Complication Management in Outpatient Spine Surgery

Publication date: Available online 12 June 2018

Source: Seminars in Spine Surgery

Author(s): Brittany E. Haws, Benjamin Khechen, Jordan A. Guntin, Kaitlyn L. Cardinal, Kern Singh

Abstract

This paper aims to examine essential topics regarding outpatient surgery centers and complication management that should be considered when performing surgery at these facilities. In recent years, outpatient surgery centers have become increasingly utilities due to the reduced associated healthcare costs and overall patient satisfaction. However, with advancements in the type of surgeries that can be performed at these centers, more steps need to be taken to ensure the assessment and management of complications is adequate. Surgeons should consider the possible risks for complications and create protocols in the event of a complication specifically designed for an outpatient surgery center.

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Spinescope

Publication date: June 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 2

Author(s): Scott D. Boden

https://ift.tt/2NRnB3X

How to implement a value-based spine program: Perspectives from hospital for special surgery

Publication date: June 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 2

Author(s): Catherine H. MacLean, Joel M. Press, Chad M. Craig, Frank J. Schwab, Todd J. Albert

Abstract

Spine disorders are common, cause significant pain and functional limitation, and are costly. Variation in the utilization of services and outcomes of spine care have raised questions among payers about the value of the spine care they are buying. Value for spine care can be achieved through a focus on delivering the highest quality and most appropriate care consistent with patient preferences. A coordinated, multidisciplinary approach is needed to achieve high-value care. Routine measurement of outcomes is needed to prove it.

https://ift.tt/2Lk3Lgh

Value in lumbar spine fusion: Minimally invasive versus traditional open surgery

Publication date: June 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 2

Author(s): Fady Y. Hijji, Ankur S. Narain, Kelly H. Yom, Krishna T. Kudaravalli, Kern Singh

Abstract

In the evolving healthcare climate, healthcare resource allocation will begin to favor surgical treatments that exhibit value through both clinical and cost-effectiveness. Lumbar pathology is extremely prevalent in the United States, resulting in a substantial portion of healthcare expenditure. Open lumbar fusions are an effective treatment for degenerative lumbar pathology; however, these procedures have exhibited extremely high and potentially unsustainable costs. Minimally invasive (MIS) techniques have previously demonstrated to reduce costs while maintaining or improving clinical effectiveness. The present review addresses the current literature comparing the values of open and MIS lumbar fusion techniques.

https://ift.tt/2NSOKnt

Quality and safety improvement initiatives in complex spine surgery

Publication date: June 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 2

Author(s): Rajiv K. Sethi, Quinlan D. Buchlak, Jean-Christophe Leveque, Anna K. Wright, Vijay V. Yanamadala

Abstract

The global health policy landscape is shifting. Health care is moving toward a value-based system with emphasis on reduced adverse events, improved patient outcomes, and increased cost efficiency. Studies have demonstrated that complex adult lumbar scoliosis surgery is accompanied by high variability in complication rates, which may be prevented with improved delivery of evidence-based care. In particular, standardized, systematic, multidisciplinary perioperative care protocols have been shown to significantly reduce the likelihood of a spectrum of negative outcomes associated with complex adult lumbar scoliosis surgery. This paper presents a review and analysis of multiple quality and safety improvement initiatives and methodologies in adult complex spine surgery. Achieving maximal quality and safety improvements in this field appears to require clinicians to go beyond focusing on specific elements of clinical practice and pay attention to optimizing the perioperative system. Two novel conceptual models were developed: the SpineSIM-D and the SpineSIM-C. They synthesize key success factors operating at the individual, team, and organizational levels to guide future quality and safety improvement initiatives. Comprehensive, systematic perioperative protocols that are multidisciplinary in nature appear to be rare in the field of complex spine surgery and have the potential to further improve quality and safety thereby meeting the requirements of health care's value-driven future.

https://ift.tt/2JpMdxs

Enhanced recovery after surgery (ERAS)—Concepts, components, and application to spine surgery

Publication date: June 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 2

Author(s): Thomas W. Wainwright, Michael Y. Wang, Tikki Immins, Robert G. Middleton

Abstract

This article describes the concept of Enhanced Recovery after Surgery (ERAS) and its application to spine surgery. ERAS is a multimodal approach designed to reduce the surgical stress response and accelerate recovery following surgery. It is a multi-disciplinary, patient-centred approach that employs an evidenced-based pathway of standardised care. It has been proven across a range of surgical pathways but has yet to be defined and adopted in spine surgery. ERAS pathways are needed in spine surgery. Patient recovery is often long, painful, expensive, and a highly variable experience. Consequently, ERAS programs will find great utility in this subspecialty.

https://ift.tt/2NOw4F7

Shared decision-making in spine surgery

Publication date: June 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 2

Author(s): Kenneth Nwosu, Stuart Hershman, Thomas Cha

Abstract

Although relatively new, the concept of shared decision-making (SDM) has become extremely popular over the past few years, yielding a rapid rise in the development of incorporative tools. The value of the SDM process lies in the creation of an open dialog between the surgeon and patient and has been shown to demonstrate usefulness with regard to enhancing the patient experience as well as their understanding of a proposed procedure.

https://ift.tt/2Jpy3fB

Measuring costs related to spine surgery

Publication date: June 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 2

Author(s): Benjamin Weisenthal, Jeffery Hills, Silky Chotai, Ahilan Sivaganesan, Mohamad Bydon, Clinton J. Devin

Abstract

Treatment of spinal pathology is a significant contributor to the current rise in health care spending in the United States. To maximize value, the cost of spine care must be analyzed to assess for any inefficiencies. In parallel, outcomes must be tracked to ensure that any potential cost reductions do not have a negative impact on the efficacy of treatments. This article focuses on three primary topics in spinal care. We will begin with a general review of cost analysis methods, highlight specific drivers of cost, and finally offer broad solutions to help improve the value of spine care.

https://ift.tt/2NRPCsr

Patient reported outcome measures for spinal disorders

Publication date: June 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 2

Author(s): Kenneth Nwosu, Joseph Schwab

Abstract

The systematic collection of patient-based outcomes in spine care will inform the debate regarding the efficacy of various treatment and allow them to be comparable to other spine disease-specific and non-diseases-specific outcomes, and to other non-musculoskeletal diseases regarding effect on patient's global health states. Patient-based outcome measures are usually classified as generic, including global ratings of health status, as well as multidimensional measures of health-related quality of life (HRQOL) or disease-specific measures that are attributable to symptoms and functional limitations caused by a specific condition. In this article, we discuss the recommended core results that should be measured in patients with spinal disorders, instruments used to measure them, and the emergence of PROMIS (Patient-Reported Outcome Measure Information System).

https://ift.tt/2LjfkEo

Defining, measuring, and improving value in spine care

Publication date: June 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 2

Author(s): Robert S. Kaplan, Derek Haas

Abstract

This chapter discusses how to measure and improve spine care outcomes and costs. Today's commonly used outcome metrics, such as readmission and complication rates, are actually process and quality metrics. They are not the outcomes, such as improvement in pain and mobility, that patients expect to enjoy from being treated for spine pain. Similarly, existing cost measurements of spine care, derived from ratios of cost-to-charges or relative value units, are inaccurate and do not track actual resources used to treat spine care patients over complete treatment cycles. We document how to improve the value of spine care by adopting patient reported outcomes measures that can be collected in a standardized way. Similarly, more accurate cost measurement can be achieved by implementing Time-Driven Activity-Based Costing, an approach that helps clinicians identify opportunities to reduce the cost of delivering spine care without adversely affecting, and often improving, patient outcomes.

https://ift.tt/2NT1utV

Introduction

Publication date: June 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 2

Author(s): Louis G. Jenis

https://ift.tt/2JpBJOB

Contributors to Authors

Publication date: June 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 2

Author(s):

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Behavioral economics in spine care

Publication date: June 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 2

Author(s): Alok Sharan

Abstract

Basic economic theory states that humans act in a rational manner when presented with the proper information. Over the years it has been clear though that similar incentives can result in different behaviors among different individuals. The field of behavioral economics has been created as an attempt to understanding the link between incentives and behaviors. As physician payment reform evolves toward rewarding value and outcomes, understanding some of the basic tenets of behavioral economics can help providers as they attempt to navigate the new payment methodologies.

https://ift.tt/2Li9N0U

Secondary fracture prevention in spine surgery

Publication date: March 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 1

Author(s): Paul A. Anderson, Kristyn Hare, Eeric Truumees

Abstract

A fragility fracture is associated with high likelihood of further fracture and the risk is reduced by quality improvement programs to provide osteoporotic care and rehabilitation. Unfortunately, these treatments are offered to less than 20% of patients who have fragility fractures. Multiple types of secondary fracture prevention programs are available and all have been shown to increase diagnostic testing and pharmacologic treatments in a cost-effective manner. The American Orthopaedic Association's "Own the Bone" is one such comprehensive quality improvement program that provides leadership and offers patients access to preventive care. Spine surgeons should take the lead to make sure that patients with fragility spinal fractures receive secondary fracture prevention.

https://ift.tt/2NQYtun

What is the future of patient-specific vertebral fracture prediction?

Publication date: March 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 1

Author(s): Hugo Giambini, Bradford L. Currier, Michael J. Yaszemski, Ahmad Nassr

Abstract

This paper aims to introduce a few alternative methodologies for prediction of vertebral fractures, the most common type being fragility fracture in the elderly. Current methods, such as DXA, for diagnosing osteoporosis and predicting the risk of vertebral failure, are often not accurate thereby preventing those patients at risk from receiving adequate treatment. Robust fracture prediction models for vertebral fracture risk should not only include BMD, as measured by DXA, but should incorporate a wide range of factors including bone geometry, bone mineral distribution within the vertebral body, daily living activities, and spine musculature. One promising technique is finite element modeling, which has been developed over the past several decades and implements clinical imaging, such as quantitative computed tomography (QCT), and engineering fundamentals to more accurately predict the risk of fracture. Other imaging tools that assess bone mineral distribution and structure at the microscopic level include micro-CT or high-resolution peripheral QCT (HR-pQCT). These newer techniques hold the promise of more accurate diagnosis of osteoporosis and those at risk for vertebral insufficiency fractures before they occur.

https://ift.tt/2Lk0E87

Spinescope

Publication date: March 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 1

Author(s): Scott D. Boden

https://ift.tt/2NQly04

Complex spinal surgery in patients with osteoporosis: Tips and tricks for achieving adequate constructs and avoiding complications

Publication date: March 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 1

Author(s): David P. Falk, Evan J. Smith, Sachin Gupta, Warren Yu, Joseph R. O'Brien

Abstract

Osteoporosis presents a unique set of challenges for instrumentation and correction of spinal deformity, both due to the unique pathology created by the disease and the technical considerations for obtaining spinal fixation. As a result, the spine surgeon is faced with the challenge of needing a robust reduction method to achieve stability in a relatively weak medium. Complications from fixation failure most frequently present as pedicle screw pullout and junctional failure. Many solutions have been offered to improve construct strength from preoperative therapeutics to intraoperative surgical adjuncts. From our experience, we review several promising strategies.

https://ift.tt/2JpMb8O

Spinal implant options to optimize fixation in patients with osteopenia/osteoporosis

Publication date: March 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 1

Author(s): Sohrab Virk, Elizabeth Yu

Abstract

The challenges presented by osteoporotic spines for creating a strong bone–implant interface are substantial. Many devices have been specifically designed to enhance fixation of screws, hooks, and cages in order to create an optimal healing environment for patients with low bone mineral density. Screw design has been enhanced via differing screw pitches, shapes, materials, coating, and sizes in order to enhance fixation in both the posterior and anterior osteoporotic spine. Several novel designs for cages, plates, anchors, hooks, and bands can be used to achieve fixation as well. With appropriate surgical technique, these technological advances can dramatically improve fixation for a construct to treat osteoporotic spines.

https://ift.tt/2NQlxJy

Do bisphosphonates affect fusion rates? How to manage these medications in the perioperative time frame

Publication date: March 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 1

Author(s): Emmanuel N. Menga, Antonio J. Webb, Addisu Mesfin

Abstract

Various treatment options are available for the management of patients with osteoporosis including bisphosphonates. While bisphosphonates have demonstrated effectiveness at reducing the risk of vertebral osteoporotic fractures, their mechanisms of action may render them contraindicated in the setting of spinal arthrodesis. Research studies reporting on the effects of bisphosphonate osteoporotic medications on spinal fusion remain limited, inconsistent and controversial with no clear guidelines. Future randomized and multi-center studies are needed that further examine the questions of bisphosphonates and spinal fusion.

https://ift.tt/2JoNXqE

Can medical management with teriparatide improve spinal surgery outcomes in patients with spinal osteoporosis/osteopenia?

Publication date: March 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 1

Author(s): Muhammad Shakib Akhter, Hussein Ali El-Khechen, Rakesh Patel, Ilyas S. Aleem

Abstract

Osteopenia and osteoporosis have become increasingly common in the elderly population, as has the concern from treating spinal surgeons. Many adverse surgical outcomes have been associated with poor bone quality, including decreased fusion rates, hardware complications, and osteoporotic fractures. Teriparatide, a recombinant form of parathyroid hormone, has been used as a major pharmaceutical intervention in osteoporosis treatment. This article provides an overview of the mechanism of teriparatide followed by a detailed review of the literature concerning outcomes of medical management with teriparatide in both animal models and humans with osteoporosis/osteopenia. Improved fusion rates and duration, as well as reduced osteoporosis-related complications are evident upon reviewing clinical and radiographic outcomes of teriparatide therapy in spinal surgery patients.

https://ift.tt/2NOw1sV

Targeting epigenetics using synthetic lethality in precision medicine.

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Targeting epigenetics using synthetic lethality in precision medicine.

Cell Mol Life Sci. 2018 Jul 12;:

Authors: Chen ES

Abstract
Technological breakthroughs in genomics have had a significant impact on clinical therapy for human diseases, allowing us to use patient genetic differences to guide medical care. The "synthetic lethal approach" leverages on cancer-specific genetic rewiring to deliver a therapeutic regimen that preferentially targets malignant cells while sparing normal cells. The utility of this system is evident in several recent studies, particularly in poor prognosis cancers with loss-of-function mutations that become "treatable" when two otherwise discrete and unrelated genes are targeted simultaneously. This review focuses on the chemotherapeutic targeting of epigenetic alterations in cancer cells and consolidates a network that outlines the interplay between epigenetic and genetic regulators in DNA damage repair. This network consists of numerous synergistically acting relationships that are druggable, even in recalcitrant triple-negative breast cancer. This collective knowledge points to the dawn of a new era of personalized medicine.

PMID: 30003270 [PubMed - as supplied by publisher]

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New Insights Into DNA Helicases as Druggable Targets for Cancer Therapy.

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New Insights Into DNA Helicases as Druggable Targets for Cancer Therapy.

Front Mol Biosci. 2018;5:59

Authors: Datta A, Brosh RM

Abstract
Small molecules that deter the functions of DNA damage response machinery are postulated to be useful for enhancing the DNA damaging effects of chemotherapy or ionizing radiation treatments to combat cancer by impairing the proliferative capacity of rapidly dividing cells that accumulate replicative lesions. Chemically induced or genetic synthetic lethality is a promising area in personalized medicine, but it remains to be optimized. A new target in cancer therapy is DNA unwinding enzymes known as helicases. Helicases play critical roles in all aspects of nucleic acid metabolism. We and others have investigated small molecule targeted inhibition of helicase function by compound screens using biochemical and cell-based approaches. Small molecule-induced trapping of DNA helicases may represent a generalized mechanism exemplified by certain topoisomerase and PARP inhibitors that exert poisonous consequences, especially in rapidly dividing cancer cells. Taking the lead from the broader field of DNA repair inhibitors and new information gleaned from structural and biochemical studies of DNA helicases, we predict that an emerging strategy to identify useful helicase-interacting compounds will be structure-based molecular docking interfaced with a computational approach. Potency, specificity, drug resistance, and bioavailability of helicase inhibitor drugs and targeting such compounds to subcellular compartments where the respective helicases operate must be addressed. Beyond cancer therapy, continued and new developments in this area may lead to the discovery of helicase-interacting compounds that chemically rescue clinically relevant helicase missense mutant proteins or activate the catalytic function of wild-type DNA helicases, which may have novel therapeutic application.

PMID: 29998112 [PubMed]

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Initiation of homologous recombination at DNA nicks.

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Initiation of homologous recombination at DNA nicks.

Nucleic Acids Res. 2018 Jul 09;:

Authors: Maizels N, Davis L

Abstract
Discontinuities in only a single strand of the DNA duplex occur frequently, as a result of DNA damage or as intermediates in essential nuclear processes and DNA repair. Nicks are the simplest of these lesions: they carry clean ends bearing 3'-hydroxyl groups that can undergo ligation or prime new DNA synthesis. In contrast, single-strand breaks also interrupt only one DNA strand, but they carry damaged ends that require clean-up before subsequent steps in repair. Despite their apparent simplicity, nicks can have significant consequences for genome stability. The availability of enzymes that can introduce a nick almost anywhere in a large genome now makes it possible to systematically analyze repair of nicks. Recent experiments demonstrate that nicks can initiate recombination via pathways distinct from those active at double-strand breaks (DSBs). Recombination at targeted DNA nicks can be very efficient, and because nicks are intrinsically less mutagenic than DSBs, nick-initiated gene correction is useful for genome engineering and gene therapy. This review revisits some physiological examples of recombination at nicks, and outlines experiments that have demonstrated that nicks initiate homology-directed repair by distinctive pathways, emphasizing research that has contributed to our current mechanistic understanding of recombination at nicks in mammalian cells.

PMID: 29986051 [PubMed - as supplied by publisher]

https://ift.tt/2zmWQBy

Targeted Next-Generation Sequencing in Men with Metastatic Prostate Cancer: a Pilot Study.

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Targeted Next-Generation Sequencing in Men with Metastatic Prostate Cancer: a Pilot Study.

Target Oncol. 2018 Jul 04;:

Authors: Barata PC, Mendiratta P, Heald B, Klek S, Grivas P, Sohal DPS, Garcia JA

Abstract
INTRODUCTION: Tumor profiling by targeted next-generation sequencing (tNGS) and personalized treatment based on these results is becoming increasingly common in patients with metastatic solid tumors, but it remains unclear whether this strategy results in benefit to patients with metastatic prostate cancer (mPCa).
OBJECTIVE: To assess the clinical utility of tNGS in treatment decision-making for patients with mPCa.
PATIENTS AND METHODS: Patients with available genomic profiling using tumor tissue (FoundationOne, F1) or cell-free DNA (FoundationACT, Guardant360) were included. Targetable genomic alterations (tGA) included a change in the copy number or mutations in DNA repair genes, mismatch repair genes, PTEN, cyclin-dependent kinases, ERBB2, BRAF, TSC, and the PIK3/mTOR pathway.
RESULTS: The study included 66 patients, 86% of which had metastatic castration-resistant prostate cancer (mCRPC), and who had received a median of 3 (range 0-7) treatments prior to tNGS. The most frequent alterations were found in TP53 (42%), PTEN (35%), androgen receptor (AR) (30%), DNA repair (30%), PIK3CA signaling pathway (21%), cyclin-dependent kinases (15%), BRAF (9%), and MMR/MSI (6%) genes. Among the 45 (68%) tGA+ patients, tNGS influenced treatment in 13 (29%) [PARP inhibitor (n = 7), mTOR inhibitor (n = 4), anti-PD-1 (n = 2), anti-HER2 (n = 1)]. The median progression-free survival (PFS) was 4.1 months [95% confidence interval (CI), 2.8-5.4]. Among tGA+ patients who did not receive tNGS-based therapy, systemic treatment (n = 17) included chemotherapy (71%), new generation anti-androgen therapy (24%), and cabozantinib (6%); the median PFS was 4.3 months (95% CI, 2.6-6.0; p = 0.7 for tGA+ with personalized therapy vs. tGA+ without personalized therapy).
CONCLUSION: In this cohort, the use of tNGS was feasible, detected frequent genomic alterations, and was used late in the disease course. Further studies and larger portfolios of targeted therapy trials are needed to maximize the benefit of tNGS in this population.

PMID: 29974386 [PubMed - as supplied by publisher]

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Trinucleotide repeat instability during double-strand break repair: from mechanisms to gene therapy.

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Trinucleotide repeat instability during double-strand break repair: from mechanisms to gene therapy.

Curr Genet. 2018 Jul 05;:

Authors: Mosbach V, Poggi L, Richard GF

Abstract
Trinucleotide repeats are a particular class of microsatellites whose large expansions are responsible for at least two dozen human neurological and developmental disorders. Slippage of the two complementary DNA strands during replication, homologous recombination or DNA repair is generally accepted as a mechanism leading to repeat length changes, creating expansions and contractions of the repeat tract. The present review focuses on recent developments on double-strand break repair involving trinucleotide repeat tracts. Experimental evidences in model organisms show that gene conversion and break-induced replication may lead to large repeat tract expansions, while frequent contractions occur either by single-strand annealing between repeat ends or by gene conversion, triggering near-complete contraction of the repeat tract. In the second part of this review, different therapeutic approaches using highly specific single- or double-strand endonucleases targeted to trinucleotide repeat loci are compared. Relative efficacies and specificities of these nucleases will be discussed, as well as their potential strengths and weaknesses for possible future gene therapy of these dramatic disorders.

PMID: 29974202 [PubMed - as supplied by publisher]

https://ift.tt/2KURJx3

Genetic characterisation of molecular targets in carcinoma of unknown primary.

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Genetic characterisation of molecular targets in carcinoma of unknown primary.

J Transl Med. 2018 Jul 04;16(1):185

Authors: Clynick B, Dessauvagie B, Sterrett G, Harvey NT, Allcock RJN, Saunders C, Erber W, Meehan K

Abstract
BACKGROUND: Carcinoma of unknown primary (CUP) is a metastatic epithelial malignancy in the absence of an identifiable primary tumour. Prognosis for patients with CUP is poor because treatment options are generally limited to broad spectrum chemotherapy. A shift towards personalised cancer management based on mutation profiling offers the possibility of new treatment paradigms. This study has explored whether actionable, oncogenic driver mutations are present in CUP that have potential to better inform treatment decisions.
METHODS: Carcinoma of unknown primary cases (n = 21) were selected and DNA was isolated from formalin-fixed paraffin embedded sections prior to amplification and sequencing. Two distinct yet complementary targeted gene panels were used to assess variants in up to 76 known cancer-related genes for the identification of biologically relevant and actionable mutations.
RESULTS: Variants were detected in 17/21 cases (81%) of which 11 (52%) were potentially actionable with drugs currently approved for use in known primary cancer types or undergoing clinical trials. The most common variants detected were in TP53 (47%), KRAS (12%), MET (12%) and MYC (12%). Differences at the molecular level were seen between common CUP histological subtypes. CUP adenocarcinomas and poorly differentiated carcinomas harboured the highest frequency of variants in genes involved in signal transduction pathways (e.g. MET, EGFR, HRAS, KRAS, and BRAF). In contrast, squamous cell carcinoma exhibited a higher frequency of variants in cell cycle control and DNA repair genes (e.g. TP53, CDKN2A and MLH1).
CONCLUSION: Taken together, mutations in biologically relevant genes were detected in the vast majority of CUP tumours, of which half provided a potentially novel treatment option not generally considered in CUP.

PMID: 29973234 [PubMed - in process]

https://ift.tt/2zgdSkH

Temozolomide and Pituitary Tumors: Current Understanding, Unresolved Issues, and Future Directions.

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Temozolomide and Pituitary Tumors: Current Understanding, Unresolved Issues, and Future Directions.

Front Endocrinol (Lausanne). 2018;9:318

Authors: Syro LV, Rotondo F, Camargo M, Ortiz LD, Serna CA, Kovacs K

Abstract
Temozolomide, an alkylating agent, initially used in the treatment of gliomas was expanded to include pituitary tumors in 2006. After 12 years of use, temozolomide has shown a notable advancement in pituitary tumor treatment with a remarkable improvement rate in the 5-year overall survival and 5-year progression-free survival in both aggressive pituitary adenomas and pituitary carcinomas. In this paper, we review the mechanism of action of temozolomide as alkylating agent, its interaction with deoxyribonucleic acid repair systems, therapeutic effects in pituitary tumors, unresolved issues, and future directions relating to new possibilities of targeted therapy.

PMID: 29963012 [PubMed]

https://ift.tt/2lOJ5lh

Uncovering the fine print of the CreERT2-LoxP system while generating a conditional knockout mouse model of Ssrp1 gene.

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Uncovering the fine print of the CreERT2-LoxP system while generating a conditional knockout mouse model of Ssrp1 gene.

PLoS One. 2018;13(6):e0199785

Authors: Sandlesh P, Juang T, Safina A, Higgins MJ, Gurova KV

Abstract
FAcilitates Chromatin Transcription (FACT) is a complex of SSRP1 and SPT16 that is involved in chromatin remodeling during transcription, replication, and DNA repair. FACT has been mostly studied in cell-free or single cell model systems because general FACT knockout (KO) is embryonically lethal (E3.5). FACT levels are limited to the early stages of development and stem cell niches of adult tissues. FACT is upregulated in poorly differentiated aggressive tumors. Importantly, FACT inhibition (RNAi) is lethal for tumors but not normal cells, making FACT a lucrative target for anticancer therapy. To develop a better understanding of FACT function in the context of the mammalian organism under normal physiological conditions and in disease, we aimed to generate a conditional FACT KO mouse model. Because SPT16 stability is dependent on the SSRP1-SPT16 association and the presence of SSRP1 mRNA, we targeted the Ssrp1 gene using a CreERT2- LoxP approach to generate the FACT KO model. Here, we highlight the limitations of the CreERT2-LoxP (Rosa26) system that we encountered during the generation of this model. In vitro studies showed an inefficient excision rate of ectopically expressed CreERT2 (retroviral CreERT2) in fibroblasts with homozygous floxed Ssrp1. In vitro and in vivo studies showed that the excision efficiency could only be increased with germline expression of two alleles of Rosa26CreERT2. The expression of one germline Rosa26CreERT2 allele led to the incomplete excision of Ssrp1. The limited efficiency of the CreERT2-LoxP system may be sufficient for studies involving the deletion of genes that interfere with cell growth or viability due to the positive selection of the phenotype. However, it may not be sufficient for studies that involve the deletion of genes supporting growth, or those crucial for development. Although CreERT2-LoxP is broadly used, it has limitations that have not been widely discussed. This paper aims to encourage such discussions.

PMID: 29953487 [PubMed - in process]

https://ift.tt/2tIVz1s

Profiles of Radioresistance Mechanisms in Prostate Cancer.

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Profiles of Radioresistance Mechanisms in Prostate Cancer.

Crit Rev Oncog. 2018;23(1-2):39-67

Authors: Chaiswing L, Weiss HL, Jayswal RD, Clair DKS, Kyprianou N

Abstract
Radiation therapy (RT) is commonly used for the treatment of localized prostate cancer (PCa). However, cancer cells often develop resistance to radiation through unknown mechanisms and pose an intractable challenge. Radiation resistance is highly unpredictable, rendering the treatment less effective in many patients and frequently causing metastasis and cancer recurrence. Understanding the molecular events that cause radioresistance in PCa will enable us to develop adjuvant treatments for enhancing the efficacy of RT. Radioresistant PCa depends on the elevated DNA repair system and the intracellular levels of reactive oxygen species (ROS) to proliferate, self-renew, and scavenge anti-cancer regimens, whereas the elevated heat shock protein 90 (HSP90) and the epithelial-mesenchymal transition (EMT) enable radioresistant PCa cells to metastasize after exposure to radiation. The up-regulation of the DNA repairing system, ROS, HSP90, and EMT effectors has been studied extensively, but not targeted by adjuvant therapy of radioresistant PCa. Here, we emphasize the effects of ionizing radiation and the mechanisms driving the emergence of radioresistant PCa. We also address the markers of radioresistance, the gene signatures for the predictive response to radiotherapy, and novel therapeutic platforms for targeting radioresistant PCa. This review provides significant insights into enhancing the current knowledge and the understanding toward optimization of these markers for the treatment of radioresistant PCa.

PMID: 29953367 [PubMed - in process]

https://ift.tt/2tF5kyx

Extracellular vesicles and ctDNA in lung cancer: biomarker sources and therapeutic applications.

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Extracellular vesicles and ctDNA in lung cancer: biomarker sources and therapeutic applications.

Cancer Chemother Pharmacol. 2018 Jun 08;:

Authors: Huang C, Liu S, Tong X, Fan H

Abstract
Lung cancer is the leading cause of cancer death in the world. Recently, targeted therapy and anti-programmed cell death receptor 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) immunotherapy have made great progress in treatment of lung cancer. However, responses to these therapies are variable, influenced by genetic alterations, high microsatellite instability and mismatch repair deficiency. Liquid biopsy of extracellular vesicles and circulating tumor DNA (ctDNA) emerges as a new promising non-invasive means that enables not only biomarker determination, but also continuous monitoring of cancer treatment. Notably, tumor extracellular vesicles play important roles in tumor formation and progression, and also serve as natural carriers for anti-tumor drugs and short-interfering RNA. In this review, we summarize the latest progress in understanding the relationships of extracellular vesicles and ctDNA in cancer biology, diagnosis and drug delivery. In particular, the application of extracellular vesicles and ctDNA in anti-PD-1/PD-L1 immunotherapy is discussed.

PMID: 29948020 [PubMed - as supplied by publisher]

https://ift.tt/2yRSOke

The HDAC6/8/10 inhibitor TH34 induces DNA damage-mediated cell death in human high-grade neuroblastoma cell lines.

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The HDAC6/8/10 inhibitor TH34 induces DNA damage-mediated cell death in human high-grade neuroblastoma cell lines.

Arch Toxicol. 2018 Jun 09;:

Authors: Kolbinger FR, Koeneke E, Ridinger J, Heimburg T, Müller M, Bayer T, Sippl W, Jung M, Gunkel N, Miller AK, Westermann F, Witt O, Oehme I

Abstract
High histone deacetylase (HDAC) 8 and HDAC10 expression levels have been identified as predictors of exceptionally poor outcomes in neuroblastoma, the most common extracranial solid tumor in childhood. HDAC8 inhibition synergizes with retinoic acid treatment to induce neuroblast maturation in vitro and to inhibit neuroblastoma xenograft growth in vivo. HDAC10 inhibition increases intracellular accumulation of chemotherapeutics through interference with lysosomal homeostasis, ultimately leading to cell death in cultured neuroblastoma cells. So far, no HDAC inhibitor covering HDAC8 and HDAC10 at micromolar concentrations without inhibiting HDACs 1, 2 and 3 has been described. Here, we introduce TH34 (3-(N-benzylamino)-4-methylbenzhydroxamic acid), a novel HDAC6/8/10 inhibitor for neuroblastoma therapy. TH34 is well-tolerated by non-transformed human skin fibroblasts at concentrations up to 25 µM and modestly impairs colony growth in medulloblastoma cell lines, but specifically induces caspase-dependent programmed cell death in a concentration-dependent manner in several human neuroblastoma cell lines. In addition to the induction of DNA double-strand breaks, HDAC6/8/10 inhibition also leads to mitotic aberrations and cell-cycle arrest. Neuroblastoma cells display elevated levels of neuronal differentiation markers, mirrored by formation of neurite-like outgrowths under maintained TH34 treatment. Eventually, after long-term treatment, all neuroblastoma cells undergo cell death. The combination of TH34 with plasma-achievable concentrations of retinoic acid, a drug applied in neuroblastoma therapy, synergistically inhibits colony growth (combination index (CI) < 0.1 for 10 µM of each). In summary, our study supports using selective HDAC inhibitors as targeted antineoplastic agents and underlines the therapeutic potential of selective HDAC6/8/10 inhibition in high-grade neuroblastoma.

PMID: 29947893 [PubMed - as supplied by publisher]

https://ift.tt/2yPMQAr

Sensitization of prostate cancer to radiation therapy: Molecules and pathways to target.

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Sensitization of prostate cancer to radiation therapy: Molecules and pathways to target.

Radiother Oncol. 2018 Jun 18;:

Authors: Yao M, Rogers L, Suchowerska N, Choe D, Al-Dabbas MA, Narula RS, Lyons JG, Sved P, Li Z, Dong Q

Abstract
Radiation therapy is used to treat cancer by radiation-induced DNA damage. Despite the best efforts to eliminate cancer, some cancer cells survive irradiation, resulting in cancer progression or recurrence. Alteration in DNA damage repair pathways is common in cancers, resulting in modulation of their response to radiation. This article focuses on the recent findings about molecules and pathways that potentially can be targeted to sensitize prostate cancer cells to ionizing radiation, thereby achieving an improved therapeutic outcome.

PMID: 29929859 [PubMed - as supplied by publisher]

https://ift.tt/2MO8TKG

Augmentation of the therapeutic efficacy of WEE1 kinase inhibitor AZD1775 by inhibiting the YAP-E2F1-DNA damage response pathway axis.

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Augmentation of the therapeutic efficacy of WEE1 kinase inhibitor AZD1775 by inhibiting the YAP-E2F1-DNA damage response pathway axis.

FEBS Open Bio. 2018 Jun;8(6):1001-1012

Authors: Oku Y, Nishiya N, Tazawa T, Kobayashi T, Umezawa N, Sugawara Y, Uehara Y

Abstract
The main reasons for failure of cancer chemotherapy are intrinsic and acquired drug resistance. The Hippo pathway effector Yes-associated protein (YAP) is associated with resistance to both cytotoxic and molecular targeted drugs. Several lines of evidence indicate that YAP activates transcriptional programmes to promote cell cycle progression and DNA damage responses. Therefore, we hypothesised that YAP is involved in the sensitivity of cancer cells to small-molecule agents targeting cell cycle-related proteins. Here, we report that the inactivation of YAP sensitises the OVCAR-8 ovarian cancer cell line to AZD1775, a small-molecule WEE1 kinase inhibitor. The accumulation of DNA damage and mitotic failures induced by AZD1775-based therapy were further enhanced by YAP depletion. YAP depletion reduced the expression of the Fanconi anaemia (FA) pathway components required for DNA repair and their transcriptional regulator E2F1. These results suggest that YAP activates the DNA damage response pathway, exemplified by the FA pathway and E2F1. Furthermore, we aimed to apply this finding to combination chemotherapy against ovarian cancers. The regimen containing dasatinib, which inhibits the nuclear localisation of YAP, improved the response to AZD1775-based therapy in the OVCAR-8 ovarian cancer cell line. We propose that dasatinib acts as a chemosensitiser for a subset of molecular targeted drugs, including AZD1775, by targeting YAP.

PMID: 29928579 [PubMed]

https://ift.tt/2KcBlYk

Profiles of Brain Metastases: Prioritization of Therapeutic Targets.

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Profiles of Brain Metastases: Prioritization of Therapeutic Targets.

Int J Cancer. 2018 Jun 19;:

Authors: Ferguson SD, Zheng S, Xiu J, Zhou S, Khasraw M, Brastianos PK, Kesari S, Hu J, Rudnick J, Salacz ME, Piccioni D, Huang S, Davies MA, Glitza IC, Heymach JV, Zhang J, Ibrahim NK, DeGroot JF, McCarty J, O'Brien BJ, Sawaya R, Verhaak RGW, Reddy SK, Priebe W, Gatalica Z, Spetzler D, Heimberger AB

Abstract
We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of non-small cell lung cancer, breast cancer, and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next-generation sequencing with a targeted 47-gene panel), protein expression (assayed by immunohistochemistry), and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification, and mutations among brain metastases, extracranial metastases, and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8178 non-small cell lung cancers (5098 primaries; 2787 systemic metastases; 293 brain metastases), 7064 breast cancers (3496 primaries; 3469 systemic metastases; 99 brain metastases), and 1757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1, and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication, and/or repair. This article is protected by copyright. All rights reserved.

PMID: 29923182 [PubMed - as supplied by publisher]

https://ift.tt/2MKLeut

A Family of Rhodium Complexes with Selective Toxicity toward Mismatch Repair-Deficient Cancers.

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A Family of Rhodium Complexes with Selective Toxicity toward Mismatch Repair-Deficient Cancers.

J Am Chem Soc. 2018 04 25;140(16):5612-5624

Authors: Boyle KM, Barton JK

Abstract
Rhodium metalloinsertors are a unique set of metal complexes that bind specifically to DNA base pair mismatches in vitro and kill mismatch repair (MMR)-deficient cells at lower concentrations than their MMR-proficient counterparts. A family of metalloinsertors containing rhodium-oxygen ligand coordination, termed "Rh-O" metalloinsertors, has been prepared and shown to have a significant increase in both overall potency and selectivity toward MMR-deficient cells regardless of structural changes in the ancillary ligands. Here we describe DNA-binding and cellular studies with the second generation of Rh-O metalloinsertors in which an ancillary ligand is varied in both steric bulk and lipophilicity. These complexes, of the form [Rh(L)(chrysi)(PPO)]2+, all include the O-containing PPO ligand (PPO = 2-(pyridine-2-yl)propan-2-ol) and the aromatic inserting ligand chrysi (5,6-chrysene quinone diimine) but differ in the identity of their ancillary ligand L, where L is a phenanthroline or bipyridyl derivative. The Rh-O metalloinsertors in this family all show micromolar binding affinities for a 29-mer DNA hairpin containing a single CC mismatch. The complexes display comparable lipophilic tendencies and p Ka values of 8.1-9.1 for dissociation of an imine proton on the chrysi ligand. In cellular proliferation and cytotoxicity assays with MMR-deficient cells (HCT116O) and MMR-proficient cells (HCT116N), the complexes containing the phenanthroline-derived ligands show highly selective cytotoxic preference for the MMR-deficient cells at nanomolar concentrations. Using mass spectral analyses, it is shown that the complexes are taken into cells through a passive mechanism and exhibit low accumulation in mitochondria, an off-target organelle that, when targeted by parent metalloinsertors, can lead to nonselective cytotoxicity. Overall, these Rh-O metalloinsertors have distinct and improved behavior compared to previous generations of parent metalloinsertors, making them ideal candidates for further therapeutic assessment.

PMID: 29620877 [PubMed - indexed for MEDLINE]

https://ift.tt/2Eq3GTZ

CRISPR/Cas9-mediated Targeted Integration In Vivo Using a Homology-mediated End Joining-based Strategy.

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CRISPR/Cas9-mediated Targeted Integration In Vivo Using a Homology-mediated End Joining-based Strategy.

J Vis Exp. 2018 03 12;(133):

Authors: Yao X, Wang X, Liu J, Shi L, Huang P, Yang H

Abstract
As a promising genome editing platform, the CRISPR/Cas9 system has great potential for efficient genetic manipulation, especially for targeted integration of transgenes. However, due to the low efficiency of homologous recombination (HR) and various indel mutations of non-homologous end joining (NHEJ)-based strategies in non-dividing cells, in vivo genome editing remains a great challenge. Here, we describe a homology-mediated end joining (HMEJ)-based CRISPR/Cas9 system for efficient in vivo precise targeted integration. In this system, the targeted genome and the donor vector containing homology arms (~800 bp) flanked by single guide RNA (sgRNA) target sequences are cleaved by CRISPR/Cas9. This HMEJ-based strategy achieves efficient transgene integration in mouse zygotes, as well as in hepatocytes in vivo. Moreover, a HMEJ-based strategy offers an efficient approach for correction of fumarylacetoacetate hydrolase (Fah) mutation in the hepatocytes and rescues Fah-deficiency induced liver failure mice. Taken together, focusing on targeted integration, this HMEJ-based strategy provides a promising tool for a variety of applications, including generation of genetically modified animal models and targeted gene therapies.

PMID: 29578506 [PubMed - indexed for MEDLINE]

https://ift.tt/2uvcVzp

Regulation of G2/M Transition by Inhibition of WEE1 and PKMYT1 Kinases.

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Regulation of G2/M Transition by Inhibition of WEE1 and PKMYT1 Kinases.

Molecules. 2017 Nov 23;22(12):

Authors: Schmidt M, Rohe A, Platzer C, Najjar A, Erdmann F, Sippl W

Abstract
In the cell cycle, there are two checkpoint arrests that allow cells to repair damaged DNA in order to maintain genomic integrity. Many cancer cells have defective G1 checkpoint mechanisms, thus depending on the G2 checkpoint far more than normal cells. G2 checkpoint abrogation is therefore a promising concept to preferably damage cancerous cells over normal cells. The main factor influencing the decision to enter mitosis is a complex composed of Cdk1 and cyclin B. Cdk1/CycB is regulated by various feedback mechanisms, in particular inhibitory phosphorylations at Thr14 and Tyr15 of Cdk1. In fact, Cdk1/CycB activity is restricted by the balance between WEE family kinases and Cdc25 phosphatases. The WEE kinase family consists of three proteins: WEE1, PKMYT1, and the less important WEE1B. WEE1 exclusively mediates phosphorylation at Tyr15, whereas PKMYT1 is dual-specific for Tyr15 as well as Thr14. Inhibition by a small molecule inhibitor is therefore proposed to be a promising option since WEE kinases bind Cdk1, altering equilibria and thus affecting G2/M transition.

PMID: 29168755 [PubMed - indexed for MEDLINE]

https://ift.tt/2KVSVkm

Changes in gene expression variability reveal a stable synthetic lethal interaction network in BRCA2-ovarian cancers.

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Changes in gene expression variability reveal a stable synthetic lethal interaction network in BRCA2-ovarian cancers.

Methods. 2017 12 01;131:74-82

Authors: Bueno R, Mar JC

Abstract
Synthetic lethal interactions (SLIs) are robust mechanisms that provide cells with the ability to remain viable despite having mutations in genes critical to the DNA damage response, a core cellular process. Studies in model organisms such as S. cerevisiae showed that thousands of genes important in maintaining DNA integrity cooperated in a SLI network. Two genes participate in a SLI when a mutation in one gene has no effect on the cell, but mutations in both interacting genes are lethal. Furthermore in C. elegans, a mutation in a critical gene that is important for development induced a change in expression variability in the synthetic lethal interactor. In cancer, targeting SLIs shows promise in selectively killing cancer cells. For example, targeting PARP1 is an effective treatment for BRCA1/2- breast and ovarian cancers. Although PARP1 is already identified as having a SLI with BRCA1/2-, computationally searching for other genes that cooperate in the SLI network could highlight genes that may have promise for being a cancer-specific drug target. Using RNA sequencing data for ovarian cancer patients with BRCA2 mutations and the R Bioconductor package pathVar, we showed that genes whose expression changes to an invariant, stable expression state are likely candidates for SLIs with BRCA2. Our results highlight the interactions between the genes with predicted SLIs and protein-coding genes that are functionally important in the DNA damage response. The method of analyzing expression variability to computationally identify genes with SLIs can be applied to query SLIs in other tumor types.

PMID: 28754563 [PubMed - indexed for MEDLINE]

https://ift.tt/2MP2ZsM

Novel insights into a reputably irreversible process: combined mRNA and miRNA profiling of tissue from vesicourethral anastomotic stenosis after radical prostatectomy.

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Novel insights into a reputably irreversible process: combined mRNA and miRNA profiling of tissue from vesicourethral anastomotic stenosis after radical prostatectomy.

World J Urol. 2017 Nov;35(11):1701-1711

Authors: Worst TS, Daskalova K, Steidler A, Berner-Leischner K, Röth R, Niesler B, Weis CA, Kriegmair MC, Erben P, Pfalzgraf D

Abstract
PURPOSE: Until recently, tissue fibrosis-ultimately leading to permanent scaring-has been considered an irreversible process. However, recent findings indicate that it may be reversible after all. Vesicourethral anastomotic stenosis (VUAS) as fibrous narrowing is a frequent complication after radical prostatectomy with high recurrence rates and requires invasive treatment. The pathophysiology is poorly understood. Therefore, a combined mRNA and miRNA transcription profiling in tissue from VUAS was performed using nCounter technology.
METHODS: To assess tissue morphology and fiber composition, histochemical staining was performed. RNA expression of healthy and fibrotic tissue of twelve patients was analyzed using the human miRNA panel v3 and mRNA PanCancer pathway panel on the nCounter gene1 system and qRT-PCR. Differential expression data analysis was performed using the nSolver software implementing the R-based advanced pathway analysis tool. miRWalk2.0 was used for miRNA target prediction.
RESULTS: More linearized tissue architecture, increased collagens, and decreased elastic fibers were observed in VUAS samples. 23 miRNAs and 118 protein coding genes were differentially expressed (p < 0.01) in fibrotic tissue. miRNA target prediction and overlap analysis indicated an interaction of the strongest deregulated miRNAs with 29 deregulated mRNAs. Pathway analysis revealed alterations in DNA repair, cell cycle regulation, and TGF-beta signaling. qRT-PCR confirmed differential expression of top deregulated miRNAs and mRNAs.
CONCLUSIONS: In VUAS tissue, severe alterations on mRNA and miRNA level are found. These consistent changes give insights into the pathogenesis of VUAS after radical prostatectomy and point to future options for transcriptomics-based risk stratification and targeted therapies.

PMID: 28634911 [PubMed - indexed for MEDLINE]

https://ift.tt/2tzV3ll

Enhancing radiosensitization in EphB4 receptor-expressing Head and Neck Squamous Cell Carcinomas.

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Enhancing radiosensitization in EphB4 receptor-expressing Head and Neck Squamous Cell Carcinomas.

Sci Rep. 2016 12 12;6:38792

Authors: Bhatia S, Hirsch K, Sharma J, Oweida A, Griego A, Keysar S, Jimeno A, Raben D, Krasnoperov V, Gill PS, Pasquale EB, Wang XJ, Karam SD

Abstract
Members of the Eph family of receptor tyrosine kinases have been implicated in a wide array of human cancers. The EphB4 receptor is ubiquitously expressed in head and neck squamous cell carcinoma (HNSCC) and has been shown to impart tumorigenic and invasive characteristics to these cancers. In this study, we investigated whether EphB4 receptor targeting can enhance the radiosensitization of HNSCC. Our data show that EphB4 is expressed at high to moderate levels in HNSCC cell lines and patient-derived xenograft (PDX) tumors. We observed decreased survival fractions in HNSCC cells following EphB4 knockdown in clonogenic assays. An enhanced G2 cell cycle arrest with activation of DNA damage response pathway and increased apoptosis was evident in HNSCC cells following combined EphB4 downregulation and radiation compared to EphB4 knockdown and radiation alone. Data using HNSCC PDX models showed significant reduction in tumor volume and enhanced delay in tumor regrowth following sEphB4-HSA administration with radiation compared to single agent treatment. sEphB4-HSA is a protein known to block the interaction between the EphB4 receptor and its ephrin-B2 ligand. Overall, our findings emphasize the therapeutic relevance of EphB4 targeting as a radiosensitizer that can be exploited for the treatment of human head and neck carcinomas.

PMID: 27941840 [PubMed - indexed for MEDLINE]

https://ift.tt/2gIsEFm

Long-term reprogramming of the innate immune system.

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Long-term reprogramming of the innate immune system.

J Leukoc Biol. 2018 Jul 12;:

Authors: Dominguez-Andres J, Netea MG

Abstract
During the last few years, a growing body of evidence has shown that immunological memory is not an exclusive trait of lymphocytes, as many inflammatory insults can alter the functionality and the responsiveness of the innate immune system in the long term. Innate immune cells, such as monocytes, macrophages, dendritic cells, and NK cells can be influenced by the encounters with inflammatory stimuli, undergoing functional reprogramming and developing changed responses to subsequent chellenges. The long-term reprogramming depends on the rewiring of cell metabolism and epigenetic processes, and they stay at the basis of induction of both innate immune memory (also termed trained immunity) and innate immune tolerance. Here, we review the central role that the effects of this long-term reprogramming of innate immune cells plays in a number of clinically relevant conditions such as vaccination, atherosclerosis, sepsis, and cancer.

PMID: 29999546 [PubMed - as supplied by publisher]

https://ift.tt/2ujeUrh

Microenvironmental derived factors modulating dendritic cell function and vaccine efficacy: the effect of prostanoid receptor and nuclear receptor ligands.

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Microenvironmental derived factors modulating dendritic cell function and vaccine efficacy: the effect of prostanoid receptor and nuclear receptor ligands.

Cancer Immunol Immunother. 2018 Jul 11;:

Authors: Raaijmakers TK, Ansems M

Abstract
Dendritic cells (DCs) are widely used in DC-based immunotherapies because of their capacity to steer immune responses. So far treatment success is limited and more functional knowledge on how DCs initiate and stably drive specific responses is needed. Many intrinsic and extrinsic factors contribute to how DCs skew the immune response towards immunity or tolerance. The origin and type of DC, its maturation status, but also factors they encounter in the in vitro or in vivo microenvironment they reside in during differentiation and maturation affect this balance. Treatment success of DC vaccines will, therefore, also depend on the presence of these factors during the process of vaccination. Identification and further knowledge of natural and pharmacological compounds that modulate DC differentiation and function towards a specific response may help to improve current DC-based immunotherapies. This review focuses on factors that could improve the efficacy of DC vaccines in (pre-)clinical studies to enhance DC-based immunotherapy, with a particular emphasis on compounds acting on prostanoid or nuclear receptor families.

PMID: 29998375 [PubMed - as supplied by publisher]

https://ift.tt/2NQZ0MP

Dendritic Cells in the Cross Hair for the Generation of Tailored Vaccines.

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Dendritic Cells in the Cross Hair for the Generation of Tailored Vaccines.

Front Immunol. 2018;9:1484

Authors: Gornati L, Zanoni I, Granucci F

Abstract
Vaccines represent the discovery of utmost importance for global health, due to both prophylactic action to prevent infections and therapeutic intervention in neoplastic diseases. Despite this, current vaccination strategies need to be refined to successfully generate robust protective antigen-specific memory immune responses. To address this issue, one possibility is to exploit the high efficiency of dendritic cells (DCs) as antigen-presenting cells for T cell priming. DCs functional plasticity allows shaping the outcome of immune responses to achieve the required type of immunity. Therefore, the choice of adjuvants to guide and sustain DCs maturation, the design of multifaceted vehicles, and the choice of surface molecules to specifically target DCs represent the key issues currently explored in both preclinical and clinical settings. Here, we review advances in DCs-based vaccination approaches, which exploit direct in vivo DCs targeting and activation options. We also discuss the recent findings for efficient antitumor DCs-based vaccinations and combination strategies to reduce the immune tolerance promoted by the tumor microenvironment.

PMID: 29997628 [PubMed]

https://ift.tt/2Ln0rRG

Antigen phagocytosis by B cells is required for a potent humoral response.

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Antigen phagocytosis by B cells is required for a potent humoral response.

EMBO Rep. 2018 Jul 09;:

Authors: Martínez-Riaño A, Bovolenta ER, Mendoza P, Oeste CL, Martín-Bermejo MJ, Bovolenta P, Turner M, Martínez-Martín N, Alarcón B

Abstract
Successful vaccines rely on activating a functional humoral response that results from promoting a proper germinal center (GC) reaction. Key in this process is the activation of follicular B cells that need to acquire antigens and to present them to cognate CD4 T cells. Here, we report that follicular B cells can phagocytose large antigen-coated particles, a process thought to be exclusive of specialized antigen-presenting cells such as macrophages and dendritic cells. We show that antigen phagocytosis by B cells is BCR-driven and mechanistically dependent on the GTPase RhoG. Using Rhog-/- mice, we show that phagocytosis of antigen by B cells is important for the development of a strong GC response and the generation of high-affinity class-switched antibodies. Importantly, we show that the potentiation effect of alum, a common vaccine adjuvant, requires direct phagocytosis of alum-antigen complexes by B cells. These data suggest a new avenue for vaccination approaches by aiming to deliver 1-3 μm size antigen particles to follicular B cells.

PMID: 29987136 [PubMed - as supplied by publisher]

https://ift.tt/2NPXYR2

Immune Curbing of Cancer Stem Cells by CTLs Directed to NANOG.

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Immune Curbing of Cancer Stem Cells by CTLs Directed to NANOG.

Front Immunol. 2018;9:1412

Authors: Wefers C, Schreibelt G, Massuger LFAG, de Vries IJM, Torensma R

Abstract
Cancer stem cells (CSCs) have been identified as the source of tumor growth and disease recurrence. Eradication of CSCs is thus essential to achieve durable responses, but CSCs are resistant to current anti-tumor therapies. Novel therapeutic approaches that specifically target CSCs will, therefore, be crucial to improve patient outcome. Immunotherapies, which boost the body's own immune system to eliminate cancerous cells, could be an alternative approach to target CSCs. Vaccines of dendritic cells (DCs) loaded with tumor antigens can evoke highly specific anti-tumor T cell responses. Importantly, DC vaccination also promotes immunological memory formation, paving the way for long-term cancer control. Here, we propose a DC vaccination that specifically targets CSCs. DCs loaded with NANOG peptides, a protein required for maintaining stem cell properties, could evoke a potent anti-tumor immune response against CSCs. We hypothesize that the resulting immunological memory will also control newly formed CSCs, thereby preventing disease recurrence.

PMID: 29971070 [PubMed]

https://ift.tt/2JpB5AD

Lenalidomide and Programmed Death-1 Blockade Synergistically Enhances the Effects of Dendritic Cell Vaccination in a Model of Murine Myeloma.

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Lenalidomide and Programmed Death-1 Blockade Synergistically Enhances the Effects of Dendritic Cell Vaccination in a Model of Murine Myeloma.

Front Immunol. 2018;9:1370

Authors: Vo MC, Jung SH, Chu TH, Lee HJ, Lakshmi TJ, Park HS, Kim HJ, Rhee JH, Lee JJ

Abstract
The therapeutic efficacy of dendritic cell (DC)-based immunotherapy may be potentiated in combination with other anticancer therapies that enhance DC function by modulating immune responses and the tumor microenvironment. In this study, we investigated the efficacy of DC vaccination in combination with lenalidomide and programmed death (PD)-1 blockade in a model of murine myeloma. MOPC-315 cell lines were injected subcutaneously to establish myeloma-bearing mice and the following five test groups were established: PBS control, DCs, DCs + lenalidomide, DCs + PD-1 blockade, and DCs + lenalidomide + PD-1 blockade. The combination of DCs plus lenalidomide and PD-1 blockade more potently inhibited tumor growth compared to the other groups. This effect was associated with a reduction in immune suppressor cells (such as myeloid-derived suppressor cells, M2 macrophages, and regulatory T cells) and an increase in immune effector cells [such as CD4+ and CD8+ T cells, natural killer (NK) cells, and M1 macrophages] in the spleen. Functional activities of cytotoxic T lymphocytes and NK cells were also enhanced by the triple combination. Levels of immunosuppressive cytokines, such as TGF-β and IL-10, were significantly reduced in the tumor microenvironment. These findings suggest that the combination of DCs plus lenalidomide and PD-1 blockade synergistically establishes a robust anti-myeloma immunity through a two-way mechanism, which inhibits immunosuppressive cells while activating effector cells with superior polarization of the Th1/Th2 balance in favor of the tumor immune response. This result should provide an experimental ground for incorporating check point inhibitors to existing immunotherapeutic modalities against multiple myeloma.

PMID: 29967612 [PubMed]

https://ift.tt/2zax2s3

Pilot study of WT1 peptide-pulsed dendritic cell vaccination with docetaxel in esophageal cancer.

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Pilot study of WT1 peptide-pulsed dendritic cell vaccination with docetaxel in esophageal cancer.

Oncol Lett. 2018 Jul;16(1):1348-1356

Authors: Matsuda T, Takeuchi H, Sakurai T, Mayanagi S, Booka E, Fujita T, Higuchi H, Taguchi J, Hamamoto Y, Takaishi H, Kawakubo H, Okamoto M, Sunamura M, Kawakami Y, Kitagawa Y

Abstract
In the present study, the immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell (DC) vaccination combined with docetaxel (DCDOC) in advanced esophageal cancer patients who had already received first-line chemotherapy was investigated. Ten HLA-A*2402 patients were treated with docetaxel (50 mg/m2) on day 1 and WT1 peptide-pulsed DC vaccination (1×107 cells) on days 15 and 22 (repeated every 4 weeks for 3 cycles). The delayed-type hypersensitivity skin test, HLA tetramer assay and interferon-γ enzyme-linked immunospot (ELISPOT) assay were used to evaluate the induction of a WT1-specific immune response. Median overall survival was 5 months (range, 1.1-11.6). The clinical effect of DCDOC therapy was not observed and only 1 patient could complete the protocol therapy. Disease progression was observed in 9 patients and 1 patient succumbed to fatality during the second cycle of therapy. As a pilot study, it was not possible to evaluate the safety of WT1 peptide-pulsed DCDOC therapy for esophageal squamous cell cancer. However, a WT1-specific response in 6 patients, as indicated by the ELISPOT or HLA/WT1-tetramer assay, was demonstrated. The results suggested that the positive immune response had significant relevance on the low percentage of CD11b+ and CD66b+ granulocytic myeloid-derived suppressor cells in CD15+ cells. Furthermore, DCDOC elicited a WT1-specific immune response regardless of the myelosuppression associated with docetaxel. The present findings support future studies and further work to assess DCDOC as an adjuvant therapy for esophageal cancer will be performed. The present clinical trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry on November 11th, 2011, no. UMIN000006704.

PMID: 29963201 [PubMed]

https://ift.tt/2KIN8xy

The Conventional Nature of Non-MHC-Restricted T Cells.

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The Conventional Nature of Non-MHC-Restricted T Cells.

Front Immunol. 2018;9:1365

Authors: Lepore M, Mori L, De Libero G

Abstract
The definition "unconventional T cells" identifies T lymphocytes that recognize non-peptide antigens presented by monomorphic antigen-presenting molecules. Two cell populations recognize lipid antigens and small metabolites presented by CD1 and MR1 molecules, respectively. A third cell population expressing the TCR Vγ9Vδ2 is stimulated by small phosphorylated metabolites. In the recent past, we have learnt a lot about the selection, tissue distribution, gene transcription programs, mode of expansion after antigen recognition, and persistence of these cells. These studies depict their functions in immune homeostasis and diseases. Current investigations are revealing that unconventional T cells include distinct sub-populations, which display unexpected similarities to classical MHC-restricted T cells in terms of TCR repertoire diversity, antigen specificity variety, functional heterogeneity, and naïve-to-memory differentiation dynamic. This review discusses the latest findings with a particular emphasis on these T cells, which appear to be more conventional than previously appreciated, and with the perspective of using CD1 and MR1-restricted T cells in vaccination and immunotherapy.

PMID: 29963057 [PubMed]

https://ift.tt/2NSi3Xg

Toll-Like Receptor 4 Triggering Promotes Cytosolic Routing of DC-SIGN-Targeted Antigens for Presentation on MHC Class I.

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Toll-Like Receptor 4 Triggering Promotes Cytosolic Routing of DC-SIGN-Targeted Antigens for Presentation on MHC Class I.

Front Immunol. 2018;9:1231

Authors: Horrevorts SK, Duinkerken S, Bloem K, Secades P, Kalay H, Musters RJ, van Vliet SJ, García-Vallejo JJ, van Kooyk Y

Abstract
DC-SIGN is an antigen uptake receptor expressed on dendritic cells (DCs) with specificity for glycans present on a broad variety of pathogens and is capable of directing its cargo to MHC-I and MHC-II pathways for the induction of CD8+ and CD4+ T cell responses, respectively. Therefore, DC-SIGN is a very promising target for the delivery of antigen for anti-cancer vaccination. Although the endocytic route leading to MHC-II presentation is characterized to a large extent, the mechanisms controlling DC-SIGN targeted cross-presentation of exogenous peptides on MHC-I, are not completely resolved yet. In this paper, we used imaging flow cytometry and antigen-specific CD8+ T cells to investigate the intracellular fate of DC-SIGN and its cargo in human DCs. Our data demonstrates that immature DCs and toll-like receptor 4 (TLR4) stimulated DCs had similar internalization capacity and were both able to cross-present antigen targeted via DC-SIGN. Interestingly, simultaneous triggering of TLR4 and DC-SIGN on DCs resulted in the translocation of cargo to the cytosol, leading to proteasome-dependent processing and increased CD8+ T cell activation. Understanding the dynamics of DC-SIGN-mediated uptake and processing is essential for the design of optimal DC-SIGN-targeting vaccination strategies aimed at enhancing CD8+ T cell responses.

PMID: 29963041 [PubMed]

https://ift.tt/2JtNq76

GM-CSF improves the immune response to the diphtheria-component in a multivalent vaccine.

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GM-CSF improves the immune response to the diphtheria-component in a multivalent vaccine.

Vaccine. 2018 07 25;36(31):4672-4680

Authors: Grasse M, Meryk A, Miggitsch C, Grubeck-Loebenstein B

Abstract
Multivalent tetanus and diphtheria toxoid containing vaccines belong to the most frequently applied vaccines. However, there is an imbalance in the degree of protection against the two antigens with insufficient long-term protection against diphtheria, particularly in the elderly population. We have previously reported a positive correlation between granulocyte macrophage-colony stimulating factor (GM-CSF) and the production of diphtheria-specific antibodies. Therefore, in the present study we analyzed the effects of in vivo applied recombinant GM-CSF on immunization with multivalent tetanus/diphtheria vaccine in mice of different age. In vivo application of GM-CSF lead to enhanced production of diphtheria-specific antibodies as well as more diphtheria-specific CD4+ T cells following vaccination with multivalent tetanus/diphtheria vaccine. In contrast, the humoral and cellular immune response to the tetanus component was unaltered. Furthermore, application of GM-CSF resulted in more splenic CD11b+ dendritic cells (DCs) with a higher MHC-II expression. GM-CSF also induced a stronger recruitment of CD11b+ DCs to the injected muscle. Most remarkably, GM-CSF was able to boost the diphtheria-specific immune response to the multivalent vaccine in aged mice. This study demonstrates that local administration of GM-CSF is able to improve immune responsiveness to the diphtheria component of multivalent tetanus/diphtheria vaccine in young and old mice. This information could be useful for the future design of vaccines for the elderly.

PMID: 29961602 [PubMed - in process]

https://ift.tt/2Nl2F5m

Liposomal vaccine formulations as prophylactic agents: design considerations for modern vaccines.

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Liposomal vaccine formulations as prophylactic agents: design considerations for modern vaccines.

J Nanobiotechnology. 2017 Nov 17;15(1):83

Authors: De Serrano LO, Burkhart DJ

Abstract
Vaccinology is one of the most important cornerstones in modern medicine, providing better quality of life. The human immune system is composed of innate and adaptive immune processes that interplay when infection occurs. Innate immunity relies on pathogen-associated molecular patterns which are recognized by pathogen recognition receptors localized in antigen presenting cells. After antigen processing and presentation, CD4+ T cell polarization occurs, further leading to B cell and CD8+ activation and humoral and cell-mediated adaptive immune responses. Liposomes are being employed as vaccine technologies and their design is of importance to ensure proper immune responses. Physicochemical parameters like liposome size, charge, lamellarity and bilayer fluidity must be completely understood to ensure optimal vaccine stability and efficacy. Liposomal vaccines can be developed to target specific immune cell types for the induction of certain immune responses. In this review, we will present promising liposomal vaccine approaches for the treatment of important viral, bacterial, fungal and parasitic infections (including tuberculosis, TB). Cationic liposomes are the most studied liposome types due to their enhanced interaction with the negatively charged immune cells. Thus, a special section on the cationic lipid dimethyldioctadecylammonium and TB is also presented.

PMID: 29149896 [PubMed - indexed for MEDLINE]

https://ift.tt/2zQ3H52

SjCRT, a recombinant Schistosoma japonicum calreticulin, induces maturation of dendritic cells and a Th1-polarized immune response in mice.

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SjCRT, a recombinant Schistosoma japonicum calreticulin, induces maturation of dendritic cells and a Th1-polarized immune response in mice.

Parasit Vectors. 2017 Nov 13;10(1):570

Authors: Ma L, Li D, Yuan C, Zhang X, Ta N, Zhao X, Li Y, Feng X

Abstract
BACKGROUND: It is well known that immunization of radiation-attenuated (RA) schistosoma cercariae or schistosomula can induce high levels of protective immunity against schistosoma cercariae reinfection in many animals. Many studies have shown that the Th1 cellular immune response is crucial for the protective effect elicited by RA schistosomula. However, the molecular mechanism of this strong protective immunity remains unclear.
METHODS: The expression profiles of Schistosoma japonicum calreticulin (SjCRT) in RA and normal schistosoma-derived cells were investigated by flow cytometry. The effect of recombinant SjCRT (rSjCRT) on mouse dendritic cells (DCs) was determined by FACS, ELISA and RT-PCR analysis. We also analyzed the effects of SjCRT on the activation of spleen cells from mice immunized with rSjCRT by detecting lymphocyte proliferation and the cytokine profiles of splenocytes.
RESULTS: We found that the expression level of SjCRT in the cells from RA larvae was significantly higher than that in cells from normal schistosomula at early stages of development (day 4). The results of effect of rSjCRT on mouse DCs showed that rSjCRT could induce phenotypic and functional maturation of DCs, and SjCRT bound to the surface of DCs through the CD91 receptor and could be engulfed by DCs. The results of activation of splenocytes from mice immunized with rSjCRT also demonstrate that rSjCRT can effectively stimulate the proliferative response of splenic lymphocytes, elicit splenocytes from immunized mice to secrete high levels of IFN-γ, TNF-α and IL-4, and activate CD4+ T cells to produce high levels of IFN-γ.
CONCLUSION: SjCRT is one of the immunostimulatory molecules released from RA schistosomula cells, might play a crucial role in conferring a Th1-polarized immune response induced by RA cercariae/schistosomula in mice, and is a candidate molecule responsible for the high levels of protective immunity induced by RA schistosomula.

PMID: 29132406 [PubMed - indexed for MEDLINE]

https://ift.tt/2NPXPgs

Enhanced effects of DNA vaccine against botulinum neurotoxin serotype A by targeting antigen to dendritic cells.

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Enhanced effects of DNA vaccine against botulinum neurotoxin serotype A by targeting antigen to dendritic cells.

Immunol Lett. 2017 Oct;190:118-124

Authors: Chen BY, Zhou G, Li QL, Lu JS, Shi DY, Pang XB, Zhou XW, Yu YZ, Huang PT

Abstract
As dendritic cells (DCs) play a critical role in priming antigen-specific immune responses, the efficacy of DNA vaccines may be enhanced by targeting the encoded antigen proteins to DCs. In this study, we constructed a DC-targeted DNA vaccine encoding the Hc domain of botulinum neurotoxin serotype A (AHc) fused with scDEC, a single-chain Fv antibody (scFv) specific for the DC-restricted antigen-uptake receptor DEC205. Intramuscular injections of mice with the DC-targeted DNA vaccine (pVAX1-scDEC-AHc) stimulated more DCs to mature than the non-targeted DNA vaccine (pVAX1-SAHc) in the splenocytes. The DC-targeted DNA vaccine could induce more DCs maturation at the site of inoculation. The DC-targeted DNA vaccine induced stronger AHc-specific humoral immune responses, lymphocyte proliferative responses and protective potency against BoNT/A in mice than did pVAX1-SAHc. Moreover, the DC-targeting DNA vaccine provided effective protection after only two inoculations. In summary, these results showed that the DC-targeted fusion DNA vaccine could generate strong immunity, indicating that maturation of DCs induced by pVAX1-scDEC-AHc may be helpful for priming and boosting immune responses. Thus, we propose that the strategy of targeting antigen to DCs in vivo via DEC205 can enhance effectively the potency of DNA vaccines against BoNTs or other pathogens in an animal model.

PMID: 28802641 [PubMed - indexed for MEDLINE]

https://ift.tt/2JtN7sY

The First Case Report of West Nile Virus-Induced Acute Flaccid Quadriplegia in Canada

The 1999 New York City outbreak of West Nile virus (WNV) was associated with a high incidence of West Nile virus neuroinvasive disease (WNVND) where the outcomes for these patients were very poor. We describe a case of West Nile virus neuroinvasive disease (WNVND) characterized by acute flaccid quadriplegia with a favorable outcome in Winnipeg, Manitoba, Canada.

https://ift.tt/2uzDmnA

Isocentric Navigation for the Training of Percutaneous Endoscopic Transforaminal Discectomy: A Feasibility Study

Background. Percutaneous endoscopic transforaminal discectomy (PETD) is usually chosen for lumbar disc herniation due to its obvious advantages such as small incision and absence of nerve or muscular traction. However, learning PETD is a great challenge for inexperienced surgeons. Objective. The study aimed to investigate whether isocentric navigation would be beneficial in PETD training. Methods. A total of 117 inexperienced surgeons were trained with PETD at L2/3, L3/4, L4/5, and L5/S1 on the cadavers without (Group A n=58) or with (Group B n=59) isocentric navigation. Puncture times, fluoroscopy times, exposure time, and radiation dose were recorded and analyzed. Questionnaires were conducted before and after the training program. Result. Isocentric navigation could improve young surgeons' satisfaction with the training program and decrease the puncture times, fluoroscopy times, exposure time, and radiation dose significantly (P

https://ift.tt/2zHO9Ss

Isolation of Retinal Arterioles for Ex Vivo Cell Physiology Studies

This manuscript describes a straightforward protocol for the isolation of arterioles from the rat retina that can be used in electrophysiological, calcium imaging and pressure myography studies.

https://ift.tt/2LhUjdb

Survival benefit of pure dose-dense chemotherapy in breast cancer: a meta-analysis of randomized controlled trials

Abstract

Background

Dose-dense chemotherapy is a widely accepted regimen for high-risk breast cancer patients. However, conflicting survival benefits of pure dose-dense chemotherapy have been reported in different randomized controlled trials (RCTs). This meta-analysis aimed to further assess the efficacy and safety of pure dose-dense chemotherapy in breast cancer.

Methods

A literature search of electronic databases and websites was performed to identify phase III RCTs reporting the efficacy and toxicity of pure dose-dense chemotherapy. The endpoints of interest were overall survival (OS), disease-free survival (DFS), and toxicities. The hazard ratios (HRs) of death and recurrence and the odds ratios (ORs) of adverse events were estimated and pooled.

Results

Seven studies (five trials) were eligible, encompassing a total of 9851 patients. Patients treated with dose-dense chemotherapy obtained better DFS (HR = 0.83; 95% CI 0.75–0.91; p = 0.0001) than those treated with the conventional schedule, while OS benefit of dose-dense chemotherapy was less impressive (HR = 0.86; 95% CI 0.73–1.02; p = 0.08). However, significant OS benefit was observed in node-positive patients (HR = 0.77; 95% CI 0.66–0.90; p = 0.001). The incidence of anemia, pain, and transaminase elevation was higher in the dose-dense chemotherapy arm.

Conclusions

Dose-dense chemotherapy leads to better prognosis; these findings suggest that it may be a potentially preferred treatment for breast cancer patients, particularly for women with lymph node involvement. However, more RCTs are warranted to better define the best candidates for dose-dense chemotherapy.

https://ift.tt/2KVeP7w

Therapeutic and prophylactic gastrectomy in a family with hereditary diffuse gastric cancer secondary to a CDH1 mutation: a case series

Abstract

Background

Gastric cancer is the fifth most prevalent and the third most lethal cancer worldwide, causing approximately 720,000 deaths annually. Although most cases of gastric cancers are sporadic, one of its inherited forms, hereditary diffuse gastric cancer (HDGC), constitutes about 1–3% of cases. Interestingly, females in families with HDGC are also predisposed to developing lobular breast cancer (LBC). Recent analyses have identified loss-of-function germline mutations in cadherein-1 (CDH1) as a culprit in HDGC and LBC. This discovery fueled several sequencing analyses and case series reports analyzing the pattern of inheritance of CDH1 and its propensity to induce HDGC. In 2015, a multinational and multidisciplinary task force updated the guidelines and criteria for screening, diagnosing, and managing HDGC.

Case presentation

Here, we present a case series of three siblings with family history of HDGC who tested positive for the CDH1 mutation and describe their surgical treatment course, post-operative management, and follow-up as they pertain to the updated guidelines.

Conclusions

Despite recent updates in guidelines in the diagnosis and management of HDGC, the disease remains challenging to address with patients given the high level of uncertainty and the comorbidities associated with prophylactic intervention. We strongly recommend that an interdisciplinary team inclusive of clinical and surgical oncologists, along with geneticists, social work, and psychological support, should follow the patients in a longitudinal and comprehensive manner in order to achieve full recovery and return to normalcy, as with our patients.

https://ift.tt/2NhXZfD

Treatment options for PNET liver metastases: a systematic review

Abstract

Background

Pancreatic neuroendocrine tumors (PNETs) are rare pancreatic neoplasms. About 40–80% of patients with PNET are metastatic at presentation, usually involving the liver (40–93%). Liver metastasis represents the most significant prognostic factor. The aim of this study is to present an up-to-date review of treatment options for patients with liver metastases from PNETs.

Methods

A systematic literature search was performed using the PubMed database to identify all pertinent studies published up to May 2018.

Results

The literature search evaluated all the therapeutic options for patients with liver metastases of PNETs, including surgical treatment, loco-regional therapies, and pharmacological treatment. All the different treatment options showed particular indications in different presentations of liver metastases of PNET. Surgery remains the only potentially curative therapeutic option in patients with PNETs and resectable liver metastases, even if relapse rates are high. Efficacy of medical treatment has increased with advances in targeted therapies, such as everolimus and sunitinib, and the introduction of radiolabeled somatostatin analogs. Several techniques for loco-regional control of metastases are available, including chemo- or radioembolization.

Conclusions

Treatment of patients with PNET metastases should be multidisciplinary and must be personalized according to the features of individual patients and tumors.

https://ift.tt/2KVeQIC