Abstract Cervical cancer can be prevented and highly curable if detected early. Current guidelines recommend women to receive cervical cancer screening starting at age 21. Our study aims to investigate how improving continuity of care (COC) may influence guideline concordance of cervical cancer screening. Using the eligibility and claims data, we created a person-month panel data set for women who were enrolled in Oregon Medicaid for at least 80% of the period from 2008 to 2015....
Mon Jun 15, 2020 03:00
Purpose:To investigate how induced tumor heterogeneity influences immune responses to radiotherapy with different proportions of mixed immune-responsive and unresponsive tumor cells in a triple-negative breast cancer model. It is hypothesized that studying the immune environment of mixed tumors and responses to radiotherapy could nominate immune active therapies to enhance immune responses after radiotherapy. Experimental Design:Evaluate efficacy and immune responses generated by radiotherapy in...
Mon Jun 15, 2020 10:06
It has been demonstrated that, in early breast cancer, there is no survival benefit to additional treatment once a patient has achieved a pathologic complete response (pCR). Together with the well-established prognostic association between pCR and survival, this presents a strong rationale for escalation/deescalation of neoadjuvant treatment based upon response. See related article by Spring et al., p. 2838
Mon Jun 15, 2020 10:06
Purpose:Interpatient clinical variability in soft-tissue sarcomas (STS) highlights the need for novel prognostic markers supporting patient risk stratification. As sarcomas might exhibit a more mesenchymal or a more epithelial state, we focused on epithelial–mesenchymal and mesenchymal–epithelial transitions (EMT/MET) for prognostic clues, and selected three histotypes with variable aggressiveness. Experimental Design:The expression of EMT/MET-related factors was measured by qRT-PCR in 55 tumor...
Mon Jun 15, 2020 10:06
PSMA radioligand therapy is a promising new class of therapy for prostate cancer. Heterogeneity of PSMA expression is an important factor explaining variability in clinical results. The ability to visualize the target with theranostics provides unique mechanistic insights. Potential clinically applicable strategies to improve patient selection and optimize therapeutic efficacy are discussed. See related article by Current et al., p. 2946
Mon Jun 15, 2020 10:06
Purpose:We initiated a clinical trial to determine the proportion of breast cancer survivors achieving ≥5% weight loss using a remotely delivered weight loss intervention (POWER-remote) or a self-directed approach, and to determine the effects of the intervention on biomarkers of cancer risk including metabolism, inflammation, and telomere length. Experimental Design:Women with stage 0–III breast cancer, who completed local therapy and chemotherapy, with a body mass index ≥25 kg/m2 were randomized...
Mon Jun 15, 2020 10:06
In the era of cancer immunotherapy, there is significant interest in combining conventional cancer therapies, such as radiotherapy, with drugs that stimulate the immune system. The observation that ionizing radiation applied to murine tumors delays the growth of distant tumors ("abscopal effect") and that this effect is potentiated by immunostimulatory drugs, led to clinical trials in which often only one lesion is irradiated in combination with immunotherapy drugs. The results of these initial clinical...
Mon Jun 15, 2020 10:06
A Quantitative Centrosomal Amplification Score Predicts Local Recurrence of Ductal Carcinoma In Situ
Purpose:The purpose of this study is to predict risk of local recurrence (LR) in ductal carcinoma in situ (DCIS) with a new visualization and quantification approach using centrosome amplification (CA), a cancer cell–specific trait widely associated with aggressiveness. Experimental Design:This first-of-its-kind methodology evaluates the severity and frequency of numerical and structural CA present within DCIS and assigns a quantitative centrosomal amplification score (CAS) to each sample. Analyses...
Mon Jun 15, 2020 10:06
HER2+ early breast cancer is a heterogeneous disease, comprising all the intrinsic breast cancer subtypes. The only biomarker available nowadays for anti-HER2 treatment selection is HER2 status itself, but estrogen receptor (ER) status is emerging as a robust predictive marker within HER2+ disease. In this Perspective, we discuss the biological and clinical differences between patients with HER2+/ER-positive (ER+) disease versus those with HER2+/ER-negative (ER-neg) tumors, namely, short-term and...
Mon Jun 15, 2020 10:06
Purpose:Prostate-specific membrane antigen (PSMA) targeting radioligands deliver radiation to PSMA-expressing cells. However, the relationship between PSMA levels and intralesion heterogeneity of PSMA expression, and cytotoxic radiation by radioligand therapy (RLT) is unknown. Here we investigate RLT efficacy as function of PSMA levels/cell, and the fraction of PSMA+ cells in a tumor. Experimental Design:RM1 cells expressing different levels of PSMA (PSMA–, PSMA+, PSMA++, PSMA+++; study 1) or a...
Mon Jun 15, 2020 10:06
Purpose:ANG1005, a novel taxane derivative, consists of three paclitaxel molecules covalently linked to Angiopep-2, designed to cross the blood–brain and blood–cerebrospinal barriers and to penetrate malignant cells via LRP1 transport system. Preclinical and clinical evidence of efficacy with ANG1005 has been previously shown. Patients and Methods:A multicenter, open-label phase II study in adult patients with measurable recurrent brain metastases from breast cancer (BCBM), with or without leptomeningeal...
Mon Jun 15, 2020 10:06
Purpose:Malignant peripheral nerve sheath tumors (MPNST) are deadly sarcomas that lack effective therapies. In most MPNSTs, the retinoblastoma (RB1) tumor suppressor is disabled by hyperactivation of cyclin-dependent kinases (CDK), commonly through loss of CDK-inhibitory proteins such as p27(Kip1). RABL6A is an inhibitor of RB1 whose role in MPNSTs is unknown. To gain insight into MPNST development and establish new treatment options, we investigated RABL6A-RB1 signaling and CDK inhibitor–based therapy...
Mon Jun 15, 2020 10:06
Purpose:To determine the pharmacodynamic relationship between target occupancy of Bruton tyrosine kinase (BTK) and inhibition of downstream signaling. Patients and Methods:Patients with chronic lymphocytic leukemia (CLL) enrolled in a phase II clinical trial (NCT02337829) with the covalent, selective BTK inhibitor acalabrutinib donated blood samples for pharmacodynamic analyses. Study design included randomization to acalabrutinib 100 mg twice daily or 200 mg once daily and dose interruptions on...
Mon Jun 15, 2020 10:06
Purpose:Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). Patients with Fanconi anemia with HNSCC are not eligible for conventional therapies due to high toxicity in healthy cells, predominantly hematotoxicity, and the only treatment currently available is surgical resection. In this work, we searched and validated two already approved drugs as new potential therapies for HNSCC in...
Mon Jun 15, 2020 10:06
Purpose:Bruton tyrosine kinase (BTK) inhibition alone leads to incomplete responses in chronic lymphocytic leukemia (CLL). Combination therapy may reduce activation of escape pathways and deepen responses. This open-label, phase Ib, sequential dose-escalation and dose-expansion study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the selective BTK inhibitor tirabrutinib alone, in combination with the PI3K delta (PI3K) inhibitor idelalisib, or with the spleen tyrosine...
Mon Jun 15, 2020 10:06
Purpose:Cytarabine is an effective treatment for AML with associated toxicities including treatment related mortality (TRM). The purpose is to determine the clinical relevance of SNPs identified through the use of HapMap lymphoblastoid cell-based models, in predicting cytarabine response and toxicity in AML. Experimental Design:We tested clinical significance of SNPs associated with cytarabine sensitivity in children with AML treated on Children's Oncology Group regimens (CCG 2941/2961). Endpoints...
Mon Jun 15, 2020 10:06
Purpose:This first-in-human, phase I study evaluated ASTX660, an oral, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins in patients with advanced solid tumors or lymphoma. Patients and Methods:ASTX660 was administered orally once daily on a 7-day-on/7-day-off schedule in a 28-day cycle. Dose escalation followed a standard 3+3 design to determine the MTD and recommended phase II dose (RP2D). Dose expansion was conducted at the RP2D. Results:Forty-five patients received...
Mon Jun 15, 2020 10:06
Purpose:Tumor genomic features have been of particular interest because of their potential impact on the tumor immune microenvironment and response to immunotherapy. Due to the substantial heterogeneity, an integrative approach incorporating diverse molecular features is needed to characterize immunologic features underlying primary resistance to immunotherapy and for the establishment of novel predictive biomarkers. Experimental Design:We developed a pan-cancer deep machine learning model integrating...
Mon Jun 15, 2020 10:06
Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma
Purpose:Tumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL). Patients and Methods:Tavo was administered intratumorally days 1, 5, and 8...
Mon Jun 15, 2020 10:06
Purpose:ROS1 tyrosine kinase inhibitors (TKI) provide significant benefit in lung adenocarcinoma patients with ROS1 fusions. However, as observed with all targeted therapies, resistance arises. Detecting mechanisms of acquired resistance (AR) is crucial to finding novel therapies and improve patient outcomes. Experimental Design:ROS1 fusions were expressed in HBEC and NIH-3T3 cells either by cDNA overexpression (CD74/ROS1, SLC34A2/ROS1) or CRISPR-Cas9–mediated genomic engineering (EZR/ROS1). We...
Mon Jun 15, 2020 10:06
Purpose:While various studies have highlighted the prognostic significance of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAT), the impact of additional adjuvant therapy after pCR is not known. Experimental Design:PubMed was searched for studies with NAT for breast cancer and individual patient-level data was extracted for analysis using plot digitizer software. HRs, with 95% probability intervals (PI), measuring the association between pCR and overall survival (OS) or event-free...
Mon Jun 15, 2020 10:06
Purpose:Mutation of TP53 gene is a hallmark of head and neck squamous cell carcinoma (HNSCC) not yet exploited therapeutically. TP53 mutation frequently leads to the synthesis of mutant p53 proteins with gain-of-function activity, associated with radioresistance and high incidence of local recurrences in HNSCC. Experimental Design:Mutant p53–associated functions were investigated through gene set enrichment analysis in the Cancer Genome Atlas cohort of HNSCC and in a panel of 22 HNSCC cell lines....
Mon Jun 15, 2020 10:06
Purpose:Treatment with PD-(L)1 blockade can produce remarkably durable responses in patients with non–small cell lung cancer (NSCLC). However, a significant fraction of long-term responders ultimately progress and predictors of late progression are unknown. We hypothesized that circulating tumor DNA (ctDNA) analysis of long-term responders to PD-(L)1 blockade may differentiate those who will achieve ongoing benefit from those at risk of eventual progression. Experimental Design:In patients with...
Mon Jun 15, 2020 10:06
Purpose:To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs. Experimental Design:Matched case–control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months...
Mon Jun 15, 2020 10:06
Purpose:Salivary gland carcinomas (SGC) are rare, aggressive cancers with high rates of recurrence and distant metastasis. These factors, and a lack of active systemic therapies, contribute to poor clinical outcome. Response rates with immune checkpoint blockade have been low, although clinical data remain sparse. To improve the efficacy of therapies, a more comprehensive understanding of relevant molecular alterations and immunologic processes is needed. Experimental Design:To characterize the...
Mon Jun 15, 2020 10:06
Purpose:Vincristine combined with camptothecin derivatives showed synergy in preclinical pediatric cancer models, and the combinations are effective in treatment of childhood solid tumors. We determined whether the synergy between vincristine and irinotecan extends to eribulin, another microtubule inhibitor. Experimental Design:Vincristine or eribulin, alone or combined with irinotecan, was studied in 12 xenograft models. Tumor regression and time to event were used to assess antitumor activity....
Mon Jun 15, 2020 10:06
Purpose:Glioblastoma multiforme is a highly aggressive form of brain cancer whose location, tendency to infiltrate healthy surrounding tissue, and heterogeneity significantly limit survival, with scant progress having been made in recent decades. Experimental Design:123I-MAPi (Iodine-123 Meitner-Auger PARP1 inhibitor) is a precise therapeutic tool composed of a PARP1 inhibitor radiolabeled with an Auger- and gamma-emitting iodine isotope. Here, the PARP inhibitor, which binds to the DNA repair...
Mon Jun 15, 2020 10:06
Purpose:Both weight loss and low-carbohydrate diets (LCD) without weight loss prolong survival in prostate cancer models. Few human trials have tested weight loss or LCD on prostate cancer. Experimental Design:We conducted a multi-site randomized 6-month trial of LCD versus control on PSA doubling time (PSADT) in patients with prostate cancer with biochemical recurrence (BCR) after local treatment. Eligibility included body mass index (BMI) ≥ 24 kg/m2 and PSADT 3 to 36 months. The LCD arm was instructed...
Mon Jun 15, 2020 10:06
Purpose:Several aggressive pediatric cancers harbor alterations in SMARCB1, including rhabdoid tumors, epithelioid sarcoma, and chordoma. As tumor profiling has become more routine in clinical care, we investigated the relationship between SMARCB1 genetic variants identified by next-generation sequencing (NGS) and INI1 protein expression. Therapeutic approaches for INI1-deficient tumors are limited. Early reports suggest a potential role for immune checkpoint inhibition in these patients. Thus, we...
Mon Jun 15, 2020 10:06
Purpose:SMAD4 loss causes genomic instability and the initiation/progression of head and neck squamous cell carcinoma (HNSCC). Here, we study whether SMAD4 loss sensitizes HNSCCs to olaparib (PARP inhibitor) in combination with radiotherapy (RT). Experimental Design:We analyzed HNSCC The Cancer Genome Atlas data for SMAD4 expression in association with FANC/BRCA family gene expression. Human HNSCC cell lines were screened for sensitivity to olaparib. Isogenic HNSCC cell lines were generated to...
Mon Jun 15, 2020 10:06
Related ArticlesRisk factors for residual mouth breathing in children who had completely resolved obstructive sleep apnea after adenotonsillectomy. Eur Arch Otorhinolaryngol. 2020 Jun 13;: Authors: Bae J, Kim DK Abstract PURPOSE: Adenotonsillectomy is the first-line treatment for pediatric obstructive sleep apnea (OSA). However, although completely resolved OSA after adenotonsillectomy, some children still showed persistence of mouth breathing. Therefore,...
Mon Jun 15, 2020 15:54
Related ArticlesSleep-Disordered Breathing in Children with Prader-Willi Syndrome in Relation to Growth Hormone Therapy Onset. Horm Res Paediatr. 2020 Jun 12;:1-9 Authors: Zimmermann M, Laemmer C, Woelfle J, Fimmers R, Gohlke B Abstract OBJECTIVE: The aim of this study was to consider sleep apnea in Prader-Willi syndrome (PWS) children depending on age at growth hormone (GH) therapy onset. STUDY DESIGN: We analyzed longitudinally cardiorespiratory...
Mon Jun 15, 2020 15:54
Related ArticlesSleepwalking and sleep-related eating associated with atypical antipsychotic medications: Case series and systematic review of literature. Gen Hosp Psychiatry. 2020 Jun 06;65:74-81 Authors: Chopra A, Patel RS, Baliga N, Narahari A, Das P Abstract BACKGROUND: Sleep walking (SW) is a parasomnia behavior characterized by repetitious occurrence of ambulation during a partial arousal from non-rapid eye movement (NREM) sleep. Sleep-related...
Mon Jun 15, 2020 15:54
Related ArticlesStrategies for testing intervention matching schemes in cancer. Clin Pharmacol Ther. 2020 Jun 14;: Authors: Schork NJ, Goetz LH, Lowey J, Trent J Abstract Personalized Medicine, or the tailoring of health interventions to an individual's nuanced and often unique genetic, biochemical, physiological, behavioral and/or exposure profile, is seen by many as a biological necessity given the great heterogeneity of pathogenic processes underlying...
Mon Jun 15, 2020 14:23
Related ArticlesRate of Peritoneal Carcinomatosis in Resected Stage II and III Colon Cancer. Ann Surg Oncol. 2020 Jun 14;: Authors: Choi AH, Farzaneh C, Kejriwal N, Calidas A, Cordero-Caban K, Roman M, Kwong MLM, Selleck MJ, Pigazzi A, Jafari D, Senthil M Abstract INTRODUCTION: Incidence of peritoneal carcinomatosis (PC) after curative resection of stage II and III colon cancer varies widely. Although certain features are considered high risk for...
Mon Jun 15, 2020 14:23
Related ArticlesReflux and dental disorders in the pediatric population: A systematic review. Int J Pediatr Otorhinolaryngol. 2020 Jun 08;136:110166 Authors: Lechien JR, Calvo-Henriquez C, Chiesa-Estomba CM, Barillari MR, Trozzi M, Meucci D, Peer S, Ben Abdelouahed F, Schindler A, Saussez S Abstract OBJECTIVES: To investigate the role of laryngopharyngeal reflux (LPR) or gastroesophageal reflux disease (GERD) in the development of dental disorders...
Mon Jun 15, 2020 14:23
Related ArticlesTelehealth in Uro-oncology Beyond the Pandemic: Toll or Lifesaver? Eur Urol Focus. 2020 Jun 10;: Authors: Rodler S, Apfelbeck M, Schulz GB, Ivanova T, Buchner A, Staehler M, Heinemann V, Stief C, Casuscelli J Abstract BACKGROUND: Telehealth services are rapidly embraced in uro-oncology due to the current coronavirus disease 2019 (COVID-19) pandemic. OBJECTIVE: To determine patients' perspective on adoption of telehealth...
Mon Jun 15, 2020 14:23
Related ArticlesIn The Blood: Connecting Variant to Function In Human Hematopoiesis. Trends Genet. 2020 Jun 10;: Authors: Nandakumar SK, Liao X, Sankaran VG Abstract Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with a range of human diseases and traits. However, understanding the mechanisms by which these genetic variants have an impact on associated diseases and traits, often referred to as the...
Mon Jun 15, 2020 14:23
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