1.
Phytomedicine. 2020 Apr 16;70:153227. doi: 10.1016/j.phymed.2020.153227. [Epub ahead of print]
Breast Tumor Microenvironment: Emerging target of therapeutic phytochemicals.
Abstract
Triple negative breast cancer (TNBC) is the most aggressive and challenging form of breast cancers. Tumor microenvironment (TME) of TNBC is associated with induction of metastasis, immune system suppression, escaping immune detection and drug resistance. TME is highly complex and heterogeneous, consists of tumor cells, stromal cells and immune cells. The rapid expansion of tumors induce hypoxia, which concerns the reprogramming of TME components. The reciprocal communication of tumor cells and TME cells predisposes cancer cells to metastasis by modulation of developmental pathways, Wnt, notch, hedgehog and their related mechanisms in TME. Dietary phytochemicals are non-toxic and associated with various human health benefits and remarkable spectrum of biological activities. The phytochemicals serve as vital resources for drug discovery and also as a source for breast cancer therapy. The novel properties of dietary phytochemicals propose platform for modulation of tumor signaling, overcoming drug resistance, and targeting TME. Therefore, TME could serve as promising target for the treatment of TNBC. This review presents current status and implications of experimentally evaluated therapeutic phytochemicals as potential targeting agents of TME, potential nanosystems for targeted delivery of phytochemicals and their current challenges and future implications in TNBC treatment. The dietary phytochemicals especially curcumin with significant delivery system could prevent TNBC development as it is considered safe and well tolerated in phase II clinical trials.
Copyright © 2020 Elsevier GmbH. All rights reserved.
KEYWORDS:
Chemoresistance; Metastasis; Phytochemicals; TME; TNBC
2.
Oncologist. 2020 Apr 27. doi: 10.1634/theoncologist.2019-0646. [Epub ahead of print]
EMA Review of Axicabtagene Ciloleucel (Yescarta) for the Treatment of Diffuse Large B-Cell Lymphoma.
Papadouli I1, Mueller-Berghaus J2, Beuneu C3, Ali S1, Hofner B2, Petavy F1, Tzogani K1, Miermont A3, Norga K3,4, Kholmanskikh O3, Leest T3, Schuessler-Lenz M2, Salmonson T5, Gisselbrecht C6, Garcia JL1, Pignatti F1.
Abstract
On June 28, 2018, the Committee for Advanced Therapies and the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Yescarta for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma, after two or more lines of systemic therapy. Yescarta, which was designated as an orphan medicinal product and included in the European Medicines Agency's Priority Medicines scheme, was granted an accelerated review timetable. The active substance of Yescarta is axicabtagene ciloleucel, an engineered autologous T-cell immunotherapy product whereby a patient's own T cells are harvested and genetically modified ex vivo by retroviral transduction using a retroviral vector to express a chimeric antigen receptor (CAR) comprising an anti-CD19 single chain variable fragment linked to CD28 costimulatory domain and CD3-zeta signaling domain. The transduced anti-CD19 CAR T cells are expanded ex vivo and infused back into the patient, where they can recognize and eliminate CD19-expressing cells. The benefits of Yescarta as studied in ZUMA-1 phase II (NCT02348216) were an overall response rate per central review of 66% (95% confidence interval, 56%-75%) at a median follow-up of 15.1 months in the intention to treat population and a complete response rate of 47% with a significant duration. The most common adverse events were cytokine release syndrome, neurological adverse events, infections, pyrexia, diarrhea, nausea, hypotension, and fatigue. IMPLICATIONS FOR PRACTICE: Yescarta (axicabtagene ciloleucel) was the first chimeric antigen receptor T-cell therapy to be submitted for evaluation to the European Medicines Agency and admitted into the "priority medicine" scheme; it was granted accelerated assessment on the basis of anticipated clinical benefit in relapsed/refractory diffuse large B-cell lymphoma, a condition of unmet medical need. Indeed, Yescarta showed an overall response rate of 66% and a complete response rate of 47% with a significant duration and a manageable toxicity that compared very favorably with historical controls. Here the analysis of benefits and risks is presented, and specific challenges with this important novel product are highlighted, providing further insights and reflections for future medical research.
© AlphaMed Press 2020.
KEYWORDS:
Axicabtagene ciloleucel; CAT; CHMP; Chimeric antigen receptor; Cytokine release syndrome; Diffuse large B-cell lymphoma; Primary mediastinal B-cell lymphoma
3.
Biometrics. 2020 Apr 27. doi: 10.1111/biom.13289. [Epub ahead of print]
A Semi-parametric Bayesian approach to population finding with time-to-event and toxicity data in a randomized clinical trial.
Abstract
A utility-based Bayesian population finding (BaPoFi) method was proposed by Morita and Müller (2017, Biometrics, 1355-1365) to analyze data from a randomized clinical trial with the aim of identifying good predictive baseline covariates for optimizing the target population for a future study. The approach casts the population finding process as a formal decision problem together with a flexible probability model using a random forest to define a regression mean function. BaPoFi is constructed to handle a single continuous or binary outcome variable. In this paper, we develop BaPoFi-TTE as an extension of the earlier approach for clinically important cases of time-to-event (TTE) data with censoring, and also accounting for a toxicity outcome. We model the association of TTE data with baseline covariates using a semi-parametric failure time model with a Pólya tree prior for an unknown error term and a random forest for a flexible regression mean function. We define a utility function that addresses a trade-off between efficacy and toxicity as one of the important clinical considerations for population finding. We examine the operating characteristics of the proposed method in extensive simulation studies. For illustration, we apply the proposed method to data from a randomized oncology clinical trial. Concerns in a preliminary analysis of the same data based on a parametric model motivated the proposed more general approach.
This article is protected by copyright. All rights reserved.
KEYWORDS:
Bayesian additive regression trees; Bayesian decision problem; Efficacy-toxicity trade-off; Non-parametric Bayesian; Population finding; Pólya tree prior
4.
ANZ J Surg. 2020 Apr 27. doi: 10.1111/ans.15909. [Epub ahead of print]
Management of pleomorphic dermal sarcoma.
Abstract
BACKGROUND:
Pleomorphic dermal sarcoma (PDS) is a rare, poorly defined skin neoplasm with features similar to atypical fibroxanthoma, but with adverse histopathological characteristics indicating metastatic potential such as tumour necrosis, invasion beyond superficial subcutis or vascular and/or perineural infiltration. Optimal treatment for PDS is uncertain and reported outcomes vary due to the rarity of this diagnosis and uncertainty over histopathological categorization. The aim of this study was to review the clinical and histopathological features of PDS in a single Australian centre.
METHODS:
A retrospective review of all patients managed at the Peter MacCallum Cancer Centre with PDS between 2003 and 2017 was performed by a search of electronic records and histories reviewed.
RESULTS:
A total of 27 patients were identified, mostly elderly males (85.2%, mean age 79.8 years). Lesions were seen most commonly on the head and neck region (96.3%), predominantly on the scalp (63%). Mean tumour radial surgical excision margin was 12.8 mm. Eighteen patients (66.7%) underwent radiotherapy; 13 adjuvant, three neoadjuvant and two with palliative intent. After median follow-up of 46.4 months, two patients had recurrence (7.4%); both had inadequate deep margins at first excision. There were three all-cause deaths in the cohort. There was one disease-specific mortality with metastatic PDS disease at the time of initial presentation.
CONCLUSION:
PDS is a rare cutaneous malignancy most commonly found in the head and neck region in elderly men, which is best managed with adequate surgical excision. The role of radiotherapy is undefined and an area for future investigation.
© 2020 Royal Australasian College of Surgeons.
KEYWORDS:
sarcoma; skin neoplasm; skin surgery; surgical oncology; treatment
5.
Future Oncol. 2020 Apr 27. doi: 10.2217/fon-2019-0849. [Epub ahead of print]
Real-world treatment duration in ALK-positive non-small-cell lung cancer patients receiving brigatinib through the early access program.
Abstract
Aim: To assess time-to-treatment discontinuation (TTD) of brigatinib following treatment with ALK tyrosine kinase inhibitor(s) (TKIs) in patients with ALK-positive (ALK+) non-small-cell lung cancer (NSCLC) receiving brigatinib through the international early access program. Patients & analysis: Analysis was performed for patients with ALK+ NSCLC treated with prior ALK TKIs, including next-generation ALK TKIs. Results: Data for 604 patients (21 countries), including patients with prior next-generation ALK TKIs, were reported. The median TTD of brigatinib in patients with prior crizotinib, alectinib, ceritinib or lorlatinib was 10.0, 8.7, 10.3 and 7.5 months, respectively. Conclusion: Brigatinib appears to be effective and tolerable in real-world clinical practice regardless of prior treatment with first or NG ALK TKIs.
KEYWORDS:
alectinib; anaplastic lymphoma kinase positive non-small-cell lung cancer; brigatinib; ceritinib; compassionate use; crizotinib; early access; lorlatinib; real-world evidence; treatment duration
6.
Arch Pathol Lab Med. 2020 Apr 27. doi: 10.5858/arpa.2019-0267-OA. [Epub ahead of print]
The Development and Implementation of a Novel Electronic Consult System by a Laboratory Medicine Service: Experience From the First 2 Years of Use.
Abstract
CONTEXT.—:
A novel electronic consult (e-consult) system for a pathology and laboratory medicine service (PLMS) was implemented in 2015 at a high-complexity Veterans Administration health care facility. Consults were previously made through direct provider communication without documentation in the medical record.
OBJECTIVE.—:
To evaluate the utilization trends of the laboratory e-consult system at the Department of Veterans Affairs Connecticut facility during the first 2 years since inception.
DESIGN.—:
E-consultation involves pathology and laboratory medicine resident review followed by attending review and cosignature. E-consults to the pathology and laboratory medicine service from 2015 to 2017 were reviewed to record type of consult, requesting department, patient location, and turnaround time.
RESULTS.—:
The pathology and laboratory medicine service received 351 e-consults from 2015 to 2017. The volume varied by subsection: hematology and coagulation (215 of 351; 61%), chemistry (109 of 351; 31%), blood bank (19 of 351; 6%), and microbiology/virology (8 of 351; 2%). Hematology and coagulation consults were entirely for peripheral blood smear review (215 of 215; 100%). Chemistry consults were placed for toxicology/drugs of abuse (81 of 109; 74%), test utilization (17 of 109; 16%), or nontoxicology (11 of 109; 10%). Three services placed the majority of consults: primary care (279 of 351; 80%), hematology/oncology (39 of 351; 11%), and psychiatry (27 of 351; 8%). The median turnaround time for completion of e-consults was 1.2 days. Since e-consult implementation, the mean number of consults increased from 8.6/mo in 2015 to 18.1/mo in 2017, peaking in the last quarter of analysis in 2017 with a mean of 25.3 consults/mo.
CONCLUSIONS.—:
This novel e-consult system improved accessibility to and documentation of answers to laboratory questions and increased the visibility of the pathology and laboratory medicine service. Future goals include development of outcomes-based measures to better assess the clinical impact of e-consults.
7.
Am J Epidemiol. 2020 Apr 27. pii: kwaa065. doi: 10.1093/aje/kwaa065. [Epub ahead of print]
Cardiotoxicity of Sequential Aromatase Inhibitors Use in Women with Breast Cancer.
Abstract
The association between aromatase inhibitors and cardiovascular outcomes is controversial. While some observational studies have assessed their cardiovascular safety as up-front treatments, their cardiotoxic effects as sequential treatments with tamoxifen remains unknown. Thus, we conducted a population-based cohort study using the United Kingdom Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. A prevalent new-user design was used to propensity score match, in a 1:2 ratio, patients switching from tamoxifen to aromatase inhibitors to patients continuing tamoxifen between 1998 and 2016. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for the study outcomes (myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality). Overall, 1,962 patients switching to aromatase inhibitors were matched to 3,874 patients continuing tamoxifen. Compared with tamoxifen, aromatase inhibitors were associated with an increased risk of myocardial infarction (HR=2.08; 95% CI: 1.02, 4.27). The hazard ratio was elevated with ischemic stroke (HR=1.58; 95% CI: 0.85, 2.93), heart failure (HR=1.69; 95% CI: 0.79, 3.62), but not cardiovascular mortality (HR=0.87; 95% CI: 0.49, 1.54), with CIs including the null. The elevated HRs observed for the cardiovascular outcomes should be corroborated in future large observational studies.
© The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
KEYWORDS:
Aromatase Inhibitors; Breast Cancer; Cardiovascular Disease; Endocrine Therapy; Tamoxifen
8.
Future Oncol. 2020 Apr 27. doi: 10.2217/fon-2020-0218. [Epub ahead of print]
Idasanutlin as a new treatment option in improving the therapeutic odyssey of relapsed/refractory AML.
KEYWORDS:
AML; MDM2 inhibitor; TP53; acute myeloid leukemia; idasanutlin; relapsed or refractory
9.
Future Oncol. 2020 Apr 27. doi: 10.2217/fon-2019-0822. [Epub ahead of print]
Therapeutic status and the prospect of CRISPR/Cas9 gene editing in multiple myeloma.
Abstract
In recent years, CRISPR/Cas9, a novel gene-editing technology, has shown considerable potential in the design of novel research methods and future options for treating multiple myeloma (MM). The use of CRISPR/Cas9 promises faster and more accurate identification and validation of target genes. In this review, we summarize the current research status of the application of CRISPR technology in MM, especially in detecting the expression of MM gene, exploring the mechanism of drug action, screening for drug-resistant genes, developing immunotherapy and screening for new drug targets. Given the tremendous progress that has been made, we believe that CRISPR/Cas9 possesses great potential in MM-related clinical practice.
KEYWORDS:
CAR-T; CRISPR/Cas9; antitumor immunity; drug resistance; gene editing; gene therapy; immune checkpoints; immunotherapy; multiple myeloma; therapeutic targets
10.
Future Oncol. 2020 Apr 27. doi: 10.2217/fon-2020-0063. [Epub ahead of print]
The future of radiation-induced abscopal response: beyond conventional radiotherapy approaches.
Abstract
Advances in the immunological pharmaceuticals, such as checkpoint inhibitors and agonists, have positive implications for the future of the radiotherapy abscopal response. A once rare phenomenon, whereby distant nonirradiated tumor sites regressed after radiotherapy alone, may become more common when combined with the immune modulating agents. Radiotherapy can increase neoantigen expression, increased tumor PD-L1 expression, increase MHC class I expression, reverse exhausted CD8 T cells and increase tumor-infiltrating tumors within the tumor microenvironment. These changes in the tumor and the tumor microenvironment after radiotherapy could potentiate responses to anti-CTL-4, anti-PD-L1/PD-1 and other immunotherapy agents. Thus, advances in checkpoint inhibitors have increased interest in re-evaluation of the role of conventional radiotherapy approaches on the immune system. We reviewed newer nonconventional approaches such as SBRT-PATHY, GRID, FLASH, carbon ion and proton therapy and their role in eliciting immune responses. We believe that combining these novel radiation methods may enhance the outcome with the newly US FDA approved immune modulating agents.
KEYWORDS:
FLASH; GRID; SBRT-PATHY; abscopal response; bystander effects; carbon ion; checkpoint inhibitors; immunotherapy; nontargeted effects; proton; radiotherapy
11.
Eur J Neurol. 2020 Apr 26. doi: 10.1111/ene.14283. [Epub ahead of print]
Patient-centeredness in acute stroke care - A qualitative study from the perspectives of patients, relatives and staff.
Busetto L1, Stang C1, Hoffmann J1, Amiri H1, Seker F2, Purrucker J1, Ringleb PA1, Nagel S1, Bendszus M2, Wick W1,3, Gumbinger C1; Stroke Consortium Rhine-Neckar.
Abstract
BACKGROUND:
Although patient-centeredness is considered a key component of high-quality neurological care, it is unclear to which extent it can or should be implemented during the acute phase. Using acute stroke as an example, we aim to identify critical junctures for patient-centeredness along the acute care pathway from the perspectives of patients, relatives and staff.
METHODS:
We conducted a qualitative multi-method study including 27 non-participant observations and 37 semi-structured interviews with patients, relatives and staff. We defined junctures as critical when mentioned (as problematic) in two or three information sources (i.e. observations, staff interviews, or patient and relative interviews), as potentially critical when mentioned in one, and as uncritical when not mentioned.
RESULTS:
Post-procedure communication after thrombectomy, patients' stay at the stroke unit and decision-making around transfer, discharge and rehabilitation were identified as critical junctures for patient-centeredness. Arrival at the emergency department and the (thrombectomy) treatment itself were identified as uncritical junctures, while history-taking and treatment preparation, the treatment decision, and patients' stay at the intensive care unit were identified as potentially critical junctures.
CONCLUSIONS:
In acute stroke care, patients, relatives and staff prioritise fast over patient-centred decision-making in the most time-critical phases, especially before and during treatment. This is reversed after the procedure, when difficulties arise implementing a patient-centred approach in clinical practice. To improve patient-centeredness where it is most needed, clear guidelines and accessible resources are recommended. Future research should investigate whether insights from acute phases of stroke care are applicable to other neurological conditions as well.
This article is protected by copyright. All rights reserved.
KEYWORDS:
MeSH-Search terms: All Clinical Neurology; Medical care; Patient-centred Care; Qualitative Research; Shared Decision Making
12.
Med Phys. 2020 Apr 26. doi: 10.1002/mp.14207. [Epub ahead of print]
On the implementation of the plan-class specific reference field using multidimensional clustering of plan features and alternative strategies for improved dosimetry in modulated clinical linear accelerator treatments.
Abstract
PURPOSE:
The plan-class specific reference field concept could theoretically improve the calibration of radiation detectors in a beam environment much closer to clinical deliveries than existing broad beam dosimetry protocols. Due to a lack of quantitative guidelines and representative data, however, the pcsr field concept has not yet been widely implemented. This work utilizes quantitative plan complexity metrics from modulated clinical treatments in order to investigate the establishment of potential plan classes using two different clustering methodologies. The utility of these potential plan clusters is then further explored by analyzing their relevance to actual dosimetric correction factors.
METHODS:
Two clinical databases containing several hundred modulated plans originally delivered on two Varian linear accelerators were analyzed using 21 plan complexity metrics. In the first approach, each database's plans were further subdivided into groups based on the anatomic site of treatment and then compared to one another using a series of non-parametric statistical tests. In the second approach, objective clustering algorithms were used to seek potential plan clusters in the multidimensional complexity-metric space. Concurrently, beam- and detector-specific dosimetric corrections for a subset of the modulated clinical plans were determined using Monte Carlo for three different ionization chambers. The distributions of the dosimetric correction factors were compared to the derived plan clusters to see which plan clusters, if any, could help predict the correction factor magnitudes. Ultimately, a simplified volume averaging metric (SVAM) is shown to be much more relevant to the total dosimetric correction factor than the established plan clusters.
RESULTS:
Plan groups based on the site of treatment did not show noticeable distinction from one another in the context of the metrics investigated. An objective clustering algorithm was able to discriminate VMAT plans from step-and-shoot IMRT plans with an accuracy of 90.8%, but no clusters were found to exist at any level more specific than delivery modality. Monte Carlo determined correction factors for the modulated plans ranged from 0.970-1.104, 0.983-1.027, and 0.986-1.009 for the A12, A1SL, and A26 chambers, respectively, and were highly variable even within the treatment modality plan clusters. The magnitudes of these correction factors were explained almost entirely by volume averaging with SVAM demonstrating positive correlation with all Monte Carlo established total correction factors.
CONCLUSIONS:
Plan complexity metrics do provide some quantitative basis for the investigation of plan clusters, but an objective clustering algorithm demonstrated that quantifiable differences could only be found between VMAT and step-and-shoot beams delivered on the same treatment machine. The inherent variability of the Monte Carlo determined correction factors could not be explained solely by the modality of the treatment but were instead almost entirely dependent upon the volume averaging correction, which itself depends on the detector position within the dose distribution, dose gradients, and other factors. Considering the continued difficulty of determining a relevant plan metric to base plan clusters on, case-by-case corrections may instead obviate the need for the pcsr field concept in the future.
This article is protected by copyright. All rights reserved.
13.
Curr Med Sci. 2020 Apr;40(2):348-353. doi: 10.1007/s11596-020-2190-4. Epub 2020 Apr 26.
Effect of China's Universal Two-child Policy on the Rate of Cesarean Delivery: A Case Study of a Big Childbirth Center in China.
Abstract
China's universal two-child policy was released in October of 2015. How would this new policy influence the rate of overall cesarean delivery (CD) in China? The objective of this paper is to investigate the trend of overall CD rate with the increase of number of multiparous women based on a big childbirth center of China (a tertiary hospital) in 2016. In this study, 22 530 cases from the medical record department of a big childbirth center of China from January 1 to December 31 in 2016 were enrolled as research objects. Electronic health records of these selected objects were retrieved. According to the history of childbirth, the selected cases were divided into primiparous group containing 16 340 cases and multiparous group containing 6190 cases. Chi-square test was carried out to compare the rate of CD, neuraxial labor analgesia, maternity insurance between the two groups; t-test was performed to compare the in-hospital days and gestational age at birth between the two groups. Pearson correlation coefficient was used to evaluate the relationship among observed monthly rate of multiparas, overall CD rate, and Elective Repeat Cesarean Delivery (ERCD) rate. The results showed that the CD rate in multiparous group was 55.46%, which was higher than that in primiparous group (34.66%, P<0.05). The rate of neuraxial labor analgesia in multiparas group was 9.29%, which was lower than that in primiparas group (35.94%, P<0.05). However, the rate of maternity insurance was higher in multiparas group (57.00%) than that in primiparas group (41.08%, P<0.05). The hospital cost and in-hospital days in multiparas group were higher, and the gestational age at birth in multiparas group was lower than in primiparas group (P<0.05). The overall CD rate slightly dropped in the first 4 months of the year (P<0.05), then increased from 36.27% (April) to 43.21% (December) (P<0.05). The rate of multiparas women and ERCD had the same trend (P<0.05). There were linear correlations among the rate of overall CD, the rate of multiparas women and the rate of ERCD rate (P<0.05). With the opening of China's two-child policy, the increasing rate of overall CD is directly related with the high rate of ERCD. Trials of Labor After Cesarean Section (TOLAC) in safe mode to reduce overall CD rate are warranted in the future.
KEYWORDS:
Trial of Labor After Cesarean Section (TOLAC); cesarean delivery; elective repeat cesarean delivery
14.
Support Care Cancer. 2020 Apr 26. doi: 10.1007/s00520-020-05451-8. [Epub ahead of print]
Fruit and vegetable consumptions in relation to frequent mental distress in breast cancer survivors.
Abstract
PURPOSE:
Evidence suggests that fruit and vegetable consumptions may improve mental health among general population. However, their associations among breast cancer survivors are unclear. We planned to investigate this association via a nationwide survey in the USA.
METHODS:
We identified 7988 breast cancer survivors from 2009 Behavioral Risk Factor Surveillance System (BRFSS). Fruit juice, fruit, and vegetable consumptions were categorized as ordinal variables to approximate tertiles. Survivors who were mentally unhealthy for at least 14 days in the past 30 days were defined as having frequent mental distress (FMD). Multivariable logistic regression treating FMD as the outcome was used to calculate adjusted odd ratios (aORs) and 95% confidence intervals (CIs) for exposures. Quadratic model was used to depict the dose-response pattern in primary analysis. Subgroup analyses by adverse lifestyle behaviors were conducted; Wald tests were used to examine if there were interactions between these factors and exposures in relation to FMD.
RESULTS:
Overall, 825 (10.3%) survivors had FMD. Mean age was 67.2 years, and 89.7% of survivors were white. Juice showed non-significant associations with FMD. Moderate (aOR = 0.81, 95% CI = 0.68-0.98) and high (aOR = 0.79, 95% CI = 0.63-0.98) fruit consumptions, as well as moderate vegetable consumption (aOR = 0.78, 95% CI = 0.64-0.94), were significantly and inversely associated with FMD. The dose-response curves were consistent with results in primary analysis. No interaction was identified for adverse lifestyle behaviors.
CONCLUSION:
Fruit and vegetable, but not fruit juice, show potential preventive effects against FMD among breast cancer survivors. The conclusion should be verified by studies with clear temporality in future.
KEYWORDS:
Cancer survivorship; Epidemiology; Fruit and vegetable; Mental health; Tertiary cancer prevention
15.
JNCI Cancer Spectr. 2019 Aug 10;3(4):pkz050. doi: 10.1093/jncics/pkz050. eCollection 2019 Dec.
Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 1: Late Recurrence: Current Understanding, Clinical Considerations.
Dowling RJO1,2, Kalinsky K3,4, Hayes DF5, Bidard FC6, Cescon DW1,7, Chandarlapaty S8,9, Deasy JO10, Dowsett M11, Gray RJ12,13, Henry NL14, Meric-Bernstam F15, Perlmutter J16, Sledge GW17, Bratman SV1,18,19,2, Carey LA20, Chang MC21, DeMichele A22, Ennis M23, Jerzak KJ24, Korde LA25, Lohmann AE26,27, Mamounas EP28, Parulekar WR29, Regan MM30, Schramek D26,31, Stambolic V1,2, Thorat MA32, Whelan TJ33, Wolff AC34, Woodgett JR26, Sparano JA35, Goodwin PJ26,27.
Abstract
Disease recurrence (locoregional, distant) exerts a significant clinical impact on the survival of estrogen receptor-positive breast cancer patients. Many of these recurrences occur late, more than 5 years after original diagnosis, and represent a major obstacle to the effective treatment of this disease. Indeed, methods to identify patients at risk of late recurrence and therapeutic strategies designed to avert or treat these recurrences are lacking. Therefore, an international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. In this article, the major issues surrounding late recurrence are defined and current approaches that may be applicable to this challenge are discussed. Specifically, diagnostic tests with potential utility in late-recurrence prediction are described as well as a variety of patient-related factors that may influence recurrence risk. Clinical and therapeutic approaches are also reviewed, with a focus on patient surveillance and the implementation of extended endocrine therapy in the context of late-recurrence prevention. Understanding and treating late recurrence in estrogen receptor-positive breast cancer is a major unmet clinical need. A concerted effort of basic and clinical research is required to confront late recurrence and improve disease management and patient survival.
© The Author(s) 2019. Published by Oxford University Press.
16.
JNCI Cancer Spectr. 2019 Aug 10;3(4):pkz049. doi: 10.1093/jncics/pkz049. eCollection 2019 Dec.
Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 2: Approaches to Predict and Identify Late Recurrence, Research Directions.
Dowling RJO1,2, Sparano JA3, Goodwin PJ4,5, Bidard FC6, Cescon DW1,7, Chandarlapaty S8,9, Deasy JO10, Dowsett M11, Gray RJ12,13, Henry NL14,15, Meric-Bernstam F16, Perlmutter J17, Sledge GW18, Thorat MA19, Bratman SV1,20,21,2, Carey LA22, Chang MC23, DeMichele A24, Ennis M25, Jerzak KJ26, Korde LA27, Lohmann AE4,5, Mamounas EP28, Parulekar WR29, Regan MM30, Schramek D4,31, Stambolic V1,2, Whelan TJ32, Wolff AC33, Woodgett JR4, Kalinsky K34,35, Hayes DF36.
Abstract
Late disease recurrence (more than 5 years after initial diagnosis) represents a clinical challenge in the treatment and management of estrogen receptor-positive breast cancer (BC). An international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. The underlying biological causes of late recurrence are complex, with the processes governing cancer cell dormancy, including immunosurveillance, cell proliferation, angiogenesis, and cellular stemness, being integral to disease progression. These critical processes are described herein as well as their role in influencing risk of recurrence. Moreover, observational and interventional clinical trials are proposed, with a focus on methods to identify patients at risk of recurrence and possible strategies to combat this in patients with estrogen receptor-positive BC. Because the problem of late BC recurrence of great importance, recent advances in disease detection and patient monitoring should be incorporated into novel clinical trials to evaluate approaches to enhance patient management. Indeed, future research on these issues is planned and will offer new options for effective late recurrence treatment and prevention strategies.
© The Author(s) 2019. Published by Oxford University Press.
17.
Data Brief. 2020 Apr 24:105619. doi: 10.1016/j.dib.2020.105619. [Epub ahead of print]
The Data set for Patient Information Based Algorithm to Predict Mortality Cause by COVID-19.
Li J1, Wang L1,2, Guo S3, Xie N4, Yao L5,6, Cao Y6, Day SW7, Howard SC7, Graff JC7, Gu T8, Ji J9, Gu W1,10, Sun D6.
Abstract
The data of COVID-19 disease in China and then in South Korea were collected daily from several different official websites. The collected data included 33 death cases in Wuhan city of Hubei province during early outbreak as well as confirmed cases and death toll in some specific regions, which were chosen as representatives from the perspective of the coronavirus outbreak in China. Data were copied and pasted onto Excel spreadsheets to perform data analysis. A new methodology, Patient Information Based Algorithm (PIBA) [1], has been adapted to process the data and used to estimate the death rate of COVID-19 in real-time. Assumption is that the number of days from inpatients to death fall into a pattern of normal distribution and the scores in normal distribution can be obtained by observing 33 death cases and analysing the data [2]. We selected 5 scores in normal distribution of these durations as lagging days, which will be used in the following estimation of death rate. We calculated each death rate on accumulative confirmed cases with each lagging day from the current data and then weighted every death rate with its corresponding possibility to obtain the total death rate on each day. While the trendline of these death rate curves meet the curve of current ratio between accumulative death cases and confirmed cases at some points in the near future, we considered that these intersections are within the range of real death rates. Six tables were presented to illustrate the PIBA method using data from China and South Korea. One figure on estimated rate of infection and patients in serious condition and retrospective estimation of initially occurring time of CORID-19 based on PIBA.
© 2020 Published by Elsevier Inc.
KEYWORDS:
COVID-19; Coronavirus; Death Rate; Estimation; Normal distribution; PIBA; Prediction
18.
Exp Hematol Oncol. 2020 Apr 20;9:7. doi: 10.1186/s40164-020-00159-1. eCollection 2020.
Dual EGFR blockade with cetuximab and erlotinib combined with anti-VEGF antibody bevacizumab in advanced solid tumors: a phase 1 dose escalation triplet combination trial.
Subbiah V#1,2, Dumbrava EI#1, Jiang Y1, Thein KZ1, Naing A1, Hong DS1, Fu S1, Piha-Paul SA1, Tsimberidou AM1, Janku F1, Meric-Bernstam F1, Kurzrock R#3, Falchook G#4.
Abstract
BACKGROUND:
Angiogenesis and activation of the epidermal growth factor (EGFR) pathway play an essential role in tumor proliferation and metastasis. Targeting angiogenesis or EGFR alone does not yield adequate tumor control in most solid tumors. Overcoming intrinsic and/or acquired resistance may need a doublet or triplet therapy strategy. Herein, we report the safety and feasibility of dual EGFR blockade with EGFR monoclonal antibody and EGFR tyrosine kinase inhibitor combined with anti-VEGF antibody in advanced solid tumors.
METHODS:
We conducted a phase I study combining erlotinib, cetuximab, and bevacizumab. Patients with advanced or metastatic solid tumors (excluding colorectal and non-small cell lung cancers) were analyzed for safety, toxicity profile, and response. Anti-tumor activity was evaluated per response evaluation criteria in solid tumors (RECIST 1.0).
RESULTS:
Thirty-six patients received treatment on a range of dose-levels. The most frequent tumor types enrolled were cervical (n = 10), head and neck squamous cell (n = 10), and follicular thyroid (n = 4) cancers. The most common treatment-related grade ≥ 2 adverse events were rash (56%), hypomagnesemia (17%), pruritus (11%), diarrhea (8%), and tumor-related bleeding (8%). Seventeen of 19 patients (89%) treated at the maximum tolerated dose did not present treatment-related dose-limiting toxicity. Fifteen (63%) of the 24 evaluable patients achieved a disease control (stable disease ≥ 4 months (n = 14) and partial response (n = 1). The median number of prior lines of therapies was 3 (range 1-10).
CONCLUSIONS:
The triplet combination of erlotinib, cetuximab, and bevacizumab was well tolerated, conferring clinical benefit in heavily pretreated patients. Future studies are warranted with second or third-generation EGFR tyrosine kinase triplet combinations in the EGFR pathway aberrant patients.Trial Registration: ClinicalTrials.gov Identifier: NCT00543504. Sponsor(s): National Cancer Institute (NCI), MD Anderson Cancer Center.
© The Author(s) 2020.
KEYWORDS:
Advanced solid tumors; Cetuximab, erlotinib and bevacizumab; Dual EGFR blockade; Phase 1 dose escalation
19.
Adv Exp Med Biol. 2020;1220:93-115. doi: 10.1007/978-3-030-35805-1_7.
Relevance of CTC Clusters in Breast Cancer Metastasis.
Abstract
Metastasis is the major cause of mortality in patients with breast cancer; however, the mechanisms of tumor cell dissemination and metastasis formation are not well established yet. The study of circulating tumour cells (CTCs), the metastatic precursors of distant disease, may help in this search. CTCs can be found in the blood of cancer patients as single cells or as tumor cell aggregates, known as CTC clusters. CTC clusters have differential biological features such as an enhanced survival and metastatic potential, and they hold great promises for the evaluation of prognosis, diagnosis and therapy of the metastatic cancer. The analysis of CTC clusters offers new insights into the mechanism of metastasis and can guide towards the development of new diagnostic and therapeutic strategies to suppress cancer metastasis. This has become possible thanks to the development of improved technologies for detection of CTCs and CTC clusters. However, more efficient methods are needed in order to address important questions regarding the metastatic potential of CTC and future clinical applications. In this chapter, we explore the current knowledge on the role of CTC clusters in breast cancer metastasis, their origin, metastatic advantages and clinical importance.
KEYWORDS:
Breast cancer; CTC clusters; Circulating tumor cells (CTCs); Heterotypic CTC clusters; Homotypic CTC clusters; Metastatic potential
20.
Int J Mol Sci. 2019 Nov 29;20(23). pii: E6016. doi: 10.3390/ijms20236016.
A Snapshot of The Tumor Microenvironment in Colorectal Cancer: The Liquid Biopsy.
Abstract
The molecular profile of liquid biopsies is emerging as an alternative to tissue biopsies in the clinical management of malignant diseases. In colorectal cancer, significant liquid biopsy-based biomarkers have demonstrated an ability to discriminate between asymptomatic cancer patients and healthy controls. Furthermore, this non-invasive approach appears to provide relevant information regarding the stratification of tumors with different prognoses and the monitoring of treatment responses. This review focuses on the tumor microenvironment components which are detected in blood samples of colorectal cancer patients and might represent potential biomarkers. Exosomes released by tumor and stromal cells play a major role in the modulation of cancer progression in the primary tumor microenvironment and in the formation of an inflammatory pre-metastatic niche. Stromal cells-derived exosomes are involved in driving mechanisms that promote tumor growth, migration, metastasis, and drug resistance, therefore representing substantial signaling mediators in the tumor-stroma interaction. Besides, recent findings of specifically packaged exosome cargo in Cancer-Associated Fibroblasts of colorectal cancer patients identify novel exosomal biomarkers with potential clinical applicability. Furthermore, additional different signals emitted from the tumor microenvironment and also detectable in the blood, such as soluble factors and non-tumoral circulating cells, arise as novel promising biomarkers for cancer diagnosis, prognosis, and treatment response prediction. The therapeutic potential of these factors is still limited, and studies are in their infancy. However, innovative strategies aiming at the inhibition of tumor progression by systemic exosome depletion, exosome-mediated circulating tumor cell capturing, and exosome-drug delivery systems are currently being studied and may provide considerable advantages in the near future.
KEYWORDS:
colorectal cancer; exosomes; liquid biopsy; tumor microenvironment
21.
J BUON. 2019 Sep-Oct;24(5):1785-1792.
Current and future targets and therapies in metastatic colorectal cancer.
Abstract
Colorectal cancer (CRC) is the third most common cancer and the second cause of cancer-related deaths worldwide. Despite early diagnosis and treatment improvement, the majority of patients will still suffer from metastatic disease (mCRC), which has a poor prognosis. Molecular diversity of CRC requires personalized targeted approach for improving patient outcomes. Antiangiogenic agents proved to be beneficial in the continuum of mCRC treatment. For efficient epidermal growth factor receptor (EGFR) directed therapy, subtle molecular selection and better strategies to overcome resistance are needed. BRAF mutant and HER-2 positive mCRC will soon be provided with approved targeted treatments and check-point inhibitors demonstrated effectiveness in microsatellite instability (MSI) - high mCRC. Moreover, numeorous promising agents are entering clinical trial arena. This review summarizes actual and possible targets and current and promising agents for mCRC treatment. With broader accessibility of liquid biopsy we could track molecular evolution of CRC and target genetic alterations as they emerge.
22.
Dis Markers. 2019 Oct 23;2019:4850472. doi: 10.1155/2019/4850472. eCollection 2019.
Serum Levels of miR-143 Predict Survival in Critically Ill Patients.
Roderburg C1,2, Koch A1, Benz F1,2, Vucur M1, Spehlmann M1, Loosen SH1, Luedde M3, Rehse S4, Lurje G5, Trautwein C1, Tacke F1,2, Luedde T1,6.
Abstract
BACKGROUND AND AIMS:
Recent data suggested a potential role of miR-143 as a biomarker for systemic inflammation and infection. However, its role in critical illness and sepsis is only poorly understood.
METHODS:
We determined circulating levels of miR-143 in 218 critically ill patients, of which 135 fulfilled sepsis criteria, and compared them to 76 healthy controls. Results were correlated with clinical records.
RESULTS:
In the total cohort of critically ill patients from a medical intensive care unit (ICU), miR-143 serum levels tended to be lower compared to healthy control samples, but this difference did not reach statistical significance. In ICU patients, serum levels of miR-143 were independent of disease etiology, including the presence of sepsis, or severity of disease. Importantly, low miR-143 serum levels were associated with an unfavorable short- and long-term prognosis in ICU patients. Our study identified different optimal cut-off values at which low miR-143 serum levels predicted mortality with a high diagnostic accuracy. In line with this, concentrations of circulating miR-143 correlated with markers of organ failure such as creatinine, bilirubin, or lactate in our cohort of critically ill patients.
CONCLUSION:
Low miR-143 serum levels are indicative for an unfavorable short- and long-term prognosis in critically ill patients admitted to a medical ICU. Our data suggest a previously unrecognized role for miR-143 measurements as a novel prognostic marker in critically ill patients.
Copyright © 2019 Christoph Roderburg et al.
23.
Q J Nucl Med Mol Imaging. 2019 Dec;63(4):355-370. doi: 10.23736/S1824-4785.19.03192-3. Epub 2019 Sep 13.
CT radiomics and PET radiomics: ready for clinical implementation?
Bogowicz M1, Vuong D2, Huellner MW3, Pavic M2, Andratschke N2, Gabrys HS2, Guckenberger M2, Tanadini-Lang S2.
Abstract
INTRODUCTION:
Today, rapid technical and clinical developments result in an increasing number of treatment options for oncological diseases. Thus, decision support systems are needed to offer the right treatment to the right patient. Imaging biomarkers hold great promise in patient-individual treatment guidance. Routinely performed for diagnosis and staging, imaging datasets are expected to hold more information than used in the clinical practice. Radiomics describes the extraction of a large number of meaningful quantitative features from medical images, such as computed tomography (CT) and positron emission tomography (PET). Due to the non-invasive nature and ability to capture 3D image-based heterogeneity, radiomic features are potential surrogate markers of the cancer phenotype. Several radiomic studies are published per day, owing to encouraging results of many radiomics-based patient outcome models. Despite this comparably large number of studies, radiomics is mainly studied in proof of principle concept. Hence, a translation of radiomics from a hot topic research field into an essential clinical decision-making tool is lacking, but of high clinical interest.
EVIDENCE ACQUISITION:
Herein, we present a literature review addressing the clinical evidence of CT and PET radiomics. An extensive literature review was conducted in PubMed, including papers on robustness and clinical applications.
EVIDENCE SYNTHESIS:
We summarize image-modality related influences on the robustness of radiomic features and provide an overview of clinical evidence reported in the literature. Today, more evidence has been provided for CT imaging, however, PET imaging offers the promise of direct imaging of biological processes and functions. We provide a summary of future research directions, which needs to be addressed in order to successfully introduce radiomics into clinical medicine. In comparison to CT, more focus should be directed towards harmonization of PET acquisition and reconstruction protocols, which is important for transferable modelling.
CONCLUSIONS:
Both CT and PET radiomics are promising pre-treatment and intra-treatment biomarkers for outcome prediction. Most studies are performed in retrospective setting, however their validation in prospective data collections is ongoing.
24.
Semin Respir Crit Care Med. 2019 Jun;40(3):347-360. doi: 10.1055/s-0039-1693406. Epub 2019 Sep 16.
Malignant Mesothelioma: Has Anything Changed?
Abstract
Malignant pleural mesothelioma is a rare cancer associated with asbestos exposure and portends a dismal prognosis. Its worldwide incidence has been increasing, and treatment options are currently suboptimal and noncurative. However, since the turn of the century, several encouraging steps have been made toward improving outcomes for mesothelioma patients. An increased understanding of disease pathophysiology has led to more accurate diagnosis and staging, and the establishment of the standard of care first-line pemetrexed/platin doublet chemotherapy regimen in 2003 initially revolutionized treatment. While significant debate remains regarding the preferred approach to surgical and radiation therapy in the context of multimodal therapy, recent breakthroughs in immunotherapy offer hope for another paradigm shift in the near future. This review will summarize the current clinical approach to diagnosis, staging, and treatment of malignant pleural mesothelioma.
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
25.
J Craniofac Surg. 2020 Jan/Feb;31(1):e41-e43. doi: 10.1097/SCS.0000000000005842.
Virtual Surgical Planning for Mandible Reconstruction With a Double Barrel Fibula Flap and Immediate Implant Placement.
Abstract
This brief clinical report describes our experience with virtual surgical planning in a case of mandibulectomy and mandibular reconstruction with a double barrel vascularized osteofasciocutaneous fibula free flap and immediate implant placement in a case of mandibular ameloblastoma. Fibular segments were positioned to obtain the best result both for masticatory function and for aesthetic facial appearance. Furthermore, in this particular case, as well as being positioned for future masticatory rehabilitation, the implants have served to stabilize the fibula segments in the reconstructive intraoperative phase. A superimposition of programed surgery and 6 months postoperative computed tomography scan was performed and results are presented.
26.
Neurol Sci. 2019 Dec;40(12):2447-2457. doi: 10.1007/s10072-019-04015-x. Epub 2019 Jul 31.
Optic nerve sheath diameter: present and future perspectives for neurologists and critical care physicians.
Abstract
BACKGROUND:
Estimation of intracranial pressure (ICP) may be helpful in the management of neurological critically ill patients. It has been shown that ultrasonography of the optic nerve sheath diameter (ONSD) is a reliable tool for non-invasive estimation of increased intracranial pressure (ICP) at hospital admission or in intensive care. Less is known about the estimation of increased ICP and usefulness of ONSD in the prehospital setting. The aim of this review was to elucidate both prevailing and novel applications of ONSD for neurologists and critical care physicians.
METHODS:
In this review, we discuss the technique and the novel approach of ONSD measurement, the clinical applications of ONSD in neurology and critical care patients.
RESULTS:
ONSD measurement is simple, easy to learn, and has diverse applications. ONSD has utility for ICP measurement in intracranial hemorrhage and ischemic stroke, meningitis and encephalitis, and idiopathic intracranial hypertension (IIH). It is also valuable for lesser known syndromes, where an increase of ICP is postulated, such as acute mountain sickness and posterior reversible encephalopathy syndrome. ONSD changes develop in inflammatory or ischemic optic neuropathies. Some papers demonstrate the usefulness of ONSD studies in symptomatic intracranial hypotension.
CONCLUSIONS:
ONSD is a safe and low-cost bedside tool with the potential of screening patients who need other neuroimaging and those who may need an invasive measurement of ICP.
KEYWORDS:
Acute mountain sickness (AMS); Intracranial pressure (ICP); Optic nerve; Optic nerve sheath diameter (ONSD); Symptomatic intracranial hypotension (SIH); Transorbital ultrasonography (TSO)
27.
Postgrad Med J. 2019 Oct;95(1128):558-562. doi: 10.1136/postgradmedj-2019-136636. Epub 2019 Jul 18.
Initial management of immune thrombocytopaenia in adults based on risk stratification.
Abstract
Patients with immune thrombocytopaenia (ITP) have a wide spectrum of disease severity and bleeding risk even at similar platelet counts. Hence, additional clinical and laboratory factors may be considered in the evaluation of bleeding risk in ITP. Risk stratification based on predicted bleeding risk may help to identify high-risk patients and guide the initial management of ITP in adults requiring treatment. Recent evidence supports the use of high-dose dexamethasone therapy over prednisone in the initial management of ITP because of improved initial response rates, shorter median time to response and better safety profile. A risk-stratified approach to management of ITP is hoped to reduce bleeding complications in high-risk patients; however, the outcomes of such management approach need to be studied prospectively. Additionally, whether therapy intensification or combination of dual therapy such as intravenous immunoglobulin or rituximab in combination with dexamethasone can reduce bleeding complications in high-risk ITP should be studied in the future.
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
KEYWORDS:
bleeding risk; dexamethasone; immune thrombocytopenia; steroids; thromboelastography
28.
Semin Reprod Med. 2019 Jan;37(1):32-42. doi: 10.1055/s-0039-1692398. Epub 2019 Jun 11.
Coordinating Care for Reproductive Health Malignancies in the Veterans' Health Administration: Promising Practices, Ongoing Challenges, and Future Research.
Abstract
In cancer care, communication and coordination across the cancer continuum is paramount for delivering effective, high-quality, patient-centered care. However, achieving optimally coordinated cancer care is inherently challenging, especially in the case of Veterans Administration (VA) care for women's reproductive health cancers. Given the relatively small number of women Veterans requiring care for reproductive malignancies, VA often must rely on community providers to deliver this care, necessitating coordination across two or more health care systems. Recently, VA has invested heavily in improving care for women Veterans through several initiatives and efforts. This article reviews VA's successes, challenges, and future opportunities in research and innovation in the context of care coordination across the cancer continuum (i.e., prevention and screening, diagnosis and treatment, survivorship care, palliative and supportive care) for women Veterans with reproductive health malignancies. We describe how coordination of VA care for reproductive health malignancies currently reflects a mix of successes that demonstrate use of strong evidenced-based practices and challenges, with solutions yet to be fully developed and implemented. We conclude that there are a multitude of opportunities for future research, interventions, and potential avenues for implementing innovative approaches to coordinate VA reproductive cancer care across the cancer continuum.
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
29.
Cancer Lett. 2019 Aug 10;457:74-85. doi: 10.1016/j.canlet.2019.04.025. Epub 2019 May 2.
PD-1/PD-L1 blockade in paediatric cancers: What does the future hold?
Abstract
Checkpoint blockade (CPB) immunotherapy has shown unprecedented success in a wide range of adult malignancies, and is increasingly being employed in the treatment of advanced cancers. However, the experience in the paediatric population remains limited and the small number of single agent studies reported have shown disappointing response rates. Paediatric cancers offer unique challenges that can hinder the translation of CPB into the paediatric clinic, and combinational therapies are likely to be needed to achieve therapeutic success. As the number of paediatric trials using CPB rapidly increases, understanding the challenges that these agents may encounter in this population is of special significance to allow the design of optimal combinatorial strategies for each tumour type. Here, we offer an overview of the unique biological and immunological features of paediatric cancers as compared to adult malignancies, and how these might impact the overall success of CPB in the paediatric population. We review the growing body of pre-clinical and clinical experiences to date, and discuss future strategies involving the combination of CPB with traditionally used therapies (chemotherapy and radiotherapy) or with other newly developed immunotherapies.
Copyright © 2019 Elsevier B.V. All rights reserved.
KEYWORDS:
Challenges; Checkpoint blockade; Combinatorial therapies; Immunotherapy; PD-1/PD-L1; Paediatric cancer
30.
Proteomics. 2019 May;19(10):e1800361. doi: 10.1002/pmic.201800361.
Identification and Quantification of Proteoforms by Mass Spectrometry.
Schaffer LV1, Millikin RJ1, Miller RM1, Anderson LC2, Fellers RT3, Ge Y1,4, Kelleher NL3,5, LeDuc RD3, Liu X6,7, Payne SH8, Sun L9, Thomas PM3, Tucholski T1, Wang Z10, Wu S10, Wu Z1, Yu D10, Shortreed MR1, Smith LM1.
Abstract
A proteoform is a defined form of a protein derived from a given gene with a specific amino acid sequence and localized post-translational modifications. In top-down proteomic analyses, proteoforms are identified and quantified through mass spectrometric analysis of intact proteins. Recent technological developments have enabled comprehensive proteoform analyses in complex samples, and an increasing number of laboratories are adopting top-down proteomic workflows. In this review, some recent advances are outlined and current challenges and future directions for the field are discussed.
© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
KEYWORDS:
bioinformatics; mass spectrometry; proteoform; proteoform family; top-down proteomics
- PMID:
- 31050378
- PMCID:
- PMC6602557
- [Available on 2020-05-01]
- DOI:
- 10.1002/pmic.201800361
- [Indexed for MEDLINE]
31.
Clin Transl Gastroenterol. 2019 Feb;10(2):e00006. doi: 10.14309/ctg.0000000000000006.
Identifying Clonal Origin of Multifocal Hepatocellular Carcinoma and Its Clinical Implications.
Abstract
Hepatocellular carcinoma (HCC) is characterized by high prevalence of multifocality. Multifocal HCC can arise synchronously or metachronously either from intrahepatic metastasis (IM) or multicentric occurrence (MO). To date, there have been no established criteria to accurately distinguish whether multifocal HCC originates from IM or MO. Histopathological features remain the most convenient strategy but with subjectivity and limited accuracy. Various molecular biological techniques involving assessment of TP53 mutation status, hepatitis B virus integration sites, and chromosomal alterations have been applied to determine the clonal origin. The introduction of next-generation sequencing facilitates a more comprehensive annotation of intertumor heterogeneity, resulting in more sensitive and accurate clonal discrimination. Generally, MO-HCC has better overall survival than IM-HCC after curative resection. Adjuvant antiviral treatment has been proved to decrease post-treatment recurrence probably by reducing MO-HCC recurrence, whereas adjuvant sorafenib treatment targeting prior micrometastasis failed to reduce IM-HCC recurrence. Recent studies recommended transcatheter arterial chemoembolization (TACE) and traditional Chinese medicine Huaier granule as effective adjuvant treatments probably by preventing IM and both types of recurrences respectively. Immunotherapy that inhibits immune checkpoint interaction may be an optimal choice for both MO- and IM-HCC. In the future, effective personalized therapy against multifocal HCC may be achieved.
- PMID:
- 30829920
- PMCID:
- PMC6407817
- DOI:
- 10.14309/ctg.0000000000000006
- [Indexed for MEDLINE]
32.
J Thorac Oncol. 2019 Apr;14(4):606-616. doi: 10.1016/j.jtho.2018.12.013. Epub 2018 Dec 31.
K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways.
Scheffler M1, Ihle MA2, Hein R3, Merkelbach-Bruse S2, Scheel AH2, Siemanowski J2, Brägelmann J4, Kron A1, Abedpour N4, Ueckeroth F2, Schüller M1, Koleczko S1, Michels S1, Fassunke J2, Pasternack H5, Heydt C2, Serke M6, Fischer R1, Schulte W7, Gerigk U7, Nogova L1, Ko YD8, Abdulla DSY1, Riedel R1, Kambartel KO9, Lorenz J10, Sauerland I10, Randerath W11, Kaminsky B11, Hagmeyer L11, Grohé C12, Eisert A1, Frank R1, Gogl L1, Schaepers C1, Holzem A1, Hellmich M3, Thomas RK4, Peifer M4, Sos ML4, Büttner R2, Wolf J13.
Abstract
INTRODUCTION:
Although KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRAS-mutated NSCLC represents a genetically heterogeneous subgroup. We sought to determine genetic heterogeneity with respect to cancer-related co-mutations and their correlation with different KRAS mutation subtypes.
METHODS:
Diagnostic samples from 4507 patients with NSCLC were analyzed by next-generation sequencing by using a panel of 14 genes and, in a subset of patients, fluorescence in situ hybridization. Next-generation sequencing with an extended panel of 14 additional genes was performed in 101 patients. Molecular data were correlated with clinical data. Whole-exome sequencing was performed in two patients.
RESULTS:
We identified 1078 patients with KRAS mutations, of whom 53.5% had at least one additional mutation. Different KRAS mutation subtypes showed different patterns of co-occurring mutations. Besides mutations in tumor protein p53 gene (TP53) (39.4%), serine/threonine kinase 11 gene (STK11) (19.8%), kelch like ECH associated protein 1 gene (KEAP1) (12.9%), and ATM serine/threonine kinase gene (ATM) (11.9%), as well as MNNG HOS Transforming gene (MET) amplifications (15.4%) and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplifications (13.8%, exclusively in G12C), we found rare co-occurrence of targetable mutations in EGFR (1.2%) and BRAF (1.2%). Whole-exome sequencing of two patients with co-occurring phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation revealed clonality of mutated KRAS in one patient and subclonality in the second, suggesting different evolutionary backgrounds.
CONCLUSION:
KRAS-mutated NSCLC represents a genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways, partly associated with distinct KRAS mutation subtypes. This diversity might have implications for understanding the variability of treatment outcome in KRAS-mutated NSCLC and for future trial design.
Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
KEYWORDS:
Heterogeneity; KRAS; Mutations; Non–small cell lung cancer
33.
Neuro Oncol. 2019 Mar 18;21(4):428-439. doi: 10.1093/neuonc/noy186.
Novel methods to diagnose leptomeningeal metastases in breast cancer.
Abstract
Leptomeningeal metastases (LM) in breast cancer patients are rare but often accompanied by devastating neurological symptoms and carry a very poor prognosis, even if treated. To date, two diagnostic methods are clinically used to diagnose LM: gadolinium MRI of the brain and/or spinal cord and cytological examination of cerebrospinal fluid (CSF). Both techniques are, however, hampered by limited sensitivities, often leading to a long diagnostic process requiring repeated lumbar punctures and MRI examinations. To improve the detection rate of LM, numerous studies have assessed new techniques. In this review, we present the current workup to diagnose LM, set out an overview of novel techniques to diagnose LM, and give recommendations for future research.
© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
KEYWORDS:
biomarkers; breast cancer; cerebrospinal fluid; leptomeningeal metastases
34.
Q J Nucl Med Mol Imaging. 2019 Dec;63(4):399-407. doi: 10.23736/S1824-4785.18.03006-6. Epub 2018 Jan 17.
SUV calculation in breast cancer: which normalization should be applied when using 18F-FDG PET?
Abstract
BACKGROUND:
When using 18F-FDG PET, glucose metabolism quantification is affected by various factors. We aimed to investigate the benefit of different standardized uptake value (SUV) normalizations to improve the accuracy of 18F-FDG uptake to predict breast cancer aggressiveness and response to treatment.
METHODS:
Two hundred fifty-two women with locally advanced breast cancer treated with neoadjuvant chemotherapy (NAC) were included. Women underwent 18F-FDG PET before and after the first course of NAC. Glucose serum levels, patient heights and weights were recorded at the time of each PET exam. Four different procedures for SUV normalization of the primary tumor were used: by body weight (SUVBW) by blood glucose level (SUVG), by lean body mass (SUL) and then corrected for both lean body mass and blood glucose level (SULG).
RESULTS:
At baseline, SUL was significantly lower than SUVBW (5.9±4.0 and 9.5±6.5, respectively; P<0.0001), whereas SUVG and SUVBW were not significantly different (9.7±6.4 and 9.5±6.5, respectively; P=0.67). Concerning SUV changes (ΔSUV), the different normalizations methods did not induce significant quantitative differences. The correlation coefficients were high between the four normalizations methods of SUV1, SUV2 and ΔSUVB (R>0.95; P<0.0001). High baseline SUVBW measures were positively correlated with the biological tumor characteristics of aggressiveness and proliferation (P<0.001): ductal carcinoma, high tumor grading, high mitotic activity, negative estrogen receptor status and the TNBC subtype. ΔSUVBW was highly predictive of pCR (AUC=0.76 on ROC curve analysis; P<0.0001). The different SUV normalizations yields identical statistical results and AUC to predict tumor biological aggressiveness and response to therapy.
CONCLUSIONS:
In the present setting, SUVBW and SUL can be considered as robust measures and be used in future multicenter trials. The additional normalization of SUV by glycemia involves stringent methodologic procedures to avoid biased risk measurements and offers no statistical advantages.
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