Authors: Michels KA, Pfeiffer RM, Brinton LA, Trabert B
Journal: JAMA Oncol. 2018 Jan 18. doi: 10.1001/jamaoncol.2017.4942. [Epub ahead of print]
IMPORTANCE: Although oral contraceptive (OC) use is common, the influence of OC use on carcinogenesis is not fully understood. A recent Agency for Healthcare Research and Quality report identified a need to understand the consistency of OC use and cancer associationsacross subpopulations, including smokers and obese women.
OBJECTIVE: To determine whether associations between duration of OC use and risk of specific cancers were modified by lifestyle characteristics.
DESIGN, SETTING, AND PARTICIPANTS: The prospective NIH-AARP Diet and Health Study (enrolled 1995-1996, followed until 2011), with population-based recruitment of AARP members in 6 states and 2 metropolitan areas. All analyses included at least 100 000 women who reported OC use at enrollment. We identified 1241 ovarian, 2337 endometrial, 11 114 breast, and 3507 colorectal cancer cases during follow-up. Data analysis was performed between September 2016 and April 2017.
EXPOSURES: Duration of OC use (never or <1 year [reference], 1-4, 5-9, or ≥10 years).
MAIN OUTCOMES AND MEASURES: Development of ovarian, endometrial, breast, and colorectal cancers. We examined effect modificationby modifiable lifestyle characteristics: cigarette smoking, alcohol consumption, body mass index (BMI), and physical activity. We used Cox models adjusted for age, race, age at menarche, and the modifiers of interest.
RESULTS: The analytic population was aged 50 to 71 years (median, 62 years) at enrollment and largely white (91%) and postmenopausal (96%). For ovarian cancer, OC use-associated risk reductions strengthened with duration of use (long-term OC use [≥10 years] HR, 0.60; 95% CI, 0.47-0.76; P < .001 for trend) and were similar across modifiable lifestyle factors. Risk reductions for endometrial cancer strengthened with duration of use (long-term OC use HR, 0.66; 95% CI, 0.56-0.78; P < .001 for trend); the most pronounced reductions were among long-term OC users who were smokers (HR, 0.47; 95% CI, 0.25-0.88), had obese BMIs (0.36; 95% CI, 0.25-0.52), and who exercised rarely (HR, 0.40; 95% CI, 0.29-0.56). Associations between OC use and breast and colorectal cancers were predominantly null.
CONCLUSIONS AND RELEVANCE: Long-term OC use is consistently associated with reduced ovarian cancer risk across lifestyle factors. We observed the greatest risk reductions for endometrial cancer among women at risk for chronic diseases (ie, smokers, obese BMI). Oralcontraceptive use may be beneficial for chemoprevention for a range of women with differing baseline cancer risks.
Authors: Cheung LC, Katki HA, Chaturvedi AK, Jemal A, Berg CD
Journal: Ann Intern Med. 2018 Jan 2. doi: 10.7326/M17-2067. [Epub ahead of print]
BACKGROUND: The U.S. Preventive Services Task Force (USPSTF) recommends annual low-dose computed tomography (CT) lung cancer screening for persons aged 55 to 80 years who currently smoke or quit within the past 15 years and have at least a 30–pack-year history of cigarette smoking. The number of U.S. persons meeting USPSTF criteria for CT screening sharply decreased between 2010 and 2015. However, these criteria may exclude smokers at high risk for lung cancer who would have been selected for CT screening by individual risk calculators that more specifically account for demographic, clinical, and smoking characteristics.
OBJECTIVE: To compare USPSTF eligibility criteria with individualized, risk-based eligibility and estimate the effect of eligibility on lung cancer deaths preventable by screening since 2005.
Authors: Lee JM, Nair J, Zimmer A, Lipkowitz S, Annunziata CM, Merino MJ, Swisher EM, Harrell MI, Trepel JB, Lee MJ, Bagheri MH, Botesteanu DA, Steinberg SM, Minasian L, Ekwede I, Kohn EC
Journal: Lancet Oncol. 2018 Jan 17. pii: S1470-2045(18)30009-3. doi: 10.1016/S1470-2045(18)30009-3. [Epub ahead of print]
BACKGROUND: High-grade serous ovarian carcinoma is characterised by TP53 mutations, DNA repair defects, and genomic instability. We hypothesised that prexasertib (LY2606368), a cell cycle checkpoint kinase 1 and 2 inhibitor, would be active in BRCA wild-type disease.
METHODS: In an open-label, single-centre, two-stage, proof-of-concept phase 2 study, we enrolled women aged 18 years or older with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma. All patients had a negative family history of hereditary breast and ovarian cancer or known BRCA wild-type status, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status score 0-2, and adequate haematological, renal, hepatic, and bone-marrow function. Patients received intravenous prexasertib 105 mg/m2 administered over 1 h every 14 days in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint of investigator-assessed tumour response, based on RECIST version 1.1, was assessed per protocol (assessable patients who had undergone CT imaging at baseline and attended at least one protocol-specified follow-up) and by intention to treat. The final analysis of this cohort of patients with BRCA wild-type high-grade serous ovarian carcinoma is reported here. This ongoing trial is registered with ClinicalTrials.gov, number NCT02203513, and continues to enrol patients for the BRCA-mutated ovarian cancer cohort.
FINDINGS: Between Jan 20, 2015, and Nov 2, 2016, we enrolled 28 women with a median age of 64 years (IQR 58·0-69·5) who had previously received a median of 5·0 (IQR 2·5-5·0) systemic therapies. Most patients (22 [79%]) had platinum-resistant or platinum-refractory disease. All women received at least one dose of prexasertib, but four (14%) of 28 patients were not assessable for RECIST response. Eight (33%, 95% CI 16-55) of 24 patients assessable per protocol had partial responses. In the intention-to-treat population, eight (29%, 95% CI 13-49) of 28 had a partial responses. The most common (in >10% patients) grade 3 or 4 treatment-emergent adverse events were neutropenia in 26 (93%) of 28 patients, reduced white blood cell count in 23 (82%), thrombocytopenia in seven (25%), and anaemia in three (11%). Grade 4 neutropenia was reported in 22 (79%) patients after the first dose of prexasertib and was transient (median duration 6 days [IQR 4-8]) and recovered without growth-factor support in all cases. The treatment-related serious adverse event of grade 3 febrile neutropenia was reported in two (7%) patients. One patient died during the study due to tumour progression.
INTERPRETATION: Prexasertib showed clinical activity and was tolerable in patients with BRCA wild-type high-grade serous ovarian carcinoma. This drug warrants further development in this setting, especially for patients with platinum-resistant or platinum-refractory disease.
Authors: May-Simera HL, Wan Q, Jha BS, Hartford J, Khristov V, Dejene R, Chang J, Patnaik S, Lu Q, Banerjee P, Silver J, Insinna-Kettenhofen C, Patel D, Lotfi M, Malicdan M, Hotaling N, Maminishkis A, Sridharan R, Brooks B, Miyagishima K, Gunay-Aygun M, Pal R, Westlake C, Miller S, Sharma R, Bharti K
Journal: Cell Rep. 2018 Jan 2;22(1):189-205. doi: 10.1016/j.celrep.2017.12.038.
Primary cilia are sensory organelles that protrude from the cell membrane. Defects in the primary cilium cause ciliopathy disorders, with retinal degeneration as a prominent phenotype. Here, we demonstrate that the retinal pigment epithelium (RPE), essential for photoreceptor development and function, requires a functional primary cilium for complete maturation and that RPE maturation defects in ciliopathies precede photoreceptor degeneration. Pharmacologically enhanced ciliogenesis in wild-type induced pluripotent stem cells (iPSC)-RPE leads to fully mature and functional cells. In contrast, ciliopathy patient-derived iPSC-RPE and iPSC-RPE with a knockdown of ciliary-trafficking protein remain immature, with defective apical processes, reduced functionality, and reduced adult-specific gene expression. Proteins of the primary cilium regulate RPE maturation by simultaneously suppressing canonical WNT and activating PKCδ pathways. A similar cilium-dependent maturation pathway exists in lung epithelium. Our results provide insights into ciliopathy-induced retinal degeneration, demonstrate a developmental role for primary cilia in epithelial maturation, and provide a method to mature iPSC epithelial cells for clinical applications.
Authors: Huang Y, Mao K, Chen X, Sun MA, Kawabe T, Li W, Usher N, Zhu J, Urban JF Jr, Paul WE, Germain RN
Journal: Science. 2018 Jan 5;359(6371):114-119. doi: 10.1126/science.aam5809.
Innate lymphoid cells (ILCs) are innate counterparts of adaptive T lymphocytes, contributing to host defense, tissue repair, metabolic homeostasis, and inflammatory diseases. ILCs have been considered to be tissue-resident cells, but whether ILCs move between tissue sites during infection has been unclear. We show here that interleukin-25- or helminth-induced inflammatory ILC2s are circulating cells that arise from resting ILC2s residing in intestinal lamina propria. They migrate to diverse tissues based on sphingosine 1-phosphate (S1P)-mediated chemotaxis that promotes lymphatic entry, blood circulation, and accumulation in peripheral sites, including the lung, where they contribute to anti-helminth defense and tissue repair. This ILC2 expansion and migration is a behavioral parallel to the antigen-driven proliferation and migration of adaptive lymphocytes to effector sites and indicates that ILCs complement adaptive immunity by providing both local and distant tissue protection during infection.
Authors: Zheng H, Pomyen Y, Hernandez MO, Li C, Livak F, Tang W, Dang H, Greten TF, Davis JL, Zhao Y, Mehta M, Levin Y, Shetty J, Tran B, Budhu A, Wang XW
Journal: Hepatology. 2018 Jan 9. doi: 10.1002/hep.29778. [Epub ahead of print]
Intratumor molecular heterogeneity of hepatocellular carcinoma (HCC) is partly attributed to the presence of hepatic cancer stem cells (CSCs). Different CSC populations defined by various cell surface markers may contain different oncogenic drivers, posing a challenge in defining molecular-targeted therapeutics. We combined transcriptomic and functional analyses of HCC cells at the single cell level to assess the degree of CSC heterogeneity. We provide evidence that hepatic CSCs at the single-cell level are phenotypically, functionally and transcriptionally heterogeneous. We found that different CSC subpopulations contain distinct molecular signatures. Interestingly, distinct genes within different CSC subpopulations are independently associated with HCC prognosis, suggesting that a diverse hepatic CSC transcriptome affects intratumor heterogeneity and tumor progression.
CONCLUSION: Our work provides unique perspectives into the previously unappreciated diversity of CSC subpopulations, whose molecular heterogeneity further highlights their role in tumor heterogeneity, prognosis and hepatic CSC therapy.
Authors: White AM, Slater ME, Ng G, Hingson R, Breslow R
Journal: Alcohol Clin Exp Res. 2018 Feb;42(2):352-359. doi: 10.1111/acer.13559. Epub 2018 Jan 2.
BACKGROUND: Acute alcohol consumption and chronic alcohol consumption increase the burden placed on emergency departments (EDs) by contributing to injury and disease. Whether the prevalence of alcohol-related ED visits in the United States has changed in recent years is unknown. The purpose of this study was to examine trends in ED visits involving acute and chronic alcohol consumption in the United States by age and sex between 2006 and 2014.
METHODS: Data from the Nationwide Emergency Department Sample (NEDS), the largest all-payer ED database in the United States involving 945 hospitals in 33 states and Washington, DC, were analyzed to assess changes in prevalence and rates of ED visits involving acute and chronic alcohol consumption by age and sex over time among persons aged ≥12 between 2006 and 2014.
RESULTS: Between 2006 and 2014, the number of ED visits involving alcohol consumption increased 61.6%, from 3,080,214 to 4,976,136. The rate increased 47% from 1,223 to 1,802 per 100,000 population and the total cost of such visits increased 272% from $4.1 billion to $15.3 billion. The number of acute alcohol-related ED visits increased 51.5% from 1,801,006 to 2,728,313 and the rate increased 40% from 720.9 to 1,009.6 per 100,000 population. The number chronic alcohol-related visits increased 75.7% from 1,279,208 to 2,247,823 and the rate increased 57.9% from 502.2 to 792.9 per 100,000. The annual percentage change in rates of all alcohol-related ED visits was larger for females than for males (5.3% vs. 4.0%). Other drug involvement increased the likelihood of admission for inpatient treatment.
CONCLUSIONS: Alcohol consumption contributed to an increasing number of ED visits in the United States between 2006 and 2014, especially among females. Increased utilization of evidence-based interventions is needed.
Authors: Zhu G, Lynn GM, Jacobson O, Chen K, Liu Y, Zhang H, Ma Y, Zhang F, Tian R, Ni Q, Cheng S, Wang Z, Lu N, Yung BC, Wang Z, Lang L, Fu X, Jin A, Weiss ID, Vishwasrao H, Niu G, Shroff H, Klinman DM, Seder RA, Chen X.
Journal: Nat Commun. 2017 Dec 5;8(1):1954. doi: 10.1038/s41467-017-02191-y.
Subunit vaccines have been investigated in over 1000 clinical trials of cancer immunotherapy, but have shown limited efficacy. Nanovaccines may improve efficacy but have rarely been clinically translated. By conjugating molecular vaccines with Evans blue (EB) into albumin-binding vaccines (AlbiVax), here we develop clinically promising albumin/AlbiVax nanocomplexes that self-assemble in vivo from AlbiVax and endogenous albumin for efficient vaccine delivery and potent cancer immunotherapy. PET pharmacoimaging, super-resolution microscopies, and flow cytometry reveal almost 100-fold more efficient co-delivery of CpG and antigens (Ags) to lymph nodes (LNs) by albumin/AlbiVax than benchmark incomplete Freund's adjuvant (IFA). Albumin/AlbiVax elicits ~10 times more frequent peripheral antigen-specific CD8+cytotoxic T lymphocytes with immune memory than IFA-emulsifying vaccines. Albumin/AlbiVax specifically inhibits progression of established primary or metastatic EG7.OVA, B16F10, and MC38 tumors; combination with anti-PD-1 and/or Abraxane further potentiates immunotherapy and eradicates most MC38 tumors. Albumin/AlbiVax nanocomplexes are thus a robust platform for combination cancer immunotherapy.
Authors: Kines RC, Varsavsky I, Choudhary S, Bhattacharya D, Spring S, McLaughlin R, Kang SJ, Grossniklaus HE, Vavvas D, Monks S, MacDougall JR, de Los Pinos E, Schiller JT.
Journal: Mol Cancer Ther. 2017 Dec 14. doi: 10.1158/1535-7163.MCT-17-0953. [Epub ahead of print]
The work outlined herein describes AU-011, a novel recombinant papillomavirus-like particle (VLP) drug conjugate and its initial evaluation as a potential treatment for primary uveal melanoma. The VLP is conjugated with a phthalocyanine photosensitizer, IRDye 700DX, that exerts its cytotoxic effect through photoactivation with a near-infrared laser. We assessed the anticancer properties of AU-011 in vitro utilizing a panel of human cancer cell lines and in vivo using murine subcutaneous and rabbit orthotopic xenograft models of uveal melanoma. The specificity of VLP binding (tumor targeting), mediated through cell surface heparan sulfate proteoglycans (HSPG), was assessed using HSPG-deficient cells and by inclusion of heparin in in vitro studies. Our results provide evidence of potent and selective anticancer activity, both in vitro and in vivo AU-011 activity was blocked by inhibiting its association with HSPG using heparin and using cells lacking surface HSPG, indicating that the tumor tropism of the VLP was not affected by dye conjugation and cell association is critical for AU-011-mediated cytotoxicity. Using the uveal melanoma xenograft models, we observed tumor uptake following intravenous (murine) and intravitreal (rabbit) administration and, after photoactivation, potent dose-dependent tumor responses. Furthermore, in the rabbit orthotopic model, which closely models uveal melanoma as it presents in the clinic, tumor treatment spared the retina and adjacent ocular structures. Our results support further clinical development of this novel therapeutic modality that might transform visual outcomes and provide a targeted therapy for the early-stage treatment of patients with this rare and life-threatening disease.
Authors: Szczot M, Pogorzala LA, Solinski HJ, Young L, Yee P, Le Pichon CE, Chesler AT, Hoon MA.
Journal: Cell Rep. 2017 Dec 5;21(10):2760-2771. doi: 10.1016/j.celrep.2017.11.035.
Piezo2 is a mechanically activated ion channel required for touch discrimination, vibration detection, and proprioception. Here, we discovered that Piezo2 is extensively spliced, producing different Piezo2 isoforms with distinct properties. Sensory neurons from both mice and humans express a large repertoire of Piezo2 variants, whereas non-neuronal tissues express predominantly a single isoform. Notably, even within sensory ganglia, we demonstrate the splicing of Piezo2 to be cell type specific. Biophysical characterization revealed substantial differences in ion permeability, sensitivity to calcium modulation, and inactivation kinetics among Piezo2 splice variants. Together, our results describe, at the molecular level, a potential mechanism by which transduction is tuned, permitting the detection of a variety of mechanosensory stimuli.