1.
Biochim Biophys Acta Rev Cancer. 2020 Feb 28:188354. doi: 10.1016/j.bbcan.2020.188354. [Epub ahead of print]
Role of fibrillin-2 in the control of TGF-β activation in tumor angiogenesis and connective tissue disorders.
Abstract
Fibrillins constitute a family of large extracellular glycoproteins which multimerize to form microfibrils, an important structure in the extracellular matrix. It has long been assumed that fibrillin-2 was barely present during postnatal life, but it is now clear that fibrillin-2 molecules form the structural core of microfibrils, and are masked by an outer layer of fibrillin-1. Mutations in fibrillins give rise to heritable connective tissue disorders, including Marfan syndrome and congenital contractural arachnodactyly. Fibrillins also play an important role in matrix sequestering of members of the transforming growth factor-β family, and in context of Marfan syndrome excessive TGF-β activation has been observed. TGF-β activation is highly dependent on integrin binding, including integrin αvβ8 and αvβ6, which are upregulated upon TGF-β exposure. TGF-β is also involved in tumor progression, metastasis, epithelial-to-mesenchymal transition and tumor angiogenesis. In several highly vascularized types of cancer such as hepatocellular carcinoma, a positive correlation was found between increased TGF-β plasma concentrations and tumor vascularity. Interestingly, fibrillin-1 has a higher affinity to TGF-β and, therefore, has a higher capacity to sequester TGF-β compared to fibrillin-2. The previously reported downregulation of fibrillin-1 in tumor endothelium affects the fibrillin-1/fibrillin-2 ratio in the microfibrils, exposing the normally hidden fibrillin-2. We postulate that fibrillin-2 exposure in the tumor endothelium directly stimulates tumor angiogenesis by influencing TGF-β sequestering by microfibrils, leading to a locally higher active TGF-β concentration in the tumor microenvironment. From a therapeutic perspective, fibrillin-2 might serve as a potential target for future anti-cancer therapies. SIGNIFICANCE STATEMENT: Fibrillin-2 is exposed in the tumor endothelium due to local fibrillin-1 downregulation. This fibrillin-2 exposure in the tumor endothelium directly stimulates tumor angiogenesis by influencing TGF-β sequestering by microfibrils. The exposure of fibrillin-2 in the tumor vasculature makes fibrillin-2 a specific marker of tumor endothelial cells and, subsequently, a promising target for anti-tumor therapies.
Copyright © 2019. Published by Elsevier B.V.
KEYWORDS:
Angiogenesis; CCA; Fibrillin-2; Fibrillins; HHT; Marfan syndrome; TGF-β; Tumor angiogenesis; Tumor vasculature
2.
Cancer Med. 2020 Mar 2. doi: 10.1002/cam4.2940. [Epub ahead of print]
Cancer patients' experiences with immune checkpoint modulators: A qualitative study.
Ala-Leppilampi K1, Baker NA1, McKillop C2, Butler MO3,4, Siu LL3,4, Spreafico A3,4, Abdul Razak AR3,4, Joshua AM3,4,5, Hogg D3,4, Bedard PL3,4, Leighl N3,4, Oza AM3,4, Parsons JA1,6, Hansen AR3,4.
Abstract
BACKGROUND:
Minimal qualitative data exist on the experiences of cancer patients treated with immune checkpoint inhibitors or costimulatory antibodies. Understanding the day to day experiences of patients being treated with immune checkpoint modulators, and how these relate to their health-related quality of life, can inform future research and lead to better clinical decision-making and care. We report here the first in depth qualitative study to consider patients' diverse and complex experiences with immune checkpoint modulators, with a focus on side effects and how these impact daily life.
METHODS:
This single-center qualitative study was based on focus groups and semistructured interviews. Patients who were being treated or who had been treated with immune checkpoint modulators within the last year for a range of cancer diagnoses were recruited. Interpretive description informed our inductive, iterative approach to analysis.
RESULTS:
Eight themes were identified, characterizing the complexity of these patients' lived experiences: major categories of side effects experienced and how they impacted patient well-being; the heterogeneous nature of side effects experienced; living with uncertainty; reframing the meaning and severity of SEs; focus on survival, hope, and being positive; acceptance and adaptation; feeling supported; and faith in medical innovation. Throughout their accounts, participants highlighted the profound impact that immune checkpoint modulators had on their daily lives.
CONCLUSION:
This is the first in-depth qualitative study into patient accounts of their experiences of treatment with immune checkpoint modulators, related side effects, and how it impacted their daily lives. This research is an integral initial step in developing an instrument that will assess treatment-related side effects in patients treated with this form of therapy.
© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
KEYWORDS:
Health-related quality of life; costimulatory antibodies; immune checkpoint inhibitors; immunotherapy; patient experiences
3.
CNS Oncol. 2020 Mar 2:CNS49. doi: 10.2217/cns-2019-0023. [Epub ahead of print]
Welcome to Volume 9 of CNS Oncology.
4.
Mol Oncol. 2020 Mar 2. doi: 10.1002/1878-0261.12657. [Epub ahead of print]
Norepinephrine-CREB1-miR-373 axis promotes progression of colon cancer.
Han J1, Jiang Q1, Ma R2, Zhang H3, Tong D1, Tang K1, Wang X1, Ni L1, Miao J1, Duan B4, Yang Y5, Chen Y1, Wu F1, Han J3, Wang M6, Hou N1, Huang C1,7,8.
Abstract
The adrenergic system contributes to the stress-induced onset and progression of cancer. Adrenergic fibers are the primary source of norepinephrine (NE). The underlying mechanisms involved in NE-induced colon cancer remain to be understood. In this study, we describe the function and regulatory network of NE in the progression of colon cancer. We demonstrate that NE-induced phosphorylation of cAMP response element-binding protein 1 (CREB1) promotes proliferation, migration, and invasion of human colon cancer cells. The downstream effector of NE, CREB1, bound to the promoter of miR-373 and transcriptionally activated its expression. miR-373 expression was shown to be necessary for NE-induced cell proliferation, invasion, and tumor growth. We confirmed that proliferation and invasion of colon cancer cells are regulated in vitro and in vivo by miR-373 through targeting of the tumor suppressors TIMP2 and APC. Our data suggest that NE promotes colon cancer cell proliferation and metastasis by activating the CREB1-miR-373 axis. Study of this novel signaling axis may provide mechanistic insights into the neural regulation of colon cancer and help in the design of future clinical studies on stress biology in colorectal cancer.
This article is protected by copyright. All rights reserved.
KEYWORDS:
CREB1; Colorectal cancer; NE; TIMP2; miR-373
5.
Front Cell Dev Biol. 2020 Feb 11;8:48. doi: 10.3389/fcell.2020.00048. eCollection 2020.
A Review of Precision Oncology Knowledgebases for Determining the Clinical Actionability of Genetic Variants.
Abstract
The increased availability of tumor genetic testing and targeted cancer therapies contributes to the advancement of precision medicine in the field of oncology. Precision oncology knowledgebases provide a way of organizing clinically relevant genetic information in a way that is easily accessible for both oncologists and patients, facilitating the genetic-based clinical decision making. Many organizations and companies have built precision oncology knowledgebases, intended for multiple users. In general, these knowledgebases offer information on cancer-related genetic variants as well as their associated diagnostic, prognostic, and therapeutic implications, but they often differ in their information curations, designs, and user experiences. It is advisable that oncologists use multiple knowledgebases during their practice to have them complement each other. In the future, convergence toward common standards and formats is needed to ensure that the comprehensive knowledge across all sources can be unified to bring the oncology community closer to the achievement of the goal of precision oncology.
Copyright © 2020 Li and Warner.
KEYWORDS:
actionability; genotype-selective clinical trial; knowledgebase; precision oncology; targeted therapy; tumor genetic testing; variant interpretation
6.
Front Cell Dev Biol. 2020 Feb 12;8:33. doi: 10.3389/fcell.2020.00033. eCollection 2020.
Fat Wasting Is Damaging: Role of Adipose Tissue in Cancer-Associated Cachexia.
Abstract
Loss of body weight, especially loss of adipose tissue and skeletal muscle weight, characterizes cancer-associated cachexia (CAC). Clinically, therapeutic options for CAC are limited due to the complicated signaling between cancer and other organs. Recent research advances show that adipose tissues play a critical role during thermogenesis, glucose homeostasis, insulin sensitivity, and lipid metabolism. Understanding the adipocyte lipolysis, the formation of beige adipocytes, and the activation of brown adipocytes is vital for novel therapies for metabolic syndromes like CAC. The system-level crosstalk between adipose tissue and other organs involves adipocyte lipolysis, white adipose tissue browning, and secreted factors and metabolites. Novel CAC animal models and accumulating molecular signaling knowledge have provided mechanisms that may ultimately be translated into future therapeutic possibilities that benefit CAC patients. This mini review discusses the role of adipose tissue in CAC development, mechanism, and therapy.
Copyright © 2020 Sun, Feng, Wu, Lu, Chen and Ye.
KEYWORDS:
adipose tissue; browning; cancer cachexia; lipolysis; thermogenesis
7.
Front Oncol. 2020 Feb 11;10:103. doi: 10.3389/fonc.2020.00103. eCollection 2020.
A Cost-Effectiveness and Quality of Life Analysis of Different Approaches to the Management and Treatment of Localized Prostate Cancer.
Abstract
The aim of this study was to compare the cost-effectiveness and quality-adjusted life years (QALYs) of active monitoring (AM), radical prostatectomy (PR), and external-beam radiotherapy with neoadjuvant hormone therapy (RT) for localized prostate cancer. Microsimulations of radical prostatectomy, 3D-conformal radiotherapy, or active monitoring were performed using Medicare reimbursement schedules and clinical trial results for a target population of men aged 50-69 years with newly diagnosed localized prostate cancer (T1-T2, NX, M0) over a time horizon of 10 years. Quality-adjusted life years (QALYs) and costs were assessed and sensitivity analyses performed. Monte Carlo simulations revealed that the mean cost for AM, PR, and RT were $15,654, $18,791, and $30,378, respectively, and QALYs were 6.96, 7.44, and 7.9 years, respectively. The incremental cost-effectiveness ratio (ICER) was $6,548 for PR over AM and $68,339 for RT over PR. Results were sensitive to the number of years of follow-up and procedure cost. With relaxed assumptions for AM, the ICER of PR and RT met the societal willingness to pay (WTP) threshold of $50,000 per QALY. Compared with AM, PR was highly cost-effective. RT and PR for localized prostate cancer can be cost-effective, but RT must offer increased QALYs or decreased procedural costs to be cost-effective compared to PR. Newer and cheaper radiotherapy strategies like stereotactic body radiotherapy may play a crucial role in future early prostate cancer management.
Copyright © 2020 Harat, Harat and Martinson.
KEYWORDS:
QALY; active monitoring; cost-effectiveness analysis; prostate cancer; prostatectomy; radiotherapy
8.
Front Oncol. 2020 Feb 14;10:89. doi: 10.3389/fonc.2020.00089. eCollection 2020.
Impact of Radiochemotherapy on Immune Cell Subtypes in High-Grade Glioma Patients.
Dutoit V1,2, Philippin G1,2, Widmer V1,2, Marinari E1,2, Vuilleumier A3, Migliorini D1,2, Schaller K4, Dietrich PY1,2,3.
Abstract
Glioblastoma is a dreadful disease with very poor prognosis, median overall survival being <2 years despite standard-of-care treatment. This has led to the development of alternative strategies, among which immunotherapy is being actively tested. In particular, many clinical trials of therapeutic vaccination using peptides or tumor cells are ongoing. A major issue in implementing therapeutic vaccines in patients with high-grade glioma is that immune responses have to be elicited in the context of immunosuppressive treatments. Indeed, radiotherapy, chemotherapy, and steroids, which are part of the standard of care for patients with glioblastoma, are known to deplete leukocytes. Whether lymphopenia is beneficial or detrimental to elicitation of efficient immune responses is still debated. Here, in order to determine the impact of standard radiochemotherapy on immune cell subsets, we analyzed the phenotype and function of immune populations in 25 patients with high-grade glioma along concomitant radiochemotherapy and adjuvant chemotherapy with temozolomide. Thirteen healthy individuals were studied along the same period. We show that absolute T and B cell counts are reduced upon concomitant radiochemotherapy. Importantly, T cell counts were not restored long-term after discontinuation of treatment. In addition, the percentage of T regulatory cells among CD4 T cells was increased during the same period and was not decreased upon treatment discontinuation. Finally, we show that the ability of T cells to proliferate is transiently reduced after concomitant radiochemotherapy but is restored at the time of adjuvant TMZ cycles. Although not experimentally validated, transient reduction in proliferation associated with strong lymphopenia during radiochemotherapy may suggest that vaccine-induced T cell stimulation would be suboptimal in that period and that therapeutic vaccination should be performed outside radiochemotherapy administration. In addition, strategies aiming at depleting Treg cells should be implemented in future trials.
Copyright © 2020 Dutoit, Philippin, Widmer, Marinari, Vuilleumier, Migliorini, Schaller and Dietrich.
KEYWORDS:
cancer vaccines; glioma; immune subsets; immunotherapy; lymphopenia; radiotherapy; temozolomide
9.
Front Oncol. 2020 Feb 7;10:20. doi: 10.3389/fonc.2020.00020. eCollection 2020.
SPECT-CT Imaging of Dog Spontaneous Diffuse Large B-Cell Lymphoma Targeting CD22 for the Implementation of a Relevant Preclinical Model for Human.
Etienne F1,2, Berthaud M1, Nguyen F1,2, Bernardeau K1,3, Maurel C1, Bodet-Milin C1,4, Diab M1, Abadie J1,2, Gouilleux-Gruart V5, Vidal A6, Bourgeois M1,6, Chouin N1,2, Ibisch C1,2, Davodeau F1.
Abstract
Antibodies directed against CD22 have been used in radioimmunotherapy (RIT) clinical trials to treat patients with diffuse large B-cell lymphoma (DLBCL) with promising results. However, relevant preclinical models are needed to facilitate the evaluation and optimization of new protocols. Spontaneous DLBCL in dogs is a tumor model that may help accelerate the development of new methodologies and therapeutic strategies for RIT targeting CD22. Seven murine monoclonal antibodies specific for canine CD22 were produced by the hybridoma method and characterized. The antibodies' affinity and epitopic maps, their internalization capability and usefulness for diagnosis in immunohistochemistry were determined. Biodistribution and PET imaging on a mouse xenogeneic model of dog DLBCL was used to choose the most promising antibody for our purposes. PET-CT results confirmed biodistribution study observations and allowed tumor localization. The selected antibody, 10C6, was successfully used on a dog with spontaneous DLBCL for SPECT-CT imaging in the context of disease staging, validating its efficacy for diagnosis and the feasibility of future RIT assays. This first attempt at phenotypic imaging on dogs paves the way to implementing quantitative imaging methodologies that would be transposable to humans in a theranostic approach. Taking into account the feedback of existing human radioimmunotherapy clinical trials targeting CD22, animal trials are planned to investigate protocol improvements that are difficult to consider in humans due to ethical concerns.
Copyright © 2020 Etienne, Berthaud, Nguyen, Bernardeau, Maurel, Bodet-Milin, Diab, Abadie, Gouilleux-Gruart, Vidal, Bourgeois, Chouin, Ibisch and Davodeau.
KEYWORDS:
CD22; SPECT-CT imaging; comparative oncology; diffuse large B-cell lymphoma; dog; internalization; monoclonal antibody
10.
Front Immunol. 2020 Jan 24;11:27. doi: 10.3389/fimmu.2020.00027. eCollection 2020.
Computational Prediction and Validation of Tumor-Associated Neoantigens.
Abstract
Tumor progression is typically accompanied by an accumulation of driver and passenger somatic mutations. A handful of those mutations occur in protein coding genes which introduce non-synonymous polymorphisms. Certain substitutions may give rise to novel, tumor-associated antigens or neoantigens, presentable by cancer cells to the host adaptive immune system. As antigen recognition is the core of an effective immune response, the identification of patient tumor specific antigens derived from transformed cells is of importance for immunotherapeutic approaches. Recent technological advances in DNA sequencing of tumor genomes, advances in gene expression analysis, algorithm development for antigen predictions and methods for T-cell receptor (TCR) repertoire sequencing have facilitated the selection of candidate immunogenic neoantigens. In this regard, multiple research groups have reported encouraging results of neoantigen-based cancer vaccines that generate tumor antigen specific immune responses, both in mouse models and clinical trials. Additionally, both the quantity and quality of neoantigens has been shown to have predictive value for clinical outcomes in checkpoint-blockade immunotherapy in certain tumor types. Neoantigen recognition by vaccination or through adoptive T cell therapy may have unprecedented potential to advance cancer immunotherapy in combination with other approaches. In our review we discuss three parameters regarding neoantigens: computational methods for epitope prediction, experimental methods for epitope immunogenicity validation and future directions for improvement of those methods. Within each section, we will describe the advantages and limitations of existing methods as well as highlight pressing fundamental problems to be addressed.
Copyright © 2020 Roudko, Greenbaum and Bhardwaj.
KEYWORDS:
HLA-allele; MHC-I epitope; TCR; WES; neoantigen
11.
Am J Physiol Renal Physiol. 2020 Mar 2. doi: 10.1152/ajprenal.00496.2019. [Epub ahead of print]
Systems analysis of benign bladder disorders: insights from omics analysis.
Abstract
The signaling pathways and effectors that drive the response of the bladder to non-malignant insults or injury are incompletely defined. Interrogation of biological systems has been revolutionized by the ability to generate high content datasets that capture information on a variety of biomolecules in cells and tissues, from DNA to RNA to proteins. In oncology, such an approach has led to the identification of cancer subtypes, improved prognostic capability and has provided a basis for precision treatment of patients. In contrast, systematic molecular characterization of benign bladder disorders has lagged behind, such that our ability to uncover novel therapeutic interventions, or increase our mechanistic understanding of such conditions is limited. Here, we discuss existing literature on the application of omics approaches, including transcriptomics and proteomics, to urinary tract conditions characterized by pathological tissue remodeling. We discuss molecular pathways implicated in remodeling, challenges in the field and aspirations for omics-based research in the future.
KEYWORDS:
Proteomics; Remodeling; Single-cell sequencing; Transcriptomics; miRNA
12.
J Vasc Surg. 2020 Feb 27. pii: S0741-5214(20)30152-X. doi: 10.1016/j.jvs.2019.12.043. [Epub ahead of print]
Setting a research agenda for vascular Ehlers-Danlos syndrome using a patient and stakeholder engagement model.
Sage L1, Russo ML2, Byers PH3, Demasi J4, Morris SA5, Puryear LN3, Fulton DS6, Shalhub S7; Vascular Ehlers-Danlos Syndrome Research Collaborative.
Abstract
OBJECTIVE:
Vascular Ehlers-Danlos syndrome (vEDS) is a rare, syndromic, heritable condition with life-threatening complications that include aortic and arterial aneurysms, dissection, and rupture. This study describes the formation of the vEDS Research Collaborative and methods used for stakeholder engagement.
METHODS:
The vEDS Research Collaborative was established with an engagement award from the Patient-Centered Outcomes Research Institute to create a framework for a patient-researcher partnership. Between October 1, 2017, and September 30, 2018, the Collaborative used the Patient-Centered Outcomes Research Institute Engagement Rubric to conduct stakeholder engagement to develop a patient-centered research agenda. A modified Delphi technique was used to develop and to refine research topics and questions, gathering input from all stakeholders during three rounds of feedback.
RESULTS:
Four topic areas were deemed important: mental health and quality of life issues, creating a care team, a holistic approach to vEDS management (medical and surgical), and pregnancy management. An online survey to rank a list of 12 research questions in these topic areas in order of importance was disseminated. The questions were ranked in order of importance through an online survey (N = 197 responses). The survey showed a high degree of alignment in the top priorities among stakeholders. There was a high degree of interest in pragmatic clinical trials evaluating medical management options and health-related quality of life outcomes.
CONCLUSIONS:
The vEDS Research Collaborative has built a sustainable, coalition model of patient and stakeholder engagement, supported by the vEDS community, to identify a patient-centered, prioritized list of research questions. In articulating a shared vision for the future of vEDS research, the Collaborative has laid the groundwork for developing research protocols aligned with the highest priority questions for the individuals affected by this serious condition that can be translated into future clinical trials.
Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
KEYWORDS:
COL3A1 mutations; Patient and stakeholder engagement; Rare disease research; Research prioritization; Vascular Ehlers-Danlos syndrome
13.
Neurosurg Focus. 2020 Mar 1;48(3):E14. doi: 10.3171/2019.12.FOCUS19448.
Neurosurgical training and global health education: systematic review of challenges and benefits of in-country programs in the care of neural tube defects.
Abstract
OBJECTIVE:
The recognition that neurosurgeons harbor great potential to advocate for the care of individuals with neural tube defects (NTDs) globally has sounded as a clear call to action; however, neurosurgical care and training in low- and middle-income countries (LMICs) present unique challenges that must be considered. The objective of this study was to systematically review publications that describe the challenges and benefits of participating in neurosurgery-related training programs in LMICs in the service of individuals with NTDs.
METHODS:
Using MEDLINE (PubMed), the authors conducted a systematic review of English- and Spanish-language articles published from 1974 to 2019 that describe the experiences of in-country neurosurgery-related training programs in LMICs. The inclusion criteria were as follows-1) population/exposure: US residents, US neurosurgeons, and local in-country medical staff participating in neurosurgical training programs aimed at improving healthcare for individuals with NTDs; 2) comparison: qualitative studies; and 3) outcome: description of the challenges and benefits of neurosurgical training programs. Articles meeting these criteria were assessed within a global health education conceptual framework.
RESULTS:
Nine articles met the inclusion criteria, with the majority of the in-country neurosurgical training programs being seen in subregions of Africa (8/9 [89%]) and one in South/Central America. US-based residents and neurosurgeons who participated in global health neurosurgical training had increased exposure to rare diseases not common in the US, were given the opportunity to work with a collaborative team to educate local healthcare professionals, and had increased exposure to neurosurgical procedures involved in treating NTDs. US neurosurgeons agreed that participating in international training improved their own clinical practices but also recognized that identifying international partners, travel expenses, and interference with their current practice are major barriers to participating in global health education. In contrast, the local medical personnel learned surgical techniques from visiting neurosurgeons, had increased exposure to intraoperative decision-making, and were given guidance to improve postoperative care. The most significant challenges identified were difficulties in local long-term retention of trained fellows and staff, deficient infrastructure, and lower compensation offered for pediatric neurosurgery in comparison to adult care.
CONCLUSIONS:
The challenges and benefits of international neurosurgical training programs need to be considered to effectively promote the development of neurosurgical care for individuals with NTDs in LMICs. In this global health paradigm, future work needs to investigate further the in-country professionals' perspective, as well as the related outcomes.
KEYWORDS:
LMIC = low- and middle-income country; NTD = neural tube defect; QOL = quality of life; global health; guidelines; international health; myelomeningocele; neural tube defect; spina bifida
14.
Int J Gynecol Cancer. 2020 Feb 28. pii: ijgc-2019-000869. doi: 10.1136/ijgc-2019-000869. [Epub ahead of print]
Patient-reported outcomes at discontinuation of anti-angiogenesis therapy in the randomized trial of chemotherapy with bevacizumab for advanced cervical cancer: an NRG Oncology Group study.
Chase D1, Huang HQ2, Monk BJ3, Ramondetta LM4, Penson RT5, Gil K6, Landrum LM7, Leitao M8, Oaknin A9, Huh WK10, Pulaski HL11, Robison K12, Guntupalli SR13, Richardson D14, Salani R15, Sill MW2, Wenzel LB16, Tewari KS17.
Abstract
INTRODUCTION:
To describe patient-reported outcomes and toxicities at time of treatment discontinuation secondary to progression or toxicities in advanced/recurrent cervical cancer patients receiving chemotherapy with bevacizumab.
METHODS:
Summarize toxicity, grade, and health-related quality of life within 1 month of treatment discontinuation for women receiving chemotherapy with bevacizumab in GOG240.
RESULTS:
Of the 227 patients who received chemotherapy with bevacizumab, 148 discontinued study protocol treatment (90 for disease progression and 58 for toxicity). The median survival time from treatment discontinuation to death was 7.9 months (95% CI 5.0 to 9.0) for those who progressed versus 12.1 months (95% CI 8.9 to 23.2) for those who discontinued therapy due to toxicities. The most common grade 3 or higher toxicities included hematologic, gastrointestinal, and pain. Some 57% (84/148) of patients completed quality of life assessment within 1 month of treatment discontinuation. Those patients who discontinued treatment due to progression had a mean decline in the FACT-Cx TOI of 3.2 points versus 2.2 in patients who discontinued therapy due to toxicity. This was a 9.9 point greater decline in the FACT-Cx TOI scores than those who discontinued treatment due to progression (95% CI 2.8 to 17.0, p=0.007). The decline in quality of life was due to worsening physical and functional well-being. Those who discontinued treatment due to toxicities had worse neurotoxicity and pain.
DISCUSSION:
Patients who discontinued chemotherapy with bevacizumab for toxicity experienced longer post-protocol survival but significantly greater declination in quality of life than those with progression. Future trial design should include supportive care interventions that optimize physiologic function and performance status for salvage therapies.
© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.
KEYWORDS:
cervical cancer; gynecology; quality of life (PRO)/palliative care
15.
Curr Opin Genet Dev. 2020 Feb 27;60:17-24. doi: 10.1016/j.gde.2020.02.003. [Epub ahead of print]
DNA methylation of the TERT promoter and its impact on human cancer.
Abstract
Telomere maintenance is a hallmark of human cancer that enables replicative immortality. Most cancer cells acquire telomere maintenance by telomerase activation through expression of telomerase reverse transcriptase (TERT), a rate-limiting component of the telomerase holoenzyme. Although multiple cancer-specific genetic alterations such as gain of TERT copy number and recurrent TERT promoter mutations (TPM) have been identified, the majority of cancers still express TERT via unknown mechanisms. In the last decade, DNA methylation of the TERT promoter emerged as a putative epigenetic regulatory mechanism of telomerase activation in cancer. Here, we comparatively discuss studies that investigated the DNA methylation landscape of the TERT promoter. We further review the biological and clinical impacts of TERT promoter hypermethylation in cancer and provide insight into future applications of this phenomenon.
Copyright © 2020. Published by Elsevier Ltd.
16.
J Oral Maxillofac Surg. 2020 Feb 5. pii: S0278-2391(20)30108-7. doi: 10.1016/j.joms.2020.01.032. [Epub ahead of print]
Oral Lichen Planus-Associated Oral Cavity Squamous Cell Carcinoma Is Associated With Improved Survival and Increased Risk of Recurrence.
Abstract
PURPOSE:
We investigated the overall survival (OS), disease-specific survival (DSS), and disease-free survival among patients with oral lichen planus-associated oral cavity squamous cell carcinoma (OLP-OCSCC). The secondary objective was to assess the annual risk of tumor recurrence or second primary tumor (SPT).
MATERIALS AND METHODS:
A comparative retrospective study was performed of patients with OLP-OCSCC presenting between June 2007 and December 2018 to the Department of Oral and Maxillofacial Surgery, Michigan Medicine (Ann Arbor, MI) and patients with OCSCC in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database (1973 to 2015).
RESULTS:
A total of 87 patients with OLP-OCSCC met the inclusion criteria, and 55,165 patients with OCSCC from the SEER database were included. The proportion of women was greater in the OLP group than in the SEER group (56.3 vs 38.0%; P < .001). In the OLP group, 47.1% had no smoking history and 43.7% had no alcohol history. Most patients in the OLP group had presented with stage I disease (46.0%) compared with 31.7% in the SEER group (P = .004). Overall, the OS and DSS were significantly greater in the OLP group than in the SEER group at all points from 1 to 5 years (P ≤ .01). In the OLP group, 46 patients (52.9%) had had at least 1 recurrence or SPT. At 10 years, the predicted mean number of recurrences was 1.93 per patient (95% confidence interval, 1.56 to 2.39).
CONCLUSIONS:
OLP-OCSCC frequently affects women, nonsmokers, and nondrinkers and presents with localized disease at a high frequency. Patients with OLP-OCSCC have increased OS and DSS and a greater risk of tumor recurrence or SPT compared with OCSCC in the general population. Lifelong, frequent surveillance is recommended for patients with OLP-OCSCC owing to the risk of late recurrence. Future studies are needed to understand the pathophysiology of OLP-OCSCC.
Copyright © 2020. Published by Elsevier Inc.
17.
Clin Lymphoma Myeloma Leuk. 2020 Jan 30. pii: S2152-2650(20)30048-3. doi: 10.1016/j.clml.2020.01.011. [Epub ahead of print]
A User's Guide to Novel Therapies for Acute Myeloid Leukemia.
Abstract
Few diseases have been marked by a 40-year period of stagnation with regard to therapeutic advances and United States Food and Drug Administration (FDA) approvals, as has been the case for acute myeloid leukemia (AML). Cytarabine and anthracyclines were introduced for the treatment of AML in the 1970s, and in the ensuing 4 decades, the pharmacologic pipeline has experienced a standstill. The absence of FDA approvals in AML is not a reflection of the lack of understanding of the disease biology. The field has seen major advances from the standpoint of stem cell biology and clonal evolution, and the field has also seen some therapeutic advances, but these therapeutic advances have arisen from optimization of the same traditional cytotoxic chemotherapeutics rather than the development of novel therapies. The year 2017 marked a turning point with regard to FDA approvals. This review summarizes the salient clinical trials that led to the approval of 8 novel agents in AML in the past 2 years. For these agents, the clinical activity is often defined by specific molecular aberrations or metabolic features of AML cells. We also emphasize the principles of management of AML in the current era of genomic medicine, with a focus on considerations for targeting mutation-specific vulnerabilities in select patients. This review also highlights unique challenges to the use of novel agents in 2020, including considerations of curative potential with regards to bridging to allogeneic stem cell transplant, tolerability, financial toxicities, and microenvironmental hurdles. Finally, we discuss prospects on future immunotherapeutic investigational agents in the pharmacologic pipeline.
Copyright © 2020 Elsevier Inc. All rights reserved.
KEYWORDS:
Acute myeloid leukemia; Myelodysplastic syndrome; Myeloid malignancies; Precision medicine; Stem cell transplant; Targeted therapy
18.
Clin Breast Cancer. 2020 Jan 30. pii: S1526-8209(20)30028-8. doi: 10.1016/j.clbc.2020.01.012. [Epub ahead of print]
A Phase II Study of Pembrolizumab in Combination With Palliative Radiotherapy for Hormone Receptor-positive Metastatic Breast Cancer.
Barroso-Sousa R1, Krop IE2, Trippa L2, Tan-Wasielewski Z2, Li T2, Osmani W3, Andrews C3, Dillon D4, Richardson ET 3rd4, Pastorello RG5, Winer EP2, Mittendorf EA6, Bellon JR7, Schoenfeld JD7, Tolaney SM8.
Abstract
BACKGROUND:
The purpose of this study was to investigate whether combining pembrolizumab with palliative radiation therapy (RT) improves outcomes in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC).
PATIENTS AND METHODS:
Eligible patients had HR+/human epidermal growth factor receptor 2-negative MBC; were candidates for RT to ≥ 1 bone, soft tissue, or lymph node lesion; and had ≥ 1 lesion outside the RT field. Patients received 200 mg pembrolizumab intravenously 2 to 7 days prior to RT and on day 1 of repeating 21-day cycles. RT was delivered to a previously unirradiated area in 5 treatments each of 4 Gy. The primary endpoint was objective response rate. The study used a 2-stage design: 8 women were enrolled into the first stage, and if at least 1 of 8 patients experienced an objective response, 19 more would be enrolled. Secondary endpoints included progression-free survival, overall survival, and safety. Exploratory endpoints included association of overall response rate with programmed death-ligand 1 status and tumor-infiltrating lymphocytes.
RESULTS:
Eight patients were enrolled in stage 1. The median age was 59 years, and the median prior lines of chemotherapy for metastatic disease was 2. There were no objective responses, and the study was closed to further accrual. The median progression-free survival was 1.4 months (95% confidence interval, 0.4-2.1 months), and the median overall survival was 2.9 months (95% confidence interval, 0.9-3.6 months). All-cause adverse events occurred in 87.5% of patients, including just 1 grade 3 event (elevation of aspartate aminotransferase).
CONCLUSIONS:
RT combined with pembrolizumab did not produce an objective response in patients with heavily pre-treated HR+ MBC. Future studies should consider alternative radiation dosing and fractionation in patients with less heavily pre-treated HR+ MBC.
Copyright © 2020 Elsevier Inc. All rights reserved.
KEYWORDS:
Checkpoint blockade; Immune checkpoint inhibitor; Immunotherapy; PD-1 inhibitor; Radiation
19.
Aust J Gen Pract. 2020 Mar;49(3):139-144. doi: 10.31128/AJGP-05-19-49502.
Whole-person care in general practice: The doctor-patient relationship.
Abstract
BACKGROUND AND OBJECTIVES:
Whole-person care (WPC) is a defining feature of general practice, but it may not be consistently implemented. These authors conducted a qualitative study to define WPC and determine factors that influence its provision. Part one of this series suggested a model of WPC. Its foundation is the doctor-patient relationship; this article reports the findings concerning this theme.
METHOD:
Semi-structured interviews were conducted with 20 Australian GPs or general practice registrars and analysed using grounded theory methodology.
RESULTS:
GPs viewed the doctor-patient relationship as foundational to WPC, facilitating knowledge of the patient, trust and management. Participants' descriptions of the doctor-patient relationship were multidimensional, encompassing interacting professional, personal and business-transactional dimensions.
DISCUSSION:
The results suggest that a multidimensional doctor-patient relationship underpins WPC. It is not adequately described by a consumerist/contractual model; future work could further elucidate its nature. This relationship must be valued to provide quality WPC.
20.
Blood. 2019 Nov 14;134(20):1717-1729. doi: 10.1182/blood.2019000973.
B-cell-specific IRF4 deletion accelerates chronic lymphocytic leukemia development by enhanced tumor immune evasion.
Asslaber D1,2,3, Qi Y1,2,3, Maeding N1,2,3, Steiner M1,2,3, Denk U1,2,3, Höpner JP1,2,3, Hartmann TN1,2,3, Zaborsky N1,2,3, Greil R1,2,3, Egle A1,2,3.
Abstract
Chronic lymphocytic leukemia (CLL) is a heterogenous disease that is highly dependent on a cross talk of CLL cells with the microenvironment, in particular with T cells. T cells derived from CLL patients or murine CLL models are skewed to an antigen-experienced T-cell subset, indicating a certain degree of antitumor recognition, but they are also exhausted, preventing an effective antitumor immune response. Here we describe a novel mechanism of CLL tumor immune evasion that is independent of T-cell exhaustion, using B-cell-specific deletion of the transcription factor IRF4 (interferon regulatory factor 4) in Tcl-1 transgenic mice developing a murine CLL highly similar to the human disease. We show enhanced CLL disease progression in IRF4-deficient Tcl-1 tg mice, associated with a severe downregulation of genes involved in T-cell activation, including genes involved in antigen processing/presentation and T-cell costimulation, which massively reduced T-cell subset skewing and exhaustion. We found a strong analogy in the human disease, with inferior prognosis of CLL patients with low IRF4 expression in independent CLL patient cohorts, failed T-cell skewing to antigen-experienced subsets, decreased costimulation capacity, and downregulation of genes involved in T-cell activation. These results have therapeutic relevance because our findings on molecular mechanisms of immune privilege may be responsible for the failure of immune-therapeutic strategies in CLL and may lead to improved targeting in the future.
© 2019 by The American Society of Hematology.
- PMID:
- 31537531
- PMCID:
- PMC6895374
- DOI:
- 10.1182/blood.2019000973
- [Indexed for MEDLINE]
21.
Med Sci Monit. 2019 Aug 26;25:6405-6416. doi: 10.12659/MSM.915111.
Association of Platelet Membrane Fatty Acid Composition with Markers of Oxidative Stress in Healthy Men.
Bikulčienė I1, Golubevaitė O1, Žėkas V1, Radzevičius M1, Karčiauskaitė D1, Matuzevičienė R1, Hendrixson V1, Mažeikienė A1, Burokienė N2, Kaminskas A1, Kučinskienė ZA1.
Abstract
BACKGROUND Platelet membranes are extremely susceptible to peroxidation, forming a variety of lipid peroxides, including malondialdehyde (MDA), which has been implicated in the etiology of cardiovascular diseases. Moreover, platelet-leukocyte aggregates (PLAs) are known to contribute to advanced endothelial injury and atherogenesis. MATERIAL AND METHODS Fatty acid (FA) methyl esters of the platelet membranes of 79 apparently healthy men without any acute clinical condition at the time of the study were identified by GC/MS. MDA was measured by HPLC in blood serum, and PLAs were analyzed by whole-blood flow cytometry. Individuals were divided into quartiles according to MDA concentration and percentage of PLAs formation. The composition of platelet membrane FAs was compared to MDA concentration and the percentage of PLAs formation in apparently healthy individuals. RESULTS In quartiles (Q) with higher MDA concentration, percentage of C 16: 1ω7 (Q₁ vs. Q₃, p=0.021), C 20: 1ω9 (Q₂ vs. Q₄, p=0.028) and C 20: 5ω3 (Q₂ vs. Q₄, p=0.046) was lower. However, C 22: 5ω3 (Q₁ vs. Q₄, p=0.038) and total ω3 (Q₁ vs. Q₂, p=0.024) were higher. CONCLUSIONS MDA and the formation of platelet-monocyte aggregates stimulate the incorporation of monounsaturated fatty acids and polyunsaturated fatty acids in platelet phospholipid membranes, which may be a hallmark for a changed level of biologically active compounds required for the activation of future platelets.
22.
Ann Surg Oncol. 2019 Nov;26(12):4070-4080. doi: 10.1245/s10434-019-07645-9. Epub 2019 Aug 5.
Margin Analysis in Head and Neck Cancer: State of the Art and Future Directions.
Abstract
BACKGROUND:
The status of surgical margins is the most important prognosticator for patients undergoing surgical resection of head and neck squamous cell carcinoma (HNSCC). Despite this, analysis of surgical margins is fraught with inconsistencies, including the ways in which margins are sampled and interpreted. Fundamentally, even the definition what constitutes a "clear" (or negative) margin may vary between institutions, surgeons, and pathologists.
METHODS:
The PubMed database was queried for articles relevant to the topic, and experts in the field were consulted regarding key articles for inclusion. Abstracts were reviewed and the full text was accessed for articles of particular interest.
RESULTS:
Data regarding various approaches to traditional margin analysis have been published without consensus. Several next-generation technologies have emerged in recent years that hold promise.
CONCLUSION:
An overview and appraisal of traditional margin analysis techniques are provided. Additionally, we explore novel technologies that may assist in more accurate margin assessment, guide the extent of surgical resections intraoperatively, and inform decisions regarding adjuvant treatment postoperatively.
23.
Gynecol Endocrinol. 2019 Nov;35(11):945-948. doi: 10.1080/09513590.2019.1633298. Epub 2019 Jun 28.
Endometriosis, the great imitator - a successful case of fertility preservation in a woman receiving sterilizing treatment due to a diagnosis of rectosigmoid carcinoma.
Abstract
Bowels are the most common site of extrapelvic endometriosis. Still, colonic endometriosis often presents a diagnostic challenge, mimicking a broad spectrum of diseases including primary colonic malignancy. For women of fertile age, the consequences of endometriosis being misdiagnosed as colorectal cancer may include loss of fertility. We hereby present a case of endometriosis mimicking rectosigmoid adenocarcinoma in a young woman, where fertility preservation prior to the start of antineoplastic treatments turned out to be of crucial importance for the woman's future attempts to achieve a pregnancy and livebirth.
KEYWORDS:
Fertility preservation; colorectal adenocarcinoma; endometriosis; live birth
24.
Pancreas. 2019 Jul;48(6):837-843. doi: 10.1097/MPA.0000000000001345.
Benefit of Gemcitabine/Nab-Paclitaxel Rescue of Patients With Borderline Resectable or Locally Advanced Pancreatic Adenocarcinoma After Early Failure of FOLFIRINOX.
Vreeland TJ1, McAllister F, Javadi S2, Prakash LR1, Fogelman DR3, Ho L3, Varadhachary G3, Aloia TA1, Vauthey JN1, Lee JE1, Kim MP1, Katz MHG1, Tzeng CD1.
Abstract
OBJECTIVES:
Neoadjuvant therapy (NT) is used for advanced pancreatic ductal adenocarcinoma (PDAC). No clear guidelines exist for switching therapies when patients do not respond to initial NT. We sought to characterize patients who underwent early switch from FOLFIRINOX to gemcitabine/nab-paclitaxel (GA) as NT for PDAC.
METHODS:
We identified patients at a single institution switched from FOLFIRINOX to GA within the first 4 months of NT for PDAC during 2012-2017. We compared clinicopathologic data and oncologic outcomes.
RESULTS:
Of 25 patients who met the criteria, 21 showed a serologic or radiographic response to GA; 11 (52%) reached resection. Responders had decreased carbohydrate antigen (CA) 19-9 levels from pretreatment to post-GA (P = 0.036). Resected responders had significantly decreased CA 19-9 comparing preswitch to post-GA (P = 0.048). The only predictor of GA response was prechemotherapy CA 19-9 of less than1000 U/mL (P = 0.021). Predictors of reaching resection were head/uncinate tumor (P = 0.010) and presenting stage lower than locally advanced (P = 0.041).
CONCLUSIONS:
When patients do not respond to neoadjuvant FOLFIRINOX, early switch to GA should be considered. Future efforts should be directed toward identifying markers that will allow correct choice of initial therapy rather than attempting to rescue patients who respond poorly to first-line therapy.
25.
Gynecol Endocrinol. 2019 Nov;35(11):919-923. doi: 10.1080/09513590.2019.1611763. Epub 2019 Jun 11.
Importance of ovarian tissue cryopreservation in fertility preservation and anti-aging treatment.
Abstract
Various oncological and non-oncological diseases, as well as their treatments, can cause premature ovarian insufficiency and reduce a woman's reproductive potential. Fertility preservation is, therefore, becoming an emerging field of reproductive medicine allowing these patients to have their own biological children. The aim of this review is to analyze the importance of ovarian tissue cryopreservation as a fertility preservation method as well as its new role as a hormone replacement treatment. Although ovarian tissue cryopreservation is currently regarded as an experimental procedure, it is rapidly advancing and may become an established fertility preservation method in the near future. This method does not require ovarian stimulation or a subsequent delay in the initiation of cancer treatment. Furthermore, orthotopic ovarian tissue transplantation offers the unique opportunity of spontaneous conception. Due to the restoration of endocrine function following the procedure, ovarian tissue cryopreservation may also be used as tissue hormone replacement therapy in cases of premature ovarian insufficiency, to postpone menopause and prevent its troublesome symptoms and diseases. Even though the role of ovarian tissue cryopreservation as a new anti-aging treatment modality is quite promising, the safety and efficacy of this approach should be investigated in clinical settings.
KEYWORDS:
Ovarian tissue cryopreservation; anti-aging therapy; fertility preservation; menopause; premature ovarian insufficiency
26.
Target Oncol. 2019 Jun;14(3):247-252. doi: 10.1007/s11523-019-00643-7.
The Urinary Microbiome and Anticancer Immunotherapy: The Potentially Hidden Role of Unculturable Microbes.
Abstract
Several urinary disorders, including overactive bladder, urinary incontinence, and interstitial cystitis, are often characterized by negative urine cultures. The application of metagenomics (i.e., 16S rRNA microbial profiling or whole-genome shotgun sequencing) to urine samples has enabled the identification of previously undetected bacteria, contributing to the discovery and characterization of the urinary microbiome. The most frequent species isolated are Lactobacillus (15%), Corynebacterium (14.2%), Streptococcus (11.9%), Actinomyces (6.9%), and Staphylococcus (6.9%). Although several studies are emerging in this context, the role of urinary microbiota in the pathogenesis of infections and in tumor carcinogenesis remains unclear. Furthermore, data on the activity of gut microbiota in modulating sensitivity to immune checkpoint inhibitors in advanced cancer patients suggest that the influence of urinary microbiota on tumor response to anticancer therapy should also be investigated. Moreover, its possible relationship with tumor mutational burden, which is in turn correlated with response to immunotherapy, should be the focus of future studies. Of note, the effect of antibiotics on this complex scenario seems to deserve careful consideration.
27.
JAMA Netw Open. 2019 May 3;2(5):e193433. doi: 10.1001/jamanetworkopen.2019.3433.
Correlation of Milestone Restricted Mean Survival Time Ratio With Overall Survival Hazard Ratio in Randomized Clinical Trials of Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis.
Wang ZX1, Wu HX1,2, Xie L3, Wang YN1, Yang LP1, He MM1, Luo HY1, Ding PR4, Xie D5, Chen G4, Li YH1, Wang F1, Xu RH1.
Abstract
IMPORTANCE:
Immune checkpoint inhibitors (ICIs) have unique patterns of response and survival that differ from conventional chemotherapies. Novel intermediate end points are urgently required to detect the early signals of ICI activity.
OBJECTIVE:
To evaluate milestone rate (Kaplan-Meier estimates of survival probabilities at given time points) and milestone restricted mean survival time (RMST, the area under survival curves up to given time points) as potential intermediate end points for ICI trials.
DATA SOURCES:
Electronic databases (pre-MEDLINE, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials) were searched for randomized clinical trials published between January 1, 2000, and December 31, 2017.
STUDY SELECTION:
Phase 2 and phase 3 randomized clinical trials evaluating ICIs in advanced solid tumors.
DATA EXTRACTION AND SYNTHESIS:
Two investigators extracted the data and reconstructed individual patient data to estimate the milestone rate or milestone RMST from the published Kaplan-Meier curves.
MAIN OUTCOMES AND MEASURES:
Trial-level milestone rates or milestone RMSTs were estimated for 6-month and 9-month progression-free survival (PFS) and 9-month and 12-month overall survival (OS). A weighted linear regression model evaluated the correlations of ratios of milestone rates or milestone RMSTs with OS hazard ratios (HRs).
RESULTS:
Twenty-six trials examining 8 different tumor types were identified, including 12 892 patients. Overall survival HR was correlated with the ratio of 9-month OS milestone rate (R2 = 0.45; 95% CI, 0.27-0.74), and with the ratio of 12-month OS milestone rate (R2 = 0.40; 95% CI, 0.22-0.70). The ratio of 9-month OS milestone RMST (R2 = 0.60; 95% CI, 0.28-0.74) and ratio of 12-month OS milestone RMST were correlated with OS HR (R2 = 0.64; 95% CI, 0.42-0.78). No correlations were observed between OS HR and the ratio of 6-month or 9-month PFS milestone rates or milestone RMSTs.
CONCLUSIONS AND RELEVANCE:
Ratios of OS milestone RMSTs had a stronger correlation with OS HRs than ratios of OS milestone rates, whereas ratios of PFS milestone rates and ratios of PFS milestone RMSTs were not correlated with OS HRs. The OS milestone RMST could be further studied as an intermediate end point in future ICI trials.
- PMID:
- 31050784
- PMCID:
- PMC6503508
- DOI:
- 10.1001/jamanetworkopen.2019.3433
- [Indexed for MEDLINE]
28.
Ann Palliat Med. 2019 Sep;8(4):390-400. doi: 10.21037/apm.2019.02.05. Epub 2019 Mar 8.
Validation of Modified Breast Graded Prognostic Assessment for breast cancer patients with brain metastases: extra-cranial disease progression is an independent risk factor.
Abstract
BACKGROUND:
Breast cancer (BC) patients with brain metastases (BM) are heterogeneous with markedly variable survival. The Breast Graded Prognostic Assessment (B-GPA) and Modified B-GPA (mB-GPA) have been proposed as useful tools for stratifying survival in this population. However, extra-cranial disease progression, a clinically important variable, is not incorporated into the final model. We undertook the validation of B-GPA and mB-GPA in an Asian cohort and further explore extra-cranial disease progression as a prognostic factor.
METHODS:
Data of BC patients with newly diagnosed BM between 2006 and 2017 was extracted retrospectively from a prospectively maintained institutional database. Patients were classified based on their B-GPA and mB-GPA scores. Univariate (UVA) and multivariate analysis (MVA) using the Cox proportional hazard model were performed to investigate the factors prognostic of overall survival (OS). The Kaplan-Meier method was used to estimate OS and log-rank test to compare survival between scores. The performances of B-GPA and mB-GPA were compared using Harrell's concordance index (C-index) and Akaike information criterion (AIC).
RESULTS:
In our cohort of 282 patients, the B-GPA and mB-GPA were validated as prognostic tools for OS, demonstrating excellent separation between survival curves (P <0.001). In MVA, we found all components of mB-GPA (age, performance status, number of BM, tumour subtype) to be independent predictors of survival. C-index was 0.64 and AIC was 2,483.39 for B-GPA. mB-GPA demonstrated marginally better discrimination with a C-index of 0.65 and AIC of 2,445.78. Extra-cranial progression was an independent predictor for survival in our population (P <0.001).
CONCLUSIONS:
The mB-GPA incorporates four simple clinical variables each of independent prognostic significance. Both B-GPA and mB-GPA demonstrate moderate discriminative capabilities for OS with mB-GPA performing marginally better. Inclusion of extra-cranial disease progression as a factor in future model development may further improve its prognostic value.
KEYWORDS:
Breast cancer (BC); brain metastases (BM); extra-cranial progression; prognostication; radiotherapy
29.
Ann Palliat Med. 2019 Sep;8(4):381-389. doi: 10.21037/apm.2019.02.07. Epub 2019 Mar 14.
Early palliative care and quality of life of advanced cancer patients-a multicenter randomized clinical trial.
Franciosi V1, Maglietta G2, Degli Esposti C3, Caruso G4, Cavanna L5, Bertè R6, Bacchini G4, Bocchi L4, Piva E7, Monfredo M5, Scafuri V7, Di Cesare P5, Melotti B3, Sequino M2, Rimanti A4, Binovi C4, Ghisoni F8, Caminiti C2.
Abstract
BACKGROUND:
To compare quality of life (QoL) of patients receiving early palliative care (EPC) vs. standard oncologic care (SOC).
METHODS:
Pragmatic, multicenter, randomized trial at five University and Community Hospital Cancer Centers in Northern Italy. Advanced non-small cell lung, gastric, pancreatic and biliary tract cancer patients diagnosed within the previous 8 weeks. In the EPC arm, visits were performed systematically by a dedicated physician/nurse palliative care (PC) team, who assessed physical and psychosocial symptoms, and enacted the necessary services. In the SOC arm, PC visits were only carried out if requested. The primary outcome was the difference in the change of QoL [Functional Assessment of Cancer Therapy-General measure (FACT-G)] from baseline to 12 weeks in the two groups.
RESULTS:
From November 2014 to March 2016, 281 patients were enrolled (142 EPC, 139 SOC); 218 completed FACT-G at 12 weeks. Baseline demographic and clinical characteristics were similar for the two groups. Values of FACT-G at baseline and 12 weeks were 72.3 (SD 12.6) and 70.1 (SD 15.5) for patients enrolled in the EPC arm, vs. 71.7 (SD 14.7) and 69.6 (SD 15.5) for the SOC arm, but the change scores did not differ significantly between groups. In the multivariable analysis, adjusting for QoL at baseline, two potential prospective prognostic factors were statistically significant: lung cancer (P=0.03) and interaction of living without a partner and intervention arm (P=0.01). Dying within 6 months (P<0.001) was also statistically significant.
CONCLUSIONS:
In this study, EPC did not improve QoL in advanced cancer patients, but our findings highlight aspects which may guide future research on EPC.
KEYWORDS:
Non-small-cell lung cancer; early palliative care (EPC); gastric cancer; pancreatic cancer; randomized clinical trial
30.
Blood Adv. 2019 Feb 26;3(4):658-669. doi: 10.1182/bloodadvances.2018029983.
Inhibition of contact-mediated activation of factor XI protects baboons against S aureus-induced organ damage and death.
Silasi R1, Keshari RS1, Lupu C1, Van Rensburg WJ2, Chaaban H3, Regmi G1, Shamanaev A4, Shatzel JJ5,6, Puy C5, Lorentz CU5,7, Tucker EI5,7, Gailani D4, Gruber A5,6,7, McCarty OJT5,6, Lupu F1,8,9,10.
Abstract
Staphylococcus aureus infections can produce systemic bacteremia and inflammation in humans, which may progress to severe sepsis or septic shock, even with appropriate antibiotic treatment. Sepsis may be associated with disseminated intravascular coagulation and consumptive coagulopathy. In some types of mouse infection models, the plasma coagulation protein factor XI (FXI) contributes to the pathogenesis of sepsis. We hypothesize that FXI also contributes to the pathogenesis of sepsis in primates, and that pharmacological interference with FXI will alter the outcome of Staphylococcus aureus-induced lethality in a baboon model. Pretreatment of baboons with the anti-FXI antibody 3G3, a humanized variant of the murine monoclonal 14E11 that blocks FXI activation by FXIIa, substantially reduced the activation of coagulation, as reflected by clotting times and plasma complexes of coagulation proteases (FXIIa, FXIa, FIXa, FXa, FVIIa, and thrombin) with serpins (antithrombin or C1 inhibitor) following infusion of heat-inactivated S aureus 3G3 treatment reduced fibrinogen and platelet consumption, fibrin deposition in tissues, neutrophil activation and accumulation in tissues, cytokine production, kininogen cleavage, cell death, and complement activation. Overall, 3G3 infusion protected the structure and function of multiple vital organs, including lung, heart, liver, and kidney. All treated animals reached the end point survival (7 days), whereas all nontreated animals developed terminal organ failure within 28 hours. We conclude that FXI plays a role in the pathogenesis of S aureus-induced disseminated intravascular coagulation and lethality in baboons. The results provide proof of concept for future therapeutic interventions that may prevent sepsis-induced organ failure and save lives in certain forms of sepsis.
© 2019 by The American Society of Hematology.
- PMID:
- 30808684
- PMCID:
- PMC6391670
- DOI:
- 10.1182/bloodadvances.2018029983
- [Indexed for MEDLINE]
31.
Nat Rev Immunol. 2019 Jun;19(6):369-382. doi: 10.1038/s41577-019-0127-6.
Macrophages as regulators of tumour immunity and immunotherapy.
Abstract
Macrophages are critical mediators of tissue homeostasis, with tumours distorting this proclivity to stimulate proliferation, angiogenesis and metastasis. This had led to an interest in targeting macrophages in cancer, and preclinical studies have demonstrated efficacy across therapeutic modalities and tumour types. Much of the observed efficacy can be traced to the suppressive capacity of macrophages, driven by microenvironmental cues such as hypoxia and fibrosis. As a result, tumour macrophages display an ability to suppress T cell recruitment and function as well as to regulate other aspects of tumour immunity. With the increasing impact of cancer immunotherapy, macrophage targeting is now being evaluated in this context. Here, we discuss the results of clinical trials and the future of combinatorial immunotherapy.
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου