Repurposing Itraconazole and Hydroxychloroquine to Target Lysosomal Homeostasis in Epithelial Ovarian Cancer.

Unlabelled: Drug repurposing is an attractive option for oncology drug development. Itraconazole is an antifungal ergosterol synthesis inhibitor that has pleiotropic actions including cholesterol antagonism, inhibition of Hedgehog and mTOR pathways. We tested a panel of 28 epithelial ovarian cancer (EOC) cell lines with itraconazole to define its spectrum of activity.

Optimizing Drug Response Study Design in Patient-Derived Tumor Xenografts.

Patient-derived tumor xenograft (PDX) models were used to evaluate the effectiveness of preclinical anticancer agents. A design using 1 mouse per patient per drug (1 × 1 × 1) was considered practical for large-scale drug efficacy studies. We evaluated modifiable parameters that could increase the statistical power of this design based on our consolidated PDX experiments.

Mitochondrial Aconitase ACO2 Links Iron Homeostasis with Tumorigenicity in Non-Small Cell Lung Cancer.

Unlabelled: The ability of a patient tumor to engraft an immunodeficient mouse is the strongest known independent indicator of poor prognosis in early-stage non-small cell lung cancer (NSCLC). Analysis of primary NSCLC proteomes revealed low-level expression of mitochondrial aconitase (ACO2) in the more aggressive, engrafting tumors. Knockdown of ACO2 protein expression transformed immortalized lung epithelial cells, whereas upregulation of ACO2 in transformed NSCLC cells inhibited cell proliferation in vitro and tumor growth in vivo.

A Phase II Randomized Trial of Chemoradiation with or without Metformin in Locally Advanced Cervical Cancer.

Purpose: Tumor hypoxia is associated with poor response to radiation (RT). We previously discovered a novel mechanism of metformin: enhancing tumor RT response by decreasing tumor hypoxia. We hypothesized that metformin would decrease tumor hypoxia and improve cervical cancer response to RT.

Digital quantitative tissue image analysis of hypoxia in resected pancreatic ductal adenocarcinomas.

Background: Tumor hypoxia is theorized to contribute to the aggressive biology of pancreatic ductal adenocarcinoma (PDAC). We previously reported that hypoxia correlated with rapid tumor growth and metastasis in patient-derived xenografts. Anticipating a prognostic relevance of hypoxia in patient tumors, we developed protocols for automated semi-quantitative image analysis to provide an objective, observer-independent measure of hypoxia.

Subpathologies and genomic classifier for treatment individualization of post-prostatectomy radiotherapy.

Purpose/objective: Risk-stratification for post-prostatectomy radiotherapy (PORT) using conventional clinicopathologic indexes leads to substantial over- and under-treatment. Better patient selection could spare unnecessary toxicities and improve outcomes. We investigated the prognostic utility of unfavorable subpathologies intraductal carcinoma and cribriform architecture (IDC/CA), and a 22-gene Decipher genomic classifier (GC) in prostate cancer (PCa) patients receiving PORT.

Patient-derived tumor xenograft and organoid models established from resected pancreatic, duodenal and biliary cancers.

Patient-derived xenograft (PDX) and their xenograft-derived organoid (XDO) models that recapitulate the genotypic and phenotypic landscape of patient cancers could help to advance research and lead to improved clinical management. PDX models were established from 276 pancreato-duodenal and biliary cancer resections. Initial, passage 0 (P0) engraftment rates were 59% (118/199) for pancreatic, 86% (25/29) for duodenal, and 35% (17/48) for biliary ductal tumors.

Predicting Toxicity and Response to Pembrolizumab Through Germline Genomic HLA Class 1 Analysis.

Background: Human leukocyte antigen class 1 (HLA-1)-dependent immune activity is linked to autoimmune diseases. HLA-1-dependent CD8 T cells are required for immune checkpoint blockade antitumor activity. It is unknown if HLA-1 genotype is predictive of toxicity to immune checkpoint blockade.

Predicting response and toxicity to PD-1 inhibition using serum autoantibodies identified from immuno-mass spectrometry.

Validated biomarkers are needed to identify patients at increased risk of immune-related adverse events (irAEs) to immune checkpoint blockade (ICB). Antibodies directed against endogenous antigens can change after exposure to ICB. Patients with different solid tumors stratified into cohorts received pembrolizumab every 3 weeks in a Phase II trial (INSPIRE study).

Intratumoral heterogeneity and hypoxia gene expression signatures: Is a single biopsy adequate?

Background And Purpose: Gene expression signatures are often used to identify hypoxic tumors. However, intratumoral heterogeneity raises concern that multiple biopsies may be necessary to assess global hypoxia status. The objective of this study was to compare the impact of heterogeneity on the discriminative capacity of several previously described hypoxia gene signatures and determine if a single biopsy is sufficient to obtain a reliable estimate of hypoxia in cervical cancer.

Evaluation of Lymphadenopathy and Suspected Lymphoma in a Lymphoma Rapid Diagnosis Clinic.

Purpose: Lymphomas often present a diagnostic challenge, and for some a delay in diagnosis can negatively influence outcomes of therapy. We established a nurse practitioner-led lymphoma rapid diagnosis clinic (LRDC) with the goal of reducing wait times to definitive diagnosis. We examined the initial 30-month experience of the LRDC, and results were compared with time periods before implementation of the clinic to determine program impact.

Correction: Targeting CXCL12/CXCR4 and myeloid cells to improve the therapeutic ratio in patient-derived cervical cancer models treated with radio-chemotherapy.

Since the publication of this paper, the authors have reported that an incorrect version of Figure 1 was presented. The correct version of Figure 1 is provided.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Anaplastic lymphoma kinase 5A4 immunohistochemistry as a diagnostic assay in lung cancer: A Canadian reference testing center's results in population-based reflex testing.

Background: The presence of anaplastic lymphoma kinase (ALK) rearrangement predicts response to ALK tyrosine kinase inhibitor (TKI) therapy. Fluorescence in situ hybridization (FISH) was the initial reference standard to detect ALK rearrangement, but immunohistochemistry (IHC) using D5F3 has gained acceptance as an alternative diagnostic method. ALK IHC assays using other ALK antibodies have also been used as screening methods, but data supporting their utility as diagnostic tests have not been widely reported.

Somatic Alteration Burden Involving Non-Cancer Genes Predicts Prognosis in Early-Stage Non-Small Cell Lung Cancer.

The burden of somatic mutations and neoantigens has been associated with improved survival in cancer treated with immunotherapies, especially non-small cell lung cancer (NSCLC). However, there is uncertainty about their effect on outcome in early-stage untreated cases. We posited that the burden of mutations in a specific set of genes may also contribute to the prognosis of early NSCLC patients.

HPV-independent Vulvar Squamous Cell Carcinoma is Associated With Significantly Worse Prognosis Compared With HPV-associated Tumors.

Vulvar squamous cell carcinomas (VSCC) represent the most common carcinoma of the female external genitalia, with increasing incidence. Although high-risk human papillomavirus (HPV) infection has long been implicated in the majority of cervical and anal squamous cell carcinomas, there is uncertainty about its prevalence and prognostic impact in VSCC. In this study, we conducted a retrospective integrated morphologic and multimodal HPV analysis of a cohort of 114 VSCC cases treated at the Princess Margaret Cancer Centre/University Health Network, Toronto, Canada between 2000 and 2010.

Targeting CXCL12/CXCR4 and myeloid cells to improve the therapeutic ratio in patient-derived cervical cancer models treated with radio-chemotherapy.

Background: The CXCL12/CXCR4 chemokine pathway is involved in cervical cancer pathogenesis and radiation treatment (RT) response. We previously reported that radiochemotherapy (RTCT) and concurrent administration of the CXCR4 inhibitor plerixafor improved primary tumour response. The aims of this study were to determine optimal sequencing of RTCT and plerixafor, the mechanisms responsible for improved response and the effect of plerixafor on late intestinal toxicity.

Repeatability and reproducibility of MRI-based radiomic features in cervical cancer.

Purpose: The aims of this study are to evaluate the stability of radiomic features from T2-weighted MRI of cervical cancer in three ways: (1) repeatability via test-retest; (2) reproducibility between diagnostic MRI and simulation MRI; (3) reproducibility in inter-observer setting.

Materials And Methods: This retrospective cohort study included FIGO stage IB-IVA cervical cancer patients treated with chemoradiation between 2005 and 2014. There were three cohorts of women corresponding to each aim of the study: (1) 8 women who underwent test-retest MRI; (2) 20 women who underwent MRI on different scanners (diagnostic and simulation MRI); (3) 34 women whose diagnostic MRIs were contoured by three observers.

Characterization of Distinct Populations of Carcinoma-Associated Fibroblasts from Non-Small Cell Lung Carcinoma Reveals a Role for ST8SIA2 in Cancer Cell Invasion.

Carcinoma-associated fibroblasts (CAFs) are abundant stromal cells in tumor microenvironment that are critically involved in cancer progression. Contrasting reports have shown that CAFs can have either pro- or antitumorigenic roles, indicating that CAFs are functionally heterogeneous. Therefore, to precisely target the cancer-promoting CAF subsets, it is necessary to identify specific markers to define these subpopulations and understand their functions.

Meningioma Screening With MRI in Childhood Leukemia Survivors Treated With Cranial Radiation.

Purpose: Radiation-induced meningioma is a known late effect of cranial radiation therapy. Cranial magnetic resonance imaging (MRI) can detect small meningiomas, but its potential value as a screening tool is unknown.

Methods And Materials: MRI was used to screen asymptomatic survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation therapy ≥10 years previously.

Effect of Coexisting KRAS and TP53 Mutations in Patients Treated With Chemotherapy for Non-small-cell Lung Cancer.

Background: KRAS and TP53 are common mutations in non-small-cell lung cancer (NSCLC). The Lung Adjuvant Cisplatin Evaluation Biological Program group found adjuvant chemotherapy to be deleterious in patients with coexisting KRAS/TP53 mutations.

Patients And Methods: To validate these results, patients with NSCLC tested for KRAS and TP53 mutations and receiving chemotherapy for any stage NSCLC were selected.

Systemic Therapy Use and Outcomes After Relapse from Preoperative Radiation and Extrapleural Pneumonectomy for Malignant Pleural Mesothelioma.

Background: Multimodality therapy with preoperative radiation (RT) followed by extrapleural pneumonectomy (EP) for patients with operable malignant pleural mesothelioma (MPM) has demonstrated encouraging results. At relapse, there are few data on the tolerance and efficacy of systemic therapies after prior multimodality therapy.

Materials And Methods: We conducted a retrospective analysis of patients with relapsed MPM after RT and EPP ± adjuvant chemotherapy to determine overall survival (OS; date of relapse to death) and the proportion of patients that received systemic therapy and associated response rate (RR).

Circulating Human Papillomavirus DNA as a Biomarker of Response in Patients With Locally Advanced Cervical Cancer Treated With Definitive Chemoradiation.

Purpose: To determine whether plasma human papillomavirus (HPV) DNA predates clinical recurrence and compare its accuracy with 3-month fluorodeoxyglucose positron emission tomography (FDG-PET) in locally advanced cervical cancer.

Methods: This prospective multicenter study accrued 23 women with stage IB to IVA cervical cancer planned for definitive chemoradiation therapy (CRT). Plasma HPV DNA was measured serially by digital polymerase chain reaction, and FDG-PET was performed at 3 months post-CRT.