1
Review J Immunother Cancer
. 2019 Apr 18;7(1):109. doi: 10.1186/s40425-019-0580-6.
The Clinical Application of Cancer Immunotherapy Based on Naturally Circulating Dendritic Cells
Kalijn F Bol 1 2, Gerty Schreibelt 1, Katrin Rabold 1 3, Stefanie K Wculek 4, Julia Katharina Schwarze 5, Andrzej Dzionek 6, Alvaro Teijeira 7, Lana E Kandalaft 8, Pedro Romero 8, George Coukos 8, Bart Neyns 5, David Sancho 4, Ignacio Melero 7 9, I Jolanda M de Vries 10 11
Affiliations expand
PMID: 30999964 PMCID: PMC6471787 DOI: 10.1186/s40425-019-0580-6
Free PMC article
Abstract
Dendritic cells (DCs) can initiate and direct adaptive immune responses. This ability is exploitable in DC vaccination strategies, in which DCs are educated ex vivo to present tumor antigens and are administered into the patient with the aim to induce a tumor-specific immune response. DC vaccination remains a promising approach with the potential to further improve cancer immunotherapy with little or no evidence of treatment-limiting toxicity. However, evidence for objective clinical antitumor activity of DC vaccination is currently limited, hampering the clinical implementation. One possible explanation for this is that the most commonly used monocyte-derived DCs may not be the best source for DC-based immunotherapy. The novel approach to use naturally circulating DCs may be an attractive alternative. In contrast to monocyte-derived DCs, naturally circulating DCs are relatively scarce but do not require extensive culture periods. Thereby, their functional capabilities are preserved, the reproducibility of clinical applications is increased, and the cells are not dysfunctional before injection. In human blood, at least three DC subsets can be distinguished, plasmacytoid DCs, CD141+ and CD1c+ myeloid/conventional DCs, each with distinct functional characteristics. In completed clinical trials, either CD1c+ myeloid DCs or plasmacytoid DCs were administered and showed encouraging immunological and clinical outcomes. Currently, also the combination of CD1c+ myeloid and plasmacytoid DCs as well as the intratumoral use of CD1c+ myeloid DCs is under investigation in the clinic. Isolation and culture strategies for CD141+ myeloid DCs are being developed. Here, we summarize and discuss recent clinical developments and future prospects of natural DC-based immunotherapy.

Keywords: Cancer; Conventional dendritic cells; Cross-presenting dendritic cells; Dendritic cells; Immunotherapy; Myeloid dendritic cells; Natural dendritic cells; Plasmacytoid dendritic cells; Vaccination.

Conflict of interest statement
Ethics approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Competing interests
AD is an employee of Miltenyi Biotec. All other authors declare no conflict of interest.

Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Cited by 13 articles100 references2 figures
supplementary info
Publication types, MeSH terms, Substancesexpand
full-text links
full-text provider logo
Proceed to details Cite
 Share
2
Clinical Trial Haematologica
. 2019 Oct;104(10):1962-1973. doi: 10.3324/haematol.2018.207241. Epub 2019 Feb 21.
Pathogenic Mutations Identified by a Multimodality Approach in 117 Japanese Fanconi Anemia Patients
Minako Mori 1 2, Asuka Hira 1, Kenichi Yoshida 3, Hideki Muramatsu 4, Yusuke Okuno 4, Yuichi Shiraishi 5, Michiko Anmae 6, Jun Yasuda 7, Shu Tadaka 7, Kengo Kinoshita 7 8 9, Tomoo Osumi 10, Yasushi Noguchi 11, Souichi Adachi 12, Ryoji Kobayashi 13, Hiroshi Kawabata 14, Kohsuke Imai 15, Tomohiro Morio 16, Kazuo Tamura 6, Akifumi Takaori-Kondo 2, Masayuki Yamamoto 7 17, Satoru Miyano 5, Seiji Kojima 4, Etsuro Ito 18, Seishi Ogawa 3 19, Keitaro Matsuo 20, Hiromasa Yabe 21, Miharu Yabe 22, Minoru Takata 23
Affiliations expand
PMID: 30792206 PMCID: PMC6886416 DOI: 10.3324/haematol.2018.207241
Free PMC article
Erratum in
Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients.
Mori M, Hira A, Yoshida K, Muramatsu H, Okuno Y, Shiraishi Y, Anmae M, Yasuda J, Tadaka S, Kinoshita K, Osumi T, Noguchi Y, Adachi S, Kobayashi R, Kawabata H, Imai K, Morio T, Tamura K, Takaori-Kondo A, Yamamoto M, Miyano S, Kojima S, Ito E, Ogawa S, Matsuo K, Yabe H, Yabe M, Takata M.
Haematologica. 2020 Apr;105(4):1166-1167. doi: 10.3324/haematol.2019.245720.
PMID: 32238468 Free PMC article. No abstract available.
Abstract
Fanconi anemia is a rare recessive disease characterized by multiple congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancies. It results from mutations in one of the 22 known FANC genes. The number of Japanese Fanconi anemia patients with a defined genetic diagnosis was relatively limited. In this study, we reveal the genetic subtyping and the characteristics of mutated FANC genes in Japan and clarify the genotype-phenotype correlations. We studied 117 Japanese patients and successfully subtyped 97% of the cases. FANCA and FANCG pathogenic variants accounted for the disease in 58% and 25% of Fanconi anemia patients, respectively. We identified one FANCA and two FANCG hot spot mutations, which are found at low percentages (0.04-0.1%) in the whole-genome reference panel of 3,554 Japanese individuals (Tohoku Medical Megabank). FANCB was the third most common complementation group and only one FANCC case was identified in our series. Based on the data from the Tohoku Medical Megabank, we estimate that approximately 2.6% of Japanese are carriers of disease-causing FANC gene variants, excluding missense mutations. This is the largest series of subtyped Japanese Fanconi anemia patients to date and the results will be useful for future clinical management.

Copyright© 2019 Ferrata Storti Foundation.

Cited by 2 articles50 references3 figures
supplementary info
Publication types, MeSH terms, Substancesexpand
full-text links
full-text provider logo
Proceed to details Cite
 Share
3
Blood Adv
. 2019 Jul 23;3(14):2188-2198. doi: 10.1182/bloodadvances.2018026591.
IgA Levels at Diagnosis Predict for Infections, Time to Treatment, and Survival in Chronic Lymphocytic Leukemia
Ganchimeg Ishdorj 1, Erin Streu 2, Pascal Lambert 3, Harbhajan S Dhaliwal 4, Salaheddin M Mahmud 5 6 7, Spencer B Gibson 1 8 9, Versha Banerji 1 4, Aaron J Marshall 9, James B Johnston 1 4
Affiliations expand
PMID: 31324639 PMCID: PMC6650736 DOI: 10.1182/bloodadvances.2018026591
Free PMC article
Abstract
To better understand the relationship between baseline immunoglobulin measurements and subsequent clinical outcomes in chronic lymphocytic leukemia (CLL), we performed a retrospective analysis on 660 patients with CLL (72%), monoclonal B-cell lymphocytosis (MBL) (13%), and small lymphocytic lymphoma (SLL) (14%), diagnosed between 2005 and 2014 at CancerCare Manitoba. Of 511 patients who had their first immunoglobulin level determined within 3 months of diagnosis, abnormal (either increased or decreased) immunoglobulin M (IgM), IgG, and IgA values were observed in 58% of patients with CLL, 27% of patients with MBL, and 20% of patients with SLL. Immunoglobulin deviances were similar for MBL and CLL Rai stage 0 and for SLL and Rai stages I and II; for CLL, IgG and IgA abnormalities occurred with increasing frequency with advancing Rai stage. In contrast, the frequency of IgM abnormalities was similar in all patient groups. IgA abnormalities significantly correlated with high β2-microglobulin (B2M) expression, whereas abnormal IgG and IgA levels were associated with the use of IGHV1-69, 3-21, and 3-49 subtypes. Increases in IgG or IgM were commonly associated with the presence of a CLL-type M-band, whereas oligoclonal bands were frequently observed with increased IgA levels. Although abnormal levels of IgG and IgA at diagnosis were independent predictors for future immunoglobulin replacement, only abnormal IgA levels were associated with shorter time to first treatment and overall survival. These findings indicate that both reduced and elevated levels of IgG and IgA at diagnosis are important and independent prognostic markers for infection in CLL, with IgA being more relevant as a marker of disease progression and survival.

© 2019 by The American Society of Hematology.

Conflict of interest statement
Conflict-of-interest disclosure: The authors declare no competing financial interests.

5 figures
supplementary info
Publication types, MeSH terms, Substancesexpand
full-text links
full-text provider logo
Proceed to details Cite
 Share
4
Review Med Hypotheses
. 2019 Dec;133:109414. doi: 10.1016/j.mehy.2019.109414. Epub 2019 Sep 30.
A Potential Role of Cyclin-Dependent Kinase Inhibitor 1 (p21/WAF1) in the Pathogenesis of Endometriosis: Directions for Future Research
Nikolaos Zarkadoulas 1, Vasilios Pergialiotis 2, Dimitrios Dimitroulis 3, Konstantinos Stefanidis 4, Christos Verikokos 3, Despina N Perrea 1, Konstantinos Kontzoglou 3
Affiliations expand
PMID: 31586810 DOI: 10.1016/j.mehy.2019.109414
Abstract
Endometriosis is a common gynecological disorder that affects approximately 6-10% of the female population impairing the quality of life of patients. Several pathophysiologic pathways have been proposed as potential regulators of its severity; however, to date, the processes that trigger the onset and that influence the severity of the disease are not fully understood; hence, leading to disease recurrence in approximately 10-67% of cases. Cyclin-dependent kinase inhibitor 1 (p21/WAF1) is a protein that is a major target of p53 and is related to cell cycle arrest (it regulates transition from the G1 to the S phase) when DNA damage is detected. Its activity has been also linked to the angiogenic potential of tumors as it promotes the expression of various kinases that are responsible for endothelial development and function. Although several articles have underlined the importance of this protein in cancer cell development and tumor growth, there are no relevant data in the field of endometriosis. Indirect evidence suggests, however, that it may be involved in the pathogenesis of endometriosis as it inhibits the activity of various kinases which have been correlated with the course and severity of the disease. The present article investigates the background theory that implies the potential role of cyclin-dependent kinase inhibitor 1 (p21/WAF1) in the pathogenesis of endometriosis. Implications for future research are also provided given that indirect evidence seem to associate downregulation of p21 with decreased growth and invasiveness of human endometrial stromal cells.

Keywords: Caspase; Cip1; Endometriosis; Waf1; p21; p53.

Copyright © 2019 Elsevier Ltd. All rights reserved.

supplementary info
Publication types, MeSH terms, Substancesexpand
full-text links
full-text provider logo
Proceed to details Cite
 Share
5
Meta-Analysis Melanoma Res
. 2019 Dec;29(6):561-568. doi: 10.1097/CMR.0000000000000575.
Overall Survival After Treatment for Metastatic Uveal Melanoma: A Systematic Review and Meta-Analysis
Elina S Rantala 1 2, Micaela Hernberg 3, Tero T Kivelä 1
Affiliations expand
PMID: 30664106 PMCID: PMC6887637 DOI: 10.1097/CMR.0000000000000575
Free PMC article
Abstract
The overall survival (OS) of patients with metastatic uveal melanoma is short, the evidence for effectiveness of treatments is limited, and no consensus on the choice of treatment exists. We aimed to advance interpretation of OS as an outcome by pooling peer-reviewed data. The design is a systematic review and meta-analysis. We searched PubMed from 1 January 1980, to 29 March 2017, for articles reporting patient-level survival in Kaplan-Meier or numerical form. We digitized survival graphs, pooled individual survival times, calculated median OS by treatment modality, and compared each modality by the log-rank test and Cox regression using conventional chemotherapy (CHT) as a reference. Individual-level data were obtained from 78 articles with 2494 patients. The median OS across all treatment modalities was 1.07 years (range: 0.59-2.50 years). Pooled OS reported after isolated hepatic perfusion [median OS: 1.34 years; hazard ratio (HR): 0.92, 95% confidence interval (CI): 0.87-0.97, P = 0.0040], immunoembolization (median OS: 1.63; HR: 0.97, 95% CI: 0.95-1.00, P = 0.0080), and surgery (median OS: 1.43; HR: 0.94, 95% CI: 0.92-0.96, P < 0.0001) was longer, and after checkpoint inhibitor shorter (median OS: 0.59; HR: 1.13, 95% CI: 1.06-1.20, P < 0.0001) than after CHT (median OS: 0.91 years), but subject to identifiable confounding factors. OS following other modalities did not differ from CHT. Reported OS was unassociated with the decade of publication, but depended on the percentage of first-line treated patients. Our results suggest no clinically significant difference in OS by treatment modality or decade. Most of the difference in reported OS likely is attributable to surveillance, selection, and publication bias rather than treatment-related prolongation. Our pooled data provide benchmarks for future trials.

Cited by 9 articles39 references3 figures
supplementary info
Publication types, MeSH terms, Supplementary conceptsexpand
full-text links
full-text provider logo
Proceed to details Cite
 Share
6
Mol Cancer Ther
. 2019 Dec;18(12):2421-2432. doi: 10.1158/1535-7163.MCT-19-0028. Epub 2019 Sep 16.
Distinct Transcriptional Programming Drive Response to MAPK Inhibition in BRAF V600-Mutant Melanoma Patient-Derived Xenografts
Tianshu Feng 1, Javad Golji 1, Ailing Li 1, Xiamei Zhang 1, David A Ruddy 1, Daniel P Rakiec 1, Felipe C Geyer 1, Jane Gu 1, Hui Gao 1, Juliet A Williams 1, Darrin D Stuart 2, Matthew J Meyer 2
Affiliations expand
PMID: 31527224 DOI: 10.1158/1535-7163.MCT-19-0028
Abstract
Inhibitors targeting BRAF and its downstream kinase MEK produce robust response in patients with advanced BRAF V600-mutant melanoma. However, the duration and depth of response vary significantly between patients; therefore, predicting response a priori remains a significant challenge. Here, we utilized the Novartis collection of patient-derived xenografts to characterize transcriptional alterations elicited by BRAF and MEK inhibitors in vivo, in an effort to identify mechanisms governing differential response to MAPK inhibition. We show that the expression of an MITF-high, "epithelial-like" transcriptional program is associated with reduced sensitivity and adaptive response to BRAF and MEK inhibitor treatment. On the other hand, xenograft models that express an MAPK-driven "mesenchymal-like" transcriptional program are preferentially sensitive to MAPK inhibition. These gene-expression programs are somewhat similar to the MITF-high and -low phenotypes described in cancer cell lines, but demonstrate an inverse relationship with drug response. This suggests a discrepancy between in vitro and in vivo experimental systems that warrants future investigations. Finally, BRAF V600-mutant melanoma relies on either MAPK or alternative pathways for survival under BRAF and MEK inhibition in vivo, which in turn predicts their response to further pathway suppression using a combination of BRAF, MEK, and ERK inhibitors. Our findings highlight the intertumor heterogeneity in BRAF V600-mutant melanoma, and the need for precision medicine strategies to target this aggressive cancer.

©2019 American Association for Cancer Research.

Cited by 1 article
supplementary info
MeSH terms, Substancesexpand
full-text links
full-text provider logo
Proceed to details Cite
 Share
7
Blood Adv
. 2019 Jul 23;3(14):2230-2236. doi: 10.1182/bloodadvances.2019000151.
Tisagenlecleucel in relapsed/refractory Diffuse Large B-cell Lymphoma Patients Without Measurable Disease at Infusion
Michael R Bishop 1, Richard T Maziarz 2, Edmund K Waller 3, Ulrich Jäger 4, Jason R Westin 5, Joseph P McGuirk 6, Isabelle Fleury 7 8, Harald Holte 9, Peter Borchmann 10, Christopher Del Corral 11, Ranjan Tiwari 12, Özlem Anak 13, Rakesh Awasthi 14, Lida Pacaud 11, Vadim V Romanov 11, Stephen J Schuster 15
Affiliations expand
PMID: 31332046 PMCID: PMC6650727 DOI: 10.1182/bloodadvances.2019000151
Free PMC article
Abstract
Tisagenlecleucel demonstrated high rates of durable responses in adult patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) in the JULIET trial. Most patients (92%) received bridging therapies to control disease after study entry and before tisagenlecleucel infusion. Here, we examine the efficacy and safety of tisagenlecleucel in the subset of 7 patients who achieved complete response (CR) after bridging therapy and before tisagenlecleucel infusion. Tisagenlecleucel rapidly expanded in all 7 patients, and the transgene levels were measurable for up to 2 years after infusion. After infusion, all 7 patients were still in CR at the month 3 evaluation, and 5 of 7 patients remained progression-free >12 months. Adverse events were similar to the overall JULIET population. Cytokine release syndrome (CRS) was reported in 4 of 7 patients (grade 2 = 2 and grade 3 = 2 using the Penn grading scale), and 1 patient experienced grade 1 neurotoxicity. No patient required tocilizumab or steroids for CRS management. These data provide preliminary evidence of tisagenlecleucel efficacy in patients with r/r DLBCL without detectable disease after bridging or salvage therapies and warrant further investigation of tisagenlecleucel as consolidative therapy in future trials. This trial was registered at www.clinicaltrials.gov as #NCT02445248.

© 2019 by The American Society of Hematology.

Conflict of interest statement
Conflict-of-interest disclosure: M.R.B. provided consultant services to, was a member of an entity’s board of directors or advisory committees for, and received research funding from Novartis, Kite Pharma, and Juno Therapeutics; provided consultant services to and received honoraria from Novartis, Kite Pharma, Juno Therapeutics, Agios Pharmaceuticals, and CRISPR Therapeutics; was on a speaker’s bureau for, and received travel and honoraria from, Celgene, Kite Pharma, and Agios Pharmaceuticals; and was employed by, provided consultant services to, and received honoraria from Optum. R.T.M. received honoraria from, was a member of an entity’s board of directors or advisory committees for (Scientific Steering Committee for JULIET), and received research funding from Novartis; provided consultant services to and received honoraria from Incyte Inc, Celgene/Juno Therapeutics, and CRISPR Therapeutics; received honoraria from Kite Therapeutics; has patents for and received royalties from Athersys, Inc; was employed by Oregon Health & Science University (OHSU); and provided consultant services to, and received payment from, Novartis (this potential conflict of interest has been reviewed and managed by OHSU). E.K.W. provided consultant services to, was a member of an entity’s board of directors or advisory committees for, and received research funding from Novartis; received travel expenses from European Hematology Association; received research funding from Pharmacyclics and Celldex; provided consultant services to Kalytera; and provided consultant services to and had equity ownership in Cambium Medical Technologies and Cambium Oncology. U.J. provided consultant services to, received honoraria from, was a member of an entity’s board of directors or advisory committees for, and received research funding from Roche and Gilead; provided consultant services to, received honoraria from, and was a member of an entity’s board of directors or advisory committees for Janssen and Celgene; provided consultant services to and received honoraria from AbbVie; was a member of an entity’s board of directors or advisory committees for and received research funding from Novartis; was a member of an entity’s board of directors or advisory committees for Mundipharma, Takeda-Millennium, Amgen, AOP Orphan, GSK, Infinity, and Bioverativ; and research funding from Merck Sharp & Dohme Corporation. J.R.W. was a member of an entity’s board of directors or advisory committees for Novartis, Apotex, Kite Pharma, and Celgene. J.P.M. received honoraria, travel accommodations, and expenses from, and was a speaker for, Kite Pharma; received honoraria from, was a speaker for, and received research funding from Novartis; and received research funding from Fresenius Biotech, Astellas Pharma, Bellicum Pharmaceuticals, Gamida Cell, and Pluristem Ltd. I.F. provided consultant services to AbbVie, Novartis, Merck, Janssen, Seattle Genetics, Gilead, Lundbeck, F. Hoffmann–La Roche Ltd, and Celgene. H.H. was a member of an entity’s board of directors or advisory committees for Novartis, Takeda, Roche, and Celgene, and received research funding from Roche. P.B. provided consultant services to and received honoraria from Novartis. C.d.C., L.P., and V.V.R. were employed by Novartis. R.T. was employed by Novartis Healthcare Private Limited. Ö.A. was employed by Novartis Pharma AG. R.A. was employed by Novartis Institutes for BioMedical Research, and holds equity ownership in Novartis, Cara Therapeutics, Aeterna Zentaris, Exelixis, and Celgene. S.J.S. provided consultant services to, received honoraria from, was a member of an entity’s board of directors or advisory committees for, and received research funding from Celgene; provided consultant services to and received honoraria from Dava Oncology; received honoraria and research funding from Genentech; was a member of an entity’s board of directors or advisory committees for Gilead and Pfizer; provided consultant services to, received honoraria from, and received research funding from Merck; received honoraria from, was a member of an entity’s board of directors or advisory committees for and received research funding from Novartis; provided consultant services to, received honoraria from, and was a member of an entity’s board of directors or advisory committees for Nordic Nanovector; and received honoraria from OncLive and Physician’s Education Source.

Cited by 4 articles2 figures
supplementary info
Publication types, MeSH terms, Substances, Associated dataexpand
full-text links
full-text provider logo
Proceed to details Cite
 Share
8
J Natl Compr Canc Netw
. 2020 Jul;18(7):866-872. doi: 10.6004/jnccn.2020.7542.
Private Payer and Medicare Coverage for Circulating Tumor DNA Testing: A Historical Analysis of Coverage Policies From 2015 to 2019
Michael P Douglas 1, Stacy W Gray 2 3, Kathryn A Phillips 1 4 5
Affiliations expand
PMID: 32634780 DOI: 10.6004/jnccn.2020.7542
Abstract
Background: Clinical adoption of the sequencing of circulating tumor DNA (ctDNA) for cancer has rapidly increased in recent years. This sequencing is used to select targeted therapy and monitor nonresponding or progressive tumors to identify mechanisms of therapeutic resistance. Our study objective was to review available coverage policies for cancer ctDNA-based testing panels to examine trends from 2015 to 2019.

Methods: We analyzed publicly available private payer policies and Medicare national coverage determinations and local coverage determinations (LCDs) for ctDNA-based panel tests for cancer. We coded variables for each year representing policy existence, covered clinical scenario, and specific ctDNA test covered. Descriptive analyses were performed.

Results: We found that 38% of private payer coverage policies provided coverage of ctDNA-based panel testing as of July 2019. Most private payer policy coverage was highly specific: 87% for non-small cell lung cancer, 47% for EGFR gene testing, and 79% for specific brand-name tests. There were 8 final, 2 draft, and 2 future effective final LCDs (February 3 and March 15, 2020) that covered non-FDA-approved ctDNA-based tests. The draft and future effective LCDs were the first policies to cover pan-cancer use.

Conclusions: Coverage of ctDNA-based panel testing for cancer indications increased from 2015 to 2019. The trend in private payer and Medicare coverage is an increasing number of coverage policies, number of positive policies, and scope of coverage. We found that Medicare coverage policies are evolving to pan-cancer uses, signifying a significant shift in coverage frameworks. Given that genomic medicine is rapidly changing, payers and policymakers (eg, guideline developers) will need to continue to evolve policies to keep pace with emerging science and standards in clinical care.

Proceed to details Cite
 Share
9
Review Cancers (Basel)
. 2020 Jun 25;12(6):E1688. doi: 10.3390/cancers12061688.
Immunoglobulin M Paraproteinaemias
Louis-Pierre Girard 1 2, Cinnie Yentia Soekojo 3, Melissa Ooi 3, Li Mei Poon 3, Wee-Joo Chng 3 4 5, Sanjay de Mel 3
Affiliations expand
PMID: 32630470 DOI: 10.3390/cancers12061688
Abstract
Monoclonal paraproteinaemia is an increasingly common reason for referral to haematology services. Paraproteinaemias may be associated with life-threatening haematologic malignancies but can also be an incidental finding requiring only observation. Immunoglobulin M (IgM) paraproteinaemias comprise 15-20% of monoclonal proteins but pose unique clinical challenges. IgM paraproteins are more commonly associated with lymphoplasmacytic lymphoma than multiple myeloma and can occur in a variety of other mature B-cell neoplasms. The large molecular weight of the IgM multimer leads to a spectrum of clinical manifestations more commonly seen with IgM paraproteins than others. The differential diagnosis of B-cell and plasma cell dyscrasias associated with IgM gammopathies can be challenging. Although the discovery of MYD88 L265P and other mutations has shed light on the molecular biology of IgM paraproteinaemias, clinical and histopathologic findings still play a vital role in the diagnostic process. IgM secreting clones are also associated with a number of "monoclonal gammopathy of clinical significance" entities. These disorders pose a novel challenge from both a diagnostic and therapeutic perspective. In this review we provide a clinical overview of IgM paraproteinaemias while discussing the key advances which may affect how we manage these patients in the future.

Keywords: Waldenstrom macroglobulinaemia; immunoglobulin M; lymphoma; multiple myeloma; paraproteinaemia.

supplementary info
Publication typesexpand
Proceed to details Cite
 Share
10
Review Ann Surg Oncol
. 2020 Jul 6. doi: 10.1245/s10434-020-08787-x. Online ahead of print.
The Landmark Series: Neuroendocrine Tumor Liver Metastases
Alexandra Gangi 1, James R Howe 2
Affiliations expand
PMID: 32632880 DOI: 10.1245/s10434-020-08787-x
Abstract
Background: Neuroendocrine tumors are becoming increasingly prevalent, with many patients presenting with or developing metastatic disease to the liver.

Methods: In this landmark series paper, we highlight the critical studies that have defined the surgical management of neuroendocrine tumor liver metastases, as well as several randomized control trials which have investigated strategies for systemic control of metastatic disease.

Results: Liver-directed surgical approaches and locally ablative procedures are recommended for patients with limited, resectable, and in some cases, nonresectable tumor burden. Angiographic liver-directed techniques, such as transarterial embolization, chemoembolization, and radioembolization, offer another approach for management in patients with liver-predominant disease. Peptide receptor radionuclide therapy is a promising therapy for patients with hepatic and/or extrahepatic metastases. Various systemic medical therapies are also available as adjunct or definitive therapy for patients with metastatic disease.

Conclusions: This article reviews current data regarding management of neuroendocrine liver metastases and highlights areas for future study.

Keywords: Liver debulking; Liver metastases; Neuroendocrine; PRRT.

supplementary info
Publication types, Grant supportexpand
Proceed to details Cite
 Share
11
Maturitas
. 2020 Aug;138:8-13. doi: 10.1016/j.maturitas.2020.04.015. Epub 2020 May 11.
Multiple Myeloma: Current and Future Management in the Aging Population
Despina Fotiou 1, Ioannis Ntanasis-Stathopoulos 1, Maria Gavriatopoulou 2, Meletios Athanasios Dimopoulos 1
Affiliations expand
PMID: 32631590 DOI: 10.1016/j.maturitas.2020.04.015
Abstract
The increasing lifespan of the world population and the novel therapeutic combinations for the treatment of multiple myeloma (MM), which are more efficacious and safer, make the question of how to manage the older patient with MM increasingly relevant. Clinical trial data come mostly from subgroup analysis, as no clinical trials have been designed for elderly patients with MM, particularly the octogenarian population. Age has been traditionally used as a surrogate marker of physiological decline but does not accurately reflect frailty on its own. Validated frailty assessment tools that accurately and sensitively risk-stratify older MM patients are needed. Such tools are being increasingly incorporated into clinical trial design. We should aim to use them to offer a tailored therapeutic approach to this heterogeneous subgroup of the MM population. Risk stratification based on disease-specific and patient-specific characteristics helps set the relevant outcome measures and therapeutic goals that will allow the right choice of treatment. The treatment goal for all patients should be to prolong survival and preserve quality of life. In the fit old MM patient, good responses can be achieved by carefully selecting candidates for autologous stem cell transplant and novel triplet or quadruplet combinations. At the other end of the spectrum, quality-of-life outcome measures and toxicity minimization with dose adaptation should be the focus.

Keywords: Elderly patients; Frailty; Multiple myeloma.

Copyright © 2020 Elsevier B.V. All rights reserved.

Conflict of interest statement
Declaration of Competing Interest The authors declare that they have no conflict of interest.

full-text links
full-text provider logo
Proceed to details Cite
 Share
12
Antioxid Redox Signal
. 2020 Jul 6. doi: 10.1089/ars.2020.8077. Online ahead of print.
Measuring Reactive Sulfur Species and Thiol Oxidation States: Challenges and Cautions in Relation to Alkylation Based Protocols
Péter Nagy 1, Eva Doka 2, Tomoaki Ida 3, Takaaki Akaike 4
Affiliations expand
PMID: 32631072 DOI: 10.1089/ars.2020.8077
Abstract
Significance: Redox biology is gaining ground in research related to human physiology (metabolism, signaling), pathophysiology (cancer, cardiovascular disease, neurodegeneration) and toxicology (radiation or xenobiotic-induced damage). A major hurdle in advancing redox medicine is the current lack of understanding the mechanisms underpinning the observed detrimental or beneficial in vivo effects. In order to gain deeper insights into the underlying molecular pathways of redox regulation we need to appreciate the strengths and limitations of the currently available methods. Recent Advances: Reactive sulfur species (RSS), including cysteine derivatives of peptides and proteins along with small molecules such as hydrogen sulfide or inorganic polysulfides, are major players in redox biology. RSS-mediated regulation of protein functions is a widely studied mechanism in the field and considerable efforts have been devoted to the development of selective detection methods.

Critical issues: A large number of available methods rely on an alkylation step to freeze the dynamism of consecutive oxidation and reduction events among RSS at a particular time-point inside the cell. This process uses the assumption that alkylation blocks all redox events instantaneously. We argue that unfortunately this is often not the case, which could have serious impacts on detected sulfur species speciation and confound experimental results.

Future directions: Novel technologies and prudent optimization of existing methods to accurately characterize the dynamic redox status of the thiol proteome as well as detailed understanding of regulatory and signaling capacities of protein polysulfidation are crucial to open new routes towards therapeutic interventions.

full-text links
full-text provider logo
Proceed to details Cite
 Share
13
Review Int J Mol Sci
. 2020 Jun 30;21(13):E4691. doi: 10.3390/ijms21134691.
Immune Checkpoint Inhibitors in the Treatment of Renal Cancer: Current State and Future Perspective
Daniele Lavacchi 1, Elisa Pellegrini 1, Valeria Emma Palmieri 1, Laura Doni 1, Marinella Micol Mela 1, Fabrizio Di Maida 1, Amedeo Amedei 2, Serena Pillozzi 1, Marco Carini 1 2, Lorenzo Antonuzzo 1 2
Affiliations expand
PMID: 32630154 DOI: 10.3390/ijms21134691
Abstract
Systemic treatment of renal cancer (RCC) has undergone remarkable changes over the past 20 years with the introduction of immunotherapeutic agents targeting programmed cell death (PD-1)/programmed death-ligand 1 (PD-L1) axis, as a single-agent or combined with anti-CTLA-4 monoclonal antibodies (MoAbs) or a multi-target vascular endothelial growth factor-(VEGF) tyrosine kinase inhibitor (TKI). In this paper, we review the main evidence on the use of Immune Checkpoint Inhibitors (ICIs) for RCC treatment from the first demonstration of activity of a nivolumab single agent in a phase I trial to the novel combination strategies (anti-PD-1 plus anti-CTLA4 or anti-PD-1 plus TKI). In addition, we discuss the use of anti-PD-1/PD-L1 agents in patients with non-clear cells and rare histological subtype RCC. Then, we critically examine the current findings in biomarkers that have been proposed to be prognostic or predictive to the response of immunotherapy including immune gene expression signature, B7-H1 expression, PBRM1 loss of function, PD-L1 expression, frame shift indel count, mutations in bromodomain-containing genes in patients with MiT family translocation RCC (tRCC), high expression of the T-effector gene signature, and a high myeloid inflammation gene expression pattern. To date, a single biomarker as a predictor of response has not been established. Since the dynamic behavior of the immune response and the different impact of ICI treatment on patients with specific RCC subtypes, the integration of multiple biomarkers and further validation in clinical trials are needed.

Keywords: immune checkpoint inhibitors; predictive biomarkers; renal cell carcinoma; tyrosine kinase inhibitors.

supplementary info
Publication typesexpand
Proceed to details Cite
 Share
14
Br J Haematol
. 2019 Aug;186(3):420-430. doi: 10.1111/bjh.15920. Epub 2019 May 1.
Acute Myeloid Leukaemia Niche Regulates Response to L-asparaginase
Ilaria M Michelozzi 1, Valentina Granata 1, Giada De Ponti 1, Gaia Alberti 1, Chiara Tomasoni 1, Laura Antolini 2, Carlo Gambacorti-Passerini 3, Bernhard Gentner 4, Francesco Dazzi 5, Andrea Biondi 1 6, Tiziana Coliva 6, Carmelo Rizzari 6, Alice Pievani 1, Marta Serafini 1
Affiliations expand
PMID: 31044436 DOI: 10.1111/bjh.15920
Abstract
Eradicating the malignant stem cell is the ultimate challenge in the treatment of leukaemia. Leukaemic stem cells (LSC) hijack the normal haemopoietic niche, where they are mainly protected from cytotoxic drugs. The anti-leukaemic effect of L-asparaginase (ASNase) has been extensively investigated in acute lymphoblastic leukaemia, but only partially in acute myeloid leukaemia (AML). We explored the susceptibility of AML-LSC to ASNase as well as the role of the two major cell types that constitute the bone marrow (BM) microenvironment, i.e., mesenchymal stromal cells (MSC) and monocytes/macrophages. Whilst ASNase was effective on both CD34+ CD38+ and CD34+ CD38- LSC fractions, MSC and monocytes/macrophages partially counteracted the effect of the drug. Indeed, the production of cathepsin B, a lysosomal cysteine protease, by BM monocytic cells and by AML cells classified as French-American-British M5 is related to the inactivation of ASNase. Our work demonstrates that, while MSC and monocytes/macrophages may provide a protective niche for AML cells, ASNase has a cytotoxic effect on AML blasts and, importantly, LSC subpopulations. Thus, these features should be considered in the design of future clinical studies aimed at testing ASNase efficacy in AML patients.

Keywords: acute myeloid leukaemia; asparaginase; bone marrow microenvironment; cathepsin B; leukaemic stem cells.

© 2019 British Society for Haematology and John Wiley & Sons Ltd.

Comment in
Acute myeloid leukaemia niche regulates response to L-asparaginase.
Kaspers GJL.
Br J Haematol. 2019 Aug;186(3):397-399. doi: 10.1111/bjh.15924. Epub 2019 Apr 24.
PMID: 31020655 Free PMC article. No abstract available.
Cited by 3 articles
supplementary info
Publication types, MeSH terms, Substancesexpand
full-text links
full-text provider logo
Proceed to details Cite
 Share
15
Eur Rev Med Pharmacol Sci
. 2020 Jun;24(12):6759-6766. doi: 10.26355/eurrev_202006_21664.
The Expression and Clinical Significance of B7-H3 and miR-145 in Lung Cancer Patients With Malignant Pleural Effusion
L Huang 1
Affiliations expand
PMID: 32633367 DOI: 10.26355/eurrev_202006_21664
Abstract
Objective: To investigate the expression and clinical significance of costimulatory molecule B7-H3 and microRNA-145 (miR-145) in lung cancer patients with malignant pleural effusion.

Patients and methods: A total of 100 cases of patients with lung cancer who admitted to our hospital for treatment from March 2017 to September 2018 were selected. Forty-nine cases of patients diagnosed with malignant pleural effusion were included in the study group, and 51 cases with benign pleural effusion in the control group. The content of B7-H3 in pleural effusion of the two groups was detected by enzyme-linked immunosorbent assay (ELISA), and the expression of miR-145 in pleural effusion of the two groups was analyzed by Real-time quantitative PCR (qRT-PCR). The relationships between the expressions of B7-H3 and miR-145 and the clinicopathological characteristics were analyzed. The diagnostic value of B7-H3 and miR-145 in lung cancer was analyzed.

Results: The expression level of B7-H3 in the study group was significantly higher than that in the control group (p<0.050), while the expression level of miR-145 was significantly lower than that in the control group (p<0.050). The expression levels of B7-H3 and miR-145 in the study group were correlated with lymph node metastasis, differentiation degree of lung cancer and TNM stage (p<0.001). The sensitivity and specificity of miR-145 in single diagnosis of lung cancer were 64.71% and 79.59%, respectively. The sensitivity and specificity of B7-H3 in single diagnosis of lung cancer were 80.39% and 61.22%, respectively.

Conclusions: B7-H3 and miR-145 are abnormally expressed in lung cancer, and are closely related to the lymphatic metastasis, differentiation degree and TNM stage of lung cancer. They may be potential markers for the diagnosis of malignant pleural effusion in lung cancer in the future.

Proceed to details Cite
 Share
16
Eur Rev Med Pharmacol Sci
. 2020 Jun;24(12):6551-6560. doi: 10.26355/eurrev_202006_21639.
LncRNA DANCR Regulates Osteosarcoma Migration and Invasion by Targeting miR-149/MSI2 Axis
W Zhang 1, J-Z Li, Q-Y Tai, J-J Tang, Y-H Huang, S-B Gao
Affiliations expand
PMID: 32633342 DOI: 10.26355/eurrev_202006_21639
Abstract
Objective: As a new LncRNA, anti-differentiated non-coding RNA (DANCR) plays an important role in tumorigenesis and development, and its molecular mechanism in osteosarcoma is unclear. In this study, by investigating osteosarcoma tissue and cells, we explored the molecular mechanism by which lncRNA DANCR regulates the occurrence and development of osteosarcoma by targeting the miR-149 / MSI2 axis.

Patients and methods: In this study, osteosarcoma tissues and adjacent tissues in 109 patients were collected, and the relative expression of DANCR was detected by qPCR. The correlation between DANCR expression and clinical classification was statistically analyzed. In order to explore the potential molecular mechanism of DANCR related to tumor migration and invasion, an overexpression and silencing test was performed on the osteosarcoma cell line Saos-2, and then qPCR method was used to test the expression of miR149, and cell scratch test was used to detect invasion after DANCR silencing and miR149 overexpression. Transwell assay was used to detect the invasion after DANCR silencing and miR149 overexpression. Finally, Western blot was used to verify the expression of MSI2 protein after overexpression and silencing of miR-149.

Results: DANCR was significantly up-regulated in both osteosarcoma tissue and cells. The high expression of DANCR was significantly positively correlated with tissue typing and advanced TNM stage. DANCR can significantly reduce the migration and invasion of osteosarcoma cells. miRNA overexpression significantly reduced osteosarcoma cell migration and invasion. When miR-149 was overexpressed, MSI2 protein expression was significantly down-regulated. When miR-149 was silenced, MSI2 protein was significantly up-regulated.

Conclusions: LncRNA DANCR plays an important regulatory role in the occurrence and development of osteosarcoma. It may be used as a potential target in the treatment of osteosarcoma in the future, by targeting the miR-149/MSI2 axis to regulate the occurrence and development of osteosarcoma.

Proceed to details Cite
 Share
17
Published Erratum Future Oncol
. 2020 Jul 6. doi: 10.2217/fon-2018-0809c1. Online ahead of print.
Corrigendum
No authors listed
PMID: 32631101 DOI: 10.2217/fon-2018-0809c1
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
 Share
18
Review Curr Opin Chem Biol
. 2019 Dec;53:167-172. doi: 10.1016/j.cbpa.2019.10.001. Epub 2019 Oct 31.
Chemically Engineered Glycan-Modified Cancer Vaccines to Mobilize Skin Dendritic Cells
Sanne Duinkerken 1, R Eveline Li 1, Floortje J van Haften 1, Tanja D de Gruijl 2, Fabrizio Chiodo 1, Sjoerd T T Schetters 1, Yvette van Kooyk 3
Affiliations expand
PMID: 31678713 DOI: 10.1016/j.cbpa.2019.10.001
Abstract
Dendritic cell (DC)-targeting vaccines show great promise in increasing antitumor immunity. Glycan-engineered vaccines facilitate both DC targeting and increased uptake by DCs for processing and presentation to CD4+ and CD8+ T cells to induce tumor-specific T-cell responses. However, the complexity of various DC subsets in skin tissues, expressing different glycan-binding receptors that can mediate vaccine uptake or drainage of vaccines via lymphatics directly to the lymph node-resident DCs, complicates the success of vaccines. Moreover, the influx of inflammatory immune cells to the site of vaccination, such as monocytes that differentiate to DCs and coexpress glycan-binding receptors, may contribute to the strength of DC-targeting glycovaccines for future clinical use.

Keywords: C-type lectins; Cancer vaccines; DC-SIGN; Dendritic cells; Glycans; Immunity; Langerin.

Copyright © 2019. Published by Elsevier Ltd.

supplementary info
Publication types, MeSH terms, Substancesexpand
full-text links
full-text provider logo
Proceed to details Cite
 Share
19
Review Biomolecules
. 2020 Jun 25;10(6):E956. doi: 10.3390/biom10060956.
Bispecific Targeting of EGFR and Urokinase Receptor (uPAR) Using Ligand-Targeted Toxins in Solid Tumors
Felix Oh 1 2, Jaime F Modiano 2 3, Veronika Bachanova 2 4, Daniel A Vallera 1 2
Affiliations expand
PMID: 32630411 DOI: 10.3390/biom10060956
Abstract
Ligand-targeted toxins (LTTs) are bioengineered molecules which are composed of a targeting component linked to a toxin that induces cell death once the LTT binds its target. Bispecific targeting allows for the simultaneous targeting of two receptors. In this review, we mostly focus on the epidermal growth factor receptor (EGFR) as a target. We discuss the development and testing of a bispecific LTT targeting EGFR and urokinase-type plasminogen activator receptor (uPAR) as two attractive targets implicated in tumor growth and in the regulation of the tumor microvasculature in solid tumors. In vitro and mouse xenograft studies have shown that EGFR-targeted bispecific angiotoxin (eBAT) is effective against human solid tumors. Canine studies have shown that eBAT is both safe and effective against canine hemangiosarcoma, which is physiologically similar to human angiosarcoma. Finding the appropriate dosing strategy and sequencing of eBAT administration, in combination with other therapeutics, are among important factors for future directions. Together, the data indicate that eBAT targets cancer stem cells, it may have a role in inhibiting human tumor vasculature, and its bispecific conformation may have a role in reducing toxicity in comparative oncologic trials in dogs.

Keywords: EGFR (epidermal growth factor receptor); KDEL; LTT (ligand-targeted toxin); angiogenesis; bispecific; immunotoxin; uPAR (urokinase-type plasminogen activator receptor).

supplementary info
Publication typesexpand
Proceed to details Cite
 Share
20
Review Curr Hematol Malig Rep
. 2020 Jul 6. doi: 10.1007/s11899-020-00595-0. Online ahead of print.
Preparing Trainees to Deliver High-Value and Cost-Conscious Care in Hematology
Sarah J Nagle 1, Erin Aakhus 2 3
Affiliations expand
PMID: 32632656 DOI: 10.1007/s11899-020-00595-0
Abstract
Purpose of review: Despite national-level directives to reduce healthcare waste and promote high-value care (HVC), clinical educators struggle to equip trainees with the knowledge and skills needed to practice value-based care. In this review, we analyze ongoing efforts in graduate medical education (GME) to enhance trainee competence in delivery of high-value and cost-conscious care.

Recent findings: Surveys of residents and program directors have shown that while many training programs want to offer formal training in high-value care delivery, few succeed. Although several studies suggest that trainees model stewardship behaviors after clinical preceptors, there remains a shortage of faculty role models skilled in providing HVC. Preparing future hematologist-oncologists to provide cost-conscious care will require significant cultural change at the institutional and program levels and will depend heavily on the development of skilled clinical role models.

Keywords: Cost-effectiveness; Graduate medical education; Health economics; High value care; Medical education.

supplementary info
Publication typesexpand
Proceed to details Cite
 Share
21
BMC Palliat Care
. 2020 Jul 6;19(1):97. doi: 10.1186/s12904-020-00597-y.
General Practitioners' Perceptions of Compassionate Communities: A Qualitative Study
E Abbey 1 2, C Craig 3, C R Mayland 4 5
Affiliations expand
PMID: 32631288 DOI: 10.1186/s12904-020-00597-y
Free article
Abstract
Background: General Practitioners (GPs) face challenges when providing palliative care, including an ageing, multimorbid population, and falling GP numbers. A 'public health palliative care' approach, defined as "working with communities to improve people's experience of death, dying and bereavement", is gaining momentum. 'Compassionate communities' is one example, with a focus on linking professional health carers with supportive community networks. Primary care is central to the approach, which has been incorporated into United Kingdom GP palliative care guidance. No research to date, however, has investigated GP perspectives of these approaches. Our aim, therefore, was to explore GP perceptions of a public health approach to palliative care, and compassionate communities.

Methods: GPs working in the United Kingdom were recruited through university teaching and research networks using snowball sampling. Purposive sampling ensured wide representation of gender, level of experience and practice populations. Semi-structured, digitally audio-recorded interviews were conducted with nine GPs. Interviews were transcribed verbatim, and thematic analysis was undertaken, informed by a qualitative descriptive methodology. Interviews continued until data saturation was reached.

Results: Most participants were unfamiliar with the term 'compassionate communities', but recognised examples within their practice. Three major themes with seven subthemes were identified: 1) Perceived potential of compassionate communities, including: 'maximising use of existing community services'; 'influencing health outside of healthcare'; and 'combatting taboo', 2) Perceived challenges of compassionate communities, including: 'patient safety'; 'limited capacity of the community'; 'limited capacity of general practice', and 'applicability of public health to palliative care', and 3) The role of the GP in compassionate communities.

Conclusions: GPs recognised the importance of the wider community in caring for palliative care patients, however most were unfamiliar with the compassionate community approach. Participants held differing views regarding the application of the model, and the position of general practice within this. Further research into the approach's practical implementation, and exploring the views of other key stakeholders, would help establish the feasibility of compassionate communities in practice, and guide its future application.

Keywords: Compassionate communities; General practice; General practitioners; Palliative care; Public health; Public health palliative care; Qualitative study.

full-text links
full-text provider logo
Proceed to details Cite
 Share
22
Medicine (Baltimore)
. 2020 Jun 26;99(26):e20635. doi: 10.1097/MD.0000000000020635.
High Expression of Ghrelin and Obestatin Prepropeptide in Tumor Tissues Predicted Adverse Overall Survival in Gastric Carcinoma Patients
Xiandan Wu 1, Yongning Wu 1, Binhua Ye 1, Fubin Wu 1, Peien Wang 2
Affiliations expand
PMID: 32590738 DOI: 10.1097/MD.0000000000020635
Free article
Abstract
Background: Gastric cancer (GC) is the most prevailing digestive tract malignant tumor worldwide with high mortality and recurrence rates. However, its potential molecular mechanism and prognostic biomarkers are still not fully understood. We aim to screen novel prognostic biomarkers related to GC prognosis using comprehensive bioinformatic tools.

Methods: Four gene expression microarray data were downloaded from the Gene Expression Omnibus (GEO) database (GSE26942, GSE33335, GSE63089, and GSE79973). Differentially expressed genes (DEGs) between gastric carcinoma and normal gastric tissue samples were identified by an integrated bioinformatic analysis. Gene Ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed using statistical software R. STRING and Cytoscape software were employed to construct protein-protein interaction (PPI) networks. Hub genes with a high score of connectivity identified from the PPI network were identified. Prognostic values of hub genes were evaluated in GSE15459 dataset. Hub genes related to GC overall survival were further validated in GEPIA (Gene Expression Profiling Interactive Analysis) online tool.

Results: A total of 12 upregulated DEGs and 59 downregulated DEGs were identified when the 4 microarray data overlapped. Among them, 10 hub genes with a high score of connectivity were identified. High expression of ghrelin and obestatin prepropeptide (GHRL), BGN, TIMP metallopeptidase inhibitor 1, thrombospondin 2, secreted phosphoprotein 1, and low expression of CHGA were associated with a poor overall survival of gastric cancer (all log rank P < .05). After validation in GEPIA database, only GHRL was confirmed associated with a poor overall survival of gastric cancer (log rank P = .04).

Conclusions: GHRL could be used as a novel biomarker for the prediction of a poor overall survival of gastric cancer, and could be a novel therapeutic target for gastric cancer treatment. However, future experimental studies are still required to validate these findings.

supplementary info
MeSH terms, Substancesexpand
full-text links
full-text provider logo
Proceed to details Cite
 Share
23
Support Care Cancer
. 2020 Jul 6. doi: 10.1007/s00520-020-05565-z. Online ahead of print.
Supportive Care Needs and Service Use During Palliative Care in Family Caregivers of Patients With Advanced Cancer: A Prospective Longitudinal Study
Anneke Ullrich 1 2, Gabriella Marx 3 4, Corinna Bergelt 5, Gesine Benze 3, Youyou Zhang 6, Feline Wowretzko 6, Julia Heine 3, Lisa-Marie Dickel 3, Friedemann Nauck 3, Carsten Bokemeyer 6, Karin Oechsle 6
Affiliations expand
PMID: 32632761 DOI: 10.1007/s00520-020-05565-z
Abstract
Purpose: This study aimed to investigate the supportive care needs of family caregivers (FCs) of advanced cancer patients and their support service use at the beginning of specialist inpatient palliative care (SIPC), near the patient's death, and during bereavement.

Methods: FCs reported their needs using the Family Inventory of Needs (FIN), along with their utilization of psychosocial and bereavement support services at the beginning (N = 232) and 6-9 months after SIPC (N = 160).

Results: At the beginning of SIPC, mean of 16.9 of 20 needs were reported to be highly important, and 12.2 were reported to be met. At the time of the patient's death, 16.8 needs were highly important, and 13.8 were met. At both time points, the highest ranked need was related to information about changes in the patient's condition (100% vs. 99%), and the most frequently unmet need was related to feeling hope (73% vs. 71%). Multivariate linear regression analysis revealed a low education level to be consistently related to a greater number of highly important needs. Higher satisfaction with care and better social support was related to a greater number of met needs. Twenty-five percent of FCs had accessed at least one psychosocial support service prior to SIPC, and 30% had done so during bereavement. Among non-users of support services, > 75% indicated sufficient informal support as a barrier to service use.

Conclusions: The findings offer a useful guide for adequately addressing FCs' needs in an effort to optimize FC support. However, only a subgroup of the FCs used support services. Better information and provision of tailored services might improve FCs' situations in the future.

Keywords: Cancer; Family caregiver; Needs; Palliative care; Prospective studies; Support services.

supplementary info
Grant supportexpand
Proceed to details Cite
 Share
24
Ann Oncol
. 2020 Jul 4;S0923-7534(20)39927-0. doi: 10.1016/j.annonc.2020.06.017. Online ahead of print.
A Phase II, Multicenter, Two Cohort Study of 160 Mg Osimertinib in EGFR T790M-positive Non-Small Cell Lung Cancer Patients With Brain Metastases or Leptomeningeal Disease Who Progressed on Prior EGFR TKI Therapy
S Park 1, M-H Lee 2, M Seong 3, S T Kim 3, J-H Kang 4, B C Cho 5, K H Lee 6, E K Cho 7, J-M Sun 1, S-H Lee 1, J S Ahn 1, K Park 1, M-J Ahn 8
Affiliations expand
PMID: 32634610 DOI: 10.1016/j.annonc.2020.06.017
Abstract
Background: Up to 40% of patients with non-small cell lung cancer (NSCLC) and EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs) present with disease progression in the central nerve system (CNS), either as brain metastases (BM) or leptomeningeal metastases (LM). Osimertinib (80mg), a third generation, irreversible, oral EGFR TKI, has shown efficacy in active CNS metastases. However, efficacy of 160mg osimertinib in BM or LM is unclear.

Patients and methods: This prospective single-arm two cohort study evaluated the efficacy of 160 mg osimertinib in T790M-positive BM or LM NSCLC patients who progressed on prior EGFR TKI (NCT03257124) treatment. The primary endpoints were overall response rate (ORR) (H1=30%) for the BM cohort and overall survival (OS) (H1=5 months) for the LM cohort.

Results: The median follow-up duration was 10.1 months and 9.6 months for the BM and LM cohorts, respectively. In the BM cohort, intracranial ORR and disease control rate (DCR) were 55.0% and 77.5%, respectively. The median progression-free survival (PFS) was 7.6 months (95% confidential interval [CI] 5.0-16.6); the median OS was 16.9 months (95% CI 7.9-not reached [NR]). In the LM cohort, intracranial DCR was 92.5% and complete response (CR) rate was 12.5%. The median OS was 13.3 months (95%CI 9.1-NR); the median PFS was 8.0 months (95%CI 7.2-NR). Subgroup analyses based on previous exposure to T790M-targeting agents, including 80 mg osimertinib or other third generation EGFR TKIs, showed no difference in PFS in both the BM (n=18, P=0.39) and LM (n=17, P=0.85) cohorts. Previous radiotherapy favored PFS in the BM cohort (hazard ratio 0.42, P=0.04). The most common adverse events were decreased appetite, diarrhea, and skin rash; however, most were grade 1-2.

Conclusion: Thus, 160 mg osimertinib demonstrated promising ORR and survival benefit with a tolerable safety profile in EGFR T790M-positive NSCLC patients with CNS metastasis who progressed on prior EGFR TKIs.

Keywords: EGFR T790M; brain metastases; leptomeningeal disease; non-small cell lung cancer; osimertinib.

Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

full-text links
full-text provider logo
Proceed to details Cite
 Share
25
Pediatr Blood Cancer
. 2020 Jul 6;e28476. doi: 10.1002/pbc.28476. Online ahead of print.
Optimizing Health Literacy to Facilitate Reproductive Health Decision-Making in Adolescent and Young Adults With Cancer
Leena Nahata 1 2, Antoinette Anazodo 3 4 5, Brooke Cherven 6 7, Shanna Logan 5, Lillian R Meacham 6 7, Cathy D Meade 8, Sara Zarnegar-Lumley 9, Gwendolyn P Quinn 10
Affiliations expand
PMID: 32633029 DOI: 10.1002/pbc.28476
Abstract
Despite being considered "standard of care" by many organizations, fertility and reproductive health communications and counseling practices remain inconsistent for adolescents and young adults (AYAs) newly diagnosed with cancer and during survivorship. One factor known to affect how information is provided and received in the medical setting is health literacy. Providers should consider health literacy to optimize reproductive health communication with AYAs as they cope with their diagnosis, understand what it means for their future, process information about treatment options, learn about their potential harmful effects on fertility, make quick decisions about fertility preservation, and navigate a future family planning course. Thus, the objectives of this manuscript are to (a) summarize literature on reproductive health literacy; (b) describe health literacy frameworks; (c) examine ways to assess health literacy; and (d) identify ways to enhance clinician-patient communication in the AYA oncofertility setting.

Keywords: adolescents; cancer; health literacy; reproductive health; young adults.

© 2020 Wiley Periodicals LLC.

101 references
supplementary info
Grant supportexpand
Proceed to details Cite
 Share
26
Review Noncoding RNA
. 2020 Jul 1;6(3):E26. doi: 10.3390/ncrna6030026.
LncRNA NEAT1 in Paraspeckles: A Structural Scaffold for Cellular DNA Damage Response Systems?
Elisa Taiana 1 2, Domenica Ronchetti 1 2, Katia Todoerti 2, Lucia Nobili 1, Pierfrancesco Tassone 3, Nicola Amodio 3, Antonino Neri 1 2
Affiliations expand
PMID: 32630183 DOI: 10.3390/ncrna6030026
Abstract
Nuclear paraspeckle assembly transcript 1 (NEAT1) is a long non-coding RNA (lncRNA) reported to be frequently deregulated in various types of cancers and neurodegenerative processes. NEAT1 is an indispensable structural component of paraspeckles (PSs), which are dynamic and membraneless nuclear bodies that affect different cellular functions, including stress response. Furthermore, increasing evidence supports the crucial role of NEAT1 and essential structural proteins of PSs (PSPs) in the regulation of the DNA damage repair (DDR) system. This review aims to provide an overview of the current knowledge on the involvement of NEAT1 and PSPs in DDR, which might strengthen the rationale underlying future NEAT1-based therapeutic options in tumor and neurodegenerative diseases.

Keywords: DNA damage repair; NEAT1; cancer; lncRNA; neurodegenerative disease; paraspeckle.

supplementary info
Publication typesexpand
Proceed to details Cite
 Share
27
BMC Cancer
. 2020 Jul 6;20(1):628. doi: 10.1186/s12885-020-07121-8.
Oncolytic Vaccinia Virus GLV-1h68 Exhibits Profound Antitumoral Activities in Cell Lines Originating From Neuroendocrine Neoplasms
Linus D Kloker 1, Susanne Berchtold 1 2, Irina Smirnow 1, Julia Beil 1 2, Andreas Krieg 3, Bence Sipos 1, Ulrich M Lauer 4 5
Affiliations expand
PMID: 32631270 DOI: 10.1186/s12885-020-07121-8
Free article
Abstract
Background: Oncolytic virotherapy is an upcoming treatment option for many tumor entities. But so far, a first oncolytic virus only was approved for advanced stages of malignant melanomas. Neuroendocrine tumors (NETs) constitute a heterogenous group of tumors arising from the neuroendocrine system at diverse anatomic sites. Due to often slow growth rates and (in most cases) endocrine non-functionality, NETs are often detected only in a progressed metastatic situation, where therapy options are still severely limited. So far, immunotherapies and especially immunovirotherapies are not established as novel treatment modalities for NETs.

Methods: In this immunovirotherapy study, pancreatic NET (BON-1, QGP-1), lung NET (H727, UMC-11), as well as neuroendocrine carcinoma (NEC) cell lines (HROC-57, NEC-DUE1) were employed. The well characterized genetically engineered vaccinia virus GLV-1 h68, which has already been investigated in various clinical trials, was chosen as virotherapeutical treatment modality.

Results: Profound oncolytic efficiencies were found for NET/NEC tumor cells. Besides, NET/NEC tumor cell bound expression of GLV-1 h68-encoded marker genes was observed also. Furthermore, a highly efficient production of viral progenies was detected by sequential virus quantifications. Moreover, the mTOR inhibitor everolimus, licensed for treatment of metastatic NETs, was not found to interfere with GLV-1 h68 replication, making a combinatorial treatment of both feasible.

Conclusions: In summary, the oncolytic vaccinia virus GLV-1 h68 was found to exhibit promising antitumoral activities, replication capacities and a potential for future combinatorial approaches in cell lines originating from neuroendocrine neoplasms. Based on these preliminary findings, virotherapeutic effects now have to be further evaluated in animal models for treatment of Neuroendocrine neoplasms (NENs).

Keywords: Endocrine cancers; Immunotherapy; Neuroendocrine tumors; Vaccinia virus; Virotherapy.

full-text links
full-text provider logo
Proceed to details Cite
 Share
28
Cancers (Basel)
. 2020 Jul 2;12(7):E1768. doi: 10.3390/cancers12071768.
IGF-1R/mTOR Targeted Therapy for Ewing Sarcoma: A Meta-Analysis of Five IGF-1R-Related Trials Matched to Proteomic and Radiologic Predictive Biomarkers
Hesham M Amin 1, Ajaykumar C Morani 2, Najat C Daw 3, Salah-Eddine Lamhamedi-Cherradi 4, Vivek Subbiah 5, Brian A Menegaz 6, Deeksha Vishwamitra 1, Ghazaleh Eskandari 1, Bhawana George 1, Robert S Benjamin 4, Shreyaskumar Patel 4, Juhee Song 7, Alexander J Lazar 8, Wei-Lien Wang 8, Razelle Kurzrock 9, Alberto Pappo 10, Peter M Anderson 11, Gary K Schwartz 12, Dejka Araujo 4, Branko Cuglievan 3, Ravin Ratan 4, David McCall 3, Sana Mohiuddin 3, John A Livingston 4, Eric R Molina 6, Aung Naing 5, Joseph A Ludwig 4
Affiliations expand
PMID: 32630797 DOI: 10.3390/cancers12071768
Abstract
Background : Ten to fourteen percent of Ewing sarcoma (ES) study participants treated nationwide with IGF-1 receptor (IGF-1R)-targeted antibodies achieved tumor regression. Despite this success, low response rates and short response durations (approximately 7-weeks) have slowed the development of this therapy. Methods: We performed a meta-analysis of five phase-1b/2 ES-oriented trials that evaluated the anticancer activity of IGF-1R antibodies +/- mTOR inhibitors (mTORi). Our meta-analysis provided a head-to-head comparison of the clinical benefits of IGF-1R antibodies vs. the IGF-1R/mTOR-targeted combination. Available pretreatment clinical samples were semi-quantitatively scored using immunohistochemistry to detect proteins in the IGF-1R/PI3K/AKT/mTOR pathway linked to clinical response. Early PET/CT imaging, obtained within the first 2 weeks (median 10 days), were examined to determine if reduced FDG avidity was predictive of progression-free survival (PFS). Results: Among 56 ES patients treated at MD Anderson Cancer Center (MDACC) with IGF-1R antibodies, our analysis revealed a significant ~two-fold improvement in PFS that favored a combination of IGF-1R/mTORi therapy (1.6 vs. 3.3-months, p = 0.042). Low pIGF-1R in the pretreatment specimens was associated with treatment response. Reduced total-lesion glycolysis more accurately predicted the IGF-1R response than other previously reported radiological biomarkers. Conclusion: Synergistic drug combinations, and newly identified proteomic or radiological biomarkers of IGF-1R response, may be incorporated into future IGF-1R-related trials to improve the response rate in ES patients.

Keywords: Ewing sarcoma; PET/CT; biological therapies; biomarker; drug response; pIGF-1R.

supplementary info
Grant supportexpand
Proceed to details Cite
 Share
29
Future Oncol
. 2020 Jul 7. doi: 10.2217/fon-2020-0246. Online ahead of print.
SOLTI-1503 PROMETEO TRIAL: Combination of Talimogene Laherparepvec With Atezolizumab in Early Breast Cancer
Tomas Pascual 1 2, Juan M Cejalvo 3 4, Mafalda Oliveira 1 5 6, Maria Vidal 1 2 7 8, Estela Vega 9, Sergi Ganau 10, Ana Julve 11, Esther Zamora 5 6, Ignacio Miranda 12, Ana Delgado 13, Begoña Bermejo 3 4, Luis de la Cruz-Merino 14 15, Manel Juan 1 7 16 17, Juan M Ferrero-Cafiero 1, Jordi Canes 1, Xavier Gonzalez 1 18, Patricia Villagrasa 1, Aleix Prat 1 2 7 8
Affiliations expand
PMID: 32633563 DOI: 10.2217/fon-2020-0246
Abstract
New treatment strategies such as immune checkpoint inhibitors and oncolytic viruses are opening new possibilities in cancer therapy. Preliminary results in melanoma and other tumors showed that the combination of talimogene laherparepvec with an anti-PD-1/PD-L1 or anti-CTLA4 has greater efficacy than either therapy alone, without additional safety concerns beyond those expected for each agent. The presence of residual cancer after neoadjuvant chemotherapy in early breast cancer patients is an unmet medical need. SOLTI-1503 PROMETEO is a window of opportunity trial, which evaluates the combination of talimogene laherparepvec in combination with atezolizumab in women with operable HER2-negative breast cancer who present residual disease after neoadjuvant chemotherapy. The primary end point is the rate of residual cancer burden 0/1. Clinical Trial Registration: NCT03802604 (ClinicalTrials.gov).

Keywords: PD-L1; atezolizumab; immunotherapy; luminal B breast cancer; residual disease; talimogene laherparepvec; triple-negative breast cancer.

supplementary info
Associated dataexpand
full-text links
full-text provider logo
Proceed to details Cite
 Share