BMC Public Health. 2019 Jul 25;19(1):1001. doi: 10.1186/s12889-019-7330-z.
Estimates of past and future time trends in age-specific breast cancer incidence among women in Karachi, Pakistan: 2004-2025.
Zaheer S1,2, Shah N3, Maqbool SA4, Soomro NM5.
Author information
1
Department of Statistics, University of Karachi, Karachi, Pakistan. sidra.zaheer@duhs.edu.pk.
2
School of Public Health, Dow University of Health Sciences, OJHA Campus, Suparco road, Karachi, Pakistan. sidra.zaheer@duhs.edu.pk.
3
School of Public Health, Dow University of Health Sciences, OJHA Campus, Suparco road, Karachi, Pakistan.
4
Department of Clinical Oncology, Karachi Institute of Radiotherapy and Nuclear Medicine, Karachi, Pakistan.
5
Oncology Department, Civil Hospital, Karachi, Pakistan.
Abstract
BACKGROUND:
The current demographic trends indicate that breast cancer will pose an even greater public health concern in future for Pakistan. Details on the incidence, disease severity and mortality in respect of breast cancer are limited and without such data, therefore, future health policies or systems in respect of this disease cannot be strategically planned or implemented. The aim of this study was to examine past trends of age-specific breast cancer incidence rates (2004-2015), and to estimate the future volume of breast cancer cases in Karachi through the year 2025.

METHODS:
Two statistical methods, namely the functional time series models and the log-linear regression model were used; additionally, their real forecasting efficacy in epidemic time series was also evaluated.

RESULTS:
In the past, women aged 60-64 years had the highest overall breast cancer incidence rates, while from 2016 to 2025, large increases in breast cancer rates among women aged 50 to 64 years are expected. The total projected breast cancer incidence will increase by approximately 23.1% in 2020 to 60.7% in 2025. Cases of breast cancer diagnosed in younger women, aged 30-34 years, will increase from 70.7 to 130.6% in 2020 and 2025 relative to 2015.

CONCLUSIONS:
The breast cancer incidence appeared to have been rising more rapidly among post-menopausal women (aged 55 to 59), while a stable increase in incidence in the youngest age group (15-29 years) of women is expected. The results also infer an expected increase in incidence cases of breast cancer among middle aged women in Karachi, Pakistan. An increase in the number of incident cases of cancer has implications for understanding the health-care needs of growing population and the subsequent demands on health-care system.

KEYWORDS:
Breast cancer incidence; Forecasting; Functional time series model; Log-linear regression model

PMID: 31345204 PMCID: PMC6659231 DOI: 10.1186/s12889-019-7330-z
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42.
Med Mycol. 2019 Jun 1;57(Supplement_3):S274-S286. doi: 10.1093/mmy/myy125.
Beyond biomarkers: How enhanced CT imaging can improve the diagnostic-driven management of invasive mould disease.
Stanzani M1, Sassi C2, Battista G2, Lewis RE3.
Author information
1
Institute of Hematology, "Lorenzo e Ariosto Seràgnoli" Department of Hematology and Clinical Oncology S'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
2
Division of Radiology, Department of Experimental and Diagnostic Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
3
Clinic of Infectious Diseases, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
Abstract
CT imaging remains an essential diagnostic test for identification, staging and management of invasive mould infection (IMI) in patients with hematological malignancies. Yet the limited specificity of standard CT imaging can drive excessive antifungal use in patients, especially when more definitive diagnosis cannot be established through microbiology or invasive diagnostic procedures. CT pulmonary angiography (CTPA) is a complimentary, non-invasive approach to standard CT that allows for direct visualization of pulmonary arteries inside infiltrates for signs of angioinvasion, vessel destruction and vessel occlusion. Experience from several centers that are using CTPA as part of a standard diagnostic protocol for IMI suggests that a positive vessel occlusion sign (VOS) is the most sensitive and a specific sign of IMI in both neutropenic and non-neutropenic patients. CTPA is particularly useful in patients who develop suspected breakthrough IMI during antifungal prophylaxis because, unlike serum and/or BAL galactomannan and polymerase chain reaction (PCR) testing, the sensitivity is not reduced by antifungal therapy. A negative VOS may also largely rule-out the presence of IMI, supporting earlier discontinuation of empirical therapy. Future imaging protocols for IMI in patients with hematological malignancies will likely replace standard chest X-rays in favor of early low radiation dose CT exams for screening, with characterization of the lesions by CTPA and routine follow-up using functional/metabolic imaging such as 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (FDG-PET/CT) to assess treatment response. Hence, enhanced CT imaging techniques can improve the diagnostic-driven management of IMI management in high-risk patients with hematological malignancies.

© The Author(s) 2018. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.

KEYWORDS:
computed tomography pulmonary angiography; hematological malignancies; invasive mould disease; positron emission tomography

PMID: 31292659 DOI: 10.1093/mmy/myy125
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43.
Expert Opin Pharmacother. 2019 Aug;20(12):1503-1515. doi: 10.1080/14656566.2019.1618271. Epub 2019 May 28.
Pharmacotherapy for liposarcoma: current state of the art and emerging systemic treatments.
Suarez-Kelly LP1, Baldi GG2,3, Gronchi A4.
Author information
1
Complex General Surgical Oncology Fellow, The Ohio State University , Columbus , OH , USA.
2
"Sandro Pitigliani" Medical Oncology Department, Hospital of Prato , Prato , Italy.
3
Adult mesenchymal and Rare Tumor Unit, Department of Cancer Medicine, Fondazione IRCCS-Istituto Nazionale dei Tumori , Milan , Italy.
4
Sarcoma Service of the Department of Surgery, Fondazione IRCCS-Istituto Nazionale dei Tumori , Milan , Italy.
Abstract
Introduction: Liposarcomas are a heterogeneous group of soft tissue tumors that arise from adipose tissue and are one of the most common soft tissue sarcomas found in adults. Liposarcomas are subclassified into four subtypes with distinct histologic and biologic features that influence their treatment and management. Areas covered: This manuscript reviews the key clinicopathologic and cytogenic characteristics of the liposarcoma histologic subtypes and summarizes the results of recent clinical trials, treatment options, and future directions in the pharmacotherapy for the management of liposarcoma. Expert opinion: Despite significant advancements in the management of this disease, the treatment of liposarcoma continues to be a challenge. Surgical resection remains the mainstay of treatment for localized disease; however, use of systemic therapies in conjunction with surgery may be considered in patients where tumor shrinkage could reduce surgical morbidity and in patients with high-risk of micrometastatic disease. Anthracycline-based chemotherapy regimens remain the standard first-line treatment for unresectable/metastatic liposarcoma. Trabectedin and eribulin are currently the two most promising and evidenced-based second-line treatment options for liposarcomas. However, multiple clinical trials dedicated to patients with liposarcoma evaluating novel targeted agents are ongoing. Every effort should be made to enroll patients with liposarcoma into histotype-specific clinical trials.

KEYWORDS:
Cytotoxic Chemotherapy; liposarcoma; myxoid/round cell; pleomorphic; targeted therapy; well-/dedifferentiated

PMID: 31136210 DOI: 10.1080/14656566.2019.1618271
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44.
Front Immunol. 2019 Jan 14;9:3107. doi: 10.3389/fimmu.2018.03107. eCollection 2018.
Combining Radiotherapy With Anti-angiogenic Therapy and Immunotherapy; A Therapeutic Triad for Cancer?
Goedegebuure RSA1, de Klerk LK1,2, Bass AJ2,3, Derks S1, Thijssen VLJL1,4.
Author information
1
Amsterdam UMC, Location VUmc, Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States.
3
Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, United States.
4
Amsterdam UMC, Location VUmc, Radiation Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands.
Abstract
Radiotherapy has been used for the treatment of cancer for over a century. Throughout this period, the therapeutic benefit of radiotherapy has continuously progressed due to technical developments and increased insight in the biological mechanisms underlying the cellular responses to irradiation. In order to further improve radiotherapy efficacy, there is a mounting interest in combining radiotherapy with other forms of therapy such as anti-angiogenic therapy or immunotherapy. These strategies provide different opportunities and challenges, especially with regard to dose scheduling and timing. Addressing these issues requires insight in the interaction between the different treatment modalities. In the current review, we describe the basic principles of the effects of radiotherapy on tumor vascularization and tumor immunity and vice versa. We discuss the main strategies to combine these treatment modalities and the hurdles that have to be overcome in order to maximize therapeutic effectivity. Finally, we evaluate the outstanding questions and present future prospects of a therapeutic triad for cancer.

KEYWORDS:
angiogenesis; cancer; clinical trials; combination treatment; immune response; radiation; therapy; tumor microenvironment

PMID: 30692993 PMCID: PMC6339950 DOI: 10.3389/fimmu.2018.03107
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Select item 30614498
45.
Ann Ig. 2018 Nov-Dec;30(6):490-501. doi: 10.7416/ai.2018.2260.
Epidemiology and cost of cervical cancer care and prevention in Apulia (Italy), 2007/2016.
Bianchi FP1, Gallone MS1, Fortunato F2, Boccalini S3, Martinelli D2, Prato R2, Tafuri S1.
Author information
1
Department of Biomedical Science and Human Oncology, Aldo Moro University of Bari, Bari, Italy.
2
Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
3
Department of Health Science, University of Florence, Florence, Italy.
Abstract
BACKGROUND:
According to recent estimates, cervical cancer is worldwide the second most common cancer in females and the fourth overall. The number of deaths for cervical cancer is around 7.5% of all female cancer deaths. Cervical cancer is the only tumour with a known necessary cause, the HPV infection and, globally, HPV is the most common sexually transmitted infection. Two major approaches for cervical cancer prevention have been designed: primary prevention by HPV vaccination and secondary prevention by screening. The aim of our study is to design an overview of epidemiology, cost of the therapies and cost of prevention measures (screening and vaccines) 9 years after the introduction of anti-HPV vaccination in the Apulia Regional Immunization Program.

STUDY DESIGN:
Retrospective observational study.

METHODS:
To describe the epidemiology of cervical cancer, we analysed data from the Apulia regional archive of hospital discharge forms (SDO). We considered all records referred to cervical cancer using the ICD 9 code 180.xxx both in primary and secondary diagnosis, for the years 2007-2016. Subjects living in Apulia have been considered. Costs of hospitalization were computed considering generated Diagnosis Related Groups (DRG). To describe the Apulian screening program, we analysed data from Regional Screening Data warehouse; the cost of the single test was established according to the Tariff List from the Ministry of Health. Finally, vaccination data were extracted by Regional Immunization Database and official ex-factory price has been used to calculate the costs of immunization program.

RESULTS:
From 2007 to 2016, an important decrease in the incidence rate of cervical cancer in Apulia has been noted, ranging from 43.7 per 100,000 residents in 2007 to 21.0 per 100,000 residents in 2016. From an economic point of view, a clear reduction (39%) is observed in hospitalization costs over time. Total costs of prevention programs increased over time and globally exceed € 54,000,000, with a decreasing trend for vaccine prophylaxis and an increasing trend for screening.

CONCLUSIONS:
The incidence and costs of cervical cancer in Apulia, although already significantly decreasing, likely will be further reduced since 2027-2032, when we can observe the effects of vaccine prophylaxis on the burden of disease; on this occasion it will be also possible to quantify the actual cost-effectiveness of the vaccine. In our opinion, in the future the Apulia healthcare executives should enhance and improve the active screening test offer, without underestimating the importance of sexual education in young people, especially in those who have not had sexual debut yet.

KEYWORDS:
Costs evaluation; HPV; Primary and secondary prevention

PMID: 30614498 DOI: 10.7416/ai.2018.2249
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Select item 30536370
46.
Cancer. 2019 Jan 15;125(2):239-248. doi: 10.1002/cncr.31788. Epub 2018 Dec 10.
Impact of the human papillomavirus status on the development of high-grade cervical intraepithelial neoplasia in women negative for intraepithelial lesions or malignancy at the baseline: A 9-year Swedish nested case-control follow-up study.
Fröberg M1, Östensson E2,3, Belkić K2,4,5,6, Oštrbenk A7, Poljak M7, Mints M2, Arbyn M8, Andersson S2.
Author information
1
Department of Neurobiology, Care Sciences, and Society, Karolinska University Hospital and Institute, Stockholm, Sweden.
2
Department of Women's and Children's Health, Karolinska University Hospital and Institute, Stockholm, Sweden.
3
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
4
Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
5
Claremont Graduate University, Claremont, California.
6
Keck School of Medicine, University of Southern California, Los Angeles.
7
Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
8
Unit of Cancer Epidemiology/Belgian Cancer Centre, Scientific Institute of Public Health, Brussels, Belgium.
Abstract
BACKGROUND:
The causal relation between high-risk human papillomavirus (HPV) and cervical cancer and its precursor lesions has led to the use of sensitive HPV molecular tests for screening. This study examined the impact of the baseline HPV status on the future risk of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) among women with cytology negative for intraepithelial lesions or malignancy (NILM).

METHODS:
This was a nested case-control study including women with NILM baseline cytology participating in the Swedish cervical screening program in 2005-2007. Ninety-six cases of CIN2+ and 5 age-matched controls per case were identified through the National Cervical Screening Registry by follow-up through 2014. Baseline liquid-based cytology samples were tested for HPV. Conditional logistic regression analysis was used to calculate odds ratios (ORs) with confidence intervals (CIs).

RESULTS:
The risk of future high-grade cervical intraepithelial neoplasia (CIN) was strongly associated with the baseline HPV status. For women younger than 30 years, HPV-16/18 showed a significant association with future risk for CIN2+ (OR, 9.44; 95% CI, 3.37-26.4). Other HPV types were not significantly associated with future CIN2+ in these younger women. For women 30 years old or older, both HPV-16/18 and other HPV subtypes conferred a significant risk.

CONCLUSIONS:
The presence of HPV-16/18 among women with NILM cytology is associated with an elevated future risk of high-grade CIN. HPV types other than HPV-16/18 seem to have a greater impact on women 30 years old or older than younger women. Women with NILM cytology and HPV-16/18 need specific follow-up management within screening.

© 2018 American Cancer Society.

KEYWORDS:
case-control studies; cervical intraepithelial neoplasia; genotype; papillomaviridae; uterine cervical neoplasms

PMID: 30536370 DOI: 10.1002/cncr.31788
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47.
Curr Treat Options Oncol. 2018 Nov 15;19(12):1. doi: 10.1007/s11864-018-0572-7.
Using PARP Inhibitors in the Treatment of Patients With Ovarian Cancer.
Kurnit KC1, Coleman RL1, Westin SN2.
Author information
1
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Dr. CPB 6.3279, Houston, TX, 77030, USA.
2
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Dr. CPB 6.3279, Houston, TX, 77030, USA. swestin@mdanderson.org.
Abstract
Use of poly(ADP-ribose) polymerase (PARP) inhibitors has greatly increased over the past 5 years. With several new Food and Drug Administration (FDA) approvals, three PARP inhibitors have entered into standard of care treatment for epithelial ovarian cancer (including ovarian, fallopian tube, and primary peritoneal cancer). Olaparib and rucaparib currently have indications for treatment of recurrent BRCA mutant ovarian cancer. Olaparib, rucaparib, and niraparib all have indications for maintenance therapy in recurrent platinum-sensitive ovarian cancer after response to platinum-based therapy. In our practice, we use both olaparib and rucaparib in the recurrent setting, and all three PARP inhibitors in the maintenance setting. Choice of which PARP inhibitor to use in either setting is largely based upon baseline laboratory values, number of prior therapies, and presence of a BRCA mutation and/or homologous recombination deficiency (HRD). As (HRD) and other biomarker assessments continue to improve, we anticipate being able to better identify which patients might most benefit from PARP inhibitor therapy in the future. The clinically available PARP inhibitors are currently undergoing extensive investigations in clinical trials. Other newer agents such as talazoparib, veliparib, 2X-121, and CEP-9722 are in earlier stages of development. As more FDA-approved indications for PARP inhibitor therapy in ovarian cancer become available, we anticipate the decision of which PARP inhibitor to use will become increasingly complex.

KEYWORDS:
Maintenance; Ovarian cancer; PARP inhibitors; Targeted therapy; Treatment

PMID: 30535808 DOI: 10.1007/s11864-018-0572-7
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48.
Curr Treat Options Oncol. 2018 Nov 5;19(12):69. doi: 10.1007/s11864-018-0592-3.
Management of Advanced Small Bowel Cancer.
Puccini A1,2, Battaglin F1,3, Lenz HJ4.
Author information
1
Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 3456, Los Angeles, CA, 90033, USA.
2
Department of Medical Oncology, Ospedale Policlinico San Martino, Genoa, Italy.
3
Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, 35128, Padua, Italy.
4
Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 3456, Los Angeles, CA, 90033, USA. lenz@med.usc.edu.
Abstract
Small bower cancer is a rare disease, despite its incidence is increasing in the last decade. Both benign and malignant tumors can arise from the small intestine. The main histological cancer types are adenocarcinomas, neuroendocrine tumors, sarcomas, gastrointestinal stromal tumors (GISTs), and lymphomas. Due to the rarity of these malignances, all the currently available data are based on small studies or retrospective series, although recent breakthroughs are redirecting our approach to these patients. Immunotherapy for small bowel adenocarcinomas, several multikinase inhibitors in resistant GIST patients, as well as everolimus and 177Lu-DOTATATE in neuroendocrine tumors are only few of the novel therapeutic options that have changed, or may change in the future, the therapeutic landscape of these rare cancers. Larger and more powerful studies on the molecular profile of these tumors may lead to a better design of clinical trials, which eventually would provide our patients with more efficacious treatments to improve both overall survival and quality of life.

KEYWORDS:
Adenocarcinoma; GIST; Neuroendocrine; Small bowel cancer

PMID: 30397729 DOI: 10.1007/s11864-018-0592-3
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49.
Metab Syndr Relat Disord. 2019 Feb;17(1):53-59. doi: 10.1089/met.2018.0085. Epub 2018 Oct 30.
A Global MicroRNA Profile in Fanconi Anemia: A Pilot Study.
Degan P1, Cappelli E2, Longobardi M3, Pulliero A3, Cuccarolo P1, Dufour C2, Ravera S4, Calzia D4, Izzotti A1,3.
Author information
1
1 Mutagenesis and Preventive Oncology, Ospedale Policlinico San Martino, Genova, Italy.
2
2 Hematology, Istituto Giannina Gaslini, Genova, Italy.
3
3 Department of Health Sciences, School of Medicine, University of Genoa, Genova, Italy.
4
4 Department of Pharmacy, Biochemistry Laboratory, University of Genova, Genova, Italy.
Abstract
PURPOSE:
Fanconi anemia (FA) is a complex tumor-prone disease defined by an entangled genotype and phenotype. Despite enormous efforts in the last 20 years, a comprehensive and integrated view of the disease is still missing. The aim of this pilot study was to establish whether a global microRNA (miRNA) analysis approach could be helpful in defining aspects in FA phenotype, which might deserve future attention with the perspective to develop miRNA-based therapies.

METHODS:
miRNA array were employed to characterize the global miRNA (miRNoma) profile of FA RNA samples with respect to normal samples.

RESULTS:
We report and compare miRNA profile from two FA established cell lines and three FA patients. This analysis reveals that 36 and 64 miRNAs, respectively, are found differentially expressed (>2-fold variation and P < 0.05) in the samples from FA cell lines and FA patients. Overlap of these data results in 24 miRNAs as shared in the two sample populations. Available bioinformatics methods were used to predict target genes for the differentially expressed miRNAs and to perform pathway enrichment analysis.

CONCLUSIONS:
Seven pathway results associated with the FA phenotype. It is interesting to note that some of these pathways were previously unrelated to FA phenotype. It might be important to focus on these pathways not previously emerged as dysfunctional in FA to better define the pathophysiological context of this disease. This is the first report of a global miRNA analysis in FA.

KEYWORDS:
Fanconi anemia; KEGG pathways; cancer-prone diseases; data mining; metabolic relationships; microRNA

PMID: 30376422 DOI: 10.1089/met.2018.0085
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50.
J Immunother Cancer. 2018 Oct 22;6(1):109. doi: 10.1186/s40425-018-0420-0.
Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study.
Amin A1, Plimack ER2, Ernstoff MS3, Lewis LD4, Bauer TM5, McDermott DF6, Carducci M7, Kollmannsberger C8, Rini BI9, Heng DYC10, Knox J11, Voss MH12, Spratlin J13, Berghorn E14, Yang L14, Hammers HJ15.
Author information
1
Immunotherapy program, Levine Cancer Institute, Carolinas HealthCare System, 1024 Morehead Medical Drive, Charlotte, NC, 28204, USA. Asim.Amin@carolinashealthcare.org.
2
Division of Genitourinary Medical Oncology, Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
3
Division of Oncology, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14203, USA.
4
Department of Medicine at The Geisel School of Medicine and The Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center, Lebanon, NH, 03756, USA.
5
Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, 37203, USA.
6
Department of Medicine, Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA, 02215, USA.
7
Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA.
8
Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, V5Z 4E6, Canada.
9
Lerner College of Medicine, Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, 44195, USA.
10
Department of Oncology, Tom Baker Cancer Center, University of Calgary, Calgary, AB, T2N 4N2, Canada.
11
Cancer Clinical Research Unit (CCRU), Princess Margaret Cancer Centre, Toronto, ON, M5G 1Z5, Canada.
12
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
13
Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T6G 1Z2, Canada.
14
Oncology - Global Clinical Research, Bristol-Myers Squibb, Princeton, NJ, 08541, USA.
15
Department of Internal Medicine, UT Southwestern - Kidney Cancer Program, Dallas, TX, 75390, USA.
Erratum in
Correction to: Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study. [J Immunother Cancer. 2019]
Abstract
BACKGROUND:
Combination treatment with immune checkpoint inhibitors and antiangiogenic drugs has shown encouraging preliminary antitumor activity across various tumor types including advanced or metastatic renal cell carcinoma (aRCC). The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of nivolumab in combination with antiangiogenic tyrosine kinase inhibitors or ipilimumab. Long-term outcomes from this study for the combination of nivolumab plus sunitinib or pazopanib in aRCC are presented.

METHODS:
Patients with aRCC received nivolumab plus either sunitinib (50 mg/day, 4 weeks on/2 weeks off; N + S) or pazopanib (800 mg/day; N + P) until progression/unacceptable toxicity. The nivolumab starting dose was 2 mg/kg every 3 weeks, with planned escalation to 5 mg/kg every 3 weeks. Primary endpoints were safety and tolerability; antitumor activity was a secondary endpoint.

RESULTS:
Arm N + S enrolled 33 patients, 19 of whom were treatment-naïve; this arm advanced to the expansion phase. Median follow-up was 50.0 months. Patients experienced high frequencies of adverse events (AEs) including treatment-related AEs (100%), grade 3/4 treatment-related AEs (82%), and treatment-related AEs leading to discontinuation (39%). Investigator-assessed objective response rate (ORR) was 55% (18/33) and median progression-free survival (PFS) was 12.7 months. Median overall survival (OS) was not reached. Arm N + P enrolled 20 patients, all had ≥1 prior systemic therapy; this arm was closed due to dose-limiting toxicities and did not proceed to expansion. Median follow-up was 27.1 months. Patients treated with N + P experienced high frequencies of AEs including treatment-related AEs (100%), grade 3/4 treatment-related AEs (70%), and treatment-related AEs leading to discontinuation (25%). Investigator-assessed ORR was 45% (9/20) and median PFS was 7.2 months. Median OS was 27.9 months.

CONCLUSIONS:
The addition of standard doses of sunitinib or pazopanib to nivolumab resulted in a high incidence of high-grade toxicities limiting future development of either combination regimen. While there was no adverse impact on response and the OS outcome was notable, the findings suggest that the success of combination regimens based on immune checkpoint inhibitors and antiangiogenic drugs may be dependent on careful selection of the antiangiogenic component and dose.

TRIAL REGISTRATION:
Clinicaltrials.gov identifier: NCT01472081 . Registered 16 November 2011.

KEYWORDS:
Antiangiogenic; Immune checkpoint inhibitor; Metastatic renal cell carcinoma; Nivolumab; Pazopanib; Sunitinib; Tyrosine kinase inhibitor

PMID: 30348216 PMCID: PMC6196426 DOI: 10.1186/s40425-018-0420-0
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Select item 30285902
51.
J Immunother Cancer. 2018 Oct 3;6(1):102. doi: 10.1186/s40425-018-0391-1.
Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option.
Rohaan MW1, van den Berg JH2,3, Kvistborg P3, Haanen JBAG4,5.
Author information
1
Department of Medical Oncology, The Netherlands Cancer Institute (NKI), Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
2
Biotherapeutics Unit, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
3
Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
4
Department of Medical Oncology, The Netherlands Cancer Institute (NKI), Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. j.haanen@nki.nl.
5
Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. j.haanen@nki.nl.
Abstract
The treatment of metastatic melanoma patients with autologous tumor-infiltrating lymphocytes (TIL) shows robust, reproducible, clinical responses in clinical trials executed in several specialized centers over the world. Even in the era of targeted therapy and immune checkpoint inhibition, TIL therapy can be an additional and clinically relevant treatment line. This review provides an overview of the clinical experiences with TIL therapy thus far, including lymphodepleting regimens, the use of interleukin-2 (IL-2) and the associated toxicity. Characteristics of the TIL products and the antigen recognition pattern will be discussed, as well as the current and upcoming production strategies, including the selective expansion of specific fractions from the cell product. In addition, the future potential of TIL therapy in melanoma and other tumor types will be covered.

KEYWORDS:
Adoptive cell therapy; Antigen recognition; Combination therapy; Immunotherapy; Interleukin-2; Lymphodepletion; Melanoma; Tumor-infiltrating lymphocytes

PMID: 30285902 PMCID: PMC6171186 DOI: 10.1186/s40425-018-0391-1
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Select item 30223045
52.
J Control Release. 2018 Oct 28;288:212-226. doi: 10.1016/j.jconrel.2018.09.011. Epub 2018 Sep 14.
Novel glucosylceramide synthase inhibitor based prodrug copolymer micelles for delivery of anticancer agents.
Xu J1, Zhao W2, Sun J1, Huang Y1, Wang P3, Venkataramanan R2, Yang D3, Ma X3, Rana A4, Li S5.
Author information
1
Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
2
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
3
Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
4
Department of Surgery/Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
5
Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: sol4@pitt.edu.
Abstract
In order to improve the efficacy of chemotherapy for cancers, we have developed a novel prodrug micellar formulation to co-deliver ceramide-generating anticancer agents and ceramide degradation inhibitor (PPMP). The prodrug nanocarrier is based on a well-defined POEG-b-PPPMP diblock copolymer. The hydrophilic block of POEG-b-PPPMP is POEG, and the hydrophobic block is composed of a number of PPMP units, which could work synergistically with loaded anticancer drugs. POEG-b-PPPMP was readily synthesized via a one-step reversible addition-fragment transfer (RAFT) polymerization from a PPMP monomer. The newly synthesized polymers were self-assembled into micelles and served as a carrier for several hydrophobic anticancer drugs including DOX, PTX and C6-ceramide. POEG-b-PPPMP prodrug polymer exhibited intrinsic antitumor activity in vitro and in vivo. In addition, POEG-b-PPPMP prodrug polymer was comparable to free PPMP in selectively enhancing the production of pro-apoptotic ceramide species as well as down-regulating the mRNA expression of GCS. DOX-loaded POEG-b-PPPMP micelles exhibited an excellent stability of 42 days at 4 °C. Moreover, DOX loaded in POEG-b-PPPMP micelles showed higher levels of cytotoxicity than DOX loaded in a pharmacologically inert polymer (POEG-b-POM) and Doxil formulation in several tumor cell lines. Consistently, in a 4T1.2 murine breast cancer model, the tumor inhibition followed the order of DOX/POEG-b-PPPMP > DOX/POEG-b-POM ≥ Doxil > POEG-b-PPPMP > POEG-b-POM. Our data suggest that POEG-b-PPPMP micelles are a promising dual-functional carrier that warrants more studies in the future.

Copyright © 2018 Elsevier B.V. All rights reserved.

KEYWORDS:
Ceramide; Co-delivery; Doxorubicin; PPMP; Prodrug micelles

PMID: 30223045 PMCID: PMC6177216 DOI: 10.1016/j.jconrel.2018.09.011
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53.
J Pain Symptom Manage. 2018 Dec;56(6):878-885. doi: 10.1016/j.jpainsymman.2018.09.003. Epub 2018 Sep 14.
Fidelity and Feasibility of a Brief Emergency Department Intervention to Empower Adults With Serious Illness to Initiate Advance Care Planning Conversations.
Leiter RE1, Yusufov M2, Hasdianda MA3, Fellion LA3, Reust AC3, Block SD4, Tulsky JA5, Ouchi K6.
Author information
1
Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Division of Palliative Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. Electronic address: Richard_leiter@dfci.harvard.edu.
2
Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA.
3
Department of Emergency Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Emergency Medicine, Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Emergency Medicine, Harvard Medical School, Boston, Massachusetts, USA; Serious Illness Care Program, Ariadne Labs, Boston, Massachusetts, USA; Department of Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA.
5
Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Division of Palliative Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
6
Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Emergency Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Emergency Medicine, Harvard Medical School, Boston, Massachusetts, USA; Serious Illness Care Program, Ariadne Labs, Boston, Massachusetts, USA.
Abstract
CONTEXT:
Emergency department (ED) visits provide opportunities to empower patients to discuss advance care planning with their outpatient clinicians, but systematically developed, feasible interventions do not currently exist. Brief negotiated interview (BNI) interventions, which allow ED clinicians to efficiently motivate patients, have potential to meet this need.

OBJECTIVES:
We developed a BNI ED intervention to empower older adults with life-limiting illness to formulate and communicate medical care goals to their primary outpatient clinicians. This study assessed the fidelity and feasibility of this intervention in a high-volume ED.

METHODS:
We enrolled adult patients with serious illnesses (advanced cancer, congestive heart failure, chronic obstructive pulmonary disease, chronic kidney disease on dialysis, predicted survival <12 months) in an urban, tertiary care academic medical center ED. All participants received the BNI intervention. We video-recorded the encounters. Two reviewers assessed the recordings for intervention fidelity based on adherence to the BNI steps (Part I) and communication skills (Part II).

RESULTS:
We reviewed 46 video recordings. The mean total adherence score was 21.07/27 (SD 3.68) or 78.04%. The Part I mean adherence score was 12.07/15 (SD 2.07) or 80.47%. The Part II mean adherence score was 9.0/12 (SD 2.51) or 75%. The majority (75.6%) of recordings met the prespecified threshold for high intervention fidelity.

CONCLUSION:
ED clinicians can deliver a BNI intervention to increase advance care planning conversations with high fidelity. Future research is needed to study the intervention's efficacy in a wider patient population.

Copyright © 2018 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

KEYWORDS:
Advance care planning; brief negotiated interview; emergency department; serious illness; teachable moment

PMID: 30223014 PMCID: PMC6289886 [Available on 2019-12-01] DOI: 10.1016/j.jpainsymman.2018.09.003
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54.
Sci Rep. 2018 Aug 21;8(1):12522. doi: 10.1038/s41598-018-30978-6.
Novel oncogenic and chemoresistance-inducing functions of resistin in ovarian cancer cells require miRNAs-mediated induction of epithelial-to-mesenchymal transition.
Qiu L1, Zhang GF2, Yu L1, Wang HY1, Jia XJ1, Wang TJ3.
Author information
1
Department of Radiation Oncology, The Second Hospital of Jilin University, Changchun, China.
2
Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, China.
3
Department of Radiation Oncology, The Second Hospital of Jilin University, Changchun, China. tj_wang@yahoo.com.
Abstract
Resistin plays a role in the growth, proliferation, angiogenesis, metastasis and therapeutic resistance in different cancers. However, such effects of resistin have never been evaluated in ovarian cancer, a deadly gynecological malignancy. We observed a significant induction of ovarian cancer cells' growth, invasion and cisplatin resistance, and established a mechanism of resistin action that included induction of EMT and stemness, as evidenced by down-regulated epithelial marker e-cadherin and up-regulated mesenchymal markers vimentin/ ZEB1 and stemness markers sox2, oct4 and nanog. The mechanism also included suppression of tumor suppressor miRNAs, let-7a, miR-200c and miR-186. Over-expression of these miRNAs significantly reversed the resistin-mediated effects on invasion and chemoresistance. We further validated our results in vivo where resistin administration significantly enhanced tumor growth in mice. Our results provide first evidence for such oncogenic effects of resistin in ovarian cancer models and a rationale for future studies to further understand the mechanistic role of resistin in ovarian cancer invasiveness, metastasis and therapy resistance.

PMID: 30131543 PMCID: PMC6104088 DOI: 10.1038/s41598-018-30978-6
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55.
Oncologist. 2018 Oct;23(10):1188-1198. doi: 10.1634/theoncologist.2017-0671. Epub 2018 May 16.
Global Acceptance of Biosimilars: Importance of Regulatory Consistency, Education, and Trust.
Cazap E1, Jacobs I2, McBride A3, Popovian R4, Sikora K5.
Author information
1
Latin American & Caribbean Society of Medical Oncology, Buenos Aires, Argentina ecazap@slacom.org.
2
Pfizer Inc., New York, New York, USA.
3
The University of Arizona Cancer Center, Department of Pharmacy, University of Arizona, Tucson, Arizona, USA.
4
U.S. Government Relations, Pfizer Inc., Washington, DC, USA.
5
Proton Partners International, London, UK.
Abstract
Globally, biosimilars are expected to have a key role in improving patient access to biological therapies and addressing concerns regarding the escalating cost of health care. Indeed, in Europe, increased use of biologics and reduced drug prices have been observed after the introduction of biosimilars. Recently, several monoclonal antibody biosimilars of anticancer therapies have been approved, and numerous others are in various stages of clinical development. Biosimilars are authorized via a regulatory pathway separate from that used for generic drugs; they are also regulated separately from novel biologics. Biosimilar approval pathways in many major regulatory regions worldwide are, to a broad degree, scientifically aligned. However, owing to regional differences in health care priorities, policies, and resources, some important regulatory inconsistencies are evident. Acceptance of biosimilars by health care systems, health care professionals, and patients will be a key factor in the uptake of these therapies, and such regulatory variations could contribute to confusion and diminished confidence regarding the quality, efficacy, and reliability of these agents. Furthermore, the need for manufacturers to account for regulatory inconsistencies introduces inefficiencies and delays into biosimilar development programs. These issues should be addressed if biosimilars are to attain their maximal global potential. This review summarizes the evolution of the global biosimilar landscape and provides examples of inconsistencies between regulatory requirements in different regions. In addition, we review ongoing efforts to improve regulatory alignment and highlight the importance of education as a crucial factor in generating trust in, and acceptance of, biosimilars on a worldwide scale.

IMPLICATIONS FOR PRACTICE:
Biosimilars of monoclonal antibody anticancer therapies are beginning to emerge, and more are likely to become available for clinical use in the near future. The extent to which biosimilars can contribute to cancer care will depend on their level of acceptance by health care systems, health care professionals, and patients. A better understanding of the regulatory basis for the approval of biosimilars may enhance confidence and trust in these agents. In order to have informed discussions about treatment choices with their patients, oncologists should familiarize themselves with the biosimilar paradigm.

© AlphaMed Press 2018.

KEYWORDS:
Antineoplastic agents; Biosimilar pharmaceuticals; Monoclonal antibodies; Neoplasms; Oncologists

PMID: 29769386 PMCID: PMC6263136 DOI: 10.1634/theoncologist.2017-0671
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Conflict of interest statement
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Select item 29684136
56.
Ann Behav Med. 2018 Apr 19;52(5):412-428. doi: 10.1093/abm/kax002.
Effects of a Group-Mediated Exercise and Dietary Intervention in the Treatment of Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: Results From the IDEA-P Trial.
Focht BC1,2, Lucas AR1, Grainger E2,3, Simpson C2,3, Fairman CM1, Thomas-Ahner JM2,3, Buell J4, Monk JP2,3, Mortazavi A2,3, Clinton SK2,3.
Author information
1
Exercise and Behavioral Medicine Laboratory, Kinesiology, The Ohio State University, Columbus, OH, USA.
2
Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
3
Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, OH, USA.
4
Medical Dietetics, The Ohio State University, Columbus, OH, USA.
Abstract
BACKGROUND:
Although androgen-deprivation therapy (ADT) is the foundation of treatment for prostate cancer, the physiological impacts of ADT result in functional decline and enhanced risk of chronic disease and metabolic syndrome.

PURPOSE:
The Individualized Diet and Exercise Adherence Pilot Trial (IDEA-P) is a single-blind, randomized, pilot trial comparing the effects of a group-mediated, cognitive-behavioral (GMCB) exercise and dietary intervention (EX+D) with those of a standard-of-care (SC) control during the treatment of prostate cancer patients undergoing ADT.

METHODS:
A total of 32 prostate cancer patients (M age = 66.28, SD = 7.79) undergoing ADT were randomly assigned to the 12-week EX+D intervention (n = 16) or control (n = 16). The primary outcome in IDEA-P was change in mobility performance with secondary outcomes including body composition and muscular strength. Blinded assessment of outcomes were obtained at baseline and at 2- and 3-month follow-ups.

RESULTS:
Favorable adherence and retention rates were observed, and no serious intervention-related adverse events were documented. Intent-to-treat ANCOVA controlling for baseline value and ADT duration demonstrated that EX+D resulted in significantly greater improvements in mobility performance (p < .02), muscular strength (p < .01), body fat percentage (p < .05), and fat mass (p < .03) at 3-month follow-up, relative to control.

CONCLUSION:
Findings from the IDEA-P trial suggest that a GMCB-based EX+D intervention resulted in significant, clinically meaningful improvements in mobility performance, muscular strength, and body composition, relative to controls. Collectively, these results suggest that the EX+D was a safe and well-tolerated intervention for prostate cancer patients on ADT. The utility of implementing this approach in the treatment of prostate cancer patients on ADT should be evaluated in future large-scale efficacy trials.

CLINICAL TRIAL INFORMATION:
NCT02050906.

PMID: 29684136 PMCID: PMC6361261 DOI: 10.1093/abm/kax002
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Select item 29634364
57.
Cleft Palate Craniofac J. 2018 Nov;55(10):1430-1439. doi: 10.1177/1055665618768542. Epub 2018 Apr 10.
Exploring the Medical and Psychosocial Concerns of Adolescents and Young Adults With Craniofacial Microsomia: A Qualitative Study.
Hamilton KV1,2, Ormond KE1, Moscarello T3, Bruce JS4, Bereknyei Merrell S5, Chang KW6, Bernstein JA7,8.
Author information
1
1 Department of Genetics, Stanford, Stanford University School of Medicine, CA, USA.
2
Hamilton is now with Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
3
2 Department of Cardiovascular Medicine, Stanford Health Care, Stanford, CA, USA.
4
3 Department of Pediatrics, Stanford University School of Medicine, CA, USA.
5
4 Department of Surgery, Stanford University School of Medicine, CA, USA.
6
5 Department of Otolaryngology, Stanford University School of Medicine, CA, USA.
7
6 Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, CA, USA.
8
7 Stanford Children's Health-Lucile Packard Children's Hospital, Stanford, CA, USA.
Abstract
OBJECTIVE:
This study explores the experiences of adolescents and young adults with craniofacial microsomia, including the impact of growing up with this craniofacial condition on daily life and sense of self. The results may guide future research on optimally supporting individuals with craniofacial microsomia during this critical life phase.

DESIGN AND SETTING:
Participants were recruited through a craniofacial center, online patient support groups, and social media sites. Eleven individual semistructured interviews with participants between 12 and 22 years old were conducted by a single interviewer, transcribed, iteratively coded, and thematically analyzed.

RESULTS:
Five themes were evident in the data: (1) impact on personal growth and character development, (2) negative psychosocial impact, (3) deciding to hide or reveal the condition, (4) desire to make personal surgical decisions, and (5) struggles with hearing loss.

CONCLUSIONS:
We identified both medical and psychosocial concerns prevalent among adolescents with craniofacial microsomia. Although adolescents with craniofacial microsomia exhibit considerable resilience, the challenges they face impact their sense of self and should be addressed through psychosocial support and counseling. Further research should investigate the potential benefit of the wider use of hearing aids, as well as the involvement of patients in decision-making about reconstructive ear surgery.

KEYWORDS:
craniofacial microsomia; hearing loss; psychosocial impact; surgical decision-making

PMID: 29634364 DOI: 10.1177/1055665618768542
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58.
J Immunother Cancer. 2018 Jan 23;6(1):8. doi: 10.1186/s40425-018-0316-z.
Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations.
Gong J1, Chehrazi-Raffle A2, Reddi S2, Salgia R3.
Author information
1
Department of Medical Oncology, City of Hope National Medical Center, 1500 E Duarte St, Duarte, CA, 91010, USA.
2
Department of Internal Medicine, Harbor-UCLA Medical Center, 1000 W Carson St, Torrance, CA, 90509, USA.
3
Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Building 51, Room 101, 1500 E Duarte St, Duarte, CA, 91010, USA. rsalgia@coh.org.
Abstract
Early preclinical evidence provided the rationale for programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) blockade as a potential form of cancer immunotherapy given that activation of the PD-1/PD-L1 axis putatively served as a mechanism for tumor evasion of host tumor antigen-specific T-cell immunity. Early-phase studies investigating several humanized monoclonal IgG4 antibodies targeting PD-1 and PD-L1 in advanced solid tumors paved way for the development of the first PD-1 inhibitors, nivolumab and pembrolizumab, approved by the Food and Drug Administration (FDA) in 2014. The number of FDA-approved agents of this class is rapidly enlarging with indications for treatment spanning across a spectrum of malignancies. The purpose of this review is to highlight the clinical development of PD-1 and PD-L1 inhibitors in cancer therapy to date. In particular, we focus on detailing the registration trials that have led to FDA-approved indications of anti-PD-1 and anti-PD-L1 therapies in cancer. As the number of PD-1/PD-L1 inhibitors continues to grow, predictive biomarkers, mechanisms of resistance, hyperprogressors, treatment duration and treatment beyond progression, immune-related toxicities, and clinical trial design are key concepts in need of further consideration to optimize the anticancer potential of this class of immunotherapy.

KEYWORDS:
Biomarkers; Clinical trials; Hyperprogressors; Immune checkpoint; Immune-related toxicity; Microbiome; PD-1 inhibitor; PD-L1 inhibitor; Treatment beyond progression

PMID: 29357948 PMCID: PMC5778665 DOI: 10.1186/s40425-018-0316-z
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Select item 29100867
59.
J Allergy Clin Immunol Pract. 2018 Jul - Aug;6(4):1287-1296.e1. doi: 10.1016/j.jaip.2017.09.004. Epub 2017 Oct 31.
The Combined Utility of Ex Vivo IFN-γ Release Enzyme-Linked ImmunoSpot Assay and In Vivo Skin Testing in Patients with Antibiotic-Associated Severe Cutaneous Adverse Reactions.
Trubiano JA1, Strautins K2, Redwood AJ2, Pavlos R2, Konvinse KC3, Aung AK4, Slavin MA5, Thursky KA5, Grayson ML6, Phillips EJ7.
Author information
1
Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia; Department of Infectious Diseases, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia; National Centre for Infections in Cancer, National Health and Medical Research Council Centre of Research Excellence, Peter MacCallum Cancer Centre, Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; Department of Medicine, University of Melbourne, Parkville, Victoria, Australia. Electronic address: Jason.trubiano@austin.org.au.
2
Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.
3
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Centre, Nashville, Tenn.
4
Department of General Medicine and Infectious Diseases, Alfred Health and Monash University, Melbourne, Victoria, Australia.
5
Department of Infectious Diseases, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia.
6
Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia; Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.
7
Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia; Departments of Medicine & Pharmacology, Vanderbilt University, Nashville, Tenn.
Abstract
BACKGROUND:
For severe cutaneous adverse reactions (SCARs) associated with multiple antibiotics dosed concurrently, clinical causality is challenging and diagnostic approaches are limited, leading to constricted future antibiotic choices.

OBJECTIVE:
To examine the combined utility of in vivo and ex vivo diagnostic approaches at assigning drug causality in a cohort of patients with antibiotic-associated (AA)-SCARs.

METHODS:
Patients with AA-SCARs were prospectively recruited between April 2015 and February 2017. In vivo testing (patch testing or delayed intradermal testing) was performed to the implicated antibiotic(s) at the highest nonirritating concentration and read at 24 hours through 1 week. Ex vivo testing used patient peripheral blood mononuclear cells (PBMCs) stimulated with a range of pharmacologically relevant concentrations of implicated antibiotics to measure dose-dependent IFN-γ release from CD4+ and CD8+ T cells via an enzyme-linked immunoSpot assay.

RESULTS:
In 19 patients with AA-SCARs, combined in vivo and ex vivo testing assigned antibiotic causality in 15 (79%) patients. Ten patients (53%) with AA-SCARs were positive on IFN-γ release enzyme-linked immunoSpot assay, with an overall reported sensitivity of 52% (95% CI, 29-76) and specificity of 100% (95% CI, 79-100), with improved sensitivity noted in acute (within 1 day to 6 weeks after SCAR onset) testing (75%) and in patients with higher phenotypic scores (59%). There was increased use of narrow-spectrum beta-lactams and antibiotics from within the implicated class following testing in patients with a positive ex vivo or in vivo test result.

CONCLUSIONS:
We demonstrate the potential utility of combined in vivo and ex vivo testing in patients with AA-SCARs to assign drug causality with high specificity.

Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

KEYWORDS:
Antibiotic allergy; Delayed hypersensitivity; Stevens-Johnson syndrome; drug reaction with eosinophilia and systemic symptoms; toxic epidermal necrolysis

PMID: 29100867 PMCID: PMC5930120 DOI: 10.1016/j.jaip.2017.09.004