Influence of short-term dexamethasone on the efficacy of 177 Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer.
Derlin T1, Sommerlath Sohns JM1, Schmuck S1,2, Henkenberens C3, von Klot CAJ4, Ross TL1, Bengel FM1.
Abstract
BACKGROUND AND AIM:
Corticosteroids alone or in combination therapy are associated with favorable biochemical responses in metastatic castration-resistant prostate cancer (mCRPC). We speculated that the intermittent addition of dexamethasone may also enhance the antitumor effect of radioligand therapy (RLT) with 177 Lu-prostate-specific membrane antigen (PSMA)-617.
PATIENTS AND METHODS:
Seventy-one patients with mCRPC were treated with 1 to 5 cycles of 177 Lu-PSMA-617 (6.0-7.4 GBq per cycle) at 6 to 8 weeks intervals. Based on the clinical decision (eg, in the case of vertebral metastases), 56% of patients received 4 mg of dexamethasone for the first 5 days of each cycle. Biochemical response rates, PSA decline and progression-free survival (PFS) were analyzed after one, three, and five cycles of RLT.
RESULTS:
PSA response rates were not significantly different between patients receiving 177 Lu-PSMA-617 plus dexamethasone and those receiving 177 Lu-PSMA-617 alone after one, three, and five cycles (33% vs 39%, P = .62; 45% vs 45%, P = 1.0; and 38% vs 42%, P = .81). However, there was a nonsignificant trend for a more pronounced PSA decline in patients with bone metastases receiving adjunct dexamethasone (-21% ± 50% vs +11% ± 90%, P = .08; -21% ± 69% vs +22% ± 116%, P = .07; -13% ± 76% vs +32% ± 119%, P = .07). Median PFS tended to be longer in patients with bone metastases receiving 177 Lu-PSMA-617 plus dexamethasone (146 vs 81 days; hazard ratio: 0.87 [95% confidence interval: 0.47-1.61]; P = .20). Multiple regression analysis showed that age (P = .0110), alkaline phosphatase levels (P = .0380) and adjunct dexamethasone (P = .0285) were independent predictors of changes in PSA in patients with bone metastases.
CONCLUSIONS:
We observed high response rates to 177 Lu-PSMA-617 RLT in men with mCRPC. The short-term addition of dexamethasone to 177 Lu-PSMA-617 had no striking antitumor effect but might enhance biochemical responses in patients with bone metastases. Future trials are warranted to test this hypothesis in a prospective setting.
© 2020 The Authors. The Prostate published by Wiley Periodicals LLC.
KEYWORDS:
PSMA-617; glucocorticoids; prostate-specific membrane antigen (PSMA); steroids; therapy
2.
Phys Med Biol. 2020 Mar 18. doi: 10.1088/1361-6560/ab8109. [Epub ahead of print]
Towards customizable thin-panel low-Z detector arrays: Electrode design for increased spatial resolution ion chamber arrays.
Abstract
Purpose:The purpose of the present development is to employ 3D printing to prototype an ion chamber array with a scalable design potentially allowing increased spatial resolution and a larger active area. An additional goal is to design and fabricate a custom size thin-panel detector array with low-Z components.Method:As a proof of principle demonstration, a medium size detector array with 30×30 air-vented ion chambers was 3D-printed using PLA as frame for the electrodes. The active-area is 122 mm×120 mm with 4×4 mm2spatial resolution. External electrodes are cylindrical and made from conductive PLA. Internal electrodes are made from microwire. The array is symmetric with respect to the central plane and its thickness is 10 mm including build-up/-down plates of 2.5 mm thickness. Data acquisition is realized by biasing only selected chamber rows and reading only 30 chambers at a time.Results:To test the device for potential clinical applications, 1D dose profiles and 2D dose maps with various square and irregular fields were measured. The overall agreement with the reference doses (film and treatment planning system) was satisfactory, but the measured dose differs in the penumbra region and in the field size dependence. Both of these features are related to the thin walls between neighboring ion chambers and different lateral phantom scatter in the detector panel vs homogeneous material.Conclusions:We demonstrated feasibility of radiation detector arrays with minimal number of readout channels and low-cost electronics. The acquisition scheme based on selected row or column "activation" by bias voltage is not practical for 2D dosimetry but it allows for rapid turn-around when testing of custom arrays with the aid of multiple 1D dose profiles. Future progress in this area includes overcoming the limitations due high chamber packing ratio, which leads to the lateral scattering effects.
© 2020 Institute of Physics and Engineering in Medicine.
KEYWORDS:
3D printing; Fused Deposition Modeling; Ionization Chamber; Quality Assurance; X-Ray Dosimetry; detector array; polarity
3.
Rev Esc Enferm USP. 2020 Mar 16;54:e03541. doi: 10.1590/S1980-220X2018038003541. eCollection 2020.
Nursing diagnoses and NIC interventions in adult males undergoing radical prostatectomy.
Abstract
OBJECTIVE:
To determine NANDA-I nursing diagnoses and NIC nursing interventions in patients who underwent radical prostatectomy.
METHOD:
A cross-sectional and descriptive study was conducted in a research and teaching hospital in western Turkey between June 2016 and June 2017. The sample included adult patients diagnosed with prostate cancer in the immediate postoperative period of radical prostatectomy. Data collection was performed using Gordon's Functional Health Patterns, NANDA-International and Nursing Interventions Classification Taxonomy Systems.
RESULTS:
Participants were 54 adult patients. The main nursing diagnoses were in the classes of "physical injury", "self-care", "hydration" and "physical comfort". Some nursing diagnoses were identified in all patients, namely: "risk for deficient fluid volume", "risk for imbalanced fluid volume", "impaired urinary elimination". The most selected NIC interventions were in the classes of "risk management", "elimination management", "coping assistance", "tissue perfusion management" and "self-care facilitation".
CONCLUSION:
future studies with larger populations are needed to explore the nursing diagnoses and effects of nursing interventions on patients who underwent radical prostatectomy.
4.
PLoS One. 2020 Mar 18;15(3):e0230526. doi: 10.1371/journal.pone.0230526. eCollection 2020.
Targeted alpha therapy for chronic lymphocytic leukaemia and non-Hodgkin's lymphoma with the anti-CD37 radioimmunoconjugate 212Pb-NNV003.
Abstract
Relapse of chronic lymphocytic leukaemia and non-Hodgkin's lymphoma after standard of care treatment is common and new therapies are needed. The targeted alpha therapy with 212Pb-NNV003 presented in this study combines cytotoxic α-particles from 212Pb, with the anti-CD37 antibody NNV003, targeting B-cell malignancies. The goal of this study was to explore 212Pb-NNV003 for treatment of CD37 positive chronic lymphocytic leukaemia and non-Hodgkin's lymphoma in preclinical mouse models.An anti-proliferative effect of 212Pb-NNV003 was observed in both chronic lymphocytic leukaemia (MEC-2) and Burkitt's lymphoma (Daudi) cells in vitro. In biodistribution experiments, accumulation of 212Pb-NNV003 was 23%ID/g and 16%ID/g in Daudi and MEC-2 tumours 24 h post injection. In two intravenous animal models 90% of the mice treated with a single injection of 212Pb-NNV003 were alive 28 weeks post cell injection. Median survival times of control groups were 5-9 weeks. There was no significant difference between different specific activities of 212Pb-NNV003 with regards to therapeutic effect or toxicity. For therapeutically effective activities, a transient haematological toxicity was observed. This study shows that 212Pb-NNV003 is effective and safe in preclinical models of CD37 positive chronic lymphocytic leukaemia and non-Hodgkin's lymphoma, warranting future clinical testing.
5.
Expert Rev Anticancer Ther. 2020 Mar 18. doi: 10.1080/14737140.2020.1744438. [Epub ahead of print]
Lorlatinib for the treatment of ALK-positive metastatic non-small cell lung cancer.
Abstract
The treatment of lung cancer has changed dramatically with the development of tyrosine kinase inhibitors (TKIs) that target sensitizing somatic (gene) activations including anaplastic lymphoma kinase (ALK)-rearrangements. Despite remarkable initial responses, patients develop progressive disease via various resistance mechanisms, some of which are ALK dependent. Various next-generation ALK TKIs have been developed to improve on central nervous system (CNS) activity and also target the multitude of acquired resistance mechanisms. Of these, lorlatinib has the greatest spectrum of clinical activity against multiple ALK resistance mutations and has also demonstrated promising efficacy in patients with known brain metastases.Areas covered: We discuss the structure, pharmacology and efficacy of lorlatinib and also provide future perspectives in the management of patients with ALK-rearranged non-small cell lung cancer (NSCLC).Expert opinion: Patients invariably develop resistance during treatment with lorlatinib. Unique combinations of ALK resistance mutations may confer sensitivity to alternate ALK TKIs. There is a move towards individualized biomarker-driven treatment strategies to identify the select group of candidates that can benefit from existing therapies.
KEYWORDS:
G1202R; Lorlatinib; liquid biopsy; sequencing; third-generation ALK-TKI
6.
Am J Transplant. 2020 Mar 17. doi: 10.1111/ajt.15856. [Epub ahead of print]
Kidney retransplantation after anti-programmed cell death-1 (PD-1)-related allograft rejection.
Abstract
In this report, we describe the first kidney retransplantation performed after anti-programmed cell death-1 (PD-1)-related allograft rejection. In 2014, we administered pembrolizumab (anti-PD-1) for ~9 months to a 57-year-old kidney transplant recipient with metastatic cutaneous squamous cell carcinoma (CSCC). The patient experienced both a complete anti-tumor response and T cell-mediated allograft rejection requiring reinitiation of hemodialysis. Four-and-a-half years after initiating pembrolizumab, the patient remained without evidence of CSCC relapse and received a kidney transplant from a living unrelated donor. Ten-and-a-half months after kidney retransplantation, the allograft is functioning well and the patient's CSCC remains in remission. This case illustrates the potential for PD-1 blockade to bring about durable immune-mediated tumor control in chronically-immunosuppressed patients, and begins to address the feasibility of kidney retransplantation in patients who have previously received immune checkpoint inhibitor therapy for cancer. Results from this and future cases may help elucidate mechanisms of anti-tumor immunity and allograft tolerance, and inform updates to transplant decision models. Our report also underscores the need for clinical trials testing novel immunotherapy combinations in solid organ transplant recipients designed to uncouple anti-tumor and anti-allograft immunity.
This article is protected by copyright. All rights reserved.
7.
Adv Exp Med Biol. 2020;1248:547-618. doi: 10.1007/978-981-15-3266-5_22.
Small Molecular Immune Modulators as Anticancer Agents.
Abstract
After decades of intense effort, immune checkpoint inhibitors have been conclusively demonstrated to be effective in cancer treatments and thus are revolutionizing the concepts in the treatment of cancers. Immuno-oncology has arrived and will play a key role in cancer treatment in the foreseeable future. However, efforts to find novel methods to improve the immune response to cancer have not ceased. Small-molecule approaches offer inherent advantages over biologic immunotherapies since they can cross cell membranes, penetrate into tumor tissue and tumor microenvironment more easily, and are amenable to be finely controlled than biological agents, which may help reduce immune-related adverse events seen with biologic therapies and provide more flexibility for the combination use with other therapies and superior clinical benefit. On the one hand, small-molecule therapies can modulate the immune response to cancer by restoring the antitumor immunity, promoting more effective cytotoxic lymphocyte responses, and regulating tumor microenvironment, either directly or epigenetically. On the other hand, the combination of different mechanisms of small molecules with antibodies and other biologics demonstrated admirable synergistic effect in clinical settings for cancer treatment and may expand antibodies' usefulness for broader clinical applications. This chapter provides an overview of small-molecule immunotherapeutic approaches either as monotherapy or in combination for the treatment of cancer.
KEYWORDS:
Cancer immunotherapy; Combination therapy; Cytotoxic lymphocyte responses; Drug screening; Small molecules
8.
Front Cell Dev Biol. 2020 Feb 28;8:71. doi: 10.3389/fcell.2020.00071. eCollection 2020.
miRNAs in the Diagnosis and Prognosis of Skin Cancer.
Abstract
Skin cancer is, at present, the most common type of malignancy in the Caucasian population. Its incidence has increased rapidly in the last decade for both melanoma and non-melanoma skin cancer. Differential expression profiles of microRNAs (miRNAs) have been reported for a variety of different cancers, including skin cancers. Since miRNAs' discovery as regulators of gene expression, their importance grew in the field of oncology. miRNAs can post-transcriptionally regulate gene expression, tumor initiation, development progression, and aggressiveness. Nowadays, these short regulatory RNAs are perceived as one of the epigenetic markers for the identification of new diagnostic and/or prognostic molecular markers. Moreover, as miRNAs can drive tumorigenesis, they might eventually represent new therapy targets. Some miRNAs are pleiotropic, such as miR-214, which was found deregulated in several other tumors besides skin cancers. Some others are specific for one or more skin cancer types, like miR-21 and miR-221 for cutaneous melanoma and cutaneous squamous carcinoma or miR-155 for melanoma and cutaneous lymphoma. The goal of this review was to summarize some of the main miRNA detection technologies that are used to evaluate miRNAs in tissues and body fluids. Furthermore, their quantification limits, conformity, and robustness are discussed. Aberrant miRNA expression is analyzed for cutaneous melanoma, cutaneous squamous cell carcinoma (CSCC), skin lymphomas, cutaneous lymphoma, and Merkel cell carcinoma (MCC). In this type of disease, miRNAs are described as potential biomarkers to diagnose early lesion and/or early metastatic disease. In the future, whether in tissue or circulating in body fluids, miRNAs will gain their place in skin cancer diagnosis, prognosis, and future therapeutic targets.
Copyright © 2020 Neagu, Constantin, Cretoiu and Zurac.
KEYWORDS:
Merkel cell carcinoma; cutaneous lymphoma; cutaneous melanoma; cutaneous squamous carcinoma; miRNA
9.
J Radiosurg SBRT. 2020;6(4):325-328.
Seed, soil, and spine stereotactic radiosurgery: A unique case of metastatic dissemination.
Abstract
A 52 year-old gentleman with metastatic pheochromocytoma received single fraction spine stereotactic radiosurgery (SSRS) to an isolated L3 metastasis. Two years later, he developed widespread osseous metastatic disease involving nearly every vertebral body level with the striking exception of the treated L3 vertebrae. The "seed and soil" hypothesis of metastatic dissemination was developed over a century ago and states that tumors cells (the "seed") preferentially grow in select host tissue microenvironments (the "soil"). The high-dose radiation delivered by SSRS may have altered the microenvironment "soil" of the treated L3 vertebrae, rendering it inhospitable to the growth of future metastases. With emerging evidence in support of high-dose stereotactic radiation for oligometastatic disease, there will likely be increasing opportunity to observe and understand treatment changes in the tissue microenvironment and how it relates to the potential for metastatic seeding.
© 2020 Old City Publishing, Inc.
KEYWORDS:
SSRS; metastases
10.
Cancer Manag Res. 2020 Mar 5;12:1631-1639. doi: 10.2147/CMAR.S232930. eCollection 2020.
The Role of Adjuvant Chemoradiotherapy Over Radiotherapy After R0 Resection for Stage II-III Esophageal Squamous Cell Carcinoma.
Abstract
PURPOSE:
This study compared the effectiveness and safety of postoperative concurrent chemoradiotherapy (POCRT) containing paclitaxel (PTX) and cisplatin (DDP) with postoperative radiotherapy (PORT) after R0 resection for stage II-III thoracic esophageal squamous cell carcinoma (TESCC).
MATERIALS AND METHODS:
After propensity score matching (PSM) analysis, 87 TESCC patients treated with PORT were matched 1:1 to 87 patients who received POCRT between July 2012 and December 2018. Radiotherapy was delivered at a dose of 200 cGy per day to a total dose of 5000 cGy. Concurrent chemotherapy consisted of DDP (25 mg/m2) for 3 days plus PTX (135 mg/m2) on day 1 every 3 weeks.
RESULTS:
Patient- and disease-related characteristics were well-balanced between the two groups. The median overall survival (OS) and disease-free survival (DFS) times were 39.2 and 31.0 months, respectively. The 5-year OS and DFS rates were 31.9% and 19.1% in the PORT group and 45.1% and 35.1% in the POCRT group, respectively. Statistical significance was demonstrated by comparing OS and DFS (P=0.022 and 0.016, respectively). Additionally, subgroup analysis revealed that in node positive TESCC patients, the POCRT group was significantly different from the PORT group regarding OS and DFS (P=0.049 and 0.039, respectively). POCRT decreased distant metastasis over PORT (P=0.044) with manageable toxicities. Multivariate analysis revealed that aside from factors associated with tumor stages, treatment modality was another strong prognostic factor for both OS and DFS (P=0.015 and 0.010, respectively).
CONCLUSION:
Stage II-III TESCC patients could benefit from POCRT with manageable toxicities. Future well-designed prospective studies are highly warranted to confirm the findings in our report.
© 2020 Song et al.
KEYWORDS:
chemoradiotherapy; esophageal squamous cell carcinoma; surgery; survival
11.
Int J Nanomedicine. 2020 Feb 28;15:1373-1385. doi: 10.2147/IJN.S233989. eCollection 2020.
Transcatheter Intra-Arterial Infusion Combined with Interventional Photothermal Therapy for the Treatment of Hepatocellular Carcinoma.
Abstract
BACKGROUND:
Photothermal therapy (PTT) has great potential application in the treatment of tumors. However, due to the low penetration of near-infrared light (NIR) and the low concentration of nanomaterials in the tumor site, the application of PTT has been limited.
PURPOSE:
The objective of this study was to investigate the therapeutic effect of transcatheter intra-arterial infusion of lecithin-modified Bi nanoparticles (Bi-Ln NPs) combined with interventional PTT (IPTT) on hepatocellular carcinoma.
METHODS:
Bi-Ln NPs were prepared by emulsifying the hydrophobic Bi nanoparticles and lecithin, and the photothermal conversion and cytotoxicity of Bi-Ln NPs were then measured by infrared imaging and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, respectively. Twenty-four VX2 hepatic carcinoma rabbits were randomly divided into four groups. Rabbits in group A received Bi-Ln NPs by intra-arterial infusion and NIR laser treatment (IA Bi-Ln NPs + Laser), group B received Bi-Ln NPs by intravenous infusion and NIR laser treatment (IV Bi-Ln NPs + Laser), group C received PBS (phosphate buffer saline) via intra-arterial infusion with NIR laser treatment (IA PBS + Laser), group D received PBS via intra-arterial infusion (IA PBS). Transcatheter intra-arterial infusion was conducted by superselective intubation under digital subtraction angiography (DSA) guidance. IPTT was performed by introducing an NIR optical fiber access to the rabbit VX2 hepatic carcinoma under real-time ultrasound guidance. Magnetic resonance imaging (MRI) was performed to evaluate the tumor size. Hematoxylin and eosin (H&E) stain and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) were conducted 7 days after treatment to evaluate the necrosis rate and viability of tumor, respectively.
RESULTS:
The Bi-Ln NPs have the advantages of good biological compatibility and high photothermal conversion efficiency. Minimally invasive transcatheter intra-arterial infusion can markedly increase the concentration of Bi-Ln NPs in tumor tissues. IPTT can contribute to the significant improvement in the photothermal efficiency of Bi-Ln NPs. Compared to other groups, the group of IA Bi-Ln NPs + Laser showed a significantly higher tumor inhibition rate (TIR) of 93.38 ± 19.57%, a higher tumor necrosis rate of 83.12 ± 8.02%, and a higher apoptosis rate of (43.26 ± 10.65%) after treatment.
CONCLUSION:
Transcatheter intra-arterial infusion combined with interventional PTT (IPTT) is safe and effective in eradicating tumor cells and inhibiting tumor growth and may provide a novel and valuable choice for the treatment of hepatocellular carcinoma in the future.
© 2020 Zhou et al.
KEYWORDS:
Bi nanoparticles; hepatocellular carcinoma; interventional photothermal therapy; transcatheter intra-arterial infusion
12.
Biochem Biophys Res Commun. 2020 Mar 14. pii: S0006-291X(20)30473-3. doi: 10.1016/j.bbrc.2020.02.165. [Epub ahead of print]
Involvement of MCL1, c-myc, and cyclin D2 protein degradation in ponatinib-induced cytotoxicity against T315I(+) Ph+leukemia cells.
Inoue C1, Sobue S1, Kawamoto Y1, Nishizawa Y1, Ichihara M1, Abe A2, Hayakawa F3, Suzuki M4, Nozawa Y5, Murate T6.
Abstract
T315I mutation found in chronic myelogenous leukemia (CML) and Ph + ALL patients is the most serious one among resistance against BCR/ABL kinase inhibitors including imatinib and is only responsive to ponatinib (PNT). However, the novel strategy is required to reduce life-threatening adverse effects of PNT including ischemic cardiovascular disease. We examined the mechanism of PNT-induced cytotoxicity against a T315I(+) Ph + ALL cell line, TccY/Sr. PNT induced apoptosis (increased sub G1 cells, and cleaved caspase3 and PARP), and suppressed protein expression of MCL1, cyclin D2 and c-myc, which were reversed by a proteasome inhibitor, MG132, suggesting enhanced proteasomal degradation by PNT. Among BCL2 family inhibitors, MCL1 inhibitors (maritoclax and AZD5991) robustly induced cell death, showing the MCL1-dependent survival of TccY/Sr cells. Decreased MCL1 and c-myc expression by PNT was also observed in T315I(+) MEGA2/STIR cells. PNT suppressed PI3K activation followed by AKT inhibition and GSK3 dephosphorylation. PI3K/AKT inhibitors mimicked PNT, suggesting that PI3K/AKT signaling is important for survival of TccY/Sr cells. Moreover, GSK3 inhibitor (SB216763) reduced PNT-induced cytotoxicity and degradation of c-myc and MCL1. AZD5991 exhibited the synergistic action with PNT, anti-cancer drugs and venetoclax (BCL2 inhibitor), suggesting the utility of MCL1 inhibitor alone or in combination as a future clinical option for Ph + leukemia patients.
Copyright © 2020 Elsevier Inc. All rights reserved.
KEYWORDS:
MCL1; MCL1 inhibitors; Ponatinib; Protein degradation; T315I-positive Ph+ leukemia cell; c-myc
13.
Proc Nutr Soc. 2020 Mar 18:1-6. doi: 10.1017/S0029665120000099. [Epub ahead of print]
Nutrition and cancer: evidence gaps and opportunities for improving knowledge.
Abstract
The Nutrition Society's 1st Annual Nutrition and Cancer Networking Conference brought together scientists from the fields of Nutrition, Epidemiology, Public Health, Medical Oncology and Surgery with representatives of the public, cancer survivors and cancer charities. Speakers representing these different groups presented the challenges to collaboration, how the needs of patients and the public can be met, and the most promising routes for future research. The conference programme promoted debate on these issues to highlight current gaps in understanding and barriers to generating and implementing evidence-based nutrition advice. The main conclusions were that the fundamental biology of how nutrition influences the complex cancer risk profiles of diverse populations needs to be better understood. Individual and population level genetics interact with the environment over a lifespan to dictate cancer risk. Large charities and government have a role to play in diminishing our current potently obesogenic environment and exploiting nutrition to reduce cancer deaths. Understanding how best to communicate, advise and support individuals wishing to make dietary and lifestyle changes, can reduce cancer risk, enhance recovery and improve the lives of those living with and beyond cancer.
KEYWORDS:
Cancer; Chemotherapy; Diet; Nutrients; Prehabilitation
14.
J Ovarian Res. 2020 Mar 17;13(1):29. doi: 10.1186/s13048-020-00629-4.
Tumor burden is a potential marker of PARP inhibitor effects in ovarian cancer: a head-to-head observational series.
Abstract
BACKGROUND:
Olaparib, a poly ADP-ribose polymerase (PARP) inhibitor, has proven to be effective and safe as maintenance therapy and multiline therapy in ovarian cancer, especially in patients with BRCA mutations. This study intended to observe the influence of tumor load on the efficacy and safety of olaparib in recurrent ovarian cancer.
CASES PRESENTATION:
Three patients harbored gBRCAwt with low tumor load (LTL), while two women harbored BRCAmt with high tumor load (HTL) were recruited. Two of the three LTL patients achieved partial response, and the other showed stable disease. Both HTL patients were assessed to have progressive disease in a short time. Olaparib appears to be effective and safe for LTL recurrent ovarian cancer patients even if it is gBRCAwt, while the response is poor in HTL patients.
CONCLUSIONS:
Tumor load may be another potential marker to predict the effect of PARP inhibitors. The present head-to-head observational series provides new evidence on this issue for further research from bench to bedside in the future.
KEYWORDS:
Olaparib; Potential marker; Recurrent ovarian cancer; Tumor burden
15.
BMC Palliat Care. 2020 Mar 17;19(1):33. doi: 10.1186/s12904-020-0530-6.
Increasing preparedness for caregiving and death in family caregivers of patients with severe illness who are cared for at home - study protocol for a web-based intervention.
Abstract
BACKGROUND:
Family caregivers of patients with severe illness and in need for a palliative care approach, face numerous challenges and report having insufficient preparedness for the caregiver role as well as a need for information and psychosocial support. Preparing to care for a severely ill family members also means becoming aware of death. Feelings of being prepared are associated with positive aspects and regarded protective against negative health consequences.
METHODS:
The study adheres to the SPIRIT-guidelines (Supplementary 1), uses a pre-post design and include a web-based intervention. Inclusion criteria are; being a family caregiver of a patient with severe illness and in need of a palliative care approach. The intervention which aims to increase preparedness for caregiving and death is grounded in theory, research and clinical experience. The topics cover: medical issues, symptoms and symptom relief; communication within the couple, how to spend the time before death, being a caregiver, planning for the moment of death and; considerations of the future. The intervention is presented through videos and informative texts. The website also holds an online peer-support discussion forum. Study aims are to: evaluate feasibility in terms of framework, content, usage and partners' experiences; explore how the use of the website, influences family caregivers' preparedness for caregiving and death; explore how the use of the website influences family caregivers' knowledge about medical issues, their communication with the patient and their considerations of the future; and to investigate how the family caregivers' preparedness for caregiving and death influences their physical and psychological health and quality of life 1 year after the patient's death. Data will be collected through qualitative interviews and a study-specific questionnaire at four time-points.
DISCUSSION:
This project will provide information about whether support via a website has the potential to increase preparedness for caregiving and death and thereby decrease negative health consequences for family caregivers of patients affected by severe illness. It will provide new knowledge about intervention development, delivery, and evaluation in a palliative care context. Identification of factors before death and their association with family caregivers' preparedness and long-term health may change future clinical work.
TRIAL REGISTRATION:
The study is registered at ClinicalTrials.gov: NCT03676283.
KEYWORDS:
Family caregivers; Palliative care; Preparedness; Severe illness; Web-based intervention
16.
Cancers (Basel). 2020 Mar 15;12(3). pii: E695. doi: 10.3390/cancers12030695.
Emerging Role of Circulating Tumor Cells in Gastric Cancer.
Thanh Huong P1, Gurshaney S2, Thanh Binh N3, Gia Pham A4, Hoang Nguyen H4, Thanh Nguyen X4, Pham-The H5, Tran PT5, Truong Vu K6, Xuan Duong N7, Pelucchi C8, La Vecchia C8, Boffetta P9, Nguyen HD2, Luu HN10,11.
Abstract
With over 1 million incidence cases and more than 780,000 deaths in 2018, gastric cancer (GC) was ranked as the 5th most common cancer and the 3rd leading cause of cancer deaths worldwide. Though several biomarkers, including carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), and cancer antigen 72-4 (CA72-4), have been identified, their diagnostic accuracies were modest. Circulating tumor cells (CTCs), cells derived from tumors and present in body fluids, have recently emerged as promising biomarkers, diagnostically and prognostically, of cancers, including GC. In this review, we present the landscape of CTCs from migration, to the presence in circulation, biologic properties, and morphologic heterogeneities. We evaluated clinical implications of CTCs in GC patients, including diagnosis, prognosis, and therapeutic management, as well as their application in immunotherapy. On the one hand, major challenges in using CTCs in GC were analyzed, from the differences of cut-off values of CTC positivity, to techniques used for sampling, storage conditions, and CTC molecular markers, as well as the unavailability of relevant enrichment and detection techniques. On the other hand, we discussed future perspectives of using CTCs in GC management and research, including the use of circulating tumor microembolies; of CTC checkpoint blockade in immunotherapy; and of organoid models. Despite the fact that there are remaining challenges in techniques, CTCs have potential as novel biomarkers and/or a non-invasive method for diagnostics, prognostics, and treatment monitoring of GC, particularly in the era of precision medicine.
KEYWORDS:
circulating tumor cells; diagnostic; gastric cancer; prognostic; treatment
17.
Cancers (Basel). 2020 Mar 13;12(3). pii: E680. doi: 10.3390/cancers12030680.
Global RNA Expression and DNA Methylation Patterns in Primary Anaplastic Thyroid Cancer.
Abstract
Anaplastic thyroid cancer (ATC) is one of the most malignant tumors, with a median survival of only a few months. The tumorigenic processes of this disease have not yet been completely unraveled. Here, we report an mRNA expression and DNA methylation analysis of fourteen primary ATCs. ATCs clustered separately from normal thyroid tissue in unsupervised analyses, both by RNA expression and by DNA methylation. In expression analysis, enrichment of cell-cycle-related genes as well as downregulation of genes related to thyroid function were seen. Furthermore, ATC displayed a global hypomethylation of the genome but with hypermethylation of CpG islands. Notably, several cancer-related genes displayed a correlation between RNA expression and DNA methylation status, including MTOR, NOTCH1, and MAGI1. Furthermore, TSHR and SLC26A7, encoding the thyroid-stimulating hormone receptor and an iodine receptor highly expressed in normal thyroid, respectively, displayed low expression as well as aberrant gene body DNA methylation. This study is the largest investigation of global DNA methylation in ATC to date. It shows that aberrant DNA methylation is common in ATC and likely contributes to tumorigenesis in this disease. Future explorations of novel treatments should take this into consideration.
KEYWORDS:
DNA methylation; RNA sequencing; anaplastic thyroid cancer; formalin-fixed paraffin-embedded tissue
18.
Noncoding RNA. 2020 Mar 13;6(1). pii: E11. doi: 10.3390/ncrna6010011.
NEAT1 Long Isoform Is Highly Expressed in Chronic Lymphocytic Leukemia Irrespectively of Cytogenetic Groups or Clinical Outcome.
Ronchetti D1,2, Favasuli V1, Monti P3, Cutrona G4, Fabris S2, Silvestris I1, Agnelli L1, Colombo M4, Menichini P3, Matis S4, Gentile M5, Nurtdinov R6, Guigó R6, Baldini L1,2, Fronza G3, Ferrarini M7, Morabito F8,9, Neri A1,2, Taiana E1,2.
Abstract
The biological role and therapeutic potential of long non-coding RNAs (lncRNAs) in chronic lymphocytic leukemia (CLL) are still open questions. Herein, we investigated the significance of the lncRNA NEAT1 in CLL. We examined NEAT1 expression in 310 newly diagnosed Binet A patients, in normal CD19+ B-cells, and other types of B-cell malignancies. Although global NEAT1 expression level was not statistically different in CLL cells compared to normal B cells, the median ratio of NEAT1_2 long isoform and global NEAT1 expression in CLL samples was significantly higher than in other groups. NEAT1_2 was more expressed in patients carrying mutated IGHV genes. Concerning cytogenetic aberrations, NEAT1_2 expression in CLL with trisomy 12 was lower with respect to patients without alterations. Although global NEAT1 expression appeared not to be associated with clinical outcome, patients with the lowest NEAT1_2 expression displayed the shortest time to first treatment; however, a multivariate regression analysis showed that the NEAT1_2 risk model was not independent from other known prognostic factors, particularly the IGHV mutational status. Overall, our data prompt future studies to investigate whether the increased amount of the long NEAT1_2 isoform detected in CLL cells may have a specific role in the pathology of the disease.
KEYWORDS:
Chronic Lymphocytic Leukemia; NEAT1; lncRNA
19.
Lancet. 2020 Mar 7;395(10226):817-827. doi: 10.1016/S0140-6736(20)30165-3.
Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future.
Abstract
The development and approval of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer represents a major milestone in cancer therapeutics. Three different oral CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have significantly improved progression-free survival by a number of months when combined with endocrine therapy. More recently, improvement in overall survival has been reported with ribociclib and abemaciclib. The toxicity profile of all three drugs is well described and generally easily manageable with dose reductions when indicated. More myelotoxicity is observed with palbociclib and ribociclib, but more gastrointestinal toxicity is observed with abemaciclib. Emerging data is shedding light on the resistance mechanisms associated with CDK4/6 inhibitors, including cell cycle alterations and activation of upstream tyrosine kinase receptors. A number of clinical trials are exploring several important questions regarding treatment sequencing, combinatorial strategies, and the use of CDK4/6 inhibitors in the adjuvant and neoadjuvant settings, thereby further expanding and refining the clinical application of CDK4/6 inhibitors for patients with breast cancer.
Copyright © 2020 Elsevier Ltd. All rights reserved.
20.
Med Phys. 2019 Nov;46(11):5304-5313. doi: 10.1002/mp.13829. Epub 2019 Oct 8.
Development and validation of a 1.5 T MR-Linac full accelerator head and cryostat model for Monte Carlo dose simulations.
Abstract
PURPOSE:
To develop, implement, and validate a full 1.5 T/7 MV magnetic resonance (MR)-Linac accelerator head and cryostat model in EGSnrc for high precision dose calculations accounting for magnetic field effects that are independent from the vendor treatment planning system.
METHODS:
Primary electron beam parameters for the implemented model were adapted to be in accordance with measured dose profiles of the Elekta Unity (Elekta AB, Stockholm, Sweden). Parameters to be investigated were the mean electron energy as well as the Gaussian radial intensity and energy distributions. Energy tuning was done comparing depth dose profiles simulated with monoenergetic beams of varying energies to measurements. The optimum radial intensity distribution was found by varying the radial full width at half maximum (FWHM) and comparing simulated and measured lateral profiles. The influence of the energy distribution was investigated by comparing simulated lateral and depth dose profiles with varying energy spreads to measured data. Comparison of simulations and measurements was performed by calculating average and maximum local dose deviations. The model was validated recalculating a clinical intensity-modulated radiation therapy plan for the MR-Linac and comparing the resulting dose distribution with simulations from the commercial treatment planning system Monaco using the gamma criterion.
RESULTS:
Comparison of simulated and measured data showed that the optimum initial electron beam for MR-Linac simulations was monoenergetic with an electron energy of (7.4 ± 0.2) MeV. The optimum Gaussian radial intensity distribution has a FWHM of (2.2 ± 0.3) mm. The average relative deviations were smaller than 1% for all simulated profiles with optimum electron parameters, whereas the largest maximum deviation of 2.07% was found for the 22 × 22 cm 2 cross-plane profile. Profiles were insensitive to energy spread variations. The IMRT plan recalculated with the final MR-Linac model with optimized initial electron beam parameters showed a gamma pass rate of 99.83 % using a gamma criterion of 3%/3 mm.
CONCLUSIONS:
The EGSnrc MR-Linac model developed in this study showed good accordance with measurements and was successfully used to recalculate a first full clinical IMRT treatment plan. Thus, it shows the general possibility for future secondary dose calculations of full IMRT plans with EGSnrc, which needs further detailed investigations before clinical use.
© 2019 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.
KEYWORDS:
MR-linac; Monte Carlo simulations; magnetic resonance guided radiotherapy
21.
Expert Rev Anticancer Ther. 2019 Apr;19(4):319-326. doi: 10.1080/14737140.2019.1586539. Epub 2019 Mar 18.
Anti-BCMA antibodies in the future management of multiple myeloma.
Abstract
B-cell maturation antigen (BCMA) belongs to the tumor necrosis factor receptor family and is expressed on late B-cells and plasma cells. Serum BCMA is elevated in patients with multiple myeloma (MM) and chronic lymphocytic leukemia (CLL), and might represent a novel prognostic and monitoring tool. Serum BCMA levels can predict both progression free survival (PFS) and overall survival (OS). Several therapeutic strategies are currently under investigation including BCMA-directed monoclonal Abs (either naked or with drug conjugates, and bispecific Abs) and cellular T-cell therapies (chimeric antigen receptor T-cells) with impressive clinical results. Areas covered: This review aims to present the mechanisms of action and the available data on efficacy and safety of therapies targeting BCMA. Expert opinion: The preliminary preclinical and clinical results from the phase 1 and 2 studies have demonstrated significant activity of the anti-BCMA therapeutic strategies. The main toxicities induced include Cytokine Release Syndrome (CRS) and ocular toxicity. The management of these adverse events remains currently an issue of controversy.
KEYWORDS:
B-cell maturation antigen; BiTEs; CAR-T-cells; monoclonal antibodies; multiple myeloma
22.
Expert Rev Anticancer Ther. 2019 Apr;19(4):343-353. doi: 10.1080/14737140.2019.1585245. Epub 2019 Mar 11.
Systemic treatment of advanced hepatocellular cancer: new hope on the horizon.
Abstract
Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality in the world. The majority of the patients present at an advanced or incurable stage where neither locoregional treatment nor combination treatment of locoregional treatment and systemic therapies is feasible. For decades sorafenib was the only treatment option available for advanced HCC. However, with the advent of new and more effective therapies recently, the overall prognosis of advanced HCC has improved significantly. Areas covered: This review summarises the current systemic treatment options available and future prospects in the management of advanced HCC where patients are not suitable for locoregional treatment. Expert opinion: New effective targeted therapeutics have dramatically changed the treatment landscape for advanced HCC. The incorporation of sequential therapy including sorafenib or lenvatinib as first-line treatment and immunotherapy, regorafenib or cabozantinib as second-line treatment have significantly improved outcomes for patients with advanced HCC. Further development of novel combinations of these new agents and predictive/prognostic biomarkers are being explored. Efforts should also be made to tailor treatment to individual patients based on etiology, clinical and molecular factors.
KEYWORDS:
Hepatocellular cancer; biomarkers; future research; immunotherapy; molecular targeted agents; systemic treatment
23.
Expert Rev Anticancer Ther. 2019 Apr;19(4):309-318. doi: 10.1080/14737140.2019.1582335. Epub 2019 Feb 26.
New and important changes in breast cancer TNM: incorporation of biologic factors into staging.
Abstract
Cancer staging has historically been based solely on the anatomic extent of the tumor (T), spread to lymph nodes (N), and the presence of distant metastases (M). More recently biologic factors have been added to modify TNM stage groups to provide more accurate prognosis for patients. Areas covered: The American Joint Committee on Cancer (AJCC) updated breast cancer staging in 2016 to include T, N, M, tumor grade and expression of estrogen and progesterone receptors and HER2. Addition of these factors changed the stage group for a large fraction of cases compared to prior TNM stage groupings. This updated 'prognostic stage' provides more robust and precise prognosis information. Expert opinion: Inclusion of biological information in staging changes the meaning and the use of stage in clinical practice. This paper reviews the evidence supporting these changes, limitations affecting staging, and discusses the implications for clinical practice and the future of breast cancer staging.
KEYWORDS:
AJCC; Breast cancer; biomarkers; cancer staging; prognosis
24.
Expert Rev Anticancer Ther. 2019 Mar;19(3):245-257. doi: 10.1080/14737140.2019.1574574. Epub 2019 Feb 6.
Targeting angiogenesis in metastatic renal cell carcinoma.
Abstract
Renal cell carcinoma (RCC), and particularly its clear cell histological subtype, is commonly characterized by genetic alterations in the Von Hippel Lindau (VHL) tumor suppressor gene, leading to a typically exasperated angiogenesis. However, other biological and genetic peculiarities contribute to differentiate this malignancy from other solid tumors, including its immunogenicity. Areas covered: This review focuses on the present and future role of antiangiogenic drugs, administered either alone (as it has been in the past few years), or in combination with other agents (e.g. immune checkpoint inhibitors), in the treatment of metastatic RCC. Expert commentary: Due to its peculiar pathogenesis, it is unrealistic to expect to be able to get rid of antiangiogenic agents for the treatment of this disease; however, we do expect that combinations of VEGF/VEGFRs-targeting agents with immune checkpoint inhibitors will gradually replace antiangiogenic monotherapies as the standard of care, at least in the first line setting of metastatic RCC patients. Biomarkers discovery remains the highest priority in order to further improve the percentage of patients benefitting of our treatment.
KEYWORDS:
Tumor angiogenesis; Von Hippel Lindau gene; hypoxia-inducible factors; immunotherapy; renal cell carcinoma; tyrosine kinase inhibitors
25.
Prev Med. 2019 Feb;119:108-117. doi: 10.1016/j.ypmed.2018.12.021. Epub 2018 Dec 27.
HPV-based cervical screening: Rationale, expectations and future perspectives of the new Dutch screening programme.
Abstract
Based on scientific data showing that HPV testing provides better protection against cervical precancer and cancer than cytology, in 2011 the Dutch Health Council advised the Minister of Welfare, Health and Sports to replace cytology by HPV testing in the Dutch population-based screening programme. After a successful evaluation of the feasibility of HPV-based screening in 2014, primary HPV testing for cervical screening was implemented in 2017. The Netherlands has been one of the first countries worldwide to implement nationwide HPV-based screening and its experience with the new programme is therefore followed with great interest. In this manuscript, we present an overview of the studies that were instrumental in the choice of HPV assay and triage strategy, the adjustment of screening starting and exit ages and intervals, and the implementation of HPV self-sampling. Finally, we review the cost-effectiveness of the proposed new screening algorithm and we explore future perspectives. The rationale behind the new Dutch HPV-based screening programme, which is based on risk management, could serve as a guidance to other countries that are planning to implement HPV-based screening in the near future.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
KEYWORDS:
Cervical cancer screening; Cervical intraepithelial neoplasia; Early detection of cancer; Human papillomavirus DNA test; Triage testing
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