Review J Hematol Oncol
. 2019 Nov 21;12(1):120. doi: 10.1186/s13045-019-0823-5.
Chimeric Antigen Receptor T Cell Therapies for Multiple Myeloma
Chao Wu 1, Lina Zhang 1, Qierra R Brockman 2 3, Fenghuang Zhan 2, Lijuan Chen 4
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PMID: 31752943 PMCID: PMC6873434 DOI: 10.1186/s13045-019-0823-5
Free PMC article
Abstract
Multiple myeloma (MM) is the second most common hematologic malignancy and remains incurable despite the advent of numerous new drugs such as proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies. There is an unmet need to develop novel therapies for refractory/relapsed MM. In the past few years, chimeric antigen receptor (CAR)-modified T cell therapy for MM has shown promising efficacy in preclinical and clinical studies. Furthermore, the toxicities of CAR-T cell therapy are manageable. This article summarizes recent developments of CAR-T therapy in MM, focusing on promising targets, new technologies, and new research areas. Additionally, a comprehensive overview of antigen selection is presented along with preliminary results and future directions of CAR-T therapy development.

Keywords: Chimeric antigen receptors; Immunotherapy; Multiple myeloma; Tumor immunology.

Conflict of interest statement
The authors declare that they have no competing interests.

Cited by 4 articles101 references
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2
Review Curr Hematol Malig Rep
. 2019 Apr;14(2):127-135. doi: 10.1007/s11899-019-00505-z.
Autologous Haematopoietic Stem Cell Transplantation in Multiple Sclerosis: A Review of Current Literature and Future Directions for Transplant Haematologists and Oncologists
Joyutpal Das 1, Basil Sharrack 2, John A Snowden 3 4
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PMID: 30828772 PMCID: PMC6510794 DOI: 10.1007/s11899-019-00505-z
Free PMC article
Erratum in
Correction to: Autologous Haematopoietic Stem Cell Transplantation in Multiple Sclerosis: a Review of Current Literature and Future Directions for Transplant Haematologists and Oncologists.
Das J, Sharrack B, Snowden JA.
Curr Hematol Malig Rep. 2019 Apr;14(2):136. doi: 10.1007/s11899-019-00506-y.
PMID: 31030389 Free PMC article.
Abstract
Purpose of review: We summarise the current development of autologous haematopoietic stem cell transplantation (AHSCT) in treating multiple sclerosis (MS) and discuss future directions for the general neurologist, transplant haematologist and oncologist.

Recent findings: AHSCT was initially performed to treat MS over 20 years ago. Over recent years, the evidence base has grown, especially in relapsing-remitting MS (RRMS), with significant improvements in safety and efficacy through better patient selection, choice of transplant technique and increase in centre experience. AHSCT is now a treatment option in very carefully selected patients with severe, treatment-resistant RRMS. However, it is important for transplant haematologists and oncologists to work closely with specialist MS neurologists in patient selection, during transplant and in long-term follow-up of patients. Data should be registered into international transplant registries and, ideally, patients should be enrolled on prospective clinical trials in order to build the evidence base and refine transplant techniques.

Keywords: Aggressive multiple sclerosis; Autologous haematopoietic stem cell transplantation; Multiple sclerosis; Primary progressive multiple sclerosis; Relapsing-remitting multiple sclerosis; Secondary progressive multiple sclerosis.

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

Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.

Cited by 3 articles61 references
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3
Int J Biol Sci
. 2019 Sep 7;15(12):2607-2614. doi: 10.7150/ijbs.32889. eCollection 2019.
Osimertinib and Pterostilbene in EGFR-mutation-positive Non-Small Cell Lung Cancer (NSCLC)
Jillian Wilhelmina Paulina Bracht 1, Niki Karachaliou 1 2, Jordi Berenguer 1, Carlos Pedraz-Valdunciel 3, Martyna Filipska 3, Carles Codony-Servat 1, Jordi Codony-Servat 1, Rafael Rosell 1 3 4
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PMID: 31754333 PMCID: PMC6854375 DOI: 10.7150/ijbs.32889
Free PMC article
Abstract
Monotherapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) still leads to incomplete responses in most EGFR-mutation positive non-small cell lung cancer (NSCLC) patients, often due to acquired resistance through activation of parallel compensatory pathways. We have previously shown that co-targeting EGFR, signal transducer and activator of transcription 3 (STAT3), and Src-yes-associated protein 1 (YAP1) was highly synergistic in vitro and in vivo. In the present study, we treated EGFR-mutation positive cell lines with the combination of osimertinib plus a natural compound, pterostilbene, which has been reported to abrogate Src and STAT3 activation. Methods: Cell viability assays and immunoblotting were performed to reveal the mechanisms of action of pterostilbene, osimertinib and pterostilbene plus osimertinib in five EGFR-mutation positive NSCLC and one triple negative breast cancer (TNBC) cell lines. Results: Osimertinib plus pterostilbene yielded synergistic effects in all EGFR-mutation positive NSCLC cell lines investigated. Surprisingly, pterostilbene alone did not inhibit, nor downregulate Src phosphorylation in the EGFR-mutation positive NSCLC cell lines or the TNBC cell line, MDA-MB-231. However, the double combination of osimertinib plus pterostilbene reversed the osimertinib-induced STAT3, YAP1, and CUB domain-containing protein-1 (CDCP1) phosphorylation and slightly suppressed Src phosphorylation in PC9 and H1975 cells. Conclusion: The results of this study indicate that pterostilbene may be used to abrogate the activated resistance pathways of single osimertinib treatment in EGFR-mutation positive NSCLC. Future studies should focus on in vivo translation and confirmation of these results.

Keywords: NSCLC; Pterostilbene; osimertinib; therapy resistance.

© The author(s).

Conflict of interest statement
Competing Interests: The authors have declared that no competing interest exists.

27 references4 figures
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4
Cancer Biol Ther
. 2019;20(5):617-632. doi: 10.1080/15384047.2018.1539290. Epub 2018 Nov 21.
Dual-target MDM2/MDMX Inhibitor Increases the Sensitization of Doxorubicin and Inhibits Migration and Invasion Abilities of Triple-Negative Breast Cancer Cells Through Activation of TAB1/TAK1/p38 MAPK Pathway
Yangwei Fan 1, Mengya Li 2, Ke Ma 3, Yuan Hu 1, Jiayu Jing 1, Yu Shi 1, Enxiao Li 1, Danfeng Dong 1
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PMID: 30462562 PMCID: PMC6605999 DOI: 10.1080/15384047.2018.1539290
Free PMC article
Abstract
Triple-negative breast cancer (TNBC) has a poor prognosis mainly due to insensitivity or resistance to standard anthracycline- and taxane-based chemotherapy, urgently calling for new adjuvants to reverse drug resistance. Dual-target murine double minute 2 (MDM2) and murine double minute X (MDMX) inhibitor has been proved to play a critical part against cancer, particularly focusing on the tremendous potential to enhance the efficacy of doxorubicin (DOX), however little was reported in TNBC. In the present study, we investigated the synergistic antitumor effect of the MDM2/MDMX inhibitor with DOX using three TNBC cell lines, two in situ transplantation tumor models and 214 clinical samples. We observed that the MDM2/MDMX inhibitor combined with DOX could not only inhibit cell vitality and migration and invasion abilities, but also highly inhibit tumor growth in TNBC nude mice. Besides, co-treatment of MDM2/MDMX inhibitor and DOX suppressed epithelial to mesenchymal transition (EMT) through increasing the TAK1-binding protein 1 (TAB1), transforming growth factor β-activated kinase 1 (TAK1) and p38 mitogen-activated protein kinase (MAPK) expression. Small interfering RNA-mediated TAB1 knockdown induced the EMT, desensitized cells to DOX and enhanced the migration and invasion abilities. High MDM2/MDMX expression was positively associated with weak TAB1 expression in 214 TNBC tumor tissues confirmed by immumohistochemical staining and MDM2/MDMX/TAB1 expression was significantly related to TNBC patient survival. These findings indicate that dual-target MDM2/MDMX inhibitor could increase the sensitization of doxorubicin and inhibit migration and invasion abilities in TNBC cells through p38 MAPK pathway activation caused EMT suppression and hence could be useful in TNBC treatments in future.

Keywords: MDM2; MDMX; TAB1; doxorubicin resistance; invasion; migration; triple-negative breast cancer.

Cited by 3 articles10 figures
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5
Clinical Trial Clin Genitourin Cancer
. 2019 Dec;17(6):451-456. doi: 10.1016/j.clgc.2019.07.003. Epub 2019 Jul 23.
Phase II Study of Carfilzomib in Patients With Refractory Renal Cell Carcinoma
Elshad Hasanov 1, Rebecca S S Tidwell 2, Pablo Fernandez 3, Lauren Park 3, Charla McMichael 3, Nizar M Tannir 3, Eric Jonasch 4
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PMID: 31439537 DOI: 10.1016/j.clgc.2019.07.003
Abstract
Background: A von Hippel Lindau (VHL) mutation or functional inactivation occurs in the a large proportion of patients with clear-cell renal cell carcinoma (ccRCC), which results in the dysregulation of a number of key cellular functions. A high throughput screen and candidate compound assessment revealed that agents with proteasome inhibition properties were able to stabilize point-mutated VHL and restore some of its functions.

Patients and methods: Nine patients with histologically confirmed metastatic ccRCC with disease progression during at least 1 previous systemic therapy were treated with carfilzomib at a dose of 20 mg/m2 over 30 minutes via intravenous (I.V.) infusion on days 1 and 2 and a dose of 56 mg/m2 over 30 minutes via I.V. infusion on days 8, 9, 15, and 16 of each 4-week cycle.

Results: The study was stopped after 9 patients were enrolled because of futility. Of the 9 patients treated in the study, all patients had disease progression within 4 months, with a median time of 1.8 months (95% confidence interval, 0.8-3.6 months). No patient showed a response according to Response Evaluation Criteria In Solid Tumors. Three patients showed a best response of stable disease. The most common side effects were musculoskeletal pain, elevated creatinine level, anemia, hyperkalemia, leukopenia, lymphopenia, and fatigue.

Conclusion: Although the negative safety and efficacy results of this study do not favor the use of carfilzomib for the treatment of ccRCC, previous studies have shown selected patients achieved partial or complete response to this class of agent. Further preclinical investigations to evaluate the molecular characteristics of the patients who respond to proteasome inhibitors will better characterize the underlying mechanism of response, and might allow for the selection of an appropriate patient population in future studies.

Trial registration: ClinicalTrials.gov NCT01775930.

Keywords: Carfilzomib; Clear-cell renal cell carcinoma; Proteasome inhibitors; VHL; ccRCC.

Copyright © 2019 Elsevier Inc. All rights reserved.

Cited by 1 article
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6
Review Curr Hematol Malig Rep
. 2019 Apr;14(2):94-105. doi: 10.1007/s11899-019-00502-2.
Hematopoietic Stem Cell Transplantation in Pediatric Acute Lymphoblastic Leukemia
Pietro Merli 1, Mattia Algeri 1, Francesca Del Bufalo 1, Franco Locatelli 2 3
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PMID: 30806963 DOI: 10.1007/s11899-019-00502-2
Abstract
Purpose of review: The remarkable improvement in the prognosis of children with acute lymphoblastic leukemia (ALL) has been mainly achieved through the administration of risk-adapted therapy, including allogeneic hematopoietic stem cell transplantation (HSCT). This paper reviews the current indications to HSCT in ALL children, as well as the type of donor and conditioning regimens commonly used. Finally, it will focus on future challenges in immunotherapy.

Recent findings: As our comprehension of disease-specific risk factors improves, indications to HSCT continue to evolve. Future studies will answer the year-old question on the best conditioning regimen to be used in this setting, while a recent randomized controlled study fixed the optimal anti-thymocyte globulin dose in unrelated donor HSCT. HSCT, the oldest immunotherapy used in clinical practice, still represents the gold standard consolidation treatment for a number of pediatric patients with high-risk/relapsed ALL. New immunotherapies hold the promise of further improving outcomes in this setting.

Keywords: Acute lymphoblastic leukemia; Children; Hematopoietic stem cell transplantation; Relapsed/refractory ALL.

Cited by 2 articles93 references
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7
Review Nat Rev Dis Primers
. 2019 Sep 23;5(1):66. doi: 10.1038/s41572-019-0111-2.
Breast Cancer
Nadia Harbeck 1, Frédérique Penault-Llorca 2, Javier Cortes 3 4, Michael Gnant 5, Nehmat Houssami 6, Philip Poortmans 7 8, Kathryn Ruddy 9, Janice Tsang 10, Fatima Cardoso 11
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PMID: 31548545 DOI: 10.1038/s41572-019-0111-2
Abstract
Breast cancer is the most frequent malignancy in women worldwide and is curable in ~70-80% of patients with early-stage, non-metastatic disease. Advanced breast cancer with distant organ metastases is considered incurable with currently available therapies. On the molecular level, breast cancer is a heterogeneous disease; molecular features include activation of human epidermal growth factor receptor 2 (HER2, encoded by ERBB2), activation of hormone receptors (oestrogen receptor and progesterone receptor) and/or BRCA mutations. Treatment strategies differ according to molecular subtype. Management of breast cancer is multidisciplinary; it includes locoregional (surgery and radiation therapy) and systemic therapy approaches. Systemic therapies include endocrine therapy for hormone receptor-positive disease, chemotherapy, anti-HER2 therapy for HER2-positive disease, bone stabilizing agents, poly(ADP-ribose) polymerase inhibitors for BRCA mutation carriers and, quite recently, immunotherapy. Future therapeutic concepts in breast cancer aim at individualization of therapy as well as at treatment de-escalation and escalation based on tumour biology and early therapy response. Next to further treatment innovations, equal worldwide access to therapeutic advances remains the global challenge in breast cancer care for the future.

Comment in
Breast cancer is a systemic disease optimally treated by a multidisciplinary team.
Harbeck N.
Nat Rev Dis Primers. 2020 Apr 23;6(1):30. doi: 10.1038/s41572-020-0167-z.
PMID: 32327646 No abstract available.
Cited by 15 articles
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8
Review Nat Rev Dis Primers
. 2019 Sep 19;5(1):64. doi: 10.1038/s41572-019-0113-0.
Chromosome Instability Syndromes
A Malcolm R Taylor 1, Cynthia Rothblum-Oviatt 2, Nathan A Ellis 3, Ian D Hickson 4, Stefan Meyer 5 6, Thomas O Crawford 7, Agata Smogorzewska 8, Barbara Pietrucha 9, Corry Weemaes 10, Grant S Stewart 11
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PMID: 31537806 DOI: 10.1038/s41572-019-0113-0
Abstract
Fanconi anaemia (FA), ataxia telangiectasia (A-T), Nijmegen breakage syndrome (NBS) and Bloom syndrome (BS) are clinically distinct, chromosome instability (or breakage) disorders. Each disorder has its own pattern of chromosomal damage, with cells from these patients being hypersensitive to particular genotoxic drugs, indicating that the underlying defect in each case is likely to be different. In addition, each syndrome shows a predisposition to cancer. Study of the molecular and genetic basis of these disorders has revealed mechanisms of recognition and repair of DNA double-strand breaks, DNA interstrand crosslinks and DNA damage during DNA replication. Specialist clinics for each disorder have provided the concentration of expertise needed to tackle their characteristic clinical problems and improve outcomes. Although some treatments of the consequences of a disorder may be possible, for example, haematopoietic stem cell transplantation in FA and NBS, future early intervention to prevent complications of disease will depend on a greater understanding of the roles of the affected DNA repair pathways in development. An important realization has been the predisposition to cancer in carriers of some of these gene mutations.

Cited by 1 article
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9
Review Clin Lymphoma Myeloma Leuk
. 2019 May;19(5):255-263. doi: 10.1016/j.clml.2019.03.025. Epub 2019 Apr 1.
Multiple Myeloma: Current Advances and Future Directions
Thomas Martin 1, Carol Ann Huff 2
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PMID: 31130488 DOI: 10.1016/j.clml.2019.03.025
Abstract
There have been many advances over the past decade that have dramatically changed the way we evaluate and treat patients with multiple myeloma (MM). These advances have more than doubled the average survival for patients with MM and have been crucial to an improved quality of life. We highlight recent changes to response assessment definitions, provide a review of minimal residual disease (MRD) testing, and describe how MRD testing may drive future goals of therapy. The evolving data from trials assessing novel combinations for frontline therapy and for the treatment of relapsed disease are reviewed. We present preliminary data from the 2 most promising novel agents, both of which may soon be approved by the US Food and Drug Administration for patients with relapsed MM. Finally, we examine the exciting early data from phase 1 clinical trials investigating novel immunotherapeutics in refractory myeloma, including antibody-drug conjugates, dual-targeted T-cell-engaging antibodies, and chimeric antigen receptor T cells.

Keywords: Chimeric antigen receptor T cells; Immunotherapy; Minimal residual disease; Selinexor; T-cell engaging antibodies; Ventoclax.

Copyright © 2019 Elsevier Inc. All rights reserved.

Cited by 1 article
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10
Review Dtsch Arztebl Int
. 2019 Oct 4;116(40):670-676. doi: 10.3238/arztebl.2019.0670.
The Role of Microbiota in Preventing Multidrug-Resistant Bacterial Infections
Yascha Khodamoradi 1, Johanna Kessel, Jörg Janne Vehreschild, Maria J G T Vehreschild
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PMID: 31658936 PMCID: PMC6859878 DOI: 10.3238/arztebl.2019.0670
Free PMC article
Abstract
Background: The introduction of industrially produced antibiotics was a milestone in the history of medicine. Now, almost a century later, the adverse consequences of these highly effective drugs have become evident in the form of antibiotic-resistant infections, which are on the rise around the world. The search for solutions to this problem has involved both the introduction of newer types of antibiotics and, increasingly, the development of alternative strategies to prevent infections due to multidrug-resistant bacteria. In this article, we review the pathophysiological connection between the use of antibiotics and the occurrence of such infections. We also discuss some alternative strategies that are currently under development.

Methods: This review is based on pertinent articles that appeared from January 2000 to April 2019 and were retrieved by a selective search in the PubMed database employing the search term "(microbiota OR microbiome) AND infection." Further suggestions by our author team regarding relevant literature were considered as well.

Results: The spectrum of preventive strategies encompasses measures for the protection of the intestinal microbiota (antimicrobial stewardship, neutralization of antibiotic residues in the bowel, use of phages and species-specific antibiotics) as well as measures for its reconstitution (prebiotics, probiotics, and fecal microbiota transfer).

Conclusion: In view of the major problem that multidrug-resistant bacteria pose for the world's population and the resources now being spent on the search for a solution, derived both from public funding and from the pharmaceutical industry, we hope to see new, clinically useful approaches being developed and implemented in the near future.

2 figures
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11
Review Prostate Cancer Prostatic Dis
. 2019 Dec;22(4):522-530. doi: 10.1038/s41391-019-0151-4. Epub 2019 Apr 29.
Measuring the Unmeasurable: Automated Bone Scan Index as a Quantitative Endpoint in Prostate Cancer Clinical Trials
Jose Mauricio Mota 1, Andrew J Armstrong 2 3, Steven M Larson 4 5, Josef J Fox 5 6, Michael J Morris 7 8
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PMID: 31036925 DOI: 10.1038/s41391-019-0151-4
Abstract
Background: Up to 90% of men with metastatic castration-resistant prostate cancer (mCRPC) will have a distribution of disease that includes bone metastases demonstrated on a Technetium-99m (99mTc-MDP) bone scan. The Prostate Cancer Working Group 2 and 3 Consensus Criteria standardized the criteria for assessing progression based on the development of new lesions. These criteria have been recognized by regulatory authorities for drug approval. The bone scan index (BSI) is a method to quantitatively measure the burden of bony disease, and can assess both disease progression and regression. The automated BSI (aBSI) is a method of computer analysis to assess BSI, and is being qualified as a clinical trials endpoint.

Methods: Manual searching was used to identify the literature on BSI and aBSI. We summarize the most relevant aspects of the retrospective and prospective studies evaluating aBSI measurements, and provide a critical discussion on the potential advantages and caveats of aBSI.

Results: The development of neural artificial networks (EXINI boneBSI) to automatically determine the BSI reduces the turnaround time for assessing BSI with high reproducibility and accuracy. Several studies showed that the concordance between aBSI and BSI, as well as the interobserver concordance of aBSI, was >0.95. In a phase 3 assessment of aBSI, a doubling value increased the risk of death in 20%, pre-treatment aBSI values independently correlated with overall survival (OS) and time to symptomatic progression. Retrospective studies suggest that a decrease in aBSI after treatment may correlate with higher survival when compared with increasing aBSI.

Conclusions: aBSI provides a quantitative measurement that is feasible, reproducible, and in analyses to date correlates with OS and symptomatic progression. These findings support the aBSI to risk-stratify men with mCRPC for clinical trial enrollment. Future studies quantifying aBSI change over time as an intermediate endpoint for evaluating new systemic therapies are needed.

Cited by 2 articles
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12
Review Med Res Rev
. 2019 Sep;39(5):1923-1952. doi: 10.1002/med.21567. Epub 2019 Feb 12.
Dimethyl Fumarate, a Two-Edged Drug: Current Status and Future Directions
Nathaniel Edward Bennett Saidu 1 2, Niloufar Kavian 1 3 4, Karen Leroy 1 5, Claus Jacob 6, Carole Nicco 1, Frédéric Batteux 1 3, Jérôme Alexandre 1 7
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PMID: 30756407 DOI: 10.1002/med.21567
Abstract
Dimethyl fumarate (DMF) is a fumaric acid ester registered for the treatment of relapsing-remitting multiple sclerosis (RRMS). It induces protein succination leading to inactivation of cysteine-rich proteins. It was first shown to possess cytoprotective and antioxidant effects in noncancer models, which appeared related to the induction of the nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) pathway. DMF also displays antitumor activity in several cellular and mice models. Recently, we showed that the anticancer mechanism of DMF is dose-dependent and is paradoxically related to the decrease in the nuclear translocation of NRF2. Some other studies performed indicate also the potential role of DMF in cancers, which are dependent on the NRF2 antioxidant and cellular detoxification program, such as KRAS-mutated lung adenocarcinoma. It, however, seems that DMF has multiple biological effects as it has been shown to also inhibit the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), thus blocking downstream targets that may be involved in the development and progression of inflammatory cascades leading to various disease processes, including tumors, lymphomas, diabetic retinopathy, arthritis, and psoriasis. Herein, we present the current status and future directions of the use of DMF in various diseases models with particular emphases on its targeting of specific intracellular signal transduction cascades in cancer; to shed some light on its possible mode of action.

Keywords: DJ-1; cancer; dimethyl fumarate; immunomodulation; nuclear factor erythroid 2 (NF-E2)-related factor 2; oxidative stress; succinic-GSH.

© 2019 Wiley Periodicals, Inc.

Cited by 7 articles
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13
Clinical Trial Lancet Oncol
. 2019 Nov;20(11):1566-1575. doi: 10.1016/S1470-2045(19)30617-5. Epub 2019 Sep 24.
Vinorelbine and Continuous Low-Dose Cyclophosphamide as Maintenance Chemotherapy in Patients With High-Risk Rhabdomyosarcoma (RMS 2005): A Multicentre, Open-Label, Randomised, Phase 3 Trial
Gianni Bisogno 1, Gian Luca De Salvo 2, Christophe Bergeron 3, Soledad Gallego Melcón 4, Johannes H Merks 5, Anna Kelsey 6, Helene Martelli 7, Veronique Minard-Colin 8, Daniel Orbach 9, Heidi Glosli 10, Julia Chisholm 11, Michela Casanova 12, Ilaria Zanetti 13, Christine Devalck 14, Myriam Ben-Arush 15, Peter Mudry 16, Sima Ferman 17, Meriel Jenney 18, Andrea Ferrari 12, European paediatric Soft tissue sarcoma Study Group
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PMID: 31562043 DOI: 10.1016/S1470-2045(19)30617-5
Abstract
Background: For more than three decades, standard treatment for rhabdomyosarcoma in Europe has included 6 months of chemotherapy. The European paediatric Soft tissue sarcoma Study Group (EpSSG) aimed to investigate whether prolonging treatment with maintenance chemotherapy would improve survival in patients with high-risk rhabdomyosarcoma.

Methods: RMS 2005 was a multicentre, open-label, randomised, controlled, phase 3 trial done at 102 hospitals in 14 countries. We included patients aged 6 months to 21 years with rhabdomyosarcoma who were considered to be at high risk of relapse: those with non-metastatic incompletely resected embryonal rhabdomyosarcoma occurring at unfavourable sites with unfavourable age (≥10 years) or tumour size (>5 cm), or both; those with any non-metastatic rhabdomyosarcoma with nodal involvement; and those with non-metastatic alveolar rhabdomyosarcoma but without nodal involvement. Patients in remission after standard treatment (nine cycles of ifosfamide, vincristine, dactinomycin with or without doxorubicin, and surgery or radiotherapy, or both) were randomly assigned (1:1) to stop treatment or continue maintenance chemotherapy (six cycles of intravenous vinorelbine 25 mg/m2 on days 1, 8, and 15, and daily oral cyclophosphamide 25 mg/m2, on days 1-28). Randomisation was done by use of a web-based system and was stratified (block size of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary outcome was disease-free survival in the intention-to-treat population. Secondary outcomes were overall survival and toxicity. This trial is registered with EudraCT, number 2005-000217-35, and ClinicalTrials.gov, number NCT00339118, and follow-up is ongoing.

Findings: Between April 20, 2006, and Dec 21, 2016, 371 patients were enrolled and randomly assigned to the two groups: 186 to stop treatment and 185 to receive maintenance chemotherapy. Median follow-up was 60·3 months (IQR 32·4-89·4). In the intention-to-treat population, 5-year disease-free survival was 77·6% (95% CI 70·6-83·2) with maintenance chemotherapy versus 69·8% (62·2-76·2) without maintenance chemotherapy (hazard ratio [HR] 0·68 [95% CI 0·45-1·02]; p=0·061), and 5-year overall survival was 86·5% (95% CI 80·2-90·9) with maintenance chemotherapy versus 73·7% (65·8-80·1) without (HR 0·52 [95% CI 0·32-0·86]; p=0·0097). Toxicity was manageable in patients who received maintenance chemotherapy: 136 (75%) of 181 patients had grade 3-4 leucopenia, 148 (82%) had grade 3-4 neutropenia, 19 (10%) had anaemia, two (1%) had thrombocytopenia, and 56 (31%) had an infection. One (1%) patient had a grade 4 non-haematological toxicity (neurotoxicity). Two treatment-related serious adverse events occurred: one case of inappropriate antidiuretic hormone secretion and one of a severe steppage gait with limb pain, both of which resolved.

Interpretation: Adding maintenance chemotherapy seems to improve survival for patients with high-risk rhabdomyosarcoma. This approach will be the new standard of care for patients with high-risk rhabdomyosarcoma in future EpSSG trials.

Funding: Fondazione Città della Speranza, Association Léon Berard Enfant Cancéreux, Clinical Research Hospital Program (French Ministry of Health), and Cancer Research UK.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Comment in
Maintenance chemotherapy in rhabdomyosarcoma: the new standard of care.
Meyer WH.
Lancet Oncol. 2019 Nov;20(11):1476-1477. doi: 10.1016/S1470-2045(19)30618-7. Epub 2019 Sep 24.
PMID: 31562042 No abstract available.
Metronomic Maintenance Therapy for Rhabdomyosarcoma.
André N, Corradini N, Shaked Y.
Trends Cancer. 2019 Dec;5(12):756-759. doi: 10.1016/j.trecan.2019.10.004. Epub 2019 Nov 4.
PMID: 31813450
A new standard of care for patients with high-risk rhabdomyosarcoma?
Koscielniak E, Klingebiel T.
Lancet Oncol. 2020 Jan;21(1):e1. doi: 10.1016/S1470-2045(19)30731-4.
PMID: 31908295 No abstract available.
A new standard of care for patients with high-risk rhabdomyosarcoma?
Italiano A.
Lancet Oncol. 2020 Jan;21(1):e2. doi: 10.1016/S1470-2045(19)30784-3.
PMID: 31908302 No abstract available.
A new standard of care for patients with high-risk rhabdomyosarcoma? - Authors' reply.
Bisogno G, Ferrari A, Melcon SG, De Salvo GL, Bergeron C, Jenney M.
Lancet Oncol. 2020 Jan;21(1):e3. doi: 10.1016/S1470-2045(19)30812-5.
PMID: 31908304 No abstract available.
Cited by 5 articles
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14
BMJ Open
. 2019 Jul 18;9(7):e027182. doi: 10.1136/bmjopen-2018-027182.
Is It Possible to Automatically Assess Pretreatment Digital Rectal Examination Documentation Using Natural Language Processing? A Single-Centre Retrospective Study
Selen Bozkurt 1 2, Kathleen M Kan 3, Michelle K Ferrari 4, Daniel L Rubin 1 5, Douglas W Blayney 6, Tina Hernandez-Boussard 1 2 7, James D Brooks 4
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PMID: 31324681 PMCID: PMC6661600 DOI: 10.1136/bmjopen-2018-027182
Free PMC article
Abstract
Objectives: To develop and test a method for automatic assessment of a quality metric, provider-documented pretreatment digital rectal examination (DRE), using the outputs of a natural language processing (NLP) framework.

Setting: An electronic health records (EHR)-based prostate cancer data warehouse was used to identify patients and associated clinical notes from 1 January 2005 to 31 December 2017. Using a previously developed natural language processing pipeline, we classified DRE assessment as documented (currently or historically performed), deferred (or suggested as a future examination) and refused.

Primary and secondary outcome measures: We investigated the quality metric performance, documentation 6 months before treatment and identified patient and clinical factors associated with metric performance.

Results: The cohort included 7215 patients with prostate cancer and 426 227 unique clinical notes associated with pretreatment encounters. DREs of 5958 (82.6%) patients were documented and 1257 (17.4%) of patients did not have a DRE documented in the EHR. A total of 3742 (51.9%) patient DREs were documented within 6 months prior to treatment, meeting the quality metric. Patients with private insurance had a higher rate of DRE 6 months prior to starting treatment as compared with Medicaid-based or Medicare-based payors (77.3%vs69.5%, p=0.001). Patients undergoing chemotherapy, radiation therapy or surgery as the first line of treatment were more likely to have a documented DRE 6 months prior to treatment.

Conclusion: EHRs contain valuable unstructured information and with NLP, it is feasible to accurately and efficiently identify quality metrics with current documentation clinician workflow.

Keywords: digital rectal examination; electronic health records; natural language processing; prostate cancer; quality metrics.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Conflict of interest statement
Competing interests: None declared.

Cited by 1 article34 references2 figures
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15
Comparative Study Lancet Oncol
. 2019 Nov;20(11):1493-1505. doi: 10.1016/S1470-2045(19)30456-5. Epub 2019 Sep 11.
Progress in Cancer Survival, Mortality, and Incidence in Seven High-Income Countries 1995-2014 (ICBP SURVMARK-2): A Population-Based Study
Melina Arnold 1, Mark J Rutherford 2, Aude Bardot 3, Jacques Ferlay 3, Therese M-L Andersson 4, Tor Åge Myklebust 5, Hanna Tervonen 6, Vicky Thursfield 7, David Ransom 8, Lorraine Shack 9, Ryan R Woods 10, Donna Turner 11, Suzanne Leonfellner 12, Susan Ryan 13, Nathalie Saint-Jacques 14, Prithwish De 15, Carol McClure 16, Agnihotram V Ramanakumar 17, Heather Stuart-Panko 18, Gerda Engholm 19, Paul M Walsh 20, Christopher Jackson 21, Sally Vernon 22, Eileen Morgan 23, Anna Gavin 23, David S Morrison 24, Dyfed W Huws 25, Geoff Porter 26, John Butler 27, Heather Bryant 26, David C Currow 6, Sara Hiom 28, D Max Parkin 29, Peter Sasieni 30, Paul C Lambert 31, Bjørn Møller 32, Isabelle Soerjomataram 3, Freddie Bray 3
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PMID: 31521509 PMCID: PMC6838671 DOI: 10.1016/S1470-2045(19)30456-5
Free PMC article
Abstract
Background: Population-based cancer survival estimates provide valuable insights into the effectiveness of cancer services and can reflect the prospects of cure. As part of the second phase of the International Cancer Benchmarking Partnership (ICBP), the Cancer Survival in High-Income Countries (SURVMARK-2) project aims to provide a comprehensive overview of cancer survival across seven high-income countries and a comparative assessment of corresponding incidence and mortality trends.

Methods: In this longitudinal, population-based study, we collected patient-level data on 3·9 million patients with cancer from population-based cancer registries in 21 jurisdictions in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the UK) for seven sites of cancer (oesophagus, stomach, colon, rectum, pancreas, lung, and ovary) diagnosed between 1995 and 2014, and followed up until Dec 31, 2015. We calculated age-standardised net survival at 1 year and 5 years after diagnosis by site, age group, and period of diagnosis. We mapped changes in incidence and mortality to changes in survival to assess progress in cancer control.

Findings: In 19 eligible jurisdictions, 3 764 543 cases of cancer were eligible for inclusion in the study. In the 19 included jurisdictions, over 1995-2014, 1-year and 5-year net survival increased in each country across almost all cancer types, with, for example, 5-year rectal cancer survival increasing more than 13 percentage points in Denmark, Ireland, and the UK. For 2010-14, survival was generally higher in Australia, Canada, and Norway than in New Zealand, Denmark, Ireland, and the UK. Over the study period, larger survival improvements were observed for patients younger than 75 years at diagnosis than those aged 75 years and older, and notably for cancers with a poor prognosis (ie, oesophagus, stomach, pancreas, and lung). Progress in cancer control (ie, increased survival, decreased mortality and incidence) over the study period was evident for stomach, colon, lung (in males), and ovarian cancer.

Interpretation: The joint evaluation of trends in incidence, mortality, and survival indicated progress in four of the seven studied cancers. Cancer survival continues to increase across high-income countries; however, international disparities persist. While truly valid comparisons require differences in registration practice, classification, and coding to be minimal, stage of disease at diagnosis, timely access to effective treatment, and the extent of comorbidity are likely the main determinants of patient outcomes. Future studies are needed to assess the impact of these factors to further our understanding of international disparities in cancer survival.

Funding: Canadian Partnership Against Cancer; Cancer Council Victoria; Cancer Institute New South Wales; Cancer Research UK; Danish Cancer Society; National Cancer Registry Ireland; The Cancer Society of New Zealand; National Health Service England; Norwegian Cancer Society; Public Health Agency Northern Ireland, on behalf of the Northern Ireland Cancer Registry; The Scottish Government; Western Australia Department of Health; and Wales Cancer Network.

© This is an Open Access article published under the CC BY-NC-ND 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.

Comment in
UK's poor performance on cancer survival.
Thorlby R, Fisher R.
BMJ. 2019 Oct 28;367:l6122. doi: 10.1136/bmj.l6122.
PMID: 31658950 No abstract available.
Are health-care policies restricting further progress in cancer survival outcomes?
Patel R, Liu WK, Patel HR, Pickering L, Afshar M.
Lancet Oncol. 2019 Dec;20(12):e657. doi: 10.1016/S1470-2045(19)30749-1.
PMID: 31797783 No abstract available.
Cited by 14 articles2 figures
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16
Review Br J Haematol
. 2020 Jan;188(1):49-62. doi: 10.1111/bjh.16356.
AML Through the Prism of Molecular Genetics
Sarah Charrot 1, Hannah Armes 1, Ana Rio-Machin 1, Jude Fitzgibbon 1
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PMID: 31863468 DOI: 10.1111/bjh.16356
Abstract
Modern management of acute myeloid leukaemia (AML) relies on the integration of phenotypic and genetic data to assign classification, establish prognosis, enhance monitoring and guide treatment. The prism through which we can now disperse a patient's leukaemia, interpret and apply our understanding has fundamentally changed since the completion of the first whole-genome sequencing (WGS) of an AML patient in 2008 and where possible, many clinicians would now prefer to delay treatment decisions until the karyotype and genetic status of a new patient is known. The success of global sequencing initiatives such as The Cancer Genome Atlas (TCGA) have brought us significantly closer to cataloguing the full spectrum of coding mutations involved in human malignancy. Indeed, genetic capability has raced ahead of our capacity to apply much of this knowledge into clinical practice and we are in the peculiar position of having routine access to genetic information on an individual patient's leukaemia that cannot be reliably interpreted or utilised. This is a measure of how rapid the progress has been, and this rate of change is likely to continue into the foreseeable future as research intensifies on the non-coding genome and the epigenome, as we scrutinise disease at a single cell level, and as initiatives like Beat AML and the Harmony Alliance progress. In this review, we will examine how interrogation of the coding genome is revolutionising our understanding of AML and improving our ability to underscore differences between paediatric and adult onset, sporadic and inherited forms of disease. We will look at how this knowledge is informing improvements in outcome prediction and the development of novel treatments, bringing us a step closer to personalised therapy for myeloid malignancy.

Keywords: acute myeloid leukaemia; germline predisposition; molecular genetics; next generation sequencing.

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

94 references
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17
Orphanet J Rare Dis
. 2019 Oct 28;14(1):235. doi: 10.1186/s13023-019-1206-2.
Growth Characteristics and Therapeutic Decision Markers in Von Hippel-Lindau Disease Patients With Renal Cell Carcinoma
Patrick Schuhmacher 1, Emily Kim 2 3, Felix Hahn 4, Peggy Sekula 5, Cordula Annette Jilg 6, Christian Leiber 6, Hartmut P Neumann 1, Wolfgang Schultze-Seemann 6, Gerd Walz 1, Stefan Zschiedrich 7
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PMID: 31661010 PMCID: PMC6819544 DOI: 10.1186/s13023-019-1206-2
Free PMC article
Abstract
Background: Von Hippel-Lindau (VHL) disease is a multi-systemic hereditary disease associated with several benign and malignant tumor entities, including clear cell renal cell carcinoma (ccRCC). Since ccRCCs grow slowly, nephron sparing surgery is typically performed at a tumor diameter of 3-4 cm before the tumor metastasizes. However, in the case of recurrent disease, repeated surgical intervention can impair renal function. Therefore, it is crucial to optimize the timing for surgical interventions through a better understanding of the growth kinetics of ccRCCs in VHL. We investigated tumor growth kinetics and modern volumetric assessment to guide future therapeutic decisions.

Results: The prevalence of ccRCC was 28% in a cohort of 510 VHL patients. Of 144 patients with ccRCC, 41 were followed with serial imaging which identified 102 renal tumors, which exhibited heterogeneous growth kinetics. ccRCCs grew at an average absolute growth rate of 0.287 cm/year, an average relative growth rate [(lnV1-lnV0)/(t1-t0)] of 0.42% and an average volume doubling time of 27.15 months. Women had a faster relative growth rate than men. Age and specific mutations did not influence tumor growth. Because of the tumor heterogeneity, we developed an additional cut-off volume of 40 cm3 for surgical intervention.

Conclusions: Tumor heterogeneity and differences in growth kinetics is suggestive of a state of transient tumor dormancy in ccRCCs of VHL patients. The relative growth rate has not been previously described in other studies. Volumetric assessment as an additional parameter for surgical intervention could be a useful clinical tool and needs further investigation.

Keywords: Clear cell renal cell carcinoma; Growth characteristics; Therapeutic decision markers; VHL; Von Hippel-Lindau disease; ccRCC.

Conflict of interest statement
The authors declare that they have no competing interests.

21 references6 figures
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18
Review J Cancer
. 2020 May 20;11(16):4671-4682. doi: 10.7150/jca.46329. eCollection 2020.
Recent Progress for the Techniques of MRI-Guided Breast Interventions and Their Applications on Surgical Strategy
Peng Gao 1, Xiangyi Kong 1, Ying Song 2, Yan Song 3, Yi Fang 1, Han Ouyang 2, Jing Wang 1
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PMID: 32626513 PMCID: PMC7330700 DOI: 10.7150/jca.46329
Free PMC article
Abstract
With a high sensitivity of breast lesions, MRI can detect suspicious lesions which are occult in traditional breast examination equipment. However, the lower and variable specificity of MRI makes the MRI-guided intervention, including biopsies and localizations, necessary before surgery, especially for patients who need the treatment of breast-conserving surgery (BCS). MRI techniques and patient preparation should be first carefully considered before the intervention to avoid lengthening the procedure time and compromising targeting accuracy. Doctors and radiologists need to reconfirm the target of the lesion and be very familiar with the process approach and equipment techniques involving the computer-aided diagnosis (CAD) tools and the biopsy system and follow a correct way. The basic steps of MRI-guided biopsy and localization are nearly the same regardless of the vendor or platform, and this article systematically introduces detailed methods and techniques of MRI-guided intervention. The two interventions both face different challenging situations during procedures with solutions given in the article. Post-operative statistics show that the complications of MRI-guided intervention are infrequent and mild, and MRI-guided biopsy provides the pathological information for the subsequent surgical decisions and MRI-guided localization fully prepared for follow-up surgical biopsy. New techniques for MRI-guided intervention are also elaborated in the article, which leads to future development. In a word, MRI-guided intervention is a safe, accurate, and effective technique with a low complication rate and successful MRI-guided intervention is truly teamwork with efforts from patients to surgeons, radiologists, MRI technologists, and nurses.

Keywords: Breast biopsy; Breast cancer; Breast surgery; MRI-guided; Preoperative needle localization.

© The author(s).

Conflict of interest statement
Competing Interests: The authors have declared that no competing interest exists.

101 references6 figures
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19
Cell Biochem Funct
. 2020 Jul 6. doi: 10.1002/cbf.3568. Online ahead of print.
MicroRNA-92b Acts as an Oncogene by Targeting PTEN/AKT in NSCLC
Jia-Hui Guo 1, Hai-Yun Fang 1, Jun-Mei Yang 2, Shan-Ling Liu 1, Qiang-Hua Yao 3, Yi-Juan Fan 4, Mei Zhao 5, Feng Liu 1, Quan-Wu Zhang 6, Feng-Hou Gao 1
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PMID: 32627866 DOI: 10.1002/cbf.3568
Abstract
MicroRNAs can act as tumour suppressors or oncogenes by regulating cellular differentiation, proliferation and apoptosis, and the dysregulation of miRNA is involved in the occurrence and development of NSCLC. Here, we provided evidence that miR-92b as an oncogene in NSCLC by targeting PTEN/AKT. We found that miR-92b was up-regulated in human NSCLC tissues and cell lines. MiR-92b knockdown suppressed the NSCLC cells proliferation and migration in both in vivo and in vitro models. Conversely, miR-92b overexpression induced an aggressive phenotype. Moreover, miR-92b-mediated regulation of NSCLC cell proliferation and migration depended on binding to PTEN mRNA, which then led to the degradation of PTEN and activation of the downstream AKT signalling pathway. Overall, this study revealed the oncogenic roles of miR-92b in NSCLC by targeting PTEN/AKT, and provided novel insights for future treatments of NSCLC patients. SIGNIFICANCE OF THE STUDY: MiR-92b was up-regulated in human NSCLC tissues and cell lines. Our study demonstrated that miR-92b as an oncogene in NSCLC by targeting PTEN/AKT in both in vivo and in vitro models and provided novel insights for future treatments of NSCLC patients.

Keywords: Akt; NSCLC; Oncogenesis; PTEN; microRNA-92b.

© 2020 John Wiley & Sons Ltd.

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20
Support Care Cancer
. 2020 Jun;28(6):2597-2604. doi: 10.1007/s00520-019-05049-9. Epub 2019 Oct 14.
Objectively Measured Physical Activity During Chemotherapy in Colon Cancer Patients
Hyuna Park 1 2, Minkyu Jung 3, Min Jae Kim 1 2, Jihee Min 1 2, Choong-Kun Lee 3, Sang Joon Shin 3, Seung-Hoon Beom 3, Joong Bae Ahn 4, Justin Y Jeon 5 6 7
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PMID: 31612283 DOI: 10.1007/s00520-019-05049-9
Abstract
Purpose: Although adjuvant chemotherapy can have an impact on physical activity (PA), PA level has not been studied in patients with stage II-III colon cancer. This study investigated PA levels during and between chemotherapy cycles.

Methods: We objectively measured PA levels for 2 weeks during the 2nd and 11th chemotherapy cycles. In addition, self-reported PA levels were assessed before chemotherapy initiation, during 2nd, 6th, and 12th chemotherapy cycles. This study included 22 men and 33 women with stage II-III colon cancer patients (57 ± 9 years).

Results: Before the initiation of chemotherapy, most cancer patients were minimally active. Compared with the 1st week of chemotherapy, moderate- and light-intensity PA levels significantly increased during the 2nd week of chemotherapy. Patients increased moderate- and light-intensity PA from 217.4 to 290.3 min per week and from 585.7 to 657.8 min per week, respectively (p < 0.01). PA levels did not show any difference between the 2nd and 12th cycles when objectively measured, or between baseline and 2nd, 6th, and 12th cycles when self-reported.

Conclusion: PA levels during chemotherapy cycles are initially low, and then increase towards the end of the cycle; however, PA levels do not change between chemotherapy cycles. Future work with broader and larger samples size is recommended.

Keywords: Chemotherapy; Colonic neoplasms; Exercise.

19 references
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21
Clinical Trial J Gynecol Oncol
. 2019 Nov;30(6):e112. doi: 10.3802/jgo.2019.30.e112.
A Phase II Study of Neoadjuvant Chemotherapy Plus Durvalumab and Tremelimumab in Advanced-Stage Ovarian Cancer: A Korean Gynecologic Oncology Group Study (KGOG 3046), TRU-D
Jung Yun Lee 1, Jae Weon Kim 2, Myong Cheol Lim 3, Sunghoon Kim 1, Hee Seung Kim 2, Chel Hun Choi 4, Ju Yeon Yi 5, Sang Yoon Park 3, Byoung Gie Kim 6, KGOG investigators
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PMID: 31576697 PMCID: PMC6779618 DOI: 10.3802/jgo.2019.30.e112
Free PMC article
Abstract
Background: A single-arm phase II study of neoadjuvant chemotherapy plus durvalumab and tremelimumab in the treatment of advanced-stage ovarian cancer has begun in Korea. We hypothesized that adding durvalumab (anti-programmed death-ligand 1 antibody) and tremelimumab (anti-cytotoxic T-lymphocyte-associated protein 4 antibody) to chemotherapy in treating this cancer can increase progression-free survival (PFS) with minimal effects on safety.

Methods: During treatment, serial biopsies will be performed on pre-treatment, at interval debulking surgery and progression to identify immune biomarkers and changes in the tumor microenvironment. Patients with histologically confirmed stage IIIC/IV epithelial ovarian cancer are offered durvalumab, tremelimumab plus chemotherapy for neoadjuvant chemotherapy and durvalumab plus chemotherapy for adjuvant chemotherapy. Twenty-four patients will be included from four Korean institutions within 1 year. The primary endpoint is a 12-month PFS rate.

Trial registration: ClinicalTrials.gov Identifier: NCT03899610.

Keywords: Chemotherapy; Durvalumab; Epithelial Ovarian Cancer; Immunotherapy; Tremelimumab.

Copyright © 2019. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.

Conflict of interest statement
Jung-Yun Lee received honoraria for speaker's bureaus from AstraZeneca, Janssen, Roche and research fund from AstraZeneca, Clovis Oncology, Janssen, MSD, Roche for clinical trials or contracted research. Jae-Weon Kim has served on local advisory boards for AstraZeneca, Takeda, Pfizer, Janssen. Received honoraria for speaker's bureaus from AstraZeneca, Takeda, Pfizer, Janssen, Roche. Myoung Chel Lim disclose COI with following companies on the one of the advisory board member, honoraria, research funding or travel for the meeting (AstraZeneca, Cellid, Clovis, MSD, Pfizer, Roche, Takeda & Tessa).

Cited by 2 articles10 references1 figure
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22
Head Neck
. 2020 Jul 6. doi: 10.1002/hed.26363. Online ahead of print.
Minimally Important Differences for Interpreting European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Scores in Patients With Head and Neck Cancer
Jammbe Z Musoro 1, Corneel Coens 1, Susanne Singer 2 3, Silke Tribius 4, Sjoukje F Oosting 5, Mogens Groenvold 6, Christian Simon 7, Jean-Pascal Machiels 8, Vincent Grégoire 9, Galina Velikova 10, Kim Cocks 11 12, Mirjam A G Sprangers 13, Madeleine T King 14, Andrew Bottomley 1, EORTC Head and Neck and Quality of Life Groups
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PMID: 32627261 DOI: 10.1002/hed.26363
Abstract
Background: We aimed to estimate minimally important difference (MID) for interpreting group-level change over time for European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (EORTC QLQ-C30) scores in head and neck cancer.

Methods: Data were derived retrospectively from two published EORTC trials. Clinical anchors were selected using correlation strength and clinical plausibility of the given anchor/QLQ-C30 scale pair. MIDs for within-group and between-group change were estimated via the mean change method and linear regression, respectively. Distribution-based MIDs were also examined. MIDs for two of the scales, dyspnea and nausea/vomiting, are more uncertain considering their low correlations with the anchors.

Results: Anchor-based MIDs could be determined for deterioration in 7 of the 14 QLQ-C30 scales assessed, and in 3 scales for improvement. MIDs varied by scale, direction of change, and anchor. Absolute MID values ranged from 5 to 15 points for within-group change and 4 to 12 for between-group change. Most MIDs were within 4 to 10 points.

Conclusions: Our findings, if confirmed, will aid interpreting changes in selected QLQ-C30 scale scores over time and inform sample size calculations in future clinical trials in head and neck cancer.

Keywords: EORTC QLQ-C30; head and neck cancer; health-related quality of life; minimally important difference.

© 2020 Wiley Periodicals LLC.

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23
Updates Surg
. 2020 Jun;72(2):269-280. doi: 10.1007/s13304-020-00811-9. Epub 2020 Jun 16.
The Impact of COVID-19 Pandemic on Surgical Residency Programmes in Italy: A Nationwide Analysis on Behalf of the Italian Polyspecialistic Young Surgeons Society (SPIGC)
Davide Pertile 1, Gaetano Gallo 2, Fabio Barra 3, Alessandro Pasculli 4, Paola Batistotti 1, Marco Sparavigna 1, Giuseppe Vizzielli 5, Domenico Soriero 1, Giusi Graziano 6, Salomone Di Saverio 7, Roberto Luca Meniconi 8, Eleonora Guaitoli 9, Andrea Mazzarri 10, SPIGC Working Group
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PMID: 32557207 PMCID: PMC7298929 DOI: 10.1007/s13304-020-00811-9
Free PMC article
Abstract
Introduction: Recently, Italy has been heavily hit by COVID-19 pandemic and today it is still one of the most affected countries in the world. The subsequent necessary lockdown decreed by the Italian Government had an outstanding impact on the daily life of the entire population, including that of Italian surgical residents' activity. Our survey aims to evaluate the impact of COVID-19 on the training programme of Italian surgical residents.

Materials and methods: We designed a 12-item-electronic anonymous questionnaire on SurveyMonkey© web application. The survey was composed of different sections concerning demographic characteristics and impacts of COVID-19 on the concrete participation in clinical, surgical and research activities. Future perspectives of responders after the pandemic were also investigated.

Results: Eighty hundred responses were collected, and 756 questionnaires were considered eligible to be included in the study analysis. Almost 35 and 27% of respondents experienced, respectively, complete interruption of surgical and clinical activities. A subgroup analysis, comparing the COVID-19 impact on clinical activities with demographics data, showed a statistically significant difference related to specialties (p = 0.0062) and Italian regions (p < 0.0001). Moreover, 112 residents have been moved to non-surgical units dealing with COVID-19 or, in some case, they voluntarily decided to interrupt their residency programme to support the ongoing emergency.

Conclusion: Our survey demonstrated that COVID-19 pandemic has severely impacted the educational programme of Italian surgical residents. Despite many regional differences, this survey highlighted the overall shortage of planning in the re-allocation of resources facing this unexpected health emergency.

Keywords: COVID-19; Clinical activity; Italian surgical residents; Research activity; Surgical activity; Survey.

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

22 references6 figures
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24
Clin Lung Cancer
. 2020 May 23;S1525-7304(20)30153-4. doi: 10.1016/j.cllc.2020.05.013. Online ahead of print.
Consolidative Radiotherapy in Oligometastatic Lung Cancer: Patient Selection With a Prediction Nomogram
Cole Friedes 1, Nicholas Mai 2, Sarah Hazell 1, Wei Fu 3, Peijin Han 1, Michael Bowers 1, Benjamin Levy 4, Patrick M Forde 4, Ranh Voong 1, Russell K Hales 5
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PMID: 32624411 DOI: 10.1016/j.cllc.2020.05.013
Abstract
Background: Patients with stage IV oligometastatic (≤ 3 sites) non-small-cell lung cancer have a progression-free survival (PFS) and overall survival benefit when all sites of metastatic disease and the primary tumor are treated radically with consolidative radiotherapy (cRT). However, the optimal selection of patients most likely from cRT is yet to be defined.

Patients and methods: Patients with metastatic non-small-cell lung cancer treated with definitive radiotherapy to all metastatic sites and primary tumor (2008-2019) were retrospectively identified. Univariable Cox proportional-hazards model was used to compare outcomes with demographic and clinical characteristics. A predictive nomogram model for selection of patients most likely to benefit from cRT was constructed.

Results: There were 91 patients identified with a total of 114 metastases treated. Median PFS from the start of cRT was 10.9 months (95% confidence interval [CI], 8.1-16.6), while the median survival time was 37.0 months (95% CI, 31.3-NR). On univariable modeling, patients with squamous histology (hazard ratio, 4.16; 95% CI, 1.99-8.71; P < .001) and those treated with non-stereotactic body radiotherapy hypofractionated therapy (hazard ratio, 5.43; 95% CI, 2.10-14.01; P < .001) had worse overall survival, while patients with targetable mutations (hazard ratio, 0.49; 95% CI, 0.25-0.98; P = .04) had a longer survival. Using a predictive nomogram model, patients with a solitary site of metastasis, targetable mutations, intracranial disease, and metachronous timing of oligometastases had a larger PFS benefit from cRT.

Conclusion: cRT is associated with favorable outcomes in PFS and overall survival. These results may aid in patient counseling, selection for aggressive local therapy, and stratification in future prospective clinical trials.

Keywords: Local therapy; Metachronous; Oligomet; Radiation; Synchronous.

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

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25
Lasers Med Sci
. 2020 Jul 5. doi: 10.1007/s10103-020-03091-2. Online ahead of print.
Patterns of Oral Mucositis in Advanced Oral Squamous Cell Carcinoma Patients Managed With Prophylactic Photobiomodulation Therapy-Insights for Future Protocol Development
Mariana de Pauli Paglioni 1, Karina Morais Faria 2, Natália Rangel Palmier 1, Ana Carolina Prado-Ribeiro 1 3, Reinaldo Brito E Dias 4, Henrique da Graça Pinto 4, Nathaniel Simon Treister 5, Joel B Epstein 6 7, César Augusto Migliorati 8, Alan Roger Santos-Silva 1, Thais Bianca Brandão 1 3
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PMID: 32627112 DOI: 10.1007/s10103-020-03091-2
Abstract
To characterize oral sites affected by radiation-induced oral mucositis (OM) and related clinical outcomes in oral cancer patients subjected to prophylactic photobiomodulation therapy (PBMT). This study included advanced oral squamous cell carcinoma (OSCC) patients treated with prophylactic PBMT for OM. The site distribution of OM, OM grading (CTCAE NCI, Version 4.0, 2010), OM-related pain (VAS), analgesic protocol (WHO Analgesic Ladder), and use of enteral nutrition were evaluated weekly during treatment. Data analysis was performed using descriptive statistics expressed as median values and percentages. A total of 145 OSCC patients were included. OM most frequently affected the lateral border of the tongue (44.1%), buccal mucosa (37.2%), and labial mucosa (33.8%). Keratinized oral mucosa sites, including the tongue dorsum (6.21%), retromolar trigone (8.3%), and hard palate (2.76%), were less frequently affected. Peak OM scores were observed at weeks 5, 6, and 7, with severe OM (NCI grades 3 and 4) rates of 11%, 20%, and 25%, respectively. The cumulative occurrence of severe OM was 23%, which developed as early as week 3 and as late as week 7. The highest mean value of OM-related pain (2.7) was observed at the sixth week, and 13.8% of the patients required feeding support. This study showed, compared with studies that did not provide PBMT, reduced severity of mucositis, reduced pain and analgesic use, and reduced tube feeding in patients treated with PBMT. OM involving keratinized and non-keratinized surfaces should be included in the prophylactic PBMT to reduce severe OM in future studies.

Keywords: Oral cancer; Oral mucosa site; Oral mucositis; Radiotherapy; Squamous cell carcinoma of head and neck.

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26
Review Cancer J
. May/Jun 2019;25(3):217-222. doi: 10.1097/PPO.0000000000000381.
Escape From ALL-CARTaz: Leukemia Immunoediting in the Age of Chimeric Antigen Receptors
Sisi Zheng 1, Mukta Asnani 2, Andrei Thomas-Tikhonenko
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PMID: 31135529 PMCID: PMC6617517 DOI: 10.1097/PPO.0000000000000381
Free PMC article
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has been transformative for the treatment of B-cell malignancies, with CD19- and CD22-directed CARs being prime examples. However, immunoediting and ensuing antigen loss remain the major obstacles to curative therapy in up to 25% of patients. For example, to achieve the CD19-negative phenotype, malignant cells can pick from a broad array of mechanisms, including focal loss-of-function mutations, dysregulated trafficking to the cell surface, alternative splicing, and lineage switching. In other cases, where resistance is mediated by insufficient antigen density, trogocytosis has been proposed as a possible underlying mechanism. To overcome these barriers, compensatory strategies will be needed, which could include using combinatorial CARs, harnessing epitope spreading, and targeting tumor neoantigens.

Conflict of interest statement
CONFLICT OF INTEREST STATEMENT

ATT has an interest in intellectual property “Discovery of CD19 Spliced Isoforms Resistant to CART-19.” This interest does not meet the definition of a reviewable interest under Children’s Hospital of Philadelphia’s (CHOP’s) conflict of interest policy and is therefore not a financial conflict of interest. Furthermore, this intellectual property is held by CHOP and has not been licensed or otherwise commercialized to date. However, should this technology be commercialized in the future, ATT would be entitled to a share of royalties earned by CHOP per its patent policy.

Cited by 2 articles1 figure
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27
United European Gastroenterol J
. 2020 Jul;8(6):685-694. doi: 10.1177/2050640620926837.
Metabolic Endoscopy: Today's Science-Tomorrow's Treatment
Alia Hadefi 1, Marianna Arvanitakis 1, Vincent Huberty 1, Jacques Devière 1
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PMID: 32628898 DOI: 10.1177/2050640620926837
Abstract
Obesity, type 2 diabetes mellitus (T2DM) and nonalcoholic steatohepatitis are increasing pandemic metabolic disorders. Lifestyle intervention (LSI) is the cornerstone treatment for these but is successful as standard care alone in only a few patients, given the modest weight loss at mid and long term. Conversely, bariatric surgery is the only proven effective treatment for these metabolic disorders, albeit offered only in a small percentage of cases because of its invasiveness and cost. The so-called endoscopic bariatric and metabolic therapies (EBMTs) include new, less-invasive technologies such as intragastric balloons, aspiration therapy, endoscopic sleeve gastroplasty, diversion devices, and duodenal mucosal resurfacing, currently at various stages of development. EBMTs, as an add-on to LSI, might represent an effective treatment filling the gap between medical and surgical management, taking into account, however, that obesity and its associated comorbidities constitute a chronic disease that needs lifelong therapy. In this review we describe the current scientific evidence surrounding EBMTs as well as future opportunities for such treatments in managing obesity and metabolic disorders.

Keywords: Obesity; endoscopic bariatric and metabolic therapy; metabolic disorders; nonalcoholic steatohepatitis; type 2 diabetes.

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28
Breast Cancer
. 2020 Jul 6. doi: 10.1007/s12282-020-01103-1. Online ahead of print.
Current Status of Breast Cancer Screening in High-Risk Women in Japan
Mitsuhiro Tozaki 1, Seigo Nakamura 2
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PMID: 32627143 DOI: 10.1007/s12282-020-01103-1
Abstract
Overseas, the importance for breast MRI screening for high-risk groups has been shown. However, the evidence among Japanese population was lacking. Therefore, we collaborated with the "Study on clinical and genetic characterization of hereditary breast and ovarian cancer and improvement in prognosis using genetic information in Japan" group, as part of the Comprehensive Research Project on the Promotion of Cancer Control, Health and Labour Sciences Research, and have been conducting the study entitled, "Study of the usefulness of MRI surveillance of BRCA1/2 mutation carriers" since 2014. In addition, we found that in the Japanese population also, the pathological and imaging characteristics differ between BRCA1 and BRCA2 mutation carriers, like in non-Japanese populations by the several reports. In high-risk females, risk categories such as BRCA1 or BRCA2 mutation carriers are very important. Furthermore, in the future, the optimal surveillance modalities and examination intervals would also vary according to the age, thinness of the breast (constitution), breast density (individual differences on mammography), etc.; this would be "personalized surveillance", and quality-assured MRI examination is of the essence. This review will present clinical trial data of prospective MRI surveillance in Japan, and summarize the current status of breast cancer screening in high-risk Japanese women.

Keywords: BRCA; Breast cancer screening; Hereditary breast and ovarian cancer syndrome; Magnetic resonance imaging.

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29
Muscle Nerve
. 2020 May;61(5):587-594. doi: 10.1002/mus.26833. Epub 2020 Feb 24.
Neuromuscular Ultrasound for Taxane Peripheral Neuropathy in Breast Cancer
Thomas W Lycan 1, Fang-Chi Hsu 2, Christine S Ahn 3, Alexandra Thomas 1, Francis O Walker 4, Omar P Sangueza 5, Yusuke Shiozawa 6, Sun Hee Park 6, Christopher M Peters 6, Edgar Alfonso Romero-Sandoval 7, Susan A Melin 1, Steven Sorscher 1, Katherine Ansley 1, Glenn J Lesser 1, Michael S Cartwright 4, Roy E Strowd 4
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PMID: 32052458 DOI: 10.1002/mus.26833
Abstract
Background: Our study aim was to evaluate neuromuscular ultrasound (NMUS) for the assessment of taxane chemotherapy-induced peripheral neuropathy (CIPN), the dose-limiting toxicity of this agent.

Methods: This cross-sectional study of breast cancer patients with taxane CIPN measured nerve cross-sectional area (CSA) by NMUS and compared with healthy historical controls. Correlations were determined between CSA and symptom scale, nerve conduction studies, and intraepidermal nerve fiber density (IENFD).

Results: A total of 20 participants reported moderate CIPN symptoms at a median of 3.8 months following the last taxane dose. Sural nerve CSA was 1.2 mm2 smaller than healthy controls (P ≤ .01). Older age and time since taxane were associated with smaller sural nerve CSA. For each 1 mm2 decrease in sural nerve CSA, distal IENFD decreased by 2.1 nerve/mm (R2 0.30; P = .04).

Conclusions: These data support a sensory predominant taxane neuropathy or neuronopathy and warrant future research on longitudinal NMUS assessment of CIPN.

Keywords: breast cancer; chemotherapy; neuropathy; taxane; ultrasound.

© 2020 Wiley Periodicals, Inc.

45 references
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30
Case Reports J Pathol
. 2020 Feb;250(2):183-194. doi: 10.1002/path.5359. Epub 2019 Nov 29.
Whole-genome Sequencing of Synchronous Thyroid Carcinomas Identifies Aberrant DNA Repair in Thyroid Cancer Dedifferentiation
Johan O Paulsson 1, Samuel Backman 2, Na Wang 1, Adam Stenman 1 3 4, Joakim Crona 5, Jessada Thutkawkorapin 3 6, Mehran Ghaderi 1, Emma Tham 3 6, Peter Stålberg 2, Jan Zedenius 3 4, C Christofer Juhlin 1 7
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PMID: 31621921 DOI: 10.1002/path.5359
Abstract
The genetics underlying thyroid cancer dedifferentiation is only partly understood and has not yet been characterised using comprehensive pan-genomic analyses. We investigated a unique case with synchronous follicular thyroid carcinoma (FTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC), as well as regional lymph node metastases from the PDTC and ATC from a single patient using whole-genome sequencing (WGS). The FTC displayed mutations in CALR, RB1, and MSH2, and the PDTC exhibited mutations in TP53, DROSHA, APC, TERT, and additional DNA repair genes - associated with an immense increase in sub-clonal somatic mutations. All components displayed an overrepresentation of C>T transitions with associated microsatellite instability (MSI) in the PDTC and ATC, with borderline MSI in the FTC. Clonality analyses pinpointed a shared ancestral clone enriched for mutations in TP53-associated regulation of DNA repair and identified important sub-clones for each tumour component already present in the corresponding preceding lesion. This genomic characterisation of the natural progression of thyroid cancer reveals several novel genes of interest for future studies. Moreover, the findings support the theory of a stepwise dedifferentiation process and suggest that defects in DNA repair could play an important role in the clonal evolution of thyroid cancer. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: DNA repair; clonality; dedifferentiation; thyroid carcinoma; whole-genome sequencing.

© 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Cited by 3 articles41 references
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31
Biochem Biophys Res Commun
. 2020 Jan 1;521(1):232-237. doi: 10.1016/j.bbrc.2019.10.114. Epub 2019 Oct 22.
High-throughput Screening Identified Mitoxantrone to Induce Death of Hepatocellular Carcinoma Cells With Autophagy Involvement
Bushan Xie 1, Xingxing He 2, Guihai Guo 2, Xiao Zhang 3, Jinping Li 4, Jianping Liu 5, Yingbo Lin 6
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PMID: 31653348 DOI: 10.1016/j.bbrc.2019.10.114
Abstract
The use of highly efficient high-throughput screening (HTS) platform has recently gained more attention as a plausible approach to identify de novo therapeutic application potential of conventional anti-tumor drugs for cancer treatments. In this study, we used hepatocellular carcinoma (HCC) cells as models to identify cytotoxic compounds by HTS. To identify cytotoxic compounds for potential HCC treatments, 3271 compounds from three well established small molecule libraries were screened against HCC cell lines. Thirty-two small molecules were identified from the primary screen to induce cell death. Particularly, mitoxantrone (MTX), which is an established antineoplastic drug, significantly and specifically inhibited the growth and proliferation of HCC cells in vitro. Mechanistic studies of LC3-II, p62 and phosphorylation of p70S6K in HepG2 cells revealed that MTX treatment induced mTOR-dependent autophagy activation, which was further confirmed by the autophagic flux assay using lysosomal inhibitor chloroquine (CQ). In the combined treatment of MTX and CQ, where autophagy was inhibited by CQ, the elevations of cleaved Caspase-3 and PARP were observed, indicating the enhanced apoptosis in HepG2 cells. Taken together, we hypothesize that MTX-induced autophagy plays an pro-survival role in HCC treatment. Combined treatment with autophagy inhibitor may combat the chemo-resistance of HCC to MTX treatment and therefore deserves future clinical investment.

Keywords: Autophagy; Cell death; Hepatocellular carcinoma; Mitoxantrone (MTX); Small molecule screen.

Copyright © 2019 Elsevier Inc. All rights reserved.

Cited by 1 article
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32
BJOG
. 2020 Jul 6. doi: 10.1111/1471-0528.16399. Online ahead of print.
The Influence of Learning Curve of Robot-Assisted Laparoscopy on Oncological Outcomes in Early Stage Cervical Cancer: An Observational Cohort Study
I G T Baeten 1, J P Hoogendam 1, H W R Schreuder 1, I M Jürgenliemk-Schulz 2, R H M Verheijen 1, R P Zweemer 1, C G Gerestein 1
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PMID: 32627934 DOI: 10.1111/1471-0528.16399
Abstract
Objective: To investigate the learning curve of robot-assisted laparoscopy in early stage cervical cancer and quantify impact on oncological outcomes.

Design: Observational cohort study.

Setting: Tertiary referral centre with one surgical team.

Population: All early stage cervical cancer patients treated consecutively with robot-assisted laparoscopy between 2007 and 2017.

Methods: With multivariate risk-adjusted cumulative sum analysis (RA-CUSUM), we assessed the learning curve of robot-assisted laparoscopy of a single surgical team based on cervical cancer recurrence. Subsequently, a survival analysis was conducted comparing oncological outcomes of patients treated during different phases of the learning curve.

Main outcome measures: Surgical proficiency based on recurrence, survival rates in the different learning phases.

Results: 165 cervical cancers patients were operated by robot-assisted laparoscopy, with a median follow-up of 57 months (range 3-132 months). The RA-CUSUM analysis demonstrated two phases of the learning curve: a learning phase of 61 procedures (group 1) and an experienced phase representing the 104 procedures thereafter (group 2). The 5-year disease free survival was 80.2% in group 1 and 91.1% in group 2 (P = 0.040). Both the 5-year disease-specific survival and overall survival significantly increased after the learning phase.

Conclusion: The learning phase of robot-assisted laparoscopy in early stage cervical cancer in this institutional cohort is at least 61 procedures, with higher survival rates in the patients treated thereafter. The learning curve of robot-assisted laparoscopy affects oncological outcomes and warrants more attention in the design of future studies.

Keywords: Cervical cancer; RA-CUSUM; learning curve; recurrence; robot-assisted laparoscopy; survival.

This article is protected by copyright. All rights reserved.

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33
Editorial Future Oncol
. 2020 Jul;16(19):1321-1322. doi: 10.2217/fon-2020-0372. Epub 2020 May 26.
Nasopharyngeal Swab or Clinical-Radiological Evidence: The Dark Side of the Moon for Cancer Patients in the COVID-19 Era
Antonello Veccia 1, Stefania Kinspergher 1, Mariachiara Dipasquale 1, Orazio Caffo 1
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PMID: 32452225 PMCID: PMC7249542 DOI: 10.2217/fon-2020-0372
Free PMC article
Abstract
No abstract available
Keywords: COVID-19; clinical diagnosis; lung cancer; nasopharyngeal swab.

13 references
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34
Editorial Future Oncol
. 2020 Jul;16(19):1323-1325. doi: 10.2217/fon-2020-0381. Epub 2020 May 14.
Bacillus Calmette Guérin (BCG) Vaccination Use in the Fight Against COVID-19 - What's Old Is New Again?
Ellen O'Connor 1 2, Jiasian Teh 1 2, Ashish M Kamat 3, Nathan Lawrentschuk 2 4
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PMID: 32406253 PMCID: PMC7222530 DOI: 10.2217/fon-2020-0381
Free PMC article
Abstract
No abstract available
Keywords: BCG vaccine; COVID-19; clinical trials; coronavirus; immunotherapy; mycobacterium bovis.

Cited by 1 article16 references
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35
Ginekol Pol
. 2020;91(6):352-361. doi: 10.5603/GP.2020.0081.
Recommendations of the Polish Society of Gynaecologists and Obstetricians for Removal of the Uterus by Vaginal, Laparoscopic and Abdominal Routes
Rafal Stojko 1 2, Andrzej Malinowski 3, Wlodzimierz Baranowski 4, Marcin Misiek 5, Ewa Winkowska 6, Michal Pomorski 7, Mariusz Zimmer 7
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PMID: 32627157 DOI: 10.5603/GP.2020.0081
Free article
Abstract
The recommendations represent the current procedure, which may be modified and changed where justified, after a thorough analysis of the given clinical situation, which may be the basis for their modification and updating in the future.

Keywords: hysterectomy; laparoscopic; transvaginal.

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36
Eur Urol
. 2020 Jul 2;S0302-2838(20)30455-3. doi: 10.1016/j.eururo.2020.06.026. Online ahead of print.
Re: Reconsidering Prostate Cancer Mortality - The Future of PSA Screening: Against Increasing PSA Threshold to 10 ng/ml
Alexandre R Zlotta 1, Sigrid V Carlsson 2, Antonio Finelli 3, Neil E Fleshner 3
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PMID: 32624274 DOI: 10.1016/j.eururo.2020.06.026
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