcarnitine, lysophosphatidic acid (LPA) 16:0, LPA 18:1, and lysophosphatidylcholines (lysoPCs). Multiple linear regression revealed that the incidence of HCC was associated with the levels of tyrosine, AST, lysoPCs (16:1, 20:3), oleamide, 5-hydroxyhexanoic acid, androsterone sulfate, and TUDCA (adjusted R2=0.514, P=0.036). This study showed the clinical relevance of the dysregulation of not only branched amino acids, aromatic amino acids, and lysoPCs but also bile acid biosynthesis and linoleic acid, arachidonic acid and fatty acid metabolism. Additionally, tyrosine, AST, lysoPCs (16:1, 20:3), oleamide, 5-hydroxyhexanoic acid, androsterone sulfate, and TUDCA were identified as independent variables associated with the incidence of HCC.

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Adiposity at age 10 and mammographic density among premenopausal women

Although childhood adiposity is inversely associated with breast cancer risk, the association of childhood adiposity with mammographic density in premenopausal women has not been adequately studied. We analyzed data from 365 premenopausal women who came in for screening mammography at Washington University in St. Louis from 2015 to 2016. Body size at age 10 was self-reported using Somatotype pictogram. Body mass index (BMI) at age 10 was imputed using data from Growing Up Today Study. Volpara software was used to evaluate volumetric percent density (VPD), dense volume (DV) and non-dense volume (NDV). Adjusted multivariable linear regression models were used to evaluate the associations between adiposity at age 10 and mammographic density measures. Adiposity at age 10 was inversely associated with VPD, and positively associated with NDV. A 1kg/m2 increase in BMI at age 10 was associated with a 6.4% decrease in VPD, and a 6.9% increase in NDV (p-values <0.001). Compared to women whose age 10 body sizes were 1 or 2, women with body size 3 or 4 had a 16.8% decrease in VPD, and a 26.6% increase in NDV; women with body size 5 had a 32.2% decrease in VPD, and a 58.5% increase in NDV, and women with body sizes ≥6 had a 47.8% decrease in VPD, and a 80.9% increase in NDV (p-values <0.05). The associations were attenuated, but still significant after adjusting for current BMI. Mechanistic studies to understand how childhood adiposity influences breast development, mammographic density and breast cancer in premenopausal women are needed.

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Chemotherapy induces breast cancer stemness in association with dysregulated monocytosis

Purpose: Preoperative or neoadjuvant therapy (NT) is increasingly used in patients with locally advanced or inflammatory breast cancer (BC) to allow optimal surgery and aim for pathological response. However, many BCs are resistant or relapse after treatment. Here, we investigated conjunctive chemotherapy-triggered events occurring systemically and locally, potentially promoting a cancer stem-like cell (CSC) phenotype and contributing to tumor relapse. Experimental Design: We started by comparing the effect of paired pre- and post-NT patient sera on the CSC properties of BC cells. Using cell lines, patient-derived xenograft models and primary tumors, we investigated the regulation of CSCs and tumor progression by chemotherapy-induced factors. Results: In human patients and mice, we detected a therapy-induced CSC-stimulatory activity in serum, which was attributed to therapy-associated monocytosis leading to systemic elevation of monocyte chemoattractant proteins (MCPs). The post-NT hematopoietic regeneration in the bone marrow highlighted both altered monocyte-macrophage differentiation and biased commitment of stimulated hematopoietic stem cells towards monocytosis. Chemotherapeutic agents also induce monocyte expression of MCPs through a JNK-dependent mechanism. Genetic and pharmacological inhibitions of the MCP-CCR2 pathway blocked chemotherapy's adverse effect on CSCs. Levels of nuclear Notch and ALDH1 were significantly elevated in primary BCs following NT, whereas higher levels of CCR2 in pre-NT tumors were associated with a poor response to NT. Conclusions: Our data establish a mechanism of chemotherapy-induced cancer stemness by linking the cellular events in the bone marrow and tumors, and suggest pharmacological inhibition of CCR2 as a potential co-treatment during conventional chemotherapy in neoadjuvant and adjuvant settings.

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IDO1 inhibition synergizes with radiation and PD-1 blockade to durably increase survival against advanced glioblastoma

Purpose: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults with a median survival of 15-20 months. Numerous approaches and novel therapeutics for treating GBM have been investigated in the setting of phase III clinical trials, including a recent analysis of the immune checkpoint inhibitor, Nivolumab (anti-PD-1), which failed to improve recurrent GBM patient survival. However, rather than abandoning immune checkpoint inhibitor treatment for GBM, which has shown promise in other types of cancer, ongoing studies are currently evaluating this therapeutic class when combined with other agents. Experimental Design: Here, we investigated immunocompetent orthotopic mouse models of GBM treated with the potent CNS-penetrating IDO1 enzyme inhibitor, BGB-5777, combined with anti-PD1 mAb, as well as radiation therapy (RT), based on our recent observation that tumor-infiltrating T cells directly increase immunosuppressive IDO1 levels in human GBM, the previously-described enhancement of immune cell functions after PD-1 blockade, as well as the pro-inflammatory effects of radiation. Results: Our results demonstrate a durable survival benefit from this novel three-agent treatment, but not for any single- or dual-agent combination. Unexpectedly, treatment efficacy required IDO1 enzyme inhibition in non-GBM cells, rather than tumor cells. Timing of effector T cell infiltration, animal subject age and usage of systemic chemotherapy, all directly impacted therapy-mediated survival benefit. Conclusions: These data highlight a novel and clinically-relevant immunotherapeutic approach with associated mechanistic considerations that have formed the basis of a newly-initiated phase I/II trial for GBM patients.

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Sequencing pancreatic juice: squeezing the most out of surveillance

Next-generation sequencing of pancreatic juice can detect and quantify tumor-promoting mutations, supporting imaging and cytology findings to predict the degree of dysplasia in patients at high risk for pancreatic cancer. Future studies are needed to optimize this approach and determine how it best fits into clinical practice.

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A Phase 1 Clinical Trial of Guadecitabine and Carboplatin In Platinum-Resistant, Recurrent Ovarian Cancer: Clinical, Pharmacokinetic And Pharmacodynamic Analyses

Purpose: Epigenetic changes are implicated in acquired resistance to platinum. Guadecitabine is a next-generation hypomethylating agent (HMA). Here we report the clinical results, along with pharmacokinetic (PK) and pharmacodynamic analyses of the phase 1 study of guadecitabine and carboplatin (G+C) in patients with recurrent, platinum resistant high-grade serous ovarian cancer (OC), primary peritoneal carcinoma (PPC), or fallopian tube cancer (FTC). Experimental Design: Guadecitabine was administered once daily on Days 1-5 followed by carboplatin IV on Day 8 of a 28-day cycle. Patients had either measurable or detectable disease. Safety assessments used CTCAE v4. Results: Twenty patients were enrolled and treated. Median age was 56 years (38-72). Median number of prior regimens was 7 (1-14). In the first cohort (N=6), the starting doses were guadecitabine 45 mg/m² and carboplatin AUC5. Four patients experienced dose-limiting toxicity (DLT; neutropenia and thrombocytopenia) leading to dose de-escalation of guadecitabine to 30 mg/m² and of carboplatin to AUC4. No DLTS were observed in the subsequent 14 patients. Grade ≥3AEs ≥10% were neutropenia, leukopenia, anemia, nausea, vomiting, ascites, constipation, hypokalemia, pulmonary embolism, small intestinal obstruction, and thrombocytopenia. Three patients had a partial response (PR) and six patients had stable disease (SD) >3 months, for an overall response rate (ORR) and clinical benefit rate of 15% and 45%, respectively. LINE-1 demethylation in PBMCs and promoter demethylation/gene re-expression in paired tumor biopsies/ascites were recorded. Conclusions: G+C was tolerated and induced clinical responses in a heavily pretreated platinum resistant OC population, supporting a subsequent randomized phase 2 trial.

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A Small-Molecule Splicing Modulator Targets Spliceosome-Mutant Cells [Research Watch]

The small molecule H3B-8800 binds to and modulates the SF3b complex to kill spliceosome-mutant cells.

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Umbralisib Inhibits PI3K{delta} with Less Toxicity Than Previous Inhibitors [Research Watch]

Umbralisib is well tolerated and has activity against relapsed or refractory hematologic cancers.

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Oncogenes Induce Replication Stress via Intragenic Replication Origins [Research Watch]

Oncogenes induce premature S phase, resulting in replication–transcription conflicts and replication stress.

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SETD1A Interacts with Cyclin K to Promote Leukemia Cell Survival [Research Watch]

SETD1A enhances leukemic cell growth and survival independent of its methyltransferase activity.

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Medulloblastoma Circulating Tumor Cells Form Leptomeningeal Metastases [Research Watch]

NCAM⁺CD45⁺ medulloblastoma cells were shown to be medulloblastoma circulating tumor cells (CTC).

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Colorectal tumors require NUAK1 for protection from oxidative stress [Research Articles]

Exploiting oxidative stress has recently emerged as a plausible strategy for treatment of human Cancer and anti-oxidant defences are implicated in resistance to chemo- and radiotherapy. Targeted suppression of anti-oxidant defences could thus broadly improve therapeutic outcomes. Here we identify the AMPK-related kinase NUAK1 as a key component of the anti-oxidant stress response pathway and reveal a specific requirement for this role of NUAK1 in colorectal cancer. We show that NUAK1 is activated by oxidative stress and that this activation is required to facilitate nuclear import of the anti-oxidant master regulator NRF2: Activation of NUAK1 coordinates PP1β inhibition with AKT activation in order to suppress GSK3β-dependent inhibition of NRF2 nuclear import. Deletion of NUAK1 suppresses formation of colorectal tumors, while acute depletion of NUAK1 induces regression of pre-existing autochthonous tumors. Importantly, elevated expression of NUAK1 in human colorectal cancer is associated with more aggressive disease and reduced overall survival.

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The NCX1/TRPC6 complex mediates TGF{beta}-driven migration and invasion of human hepatocellular carcinoma cells

Transforming growth factor β (TGFβ) plays an important role in the progression and metastasis of hepatocellular carcinoma (HCC), yet the cellular and molecular mechanisms underlying this role are not completely understood. In this study, we investigated the roles of Na+/Ca2+ exchanger 1 (NCX1) and canonical transient receptor potential channel 6 (TRPC6) in regulating TGFβ in human HCC. In HepG2 and Huh7 cells, TGFβ stimulated intracellular Ca2+ increases through NCX1 and TRPC6 and induced the formation of a TRPC6/NCX1 molecular complex. This complex-mediated Ca2+ signaling regulated the effect of TGFβ on the migration, invasion, and intrahepatic metastasis of human HCC cells in nude mice. TGFβ upregulated TRPC6 and NCX1 expression, and there was a positive feedback between TRPC6/NCX1 signaling and Smad signaling. Expression of both TRPC6 and NCX1 were markedly increased in native human HCC tissues, and their expression levels positively correlated with advancement of HCC in patients. These data reveal the role of the TRPC6/NCX1 molecular complex in HCC and in regulating TGFβ signaling, and they implicate TRPC6 and NCX1 as potential targets for therapy in HCC.

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Correlation of Somatic Genomic Alterations Between Tissue Genomics and ctDNA Employing Next Generation Sequencing: Analysis of Lung and Gastrointestinal Cancers.

Next Generation Sequencing (NGS) of cancer tissues is increasingly being carried out to identify somatic genomic alterations that may guide physicians to make therapeutic decisions. However, a single tissue biopsy may not reflect complete genomic architecture due to the heterogeneous nature of tumors. Circulating tumor DNA (ctDNA) analysis is a robust noninvasive method to detect and monitor genomic alterations in blood in real time. We analyzed 28 matched tissue NGS and ctDNA from gastrointestinal and lung cancers for concordance of somatic genomic alterations, driver and actionable alterations. Six patients (21%) had at least one concordant mutation between tissue and ctDNA sequencing. At the gene level, among all the mutations (n=104) detected by tissue and blood sequencing 7.7% (n=8) of mutations were concordant. Tissue and ctDNA sequencing identified driver mutations in 60% and 64% of the tested samples, respectively. We found high discordance between tissue and ctDNA testing, especially with respect to the driver and actionable alterations. Both tissue and ctDNA NGS detected actionable alterations in 25 % of patients. When somatic alterations identified by each test were combined, the total number of patients with actionable mutations increased to 32 %. Our data show significant discordance between tissue NGS and ctDNA analysis. These results suggest tissue NGS and ctDNA NGS are complementary approaches rather than exclusive of each other. When performed in isolation, tissue and ctDNA NGS can each potentially miss driver and targetable alterations, suggesting that both approaches should be incorporated to enhance mutation detection rates. Larger prospective studies are needed to better clarify this emerging precision oncology landscape

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The NCX1/TRPC6 complex mediates TGF{beta}-driven migration and invasion of human hepatocellular carcinoma cells

Transforming growth factor β (TGFβ) plays an important role in the progression and metastasis of hepatocellular carcinoma (HCC), yet the cellular and molecular mechanisms underlying this role are not completely understood. In this study, we investigated the roles of Na+/Ca2+ exchanger 1 (NCX1) and canonical transient receptor potential channel 6 (TRPC6) in regulating TGFβ in human HCC. In HepG2 and Huh7 cells, TGFβ stimulated intracellular Ca2+ increases through NCX1 and TRPC6 and induced the formation of a TRPC6/NCX1 molecular complex. This complex-mediated Ca2+ signaling regulated the effect of TGFβ on the migration, invasion, and intrahepatic metastasis of human HCC cells in nude mice. TGFβ upregulated TRPC6 and NCX1 expression, and there was a positive feedback between TRPC6/NCX1 signaling and Smad signaling. Expression of both TRPC6 and NCX1 were markedly increased in native human HCC tissues, and their expression levels positively correlated with advancement of HCC in patients. These data reveal the role of the TRPC6/NCX1 molecular complex in HCC and in regulating TGFβ signaling, and they implicate TRPC6 and NCX1 as potential targets for therapy in HCC.

http://ift.tt/2Fa5bqo

Correlation of Somatic Genomic Alterations Between Tissue Genomics and ctDNA Employing Next Generation Sequencing: Analysis of Lung and Gastrointestinal Cancers.

Next Generation Sequencing (NGS) of cancer tissues is increasingly being carried out to identify somatic genomic alterations that may guide physicians to make therapeutic decisions. However, a single tissue biopsy may not reflect complete genomic architecture due to the heterogeneous nature of tumors. Circulating tumor DNA (ctDNA) analysis is a robust noninvasive method to detect and monitor genomic alterations in blood in real time. We analyzed 28 matched tissue NGS and ctDNA from gastrointestinal and lung cancers for concordance of somatic genomic alterations, driver and actionable alterations. Six patients (21%) had at least one concordant mutation between tissue and ctDNA sequencing. At the gene level, among all the mutations (n=104) detected by tissue and blood sequencing 7.7% (n=8) of mutations were concordant. Tissue and ctDNA sequencing identified driver mutations in 60% and 64% of the tested samples, respectively. We found high discordance between tissue and ctDNA testing, especially with respect to the driver and actionable alterations. Both tissue and ctDNA NGS detected actionable alterations in 25 % of patients. When somatic alterations identified by each test were combined, the total number of patients with actionable mutations increased to 32 %. Our data show significant discordance between tissue NGS and ctDNA analysis. These results suggest tissue NGS and ctDNA NGS are complementary approaches rather than exclusive of each other. When performed in isolation, tissue and ctDNA NGS can each potentially miss driver and targetable alterations, suggesting that both approaches should be incorporated to enhance mutation detection rates. Larger prospective studies are needed to better clarify this emerging precision oncology landscape

http://ift.tt/2FMYXOt

Outcome after PSMA PET/CT based radiotherapy in patients with biochemical persistence or recurrence after radical prostatectomy

Abstract

Background

PSMA PET/CT visualises prostate cancer residual disease or recurrence at lower PSA levels compared to conventional imaging and results in a change of treatment in a remarkable high number of patients. Radiotherapy with dose escalation to the former prostate bed has been associated with improved biochemical recurrence-free survival. Thus, it can be hypothesised that PSMA PET/CT-based radiotherapy might improve the prognosis of these patients.

Methods

One hundred twenty-nine patients underwent PSMA PET/CT due to biochemical persistence (52%) or recurrence (48%) after radical prostatectomy without evidence of distant metastases (February 2014–May 2017) and received PSMA PET/CT-based radiotherapy. Biochemical recurrence free survival (PSA ≤ 0.2 ng/ml) was defined as the study endpoint.

Results

Patients with biochemical persistence were significantly more often high-risk patients with significantly shorter time interval before PSMA PET/CT than patients with biochemical recurrence. Patients with biochemical recurrence had significantly more often no evidence of disease or local recurrence only in PSMA PET/CT, whereas patients with biochemical persistence had significantly more often lymph node involvement. Seventy-three patients were started on antiandrogen therapy prior to radiotherapy due to macroscopic disease in PSMA PET/CT. Cumulatively, 70 (66–70.6) Gy was delivered to local macroscopic tumor, 66 (63–66) Gy to the prostate fossa, 61.6 (53.2–66) Gy to PET-positive lymph nodes and 50.4 (45–52.3) Gy to lymphatic pathways. Median PSA after radiotherapy was 0.07 ng/ml with 74% of patients having a PSA ≤ 0.1 ng/ml. After a median follow-up of 20 months, median PSA was 0.07 ng/ml with ongoing antiandrogen therapy in 30 patients. PET-positive patients without antiandrogen therapy at last follow-up (45 patients) had a median PSA of 0.05 ng/ml with 89% of all patients, 94% of patients with biochemical recurrence and 82% of patients with biochemical persistence having a PSA ≤ 0.2 ng/ml. Post-radiotherapy PSA ≤ 0.1 ng/ml and biochemical recurrence vs. persistence were significantly associated with a PSA ≤ 0.2 ng/ml at last follow-up.

Conclusions

PSMA PET/CT-based radiotherapy is an effective local salvage treatment option with significant PSA response in patients with biochemical recurrence or persistence after radical prostatectomy leading to deferral of long-term ADT or systemic therapy.

http://ift.tt/2HYXC7L

Outcome after PSMA PET/CT based radiotherapy in patients with biochemical persistence or recurrence after radical prostatectomy

Abstract

Background

PSMA PET/CT visualises prostate cancer residual disease or recurrence at lower PSA levels compared to conventional imaging and results in a change of treatment in a remarkable high number of patients. Radiotherapy with dose escalation to the former prostate bed has been associated with improved biochemical recurrence-free survival. Thus, it can be hypothesised that PSMA PET/CT-based radiotherapy might improve the prognosis of these patients.

Methods

One hundred twenty-nine patients underwent PSMA PET/CT due to biochemical persistence (52%) or recurrence (48%) after radical prostatectomy without evidence of distant metastases (February 2014–May 2017) and received PSMA PET/CT-based radiotherapy. Biochemical recurrence free survival (PSA ≤ 0.2 ng/ml) was defined as the study endpoint.

Results

Patients with biochemical persistence were significantly more often high-risk patients with significantly shorter time interval before PSMA PET/CT than patients with biochemical recurrence. Patients with biochemical recurrence had significantly more often no evidence of disease or local recurrence only in PSMA PET/CT, whereas patients with biochemical persistence had significantly more often lymph node involvement. Seventy-three patients were started on antiandrogen therapy prior to radiotherapy due to macroscopic disease in PSMA PET/CT. Cumulatively, 70 (66–70.6) Gy was delivered to local macroscopic tumor, 66 (63–66) Gy to the prostate fossa, 61.6 (53.2–66) Gy to PET-positive lymph nodes and 50.4 (45–52.3) Gy to lymphatic pathways. Median PSA after radiotherapy was 0.07 ng/ml with 74% of patients having a PSA ≤ 0.1 ng/ml. After a median follow-up of 20 months, median PSA was 0.07 ng/ml with ongoing antiandrogen therapy in 30 patients. PET-positive patients without antiandrogen therapy at last follow-up (45 patients) had a median PSA of 0.05 ng/ml with 89% of all patients, 94% of patients with biochemical recurrence and 82% of patients with biochemical persistence having a PSA ≤ 0.2 ng/ml. Post-radiotherapy PSA ≤ 0.1 ng/ml and biochemical recurrence vs. persistence were significantly associated with a PSA ≤ 0.2 ng/ml at last follow-up.

Conclusions

PSMA PET/CT-based radiotherapy is an effective local salvage treatment option with significant PSA response in patients with biochemical recurrence or persistence after radical prostatectomy leading to deferral of long-term ADT or systemic therapy.

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Radial nerve injury following dry needling

Robin McManus<br />Jan 26, 2018; 2018:bcr-2017-221302-bcr-2017-221302<br />Case report

http://ift.tt/2oNOha7

A meta-analysis of the efficacy of cognitive behavior therapy on quality of life and psychological health of breast cancer survivors and patients

Abstract

Objective

The aim of this study was to examine the effect of Cognitive Behavior Therapy (CBT) on Quality of Life (QOL) and psychological health of breast cancer survivors and patients.

Methods

A total of 1289 references were examined from an overall literature search in PubMed, Embase, CINAHL, and the Cochrane Database of Systematic Reviews. Randomized controlled trials assessing the efficacy of CBT compared with a range of comparators in cancer survivors. We assessed the effect of CBT using the standardized mean difference as effect size.

Results

Among 1289 abstracts and 292 full-text articles reviewed, 10 studies were included. At the post-treatment period, the pooled effect size for CBT on QOL was 0.57 (95% CI, 0.44 to 0.69; P <0.001), on depression was -1.11 (95% CI, -1.28 to -0.94; P <0.001), on stress was -0.40 (95% CI, -0.53 to -0.26; P <0.001), on anxiety was -1.10 (95% CI, -1.27 to -0.93; P <0.001), and on hyperarousal cluster of symptoms was-0.18 (95% CI, -0.30 to -0.05; P <0.001). The QOL was considered statistically medium effect sizes. The depression and anxiety were considered statistically large effect sizes.

Conclusions

CBT is an effective therapy for psychological symptoms of cancer survivors and patients, with meaningfully clinical effect sizes. These findings suggested that CBT should be used as the intervention for breast cancer survivors and patients when possible.

http://ift.tt/2FQ5MPq

A meta-analysis of the efficacy of cognitive behavior therapy on quality of life and psychological health of breast cancer survivors and patients

Abstract

Objective

The aim of this study was to examine the effect of Cognitive Behavior Therapy (CBT) on Quality of Life (QOL) and psychological health of breast cancer survivors and patients.

Methods

A total of 1289 references were examined from an overall literature search in PubMed, Embase, CINAHL, and the Cochrane Database of Systematic Reviews. Randomized controlled trials assessing the efficacy of CBT compared with a range of comparators in cancer survivors. We assessed the effect of CBT using the standardized mean difference as effect size.

Results

Among 1289 abstracts and 292 full-text articles reviewed, 10 studies were included. At the post-treatment period, the pooled effect size for CBT on QOL was 0.57 (95% CI, 0.44 to 0.69; P <0.001), on depression was -1.11 (95% CI, -1.28 to -0.94; P <0.001), on stress was -0.40 (95% CI, -0.53 to -0.26; P <0.001), on anxiety was -1.10 (95% CI, -1.27 to -0.93; P <0.001), and on hyperarousal cluster of symptoms was-0.18 (95% CI, -0.30 to -0.05; P <0.001). The QOL was considered statistically medium effect sizes. The depression and anxiety were considered statistically large effect sizes.

Conclusions

CBT is an effective therapy for psychological symptoms of cancer survivors and patients, with meaningfully clinical effect sizes. These findings suggested that CBT should be used as the intervention for breast cancer survivors and patients when possible.

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Long-term improvement of Recalcitrant Hailey-Hailey Disease with electron beam radiotherapy: Case Report and Review

Publication date: Available online 2 March 2018
Source:Practical Radiation Oncology
Author(s): Nicole Leung, Adela R. Cardones, Nicole Larrier




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Dosimetric Analysis of Stereotactic Body Radiotherapy for Pancreatic Cancer using MR-Guided Tri-60Co Unit, MR-Guided LINAC, and Conventional LINAC Based Plans

Publication date: Available online 1 March 2018
Source:Practical Radiation Oncology
Author(s): S.J. Ramey, K.R. Padgett, N. Lamichhane, H.J. Neboori, D. Kwon, E.A. Mellon, K. Brown, M. Duffy, J. Victoria, N. Dogan, L. Portelance
PurposeTo perform a dosimetric comparison of two MR-guided radiotherapy systems capable of performing on-line adaptive radiotherapy (ART) versus a conventional radiotherapy system for pancreas stereotactic body radiation therapy.Methods and MaterialsTen cases of patients with pancreatic adenocarcinoma previously treated in our institution were used for this analysis. MR-Cobalt and MR-LINAC plans were generated and compared to conventional LINAC (VMAT) plans. The prescription dose was 40Gy in five fractions covering 95% of the planning tumor volume (PTV40) for the 30 plans. The same organs at risk (OARs) dose constraints were used in all plans. Dose volume-based indices were used to compare PTV coverage and OAR sparing.ResultsThe PTV40 conformity index (CI) demonstrated higher conformity in both LINAC-based plans compared to MR-Cobalt plans. While there was no difference in mean CI betweenLINAC and MR-LINAC plans (1.08 in both), there was a large difference between LINAC and MR-Cobalt plans (1.08 vs. 1.52). Overall, 79%, 72%, and 78% of critical structure dosimetric constraints were met with LINAC, MR-Cobalt, and MR-LINAC plans. The MR-Cobalt plans delivered more dose to all OARs when compared to the LINAC plans. In contrast, the doses to the OARs of the MR-LINAC plans were similar to LINAC plans except in two cases—liver mean dose (MR-LINAC—2 .8Gy versus LINAC—2.1Gy) and volume of duodenum receiving at least 15Gy (MR-LINAC—13.2 cubic centimeters [cc] versus LINAC—15.4cc). Both differences are likely not clinically significant.ConclusionThis study demonstrates that dosimetrically similar plans were achieved with conventional LINAC and MR-LINAC while doses to OARs were statistically higher for MR-Cobalt compared to conventional LINAC plans due to low dose spillage. Given the improved tumor-tracking capabilities of MR-LINAC, further studies should evaluate potential benefits of ART-capable MR-guided LINAC treatment.



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Dosimetric Analysis of Stereotactic Body Radiotherapy for Pancreatic Cancer using MR-Guided Tri-60Co Unit, MR-Guided LINAC, and Conventional LINAC Based Plans

Publication date: Available online 1 March 2018
Source:Practical Radiation Oncology
Author(s): S.J. Ramey, K.R. Padgett, N. Lamichhane, H.J. Neboori, D. Kwon, E.A. Mellon, K. Brown, M. Duffy, J. Victoria, N. Dogan, L. Portelance
PurposeTo perform a dosimetric comparison of two MR-guided radiotherapy systems capable of performing on-line adaptive radiotherapy (ART) versus a conventional radiotherapy system for pancreas stereotactic body radiation therapy.Methods and MaterialsTen cases of patients with pancreatic adenocarcinoma previously treated in our institution were used for this analysis. MR-Cobalt and MR-LINAC plans were generated and compared to conventional LINAC (VMAT) plans. The prescription dose was 40Gy in five fractions covering 95% of the planning tumor volume (PTV40) for the 30 plans. The same organs at risk (OARs) dose constraints were used in all plans. Dose volume-based indices were used to compare PTV coverage and OAR sparing.ResultsThe PTV40 conformity index (CI) demonstrated higher conformity in both LINAC-based plans compared to MR-Cobalt plans. While there was no difference in mean CI betweenLINAC and MR-LINAC plans (1.08 in both), there was a large difference between LINAC and MR-Cobalt plans (1.08 vs. 1.52). Overall, 79%, 72%, and 78% of critical structure dosimetric constraints were met with LINAC, MR-Cobalt, and MR-LINAC plans. The MR-Cobalt plans delivered more dose to all OARs when compared to the LINAC plans. In contrast, the doses to the OARs of the MR-LINAC plans were similar to LINAC plans except in two cases—liver mean dose (MR-LINAC—2 .8Gy versus LINAC—2.1Gy) and volume of duodenum receiving at least 15Gy (MR-LINAC—13.2 cubic centimeters [cc] versus LINAC—15.4cc). Both differences are likely not clinically significant.ConclusionThis study demonstrates that dosimetrically similar plans were achieved with conventional LINAC and MR-LINAC while doses to OARs were statistically higher for MR-Cobalt compared to conventional LINAC plans due to low dose spillage. Given the improved tumor-tracking capabilities of MR-LINAC, further studies should evaluate potential benefits of ART-capable MR-guided LINAC treatment.



http://ift.tt/2oLBh4O

Long-term improvement of Recalcitrant Hailey-Hailey Disease with electron beam radiotherapy: Case Report and Review

Publication date: Available online 2 March 2018
Source:Practical Radiation Oncology
Author(s): Nicole Leung, Adela R. Cardones, Nicole Larrier




http://ift.tt/2I1NknG

Traditional herbal medicine prevents postoperative recurrence of small hepatocellular carcinoma: A randomized controlled study

BACKGROUND

To explore the clinical efficacy of traditional herbal medicine (THM) in the prevention of disease recurrence of small hepatocellular carcinoma after surgery, a prospective randomized controlled study was conducted between October 2006 and May 2010. The results indicated that THM prevented the recurrence of SHCC with an efficacy that was superior to that of transarterial chemoembolization (TACE) during a median follow-up of 26.61 months.

METHODS

The patients were followed up every 6 months, and the clinical data before October 20, 2015 were analyzed. The primary outcome measure was recurrence-free survival (RFS), and the secondary outcome measure was overall survival (OS).

RESULTS

The 364 patients included 180 in the THM group and 184 in the TACE group. At the time of the data cutoff of October 20, 2015, a total of 205 patients demonstrated disease recurrence, including 85 patients in the THM group and 120 patients in the TACE group. The median RFS of the THM and TACE groups demonstrated a statistically significant difference (P<.001). Until October 20, 2105, there were 91 deaths, including 34 in the THM group and 57 in the TACE group. The median OS demonstrated a significant difference between the 2 groups (P = .008). Multivariate analysis indicated that THM was an independent factor influencing RFS and OS.

CONCLUSIONS

The efficacy of THM was found to be superior to that of TACE in preventing disease recurrence in patients with small hepatocellular carcinoma and prolonging OS. Cancer 2018. © 2018 American Cancer Society.

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Nine-year prostate cancer survival differences between aggressive versus conservative therapy in men with advanced and metastatic prostate cancer

BACKGROUND

To the authors' knowledge, the survival benefit of local therapy in the setting of advanced prostate cancer remains unknown. The authors investigated whether prostate-directed treatment with either surgery or radiotherapy versus conservative treatment in the setting of locally advanced or metastatic disease was associated with improved survival within a cohort of men from the Centers for Disease Control and Prevention's (CDC) Breast and Prostate Cancer Data Quality and Patterns of Care Study (CDC POC-BP).

METHODS

Men diagnosed with locally advanced (cT3-T4 or N+ and M0) or metastatic prostate cancer were identified. The authors compared survival by treatment type, categorized as conservative (androgen deprivation therapy only) versus aggressive (radical prostatectomy or any type of radiotherapy). Nine-year overall survival and prostate cancer-specific survival were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to determine factors independently associated with 9-year prostate cancer-specific survival.

RESULTS

For men with advanced, nonmetastatic prostate cancer, conservative treatment alone was associated with a 4 times higher likelihood of prostate cancer mortality compared with men treated with surgery (hazard ratio, 4.18; 95% confidence interval, 1.44-12.14). In contrast, no difference was found between conservative versus aggressive treatment after adjusting for covariates for men with metastatic disease. The 9-year prostate cancer-specific survival rate was 27% for those receiving aggressive treatment versus 24% for men undergoing conservative treatment.

CONCLUSIONS

The authors did not observe a survival advantage with local therapy in addition to standard androgen deprivation therapy for men with metastatic prostate cancer. However, the results of the current study did affirm advantages in the setting of locally advanced disease. Aggressive local therapy in the setting of metastatic disease needs to be studied carefully before clinical adoption. Cancer 2018. © 2018 American Cancer Society.

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Screening for human papillomavirus-driven oropharyngeal cancer: Considerations for feasibility and strategies for research

The incidence and burden of human papillomavirus (HPV)-driven oropharyngeal cancer (OPC) is expected to increase for decades, thus motivating discussions regarding possibilities for screening. This article addresses issues related to the validity and timeliness of screening for HPV-driven OPC, and raises important questions, highlights deficits and confusion in the existing literature, and proposes needed steps in the research agenda.

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Programmed death ligand 1 testing in non–small cell lung carcinoma cytology cell block and aspirate smear preparations

BACKGROUND

Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) receptor and its ligand, programmed death ligand 1 (PD-L1), have emerged as a therapeutic approach for patients with non–small cell lung carcinoma (NSCLC). PD-L1 expression, assessed by immunohistochemistry (IHC), is used to select patients for PD-1/PD-L1 inhibitor therapy. Most studies have been performed with histology specimens, with limited data available on the performance in cytology specimens. This study evaluated PD-L1 in cytology specimens and compared the results with those from paired core-needle biopsy for concordance.

METHODS

Forty-one NSCLC fine-needle aspiration cases that had paired core-needle biopsy specimens with PD-L1 IHC were selected. A Papanicolaou-stained direct smear and a cell block section from each case were stained with a Dako PD-L1 pharmDx antibody (clone 22C3). Only slides with 100 or more tumor cells (37 smears and 38 cell blocks) were evaluated. Tumor proportion scores (TPS) were assessed on the basis of the partial/complete membranous staining of tumor cells and were correlated with those of paired core-needle biopsy.

RESULTS

All 9 smears that were negative for PD-L1 staining showed 100% concordance with the paired core-needle biopsy, whereas 28 smears with PD-L1 expression showed a similar TPS, except for 1 smear that was discordant. In contrast, 10 negative paired core-needle biopsy cases corresponded to 9 concordant negative cell blocks, whereas 1 cell block had a TPS of 1% to 5%. The remaining 28 cell blocks demonstrated PD-L1 expression, with 22 cases showing a TPS similar to that of the paired core-needle biopsy, whereas 6 cell blocks were discordant, likely because of intratumoral heterogeneity.

CONCLUSIONS

The results show that NSCLC cytology samples evaluated for PD-L1 have high concordance with paired core-needle biopsy samples and can be used for assessing PD-L1 expression. Cancer Cytopathol 2018. © 2018 American Cancer Society.

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Traditional herbal medicine prevents postoperative recurrence of small hepatocellular carcinoma: A randomized controlled study

BACKGROUND

To explore the clinical efficacy of traditional herbal medicine (THM) in the prevention of disease recurrence of small hepatocellular carcinoma after surgery, a prospective randomized controlled study was conducted between October 2006 and May 2010. The results indicated that THM prevented the recurrence of SHCC with an efficacy that was superior to that of transarterial chemoembolization (TACE) during a median follow-up of 26.61 months.

METHODS

The patients were followed up every 6 months, and the clinical data before October 20, 2015 were analyzed. The primary outcome measure was recurrence-free survival (RFS), and the secondary outcome measure was overall survival (OS).

RESULTS

The 364 patients included 180 in the THM group and 184 in the TACE group. At the time of the data cutoff of October 20, 2015, a total of 205 patients demonstrated disease recurrence, including 85 patients in the THM group and 120 patients in the TACE group. The median RFS of the THM and TACE groups demonstrated a statistically significant difference (P<.001). Until October 20, 2105, there were 91 deaths, including 34 in the THM group and 57 in the TACE group. The median OS demonstrated a significant difference between the 2 groups (P = .008). Multivariate analysis indicated that THM was an independent factor influencing RFS and OS.

CONCLUSIONS

The efficacy of THM was found to be superior to that of TACE in preventing disease recurrence in patients with small hepatocellular carcinoma and prolonging OS. Cancer 2018. © 2018 American Cancer Society.

http://ift.tt/2oKAAsB

Nine-year prostate cancer survival differences between aggressive versus conservative therapy in men with advanced and metastatic prostate cancer

BACKGROUND

To the authors' knowledge, the survival benefit of local therapy in the setting of advanced prostate cancer remains unknown. The authors investigated whether prostate-directed treatment with either surgery or radiotherapy versus conservative treatment in the setting of locally advanced or metastatic disease was associated with improved survival within a cohort of men from the Centers for Disease Control and Prevention's (CDC) Breast and Prostate Cancer Data Quality and Patterns of Care Study (CDC POC-BP).

METHODS

Men diagnosed with locally advanced (cT3-T4 or N+ and M0) or metastatic prostate cancer were identified. The authors compared survival by treatment type, categorized as conservative (androgen deprivation therapy only) versus aggressive (radical prostatectomy or any type of radiotherapy). Nine-year overall survival and prostate cancer-specific survival were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to determine factors independently associated with 9-year prostate cancer-specific survival.

RESULTS

For men with advanced, nonmetastatic prostate cancer, conservative treatment alone was associated with a 4 times higher likelihood of prostate cancer mortality compared with men treated with surgery (hazard ratio, 4.18; 95% confidence interval, 1.44-12.14). In contrast, no difference was found between conservative versus aggressive treatment after adjusting for covariates for men with metastatic disease. The 9-year prostate cancer-specific survival rate was 27% for those receiving aggressive treatment versus 24% for men undergoing conservative treatment.

CONCLUSIONS

The authors did not observe a survival advantage with local therapy in addition to standard androgen deprivation therapy for men with metastatic prostate cancer. However, the results of the current study did affirm advantages in the setting of locally advanced disease. Aggressive local therapy in the setting of metastatic disease needs to be studied carefully before clinical adoption. Cancer 2018. © 2018 American Cancer Society.

http://ift.tt/2HXouoM

Screening for human papillomavirus-driven oropharyngeal cancer: Considerations for feasibility and strategies for research

The incidence and burden of human papillomavirus (HPV)-driven oropharyngeal cancer (OPC) is expected to increase for decades, thus motivating discussions regarding possibilities for screening. This article addresses issues related to the validity and timeliness of screening for HPV-driven OPC, and raises important questions, highlights deficits and confusion in the existing literature, and proposes needed steps in the research agenda.

http://ift.tt/2oLKPNv

Programmed death ligand 1 testing in non–small cell lung carcinoma cytology cell block and aspirate smear preparations

BACKGROUND

Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) receptor and its ligand, programmed death ligand 1 (PD-L1), have emerged as a therapeutic approach for patients with non–small cell lung carcinoma (NSCLC). PD-L1 expression, assessed by immunohistochemistry (IHC), is used to select patients for PD-1/PD-L1 inhibitor therapy. Most studies have been performed with histology specimens, with limited data available on the performance in cytology specimens. This study evaluated PD-L1 in cytology specimens and compared the results with those from paired core-needle biopsy for concordance.

METHODS

Forty-one NSCLC fine-needle aspiration cases that had paired core-needle biopsy specimens with PD-L1 IHC were selected. A Papanicolaou-stained direct smear and a cell block section from each case were stained with a Dako PD-L1 pharmDx antibody (clone 22C3). Only slides with 100 or more tumor cells (37 smears and 38 cell blocks) were evaluated. Tumor proportion scores (TPS) were assessed on the basis of the partial/complete membranous staining of tumor cells and were correlated with those of paired core-needle biopsy.

RESULTS

All 9 smears that were negative for PD-L1 staining showed 100% concordance with the paired core-needle biopsy, whereas 28 smears with PD-L1 expression showed a similar TPS, except for 1 smear that was discordant. In contrast, 10 negative paired core-needle biopsy cases corresponded to 9 concordant negative cell blocks, whereas 1 cell block had a TPS of 1% to 5%. The remaining 28 cell blocks demonstrated PD-L1 expression, with 22 cases showing a TPS similar to that of the paired core-needle biopsy, whereas 6 cell blocks were discordant, likely because of intratumoral heterogeneity.

CONCLUSIONS

The results show that NSCLC cytology samples evaluated for PD-L1 have high concordance with paired core-needle biopsy samples and can be used for assessing PD-L1 expression. Cancer Cytopathol 2018. © 2018 American Cancer Society.

http://ift.tt/2F6F8o1

Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung

Abstract

Background

Lung squamous cell carcinoma (LSCC) is a major histological subtype of lung cancer. In this study, we investigated genomic alterations in LSCC and evaluated the clinical implications of mutation burden (MB) in LSCC.

Methods

Genomic alterations were determined in Japanese patients with LSCC (N = 67) using next-generation sequencing of 415 known cancer genes. MB was defined as the number of non-synonymous mutations per 1 Mbp. Programmed death-ligand 1 (PD-L1) protein expression in cancer cells was evaluated by immunohistochemical analysis.

Results

TP53 gene mutations were the most common alteration (n = 51/67, 76.1%), followed by gene alterations in cyclin-dependent kinase inhibitor 2B (CDKN2B; 35.8%), CDKN2A (31.3%), phosphatase and tensin homolog (30.0%), and sex-determining region Y-box 2 (SOX2, 28.3%). Histological differentiation was significantly poorer in tumors with high MB (greater than or equal to the median MB) compared with that in tumors with low MB (less than the median MB; p = 0.0446). The high MB group had more tumors located in the upper or middle lobe than tumors located in the lower lobe (p = 0.0019). Moreover, cancers in the upper or middle lobes had significantly higher MB than cancers in the lower lobes (p = 0.0005), and tended to show higher PD-L1 protein expression (p = 0.0573). SOX2 and tyrosine kinase non-receptor 2 amplifications were associated with high MB (p = 0.0065 and p = 0.0010, respectively).

Conclusions

The MB level differed according to the tumor location in LSCC, suggesting that the location of cancer development may influence the genomic background of the tumor.

http://ift.tt/2oLevKz

The C-Reactive Protein/Albumin Ratio is a Novel Significant Prognostic Factor in Patients with Malignant Pleural Mesothelioma: A Retrospective Multi-institutional Study

Abstract

Background

Malignant pleural mesothelioma (MPM), a devastating neoplasm, is traditionally considered to be resistant to antitumor therapy. Identification of clinical prognostic indicators is therefore needed. Although the C-reactive protein/albumin ratio (CAR) has been used to predict the prognosis of many types of malignancy, its utility in patients with MPM is unknown.

Methods

The data of 100 patients diagnosed as having MPM from 1995 to 2015 at the National Kyushu Cancer Center and Kyushu University were analyzed. The CAR was calculated as serum C-reactive protein concentration divided by albumin concentration. A cutoff for CAR was set at 0.58 according to a receiver operating characteristics curve for 1-year survival.

Results

Thirty-five of the 100 (35.0%) patients were classified as having a high CAR. A high CAR was significantly associated with advanced clinical stage (p < 0.001) and chemotherapy alone (p = 0.002). Patients with a high CAR had significantly shorter overall survival (OS) (p < 0.001) and disease- or progression-free survival (DFS/PFS) (p < 0.001). These associations between CAR and prognosis remained significant after propensity score-matching. In multivariate analysis, a high CAR was an independent predictor of shorter OS and DFS/PFS (p = 0.003 and p = 0.008, respectively). Multivariate analyses of the subgroups of patients who had received chemotherapy and of patients who had undergone surgery also showed that a high CAR was an independent predictor of shorter OS and DFS/PFS.

Conclusions

CAR is an independent predictor of prognosis in MPM patients. This prognostic index contributes to clinicians' ability to predict benefit from treatment. Further larger, prospective studies are necessary to validate these findings.

http://ift.tt/2FibWtu