Use of Response Permutation to Measure an Imaging Dataset's Susceptibility to Overfitting by Selected Standard Analysis Pipelines.

Rationale And Objectives: This study demonstrates a method for quantifying the impact of overfitting on the receiving operator characteristic curve (AUC) when using standard analysis pipelines to develop imaging biomarkers. We illustrate the approach using two publicly available repositories of radiology and pathology images for breast cancer diagnosis.

Materials And Methods: For each dataset, we permuted the outcome (cancer diagnosis) values to eliminate any true association between imaging features and outcome.

Repeatability of F-FDG uptake in metastatic bone lesions of breast cancer patients and implications for accrual to clinical trials.

Background: Standard measures of response such as Response Evaluation Criteria in Solid Tumors are ineffective for bone lesions, often making breast cancer patients that have bone-dominant metastases ineligible for clinical trials with potentially helpful therapies. In this study we prospectively evaluated the test-retest uptake variability of 2-deoxy-2-[18F]fluoro-D-glucose (F-FDG) in a cohort of breast cancer patients with bone-dominant metastases to determine response criteria. The thresholds for 95% specificity of change versus no-change were then applied to a second cohort of breast cancer patients with bone-dominant metastases.

Repeatability of 18F-FDG uptake in metastatic bone lesions of breast cancer patients and implications for accrual to clinical trials.

Background: Standard measures of response such as Response Evaluation Criteria in Solid Tumors are ineffective for bone lesions, often making breast cancer patients with bone-dominant metastases ineligible for clinical trials with potentially helpful therapies. In this study we prospectively evaluated the test-retest uptake variability of 2-deoxy-2-[F]fluoro-D-glucose (F-FDG) in a cohort of breast cancer patients with bone-dominant metastases to determine response criteria. The thresholds for 95% specificity of change versus no-change were then applied to a second cohort of breast cancer patients with bone-dominant metastases.

Summary: Appropriate Use Criteria for Estrogen Receptor-Targeted PET Imaging with 16α-F-Fluoro-17β-Fluoroestradiol.

PET imaging with 16α-F-fluoro-17β-fluoroestradiol (F-FES), a radiolabeled form of estradiol, allows whole-body, noninvasive evaluation of estrogen receptor (ER). F-FES is approved by the U.S.

Radiomic Analysis: Study Design, Statistical Analysis, and Other Bias Mitigation Strategies.

Rapid advances in automated methods for extracting large numbers of quantitative features from medical images have led to tremendous growth of publications reporting on radiomic analyses. Translation of these research studies into clinical practice can be hindered by biases introduced during the design, analysis, or reporting of the studies. Herein, the authors review biases, sources of variability, and pitfalls that frequently arise in radiomic research, with an emphasis on study design and statistical analysis considerations.

F-fluorodeoxyglucose (FDG) PET or F-fluorothymidine (FLT) PET to assess early response to aromatase inhibitors (AI) in women with ER+ operable breast cancer in a window-of-opportunity study.

Purpose: This study evaluated the ability of F-Fluorodeoxyglucose (FDG) and F-Fluorothymidine (FLT) imaging with positron emission tomography (PET) to measure early response to endocrine therapy from baseline to just prior to surgical resection in estrogen receptor positive (ER+) breast tumors.

Methods: In two separate studies, women with early stage ER+ breast cancer underwent either paired FDG-PET (n = 22) or FLT-PET (n = 27) scans prior to endocrine therapy and again in the pre-operative setting. Tissue samples for Ki-67 were taken for all patients both prior to treatment and at the time of surgery.

A Phase II Study Evaluating the Safety and Efficacy of Sunitinib Malate in Combination With Weekly Paclitaxel Followed by Doxorubicin and Daily Oral Cyclophosphamide Plus G-CSF as Neoadjuvant Chemotherapy for Locally Advanced or Inflammatory Breast Cancer.

Introduction: Neoadjuvant chemotherapy is standard treatment for locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). We hypothesized that adding sunitinib, a tyrosine kinase inhibitor with antitumor and antiangiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2-negative LABC or IBC.

Methods: We conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2-negative LABC or IBC.

F-Fluoroestradiol PET Imaging in a Phase II Trial of Vorinostat to Restore Endocrine Sensitivity in ER+/HER2- Metastatic Breast Cancer.

Histone deacetylase inhibitors (HDACIs) may overcome endocrine resistance in estrogen receptor-positive (ER+) metastatic breast cancer. We tested whether F-fluoroestradiol PET imaging would elucidate the pharmacodynamics of combination HDACIs and endocrine therapy. Patients with ER+/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer with prior clinical benefit from endocrine therapy but later progression on aromatase inhibitor (AI) therapy were given vorinostat (400 mg daily) sequentially or simultaneously with AI.

Clinical Trial Design and Development Work Group Within the Quantitative Imaging Network.

The Clinical Trial Design and Development Working Group within the Quantitative Imaging Network focuses on providing support for the development, validation, and harmonization of quantitative imaging (QI) methods and tools for use in cancer clinical trials. In the past 10 years, the Group has been working in several areas to identify challenges and opportunities in clinical trials involving QI and radiation oncology. The Group has been working with Quantitative Imaging Network members and the Quantitative Imaging Biomarkers Alliance leadership to develop guidelines for standardizing the reporting of quantitative imaging.

PTPRT epigenetic silencing defines lung cancer with STAT3 activation and can direct STAT3 targeted therapies.

Signal Transducers and Activators of Transcription-3 (STAT3), a potent oncogenic transcription factor, is constitutively activated in lung cancer, but mutations in pathway genes are infrequent. Protein Tyrosine Phosphatase Receptor-T (PTPRT) is an endogenous inhibitor of STAT3 and PTPRT loss-of-function represents one potential mechanism of STAT3 hyperactivation as observed in other malignancies. We determined the role of PTPRT promoter methylation and sensitivity to STAT3 pathway inhibitors in non-small cell lung cancer (NSCLC).

Preclinical ImmunoPET Imaging of Glioblastoma-Infiltrating Myeloid Cells Using Zirconium-89 Labeled Anti-CD11b Antibody.

Purpose: Glioblastoma is a lethal brain tumor, heavily infiltrated by tumor-associated myeloid cells (TAMCs). TAMCs are emerging as a promising therapeutic target as they suppress anti-tumor immune responses and promote tumor cell growth. Quantifying TAMCs using non-invasive immunoPET could facilitate patient stratification for TAMC-targeted treatments and monitoring of treatment efficacy.

Preclinical Dosimetry, Imaging, and Targeted Radionuclide Therapy Studies of Lu-177-Labeled Albumin-Binding, PSMA-Targeted CTT1403.

Purpose: Prostate-specific membrane antigen (PSMA) continues to be the hallmark biomarker for prostate cancer as it is expressed on nearly all prostatic tumors. In addition, increased PSMA expression correlates with castration resistance and progression to the metastatic stage of the disease. Recently, we combined both an albumin-binding motif and an irreversible PSMA inhibitor to develop the novel PSMA-targeted radiotherapeutic agent, CTT1403.

Phase II Study of Systemic High-dose Methotrexate and Intrathecal Liposomal Cytarabine for Treatment of Leptomeningeal Carcinomatosis From Breast Cancer.

Metastatic breast cancer frequently leads to brain metastases and, less commonly, leptomeningeal carcinomatosis (LC). Once cerebrospinal fluid involvement occurs, the prognosis is poor. There are limited treatment options available, but none offer significant survival benefit.

Combined Targeted Therapies for First-line Treatment of Metastatic Triple Negative Breast Cancer-A Phase II Trial of Weekly Nab-Paclitaxel and Bevacizumab Followed by Maintenance Targeted Therapy With Bevacizumab and Erlotinib.

Introduction: Angiogenesis and epidermal growth factor receptor signaling are potential therapeutic targets in triple negative breast cancer (TNBC). We hypothesized that targeting these critical pathways would prolong progression-free survival with first-line therapy for metastatic TNBC.

Patients And Methods: We conducted a phase II trial of nab-paclitaxel and bevacizumab, followed by maintenance therapy with bevacizumab and erlotinib, for patients with metastatic TNBC.

Test-Retest Reproducibility of F-FDG PET/CT Uptake in Cancer Patients Within a Qualified and Calibrated Local Network.

Calibration and reproducibility of quantitative F-FDG PET measures are essential for adopting integral F-FDG PET/CT biomarkers and response measures in multicenter clinical trials. We implemented a multicenter qualification process using National Institute of Standards and Technology-traceable reference sources for scanners and dose calibrators, and similar patient and imaging protocols. We then assessed SUV in patient test-retest studies.

Correction to: a Phase 2 Study of 16α-[18F]-Fluoro-17β-Estradiol Positron Emission Tomography (FES-PET) as a Marker of Hormone Sensitivity in Metastatic Breast Cancer (MBC).

Two data points from Table 1. (continued) were published in error. The corrected data in Table 1.

Do non-daily smokers compensate for reduced cigarette consumption when smoking very-low-nicotine-content cigarettes?

Rationale: The Food and Drug Administration is considering severely restricting the nicotine in cigarettes, to reduce smoking. A study showed that non-daily, intermittent smokers (ITS) randomized to very-low-nicotine-content cigarettes (VLNCCs) reduced their cigarette consumption.

Objectives: To assess whether increased smoking intensity of VLNCCs compensated for some of the reduced cigarette consumption.

Comparison of PD-L1 immunohistochemistry assays and response to PD-1/L1 inhibitors in advanced non-small-cell lung cancer in clinical practice.

Aims: Several studies have demonstrated analytical comparability between different PD-L1 assays, but their clinical validity in non-small-cell lung cancer in terms of response to treatment outside clinical trials has not been established. The aim of our study is to assess the analytical performance of laboratory-developed tests for Ventana SP263 and Agilent/Dako 22C3, and to investigate the association between PD-L1 assays and response to PD-1/L1 inhibitors.

Methods And Results: PD-L1 SP263 and 22C3 assays were performed on 302 consecutive non-small-cell lung carcinoma samples Both assays were optimised for use on the automated Ventana BenchMark Ultra platform.

The Use of Quantitative Imaging in Radiation Oncology: A Quantitative Imaging Network (QIN) Perspective.

Modern radiation therapy is delivered with great precision, in part by relying on high-resolution multidimensional anatomic imaging to define targets in space and time. The development of quantitative imaging (QI) modalities capable of monitoring biologic parameters could provide deeper insight into tumor biology and facilitate more personalized clinical decision-making. The Quantitative Imaging Network (QIN) was established by the National Cancer Institute to advance and validate these QI modalities in the context of oncology clinical trials.

Combined VLA-4-Targeted Radionuclide Therapy and Immunotherapy in a Mouse Model of Melanoma.

Very late antigen-4 (VLA-4; also known as integrin αβ) is expressed at high levels in aggressive and metastatic melanoma tumors and may provide an ideal target for imaging and targeted radionuclide therapy (TRT). Lu-DOTA-PEG-LLP2A (Lu-LLP2A) is a TRT that shows high affinity for VLA-4 and high uptake in B16F10 mouse melanoma tumors in vivo. Here, we report efficacy studies of Lu-LLP2A, alone and combined with immune checkpoint inhibitors (ICIs) (anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies), in B16F10 tumor-bearing mice.

Nondaily Smokers' Changes in Cigarette Consumption With Very Low-Nicotine-Content Cigarettes: A Randomized Double-blind Clinical Trial.

Importance: The US Food and Drug Administration is considering limiting cigarettes to very low nicotine levels. Cigarette consumption of nondaily intermittent smokers (ITS), who compose one-third of US adult smokers, could feasibly increase or could be unaffected if their smoking is not motivated by nicotine seeking.

Objective: To compare cigarette consumption in ITS receiving very low-nicotine-content cigarettes (VLNCCs) or identical normal-nicotine-content cigarettes (NNCCs).

Caveolin-1 promotes the tumor suppressor properties of oncogene-induced cellular senescence.

Oncogene-induced senescence (OIS) is considered a powerful tumor suppressor mechanism. Caveolin-1 acts as a scaffolding protein to functionally regulate signaling molecules. We demonstrate that a lack of caveolin-1 expression inhibits oncogenic K-Ras (K-Ras)-induced premature senescence in mouse embryonic fibroblasts and normal human bronchial epithelial cells.