Παρασκευή 1 Σεπτεμβρίου 2017

Discovery of mutations in homologous recombination genes in African-American women with breast cancer

Abstract

African-American women are more likely to develop aggressive breast cancer at younger ages and experience poorer cancer prognoses than non-Hispanic Caucasians. Deficiency in repair of DNA by homologous recombination (HR) is associated with cancer development, suggesting that mutations in genes that affect this process may cause breast cancer. Inherited pathogenic mutations have been identified in genes involved in repairing DNA damage, but few studies have focused on African-Americans. We screened for germline mutations in seven HR repair pathway genes in DNA of 181 African-American women with breast cancer, evaluated the potential effects of identified missense variants using in silico prediction software, and functionally characterized a set of missense variants by yeast two-hybrid assays. We identified five likely-damaging variants, including two PALB2 truncating variants (Q151X and W1038X) and three novel missense variants (RAD51C C135R, and XRCC3 L297P and V337E) that abolish protein–protein interactions in yeast two-hybrid assays. Our results add to evidence that HR gene mutations account for a proportion of the genetic risk for developing breast cancer in African-Americans. Identifying additional mutations that diminish HR may provide a tool for better assessing breast cancer risk and improving approaches for targeted treatment.



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Phase II basket trial of perifosine monotherapy for recurrent gynecologic cancer with or without PIK3CA mutations

Summary

Objective Perifosine exhibits anti-tumor activity by inhibiting AKT phosphorylation. The purpose of this phase II basket trial was to evaluate the efficacy and safety of perifosine monotherapy for ovarian, endometrial, and cervical cancers. Methods Recurrent or persistent ovarian, endometrial, or cervical cancer patients were assigned to PIK3CA wild-type or mutant groups. Each patient received 600 mg oral perifosine on day 1 followed by a maintenance dose of 100 mg daily. The primary endpoint was disease control rate; secondary endpoints included response rate, progression-free survival, overall survival, and safety. Immunohistochemical staining and targeted sequencing were used to explore new biomarkers in such patients. Results Sixteen and 5 ovarian, 17 and 7 endometrial, and 18 and 8 cervical cancer patients with PIK3CA wild-type and mutant, respectively, were enrolled. Disease control rates (wild-type/mutant) were 12.5/40.0%, 47.1/14.3%, and 11.1/25.0% in ovarian, endometrial, and cervical cancer, respectively. The most common grade 3/4 toxicities were anemia (22.5%) and anorexia (11.3%). Immunohistochemical staining revealed that the disease control rate in patients with negative phosphatase and tensin homolog (PTEN) expression was 50.0%, and the odds ratio of positive to negative patients was 0.24 in all patients. Conclusions Perifosine monotherapy showed good tolerability but expected efficacy was not achieved. Modest efficacy was demonstrated in ovarian cancer patients with PIK3CA mutations and endometrial cancer patients with PIK3CA wild-type; no difference was observed between PIK3CA wild-type and mutant in cervical cancer. Absence of PTEN expression may be predictive of clinical efficacy with perifosine monotherapy.



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Venous thromboembolism and hyperhomocysteinemia as first manifestation of pernicious anemia: a case series

Hyperhomocysteinemia has been suspected of favoring thrombosis. Several case–control studies and even a meta-analysis have confirmed a link between venous thrombosis and hyperhomocysteinemia. Homocysteine is d...

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An improved method for identifying SUMOylation sites of viral proteins



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DC-SIGN promotes Japanese encephalitis virus transmission from dendritic cells to T cells via virological synapses

Abstract

Skin-resident dendritic cells (DCs) likely encounter incoming viruses in the first place, and their migration to lymph nodes following virus capture may promote viral replication. However, the molecular mechanisms underlying these processes remain unclear. In the present study, we found that compared to cell-free viruses, DC-bound viruses showed enhanced capture of JEV by T cells. Additionally, JEV infection was increased by co-culturing DCs and T cells. Blocking the C-type lectin receptor DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) with neutralizing antibodies or antagonists blocked JEV transmission to T cells. Live-cell imaging revealed that DCs captured and transferred JEV viral particles to T cells via virological synapses formed at DC-T cell junctions. These findings indicate that DC-SIGN plays an important role in JEV transmission from DCs to T cells and provide insight into how JEV exploits the migratory and antigen-presenting capabilities of DCs to gain access to lymph nodes for dissemination and persistence in the host.



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mTOR kinase inhibition effectively decreases progression of a subset of neuroendocrine tumors that progress on rapalog therapy and delays cardiac impairment

Inhibition of mTOR signaling using the rapalog everolimus is an FDA-approved targeted therapy for patients with lung and gastroenteropancreatic neuroendocrine tumors (NETs). However, patients eventually progress on treatment, highlighting the need for additional therapies. We focused on pancreatic NETs (pNETs) and reasoned that treatment of these tumors upon progression on rapalog therapy, with an mTOR kinase inhibitor (mTORKi) such as CC-223 could overcome a number of resistance mechanisms in tumors and delay cardiac carcinoid disease. We performed preclinical studies using human pNET cells in vitro and injected them subcutaneously or orthotopically to determine tumor progression and cardiac function in mice treated with either rapamycin alone or switched to CC-223 upon progression. Detailed signaling and RNA sequencing analyses were performed on tumors that were sensitive or progressed on mTOR treatment. Approximately 57% of mice bearing pNET tumors which progressed on rapalog therapy showed a significant decrease in tumor volume upon a switch to CC-223. Moreover, mice treated with an mTORKi exhibited decreased cardiac dilation and thickening of heart valves than those treated with placebo or rapamycin alone. In conclusion, in the majority of pNETs that progress on rapalogs, it is possible to reduce disease progression using an mTORKi, such as CC-223. Moreover, CC-223 had an additional transient cardiac benefit on valvular fibrosis compared to placebo- or rapalog-treated mice. These results provide the preclinical rationale to further develop mTORKi clinically upon progression on rapalog therapy and to further test their long term cardioprotective benefit in those NET patients prone to carcinoid syndrome.



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Inhibition of discoidin domain receptor 1 reduces collagen-mediated tumorigenicity in pancreatic ductal adenocarcinoma

The extracellular matrix (ECM), a principal component of pancreatic ductal adenocarcinoma (PDA), is rich in fibrillar collagens that facilitate tumor cell survival and chemoresistance. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that specifically binds fibrillar collagens and has been implicated in promoting cell proliferation, migration, adhesion, ECM remodeling, and response to growth factors. We found that collagen-induced activation of DDR1 stimulated pro-tumorigenic signaling through protein tyrosine kinase 2 (PYK2) and pseudopodium-enriched atypical kinase 1 (PEAK1) in pancreatic cancer cells. Pharmacologic inhibition of DDR1 with an ATP competitive orally available small molecule kinase inhibitor (7rh) abrogated collagen-induced DDR1 signaling in pancreatic tumor cells and consequently reduced colony formation and migration. Furthermore, the inhibition of DDR1 with 7rh showed striking efficacy in combination with chemotherapy in orthotopic xenografts and autochthonous pancreatic tumors where it significantly reduced DDR1 activation and downstream signaling, reduced primary tumor burden, and improved chemoresponse. These data demonstrate that targeting collagen-signaling in conjunction with conventional cytotoxic chemotherapy has the potential to improve outcome for pancreatic cancer patients.



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Dual inhibition of Hedgehog and c-Met pathways for pancreatic cancer treatment

Pancreatic adenocarcinoma (PDA) is one of the most chemotherapy and radiotherapy resistant tumors. The c-Met and Hedgehog (Hh) pathways have been shown previously by our group to be key regulatory pathways in the primary tumor growth and metastases formation. Targeting both the HGF/c-Met and Hh pathways has shown promising results in pre-clinical studies; however, the benefits were not readily translated into to clinical trials with PDA patients. In this study, utilizing mouse models of PDA, we showed that inhibition of either HGF/c-Met or Hh pathways sensitize the PDA tumors to gemcitabine resulting in decreased primary tumor volume as well as significant reduction of metastatic tumor burden. However, prolonged treatment of single HGF/c-Met or Hh inhibitor leads to the resistance to these single inhibitors, likely because the single c-Met treatment leads to the enhanced expression of Shh, and vice versa. Targeting both the HGF/c-Met and Hh pathways simultaneously overcame the resistance to the single inhibitor treatment and led to a more potent anti-tumor effect in combination with the chemotherapy treatment.



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A CRISPR/Cas9-based screening for non-homologous end joining inhibitors reveals ouabain and penfluridol as radiosensitizers

Non-homologous end joining (NHEJ) is the major pathway responsible for the repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSBs), and correspondingly regulates the cellular response to IR. Identification of NHEJ inhibitors could substantially enhance the tumor radiosensitivity and improve the therapeutic efficiency of radiotherapy. In present study, we demonstrated a screening for NHEJ inhibitors by using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and high-resolution melting (HRM) analysis. Since NHEJ is regarded as an error-prone mechanism, the NHEJ-mediated ligation of the site-specific DSB induced by Cas9 nuclease would eventually cause the mutation of the targeted sequence. Then, HRM analysis, a reliable and rapid assay for detecting sequence variation, was performed to evaluate the mutation efficiency of the targeted site. Validating analysis confirmed the NHEJ activities was positively correlated with the mutation frequencies. Next, an approved drug library containing 1540 compounds was interrogated by using this screening strategy. Our results identified ouabain, a cardiotonic agent, and penfluridol, an antipsychotic agent, have the capacity to restrain NHEJ activity. Further experiments in vitro revealed the radiosensitizing effects of these compounds. Overall, we presented a cell-based screening for NHEJ inhibitors which could promote the discovery of novel radiosensitizers.



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Giant Hepatic Adenoma in a 12-Year-Old Girl



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A hierarchical Bayesian approach to calibrating the linear-quadratic model from clonogenic survival assay data

We propose a Bayesian hierarchical model applicable to the calibration of the linear-quadratic model of radiation dose–response. Experimental data used in model calibration were taken from a clonogenic survival assay conducted on human breast cancer cells (MDA-MB-231) across a range of radiation doses (0–6Gy). Employing Markov-chain Monte Carlo methods, we calibrated the proposed Bayesian hierarchical model, computed posterior distributions for the model parameters and survival fraction dose–response probability densities.

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[Corrections] Correction to Lancet Oncol 2017; 18: 1040–48

Mahajan A, Ahmed S, McAleer MF, et al. Post-operative stereotactic radiosurgery versus observationfor completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol 2017; 18: 1040–48—In the eighth paragraph in the Results of this Article, the phrase "12-month time to distant brain recurrence" should have said "12-month freedom from distant brain recurrence". This correction has been made to the online version as of Sept 1, 2017.

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[Cancer and Society] Our Short History

Karen Neulander doesn't want to die. Hard-bitten political consultant, single mother to 6-year-old Jake, and a patient with stage IV ovarian cancer, Karen wants to be the exception to the rule of the terminal diagnosis. "If someone got to be a miracle" she asks, "why couldn't it be me?" Our Short History is a heart-rending letter that tells the story of a mother coming to terms with the end of her life, and saying goodbye to her son as best she can: with feeling.

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[Clinical Picture] Hypoglossal paresis caused by a solitary breast cancer metasasis at the basal skull

A 76-year-old female patient was admitted to the neurological department of our institution in October, 2016, because of acute dysarthria. Her symptoms started 2 weeks ago at the same time as a severe cold that had developed immediately after she received an influenza vaccine.

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[Corrections] Correction to Lancet Oncol 2017; 18: 917–28

Stebbing J, Baranau Y, Baryash V, et al. CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial. Lancet Oncol 2017; 18: 917–28—In this Article, difference values representing the proportion of patients achieving pathological complete response between groups should have been listed without % signs. Additionally, the following sentence should have read "The treatment outcome difference was −0·03 (95% CI −0·11 to 0·05), with the 95% CI falling within the prespecified ±0·15 equivalence margin." These corrections have been made to the online version as of Sept 1, 2017.

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[Review] Radiotherapy for the treatment of malignant pleural mesothelioma

Malignant pleural mesothelioma is an aggressive disease that continues to be associated with poor outcomes. Although, traditionally this disease is considered to be resistant to radiotherapy, more recent evidence suggests that radiotherapy can produce positive outcomes. Over the past 15 years, the development of new, highly conformal radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT), has enabled investigators to optimise the delivery of high-dose radiotherapy to the whole of the hemithorax.

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[Comment] Questions on asparaginase-associated pancreatitis

Since its earliest conceptions by Emil Frei, Emil Freireich, and colleagues,1 the successful development of combination chemotherapy for young patients with acute lymphoblastic leukaemia has served as a sustained model for all other tumour types for all patients in the modern era of cancer therapy. With substantially improved outcomes with these multi-agent combination chemotherapy regimens from the 1960s to the present time in children with acute lymphoblastic leukaemia, more attention is now being placed on adolescents and young adults—an in-between group of patients with unique characteristics, patterns of adherence, and concerns for short-term and long-term chemotherapy-related toxicities.

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[Review] Definition and recommendations for advance care planning: an international consensus supported by the European Association for Palliative Care

Advance care planning (ACP) is increasingly implemented in oncology and beyond, but a definition of ACP and recommendations concerning its use are lacking. We used a formal Delphi consensus process to help develop a definition of ACP and provide recommendations for its application. Of the 109 experts (82 from Europe, 16 from North America, and 11 from Australia) who rated the ACP definitions and its 41 recommendations, agreement for each definition or recommendation was between 68–100%. ACP was defined as the ability to enable individuals to define goals and preferences for future medical treatment and care, to discuss these goals and preferences with family and health-care providers, and to record and review these preferences if appropriate.

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[Review] Palliative care in Africa: a scoping review from 2005–16

Since the last comprehensive review on the development of national palliative care in Africa was undertaken 12 years ago, in 2005, we did a scoping review of peer-reviewed, published articles on palliative care development between 2005–16 for each African country. The scoping review was conducted by assessing the medical literature and including local expert recommendations of suggested articles. We did a basic quality assessment of the articles using the journals' impact factor, journal quartile, and the number of citations as suitable metrics for quality consideration.

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[Corrections] Correction to Lancet Oncol 2017; 18: 1182–91

Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18: 1182–91—In this Article, in the Findings section of the Summary, and in the Results section of the main paper, "Kaplan-Meier 12-month estimate" should have been stated before the estimate "86%, 95% CI 62–95". In the Results section of the main paper, the earlier database lock date should have been September, 2016.

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[Correspondence] Primary medical therapy for BRAFV600E-mutant melanoma brain metastases—is this good enough?

We applaud Michael A Davies and colleagues1 for their phase 2 study evaluating the role of dabrafenib plus trametinib in BRAFV600E-mutant melanoma brain metastases. While this well conducted study shows clinical activity (58% achieved an intracranial response) of this combination, we urge caution in the interpretation of this study, and reconsideration of similar forthcoming study designs.

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[Cancer and Society] Liquorice: a treatment for all sorts?

Some 2400 years before the development of anaesthesia and the discovery that microorganisms can cause disease, the Greeks were writing about the healing properties of liquorice root. Its pharmacological uses have been recorded in European and Middle Eastern literature since that time. Today, liquorice is not only a staple of traditional medicine and holistic therapies, but is also being investigated for its metabolic, anticancer, and antiviral properties in many laboratories across the world.

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[Cancer and Society] “Death is an adventure”: the power of terminal diagnosis

"Do you ever wonder what you would do if you were given a terminal diagnosis and told you only have months to live?" asks filmmaker Sue Bourne in the opening of her BBC2 documentary. First broadcast in May, A Time To Live follows the lives of 12 people, most of them with cancer diagnoses, and aims to uncover via candid interviews what they have learned about themselves and about life through the process. Each feels compelled to make the most of the time they have remaining, some even undergoing radical transformation.

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[Editorial] Turning taboos into action

As the global burden of cancer continues to rise, disparities in cancer care remain ubiquitous. Stark inequalities in prevention, screening, treatment, and outcomes exist not only between high and low-income nations, but also between population subgroups within countries. In increasingly multiethnic communities, differences in the way cancer is perceived, addressed, and treated might be partly due to variation in underlying cultural influences. What can be done to reduce the health care gap?

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[Correspondence] Why is survival after pembrolizumab affected by previous radiotherapy?

The secondary subgroup analysis of the single-centre KEYNOTE-001 phase 1 trial1 by Narek Shaverdian and colleagues, with the accompanying commentary by Dirk De Ruysscher on the association of previous radiotherapy and clinical activity of pembrolizumab in advanced non-small-cell lung cancer (NSCLC), is of great interest and clinical relevance. Progression-free survival and overall survival after pembrolizumab were significantly longer in patients who had received previous radiotherapy than in those who were radiotherapy naive.

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[Correspondence] Fasting conditions in clinical oncology trials and drug labelling – Authors' reply

The main concern addressed in our Comment is that the interpretation of modified fasted intake of an oral oncolytic drug with a narrow therapeutic index can largely affect the exposure to the drug and thereby also treatment outcome, which is currently majorly ignored.

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[Correspondence] Why is survival after pembrolizumab affected by previous radiotherapy? – Authors' reply

We thank Farkhad Manapov and colleagues for their thoughtful commentary. Major limitations of our study include the absence of detailed information regarding the type, schedule, and dose of the delivered radiotherapy.1 Manapov and colleagues suggested that ablative radiotherapy might be a more potent stimulus for the immune system, and that definitive radiotherapy would correspond more to ablative rather than palliative radiotherapy. This might indeed be true; however, most patients in this study (64%) received radiotherapy with a palliative intent.

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[Correspondence] Primary medical therapy for BRAFV600E-mutant melanoma brain metastases—is this good enough? – Authors' reply

Improving outcomes in patients with melanoma brain metastases remains a major challenge. Tim J Kruser and Michael A Vogelbaum state that the results of COMBI-MB1 should be interpreted with caution because the frequency and durability of responses "pale in comparison" to recent retrospective studies of patients with melanoma brain metastases treated with stereotactic radiosurgery (SRS) and BRAF inhibitors. Of note, Kruser and Vogelbaum incorrectly state that COMBI-MB was restricted to patients with "small, asymptomatic, <5 lesions".

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[Correspondence] Fasting conditions in clinical oncology trials and drug labelling

The timing of drug administration in relation to meals could have a major effect on bioavailability and plasma concentrations of oral oncology drugs. The Comment by Floor J E Lubberman and colleagues1 provides a timely discussion on the effect of different types of fasting regimens in oncology trials on drug exposure and anticancer treatment. However, some information and arguments should be clarified.

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[Cancer and Society] The Truth About Cancer

Uruguay's emergence as a world leader in tobacco control did not go unnoticed. After the tiny South American nation introduced and enforced stringent anti-smoking measures, tobacco behemoth Phillip Morris sued Uruguay in an international tribunal. The two parties began secret negotiations. There was talk of diluting the Uruguayan legislation. But the country eventually decided to take its chances in court, and last year it prevailed.

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[Cancer and Society] While We Still Have Time

Mike and Jules: While We Still Have Time opens to alternating shots of hospital scenes and music gigs. The narrator's tone and the slow motion, black and white filming gives the story a dramatic feel, which makes us think that this will be a celebrity documentary centred on Mike Peters. Lead singer of the Welsh 80s band, The Alarm, Mike was diagnosed with lymphoma 20 years ago, but the cancer spontaneously regressed. 10 years ago he was diagnosed with leukaemia, and went into remission with chemotherapy but had a relapse last year and is now receiving an experimental drug.

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Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia

Publication date: Available online 1 September 2017
Source:Cancer Cell
Author(s): Diana Passaro, Alessandro Di Tullio, Ander Abarrategi, Kevin Rouault-Pierre, Katie Foster, Linda Ariza-McNaughton, Beatriz Montaner, Probir Chakravarty, Leena Bhaw, Giovanni Diana, François Lassailly, John Gribben, Dominique Bonnet
The biological and clinical behaviors of hematological malignancies can be influenced by the active crosstalk with an altered bone marrow (BM) microenvironment. In the present study, we provide a detailed picture of the BM vasculature in acute myeloid leukemia using intravital two-photon microscopy. We found several abnormalities in the vascular architecture and function in patient-derived xenografts (PDX), such as vascular leakiness and increased hypoxia. Transcriptomic analysis in endothelial cells identified nitric oxide (NO) as major mediator of this phenotype in PDX and in patient-derived biopsies. Moreover, induction chemotherapy failing to restore normal vasculature was associated with a poor prognosis. Inhibition of NO production reduced vascular permeability, preserved normal hematopoietic stem cell function, and improved treatment response in PDX.

Graphical abstract

image

Teaser

Passaro et al. show that acute myeloid leukemia, mainly via nitric oxide (NO), causes bone marrow vascular abnormalities and that failure to restore normal vasculature after induction chemotherapy is associated with a poor prognosis. Importantly, inhibition of NO production improves treatment response in vivo.


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Focal necrotizing myopathy with ‘dropped-head syndrome’ induced by cobimetinib in metastatic melanoma

imageTherapeutic advances derived from targeted therapy and immune checkpoint inhibitors can improve melanoma prognosis. Since 2015, cobimetinib has been approved in combination with vemurafenib in the first-line treatment for BRAF-mutated melanoma. For NRAS-mutated melanomas, MEK inhibition seems to be a therapeutic target, and association with checkpoint inhibitor provides a further therapeutic perspective. Infraclinical creatine phosphokinase (CPK) elevation is an MEK inhibitor side effect. We describe a case of focal necrotizing myopathy with 'dropped-head syndrome' induced by cobimetinib, 1 month after its introduction. The clinical presentation comprised interscapular pain, axial fatigue with cervical hypotonia, CPK elevation, intense fluorine-18-fluorodeoxyglucose uptake in cervical muscles, and necrotizing myopathy was confirmed by muscle biopsy. Cobimetinib was temporarily discontinued, resulting in CPK normalization. Re-evaluation showed partial response, motivating continuation of combination therapy with a reduced dose of cobimetinib (40 mg/day). Because prescription of targeted therapies is likely to increase, this adverse event should be known.

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Cyclic AMP-Epac signaling pathway contributes to repression of PUMA transcription in melanoma cells

imageThe universal second messenger cAMP regulates numerous cellular processes. Although the cAMP-signaling pathway leads to induction of gene transcription, it remains unknown whether this pathway contributes toward suppression of transcription. Here, we show that blockade of cAMP signaling using MDL12330A led to an increase in PUMA transcript levels, but not p21 in melanoma cells. cAMP downstream component Epac activation was essential for suppression of PUMA transcription as an Epac agonist reversed the effects of MDL12330A. These results suggest that transcriptional repression is one of the functions of the cAMP-Epac signaling pathway.

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Characteristics of melanoma in Japan: a nationwide registry analysis 2011–2013

imageThe distribution and incidence of melanoma vary among different races and ethnic groups. This study aimed to investigate the characteristics of cutaneous melanoma, mucosal melanoma, uveal melanoma, and melanoma of unknown primary (MUP) origin in a Japanese population. We studied these four types of melanoma in patients registered in Hospital Based Cancer Registries in Japan from 2011 to 2013. A total of 5566 patients with melanoma were identified. The distribution of sex, age, primary site, and clinical stage was analyzed. The number of patients, proportion in comparison with all melanoma cases, and crude incidence rate per 100 000 person-year of each melanoma type were 4481, 80.5%, and 1.24 in invasive cutaneous; 821, 14.8%, and 0.32 in mucosal; 163, 2.9%, and 0.064 in uveal; and 101, 1.8%, and 0.039 in MUP origin, respectively. Including the patients with in-situ cutaneous melanoma and stage unknown cutaneous melanoma, the crude incidence rate of cutaneous melanoma increased at 1.75. Almost half of the cutaneous melanomas were located in the lower limb. Cutaneous melanoma was the most common, but less frequent than that in western countries. Mucosal melanoma was quite rare, but its proportion and crude incidence rate were higher than those in western countries. Uveal melanoma was particularly rare, and its crude incidence rate was lower than that in western countries. MUP origin was also particularly rare, but it had almost the same incidence rate as that in other countries. Melanoma in Japan was heterogeneous among the four melanoma types and shares some attributes with that in western countries.

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Quantification of microRNA-21 and microRNA-125b in melanoma tissue

imageAlthough microRNAs (miRNAs) have emerged as potent mediators of melanoma development and progression, a precise understanding of their oncogenic role remains unclear. In this study, we analysed formalin-fixed and paraffin-embedded tissues from two separate melanoma cohorts and from a series of benign melanocytic nevi. Using three different quantification methods [array analysis, quantitative PCR (qPCR) and in-situ hybridization (ISH) quantified by digital image analysis], we found considerable miRNA dysregulation in tumours. Using array analysis, samples mainly clustered according to their biological group (benign vs. malignant) and 77 miRNAs differed significantly between nevi and melanoma samples. Increase of miR-21 and miR-142, and decrease of miR-125b, miR-211, miR-101 and miR-513c in the melanomas were verified in both cohorts using qPCR, whereas the decrease of miR-205 observed with array analysis could not be confirmed using qPCR. ISH with digital quantification showed expression of miR-21 and miR-125b in the melanocytic lesions. miR-21 ISH was increased in melanomas, whereas quantification of miR-125b showed uniform ISH expression across nevi and melanomas. Our results support the important involvement of different miRNAs in melanoma biology and may serve as solid basics for further miRNA investigations in melanoma formalin-fixed and paraffin-embedded tissue. In particular, there is increased expression of miR-21 in melanomas compared with benign nevi.

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Current status and future direction in the management of malignant melanoma

imageThe incidence of malignant melanoma is increasing rapidly on a global scale. Although some types of melanoma, for example primary cutaneous melanoma, can be managed by surgery, metastatic melanoma cannot and it has a high mortality rate. Both oncogene and immune-targeted strategies have shown marked efficacy in some patients, but their effect on overall survival is still variable. Therefore, newer therapeutic approaches are needed. Fortunately, new advances in molecular medicine have led to an understanding of an individual patient's cancer at the genomic level. This information is now being used in all stages of cancer treatment including diagnosis, treatment selection, and treatment monitoring. This new strategy of personalized medicine may lead to marked shifts in immunotherapeutic treatment approaches such as individualized cancer vaccines and adoptive transfer of genetically modified T cells. This review provides an overview of recent approaches in cancer research and expected impact on the future of treatment for metastatic melanoma.

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A unique gene expression signature is significantly differentially expressed in tumor-positive or tumor-negative sentinel lymph nodes in patients with melanoma

imageThe purpose of this study was to learn whether molecular characterization through gene expression profiling of node-positive and node-negative sentinel lymph nodes (SLNs) in patients with clinical stage I and II melanoma may improve the understanding of mechanisms of metastasis and identify gene signatures for SLNs+/SLNs− that correlate with diagnosis or clinical outcome. Gene expression profiling was performed on SLN biopsies of 48 (24 SLN+ and 24 SLN−) patients (T3a/b–T4a/b) who underwent staging of SLNs using transcriptome profiling analysis on 5 μm sections of fresh SLNs. U133A 2.0 Affymetrix gene chips were used. Significance analysis of microarrays was used to test the association between gene expression level and SLN status. Genes with fold change more than 1.5 and q value less than 0.05 were considered differentially expressed. Pathway analysis was performed using Ingenuity Pathway Analysis. The Benjamini and Hochberg method was used to adjust for multiple testing in pathway analysis. We identified 89 probe sets that were significantly differentially expressed (1.5–27-fold; q

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Meningeal melanomatosis following discontinuation of dabrafenib: implications for the maintenance of long-term complete remission

imageA subset of 10–20% of patients under continuous BRAF inhibitor monotherapy achieve long-term progression-free and overall survival. Definitive criteria for the safe cessation of BRAF inhibitor monotherapy in treatment-responsive melanoma patients are lacking. We report a patient who remained in complete remission (CR) for 5 years under dabrafenib. The treatment was withdrawn because of concerns about cardiac toxicity. Four months thereafter the patient developed neurological symptoms, including diplopia and bilateral visual loss. Meningeal melanomatosis and parenchymal brain metastases were diagnosed. Extracerebral metastases were excluded. Reinduction of dabrafenib, combined with trametinib, led to the rapid relief of the neurological symptoms, and a partial remission was confirmed radiologically. Unfortunately, the response was not maintained and the patient died 9 months later. This observation demonstrates that discontinuation of BRAF inhibition can result in loss of disease control. On the basis of this observation, we suggest that BRAF-targeted therapy should be withdrawn only when the risks of continued treatment exceed the risk for disease relapse. However, future studies are urgently required to confirm and quantify the risk for rapid disease relapse following withdrawal of BRAF inhibitor monotherapy.

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MGMT methylation correlates with melphalan pelvic perfusion survival in stage III melanoma patients: a pilot study

imageApproximately 25% of melanoma patients with locoregional metastases are nonresponsive to new molecular target therapy and immunotherapy. When metastases are located in the pelvis, melphalan hypoxic perfusion can be an optional treatment. Because methylation of MGMT promoter increases the efficacy of alkylating agents, studies on melanoma outcome of patients treated with melphalan regional chemotherapy should consider this epigenetic change. This study aims to evaluate whether the survival of stage III melanoma patients treated with melphalan regional chemotherapy may be correlated with MGMT methylation status. The metastatic tissues of 27 stage III melanoma patients with locoregional metastases located in the pelvis subjected to melphalan hypoxic pelvic perfusion were examined. The methylation status of the MGMT promoter was investigated by MS-MLPA probes analysis and the presence of the BRAF V600E mutation was analyzed by CAST-PCR. The median survival times were estimated using the Kaplan–Meier curves and were stratified according to the clinicopathological characteristics of patients and lesions. The overall median survival time was 17 months. The 1-year, 3-year, and 5-year survival rates were 66.7, 18.5, and 7.4%, respectively. Disease stage, burden, and percentage of MGMT methylation significantly affected survival. We estimated an MGMT promoter methylation cut-off of at least 14%, which was significantly associated with a longer survival after melphalan regional chemotherapy. Our data suggest that MGMT promoter methylation could be an important factor in determining which melanoma patients should receive melphalan regional chemotherapy, but its prognostic significance in the routine clinical setting needs to be clarified in a larger study.

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The safety of pembrolizumab in metastatic melanoma and rheumatoid arthritis

imageImmunotherapy has been in use for the treatment of melanoma since a very long time, but only recently have the cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody ipilimumab and programmed cell death-1 inhibitors such as nivolimumab and pembrolizumab been shown to induce marked improvements in survival in patients with metastatic melanoma. An important concern arises in terms of the safety of the use of these agents in patients with autoimmune diseases, solid organ transplant recipients on immunosuppression, patients with a history of previous hepatitis B or C, and patients with HIV infections as these patients were excluded from pivotal immunotherapy studies. Here, we report on the safety and efficacy of pembrolizumab in a melanoma patient with multiple medical problems including poorly controlled rheumatoid arthritis and we review the available literature on the use of immunotherapy and autoimmune diseases. The weight of evidence suggests that these patients should be offered the opportunity to benefit from immune check point inhibitors, with drugs targeting programmed cell death-1 being preferred. More research is required to study the long-term effects of immunotherapy on patients with autoimmune diseases.

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Prognostic significance of cyclooxygenase 2 and phosphorylated Akt1 overexpression in primary nonmetastatic and metastatic cutaneous melanomas

imageCyclooxygenase 2 (COX-2) and phosphorylated Akt1 (p-Akt1) are associated with tumor spreading, cell proliferation, high metabolism, and angiogenesis in solid tumors. This study aimed to investigate COX-2 and p-Akt1 expression in primary and metastatic melanomas by correlating with the cellular proliferation index (as revealed by minichromosome maintenance 2 expression) and the outcome of patients with malignant melanomas. Seventy-seven biopsies of malignant melanomas, including 42 primary nonmetastatic melanomas (PNMMs), 12 primary metastatic melanomas (PMMs), and 23 metastatic melanomas (MMs), were retrospectively selected. Tissue microarrays were developed and submitted for immunohistochemical staining for COX-2, p-Akt1, and minichromosome maintenance 2. Increased COX-2 cytoplasmic staining patterns were observed in PMM and MM when compared with PNMM (P=0.0011). Higher nuclear and cytoplasmic expression of p-Akt1 was more closely associated with PMM than with MM and PNMM (P

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Concurrent radiotherapy for patients with metastatic melanoma and receiving anti-programmed-death 1 therapy: a safe and effective combination

imageA combination of immune-checkpoint inhibitors and radiation therapy (RT) represents a promising therapeutic strategy in part mediated by the abscopal effect, but clinical experience related to this combination remains scarce. Clinical data and patterns of treatment were retrospectively collected from all consecutive patients with metastatic melanoma and receiving programmed-death 1 (PD-1) immune-checkpoint inhibitors. Survival data, best overall response, and acute and delayed toxicities (graded according to Common Terminology Criteria for Adverse Events, v 4.3) were compared between patients receiving concurrent RT (IR) or no irradiation (NIR). Fifty-nine patients received anti-PD-1 immunotherapy [pembrolizumab (n=28) or nivolumab (n=31)] between August 2014 and December 2015 at our institution. Among these, 29% (n=17) received palliative RT for a total of 21 sites, with a mean dose of 30 Gy delivered in 10 fractions. Acute and late toxicity profiles were similar in the two groups. After a 10-month median follow-up, the objective response rate (complete or partial response) was significantly higher in the IR group versus the NIR group (64.7 vs. 33.3%, P=0.02) and one complete responder after RT was compatible with an abscopal effect. The 6-month disease-free survival and overall survival rates for the NIR group versus the IR group were 49.7 versus 64.7% (P=0.32) and 58.8 versus 76.4% (P=0.42), respectively. We report here that the combination of RT and anti-PD-1 immunotherapy is well tolerated and leads to a significant higher tumor response rate within and outside the irradiated field, which is emphasized by the first reported case of an abscopal effect in solid tumors.

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Futility of imaging to stage melanoma patients with a positive sentinel lymph node

imageThe use of staging imaging in melanoma patients with a positive sentinel lymph node (SLN) has been reported to be of limited value. Improved accuracy resulting from the development of time-of-flight positron emission tomography (PET) and ongoing image quality improvement of computed tomography (CT) may challenge this statement. Our retrospective study assessed the clinical value of routine staging CT and PET/CT imaging in a recent cohort of asymptomatic SLN-positive patients. Between January 2011 and April 2014, 143 patients with a positive SLN were routinely staged using CT of various parts of the body or whole-body PET/CT. Scores were assigned for level of certainty for regional or distant metastases and incidental second primary malignancies. Diagnostic test performance was assessed, as well as the number and nature of ensuing additional diagnostic actions. CT was performed in 102 of 143 (71%) patients and PET/CT in 41 (29%) patients. The use of PET/CT increased over the study period. Metastases were found in two of the 143 patients (true-positive yield 1.4%). Sensitivity, specificity and positive predictive value were 11, 73 and 4% for CT and 17, 57 and 6%, respectively, for PET/CT. None of the 143 patients had a change in AJCC stage. Two other primary malignancies were found. Twenty-one (15%) patients were subjected to 37 additional investigations, referrals or procedures. Routine staging imaging with CT or PET/CT in SLN-positive patients is not useful. The yield is low and the results are often false positive, leading to unnecessary additional tests, most of which are costly and some potentially morbid.

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Malignant melanoma incidence trends in a Mediterranean population following socioeconomic transition and war: results of age–period–cohort analysis in Croatia, 1989–2013

imageThe aim of this study was to analyse trends of malignant melanoma incidence in Croatia for men and women of different age groups by birth cohorts and time periods, and to interpret them in the context of national socioeconomic changes over time and the possible implications for future prevention in South-Eastern European postcommunist countries with high mortality rates. We used the Croatian National Cancer Registry data to analyse incidence trends of malignant melanoma of the skin (ICD-9 code 172 and ICD-10 code C43) in men and women aged 25–79 years by age–period–cohort modelling. Over the 25-year period, the incidence was increasing by 5.0% annually in men and 4.6% in women. The age–period model provided the best fit for data in both sexes, with steeply increasing incidence rates, followed by a stabilization after the 2000s. On the cohort scale, incidence rates increased in successive generations of men, whereas in women, the risk of malignant melanoma attenuated in recent cohorts. Even if some progress has been achieved in recent years, the increasing melanoma incidence without concomitant declines in mortality would indicate a need to rekindle prevention efforts in the country taking the specific socioeconomic context into account.

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Clinical experience of stereotactic radiosurgery at a linear accelerator for intraocular melanoma

imageLong-term results with linear accelerator LINAC-based stereotactic radiosurgery for intraocular uveal malignant melanoma were assessed. A retrospective study was carried out of patients with uveal melanoma after a 1-day session stereotactic radiosurgery at LINAC in Slovakia. In the period 2001–2015, a group of 150 patients with uveal melanoma (139 choroidal melanoma, 11 ciliary body melanoma) was treated. The median tumor volume at baseline was 0.5 cm3 (with range from 0.2 to 1.6 cm3). Tumors ranged in size from 2.4 to 20.8 mm in basal diameter and from 2.0 to 18.3 mm in thickness. The therapeutic dose was 35.0 Gy by 99% of dose volume histogram. Older age at treatment was correlated with the largest basal tumor diameter, tumor thickness, and TNM stage. The survival after stereotactic irradiation was 96% in 1 year, 93% in 2 years, 84% in 5 years, 80% in 7 years, and 53% in 11 years. In 20 (13.3%) patients, secondary enucleation was necessary because of complications (secondary glaucoma). Enucleation-free interval ranged from 1 to 6 years. The median age at death was lower (65.7 years) for patients who died from metastatic disease than for those who died from any other cause (75.0 years). Survival rates at 5-year intervals and the need for secondary enucleation because of complications after linear accelerator irradiation are comparable to other techniques.

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Response to targeted therapy in two patients with metastatic melanoma carrying rare BRAF exon 15 mutations: A598_T599insV and V600_K601delinsE

imageConcurrent BRAF-MEK inhibition improves clinical outcomes in patients with advanced BRAF V600E/K-mutant melanoma. There is currently less evidence for the efficacy of this treatment in patients with rare BRAF non-V600E/K genotypes. We report on two patients with rare BRAF exon 15 mutations – BRAF A598_T599insV and V600_K601delinsE – obtaining clinical benefit and a radiological response to inhibitors directed against the mitogen-activated protein kinase pathway. This highlights the importance of using tests that detect both V600E/K and non-V600E/K BRAF mutations to keep open the possibility of treatment with targeted therapy in patients with uncommon, yet potentially actionable, BRAF exon 15 mutations.

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A prognostic model for resectable acral melanoma patients on the basis of preoperative inflammatory markers

imageAcral melanoma is a rare disease, but is common in Asia. Knowledge of its prognostic indicators is limited. Growing evidence indicates that inflammation plays a critical role in the development and progression of acral melanoma. We developed a novel prognostic model on the basis of preoperative inflammatory markers and examined its prognostic value in a cohort of patients. This retrospective study included 232 acral melanoma patients who underwent radical surgical resection between 2000 and 2010 at the Sun Yat-sen University Cancer Center. Significant predictive factors were identified by multivariate Cox regression analyses, and a prognostic model on the basis of these variables was constructed to predict survival. Kaplan–Meier curves were plotted to estimate overall survival. Multivariate analyses showed that C-reactive protein, albumin/globulin ratio, age, lactic dehydrogenase, and lymph node positivity were related independently to survival. After analyzing these variables, we classified patients into three risk groups. The new prognostic model identified three categories of patients with different prognoses (P

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Type 1 diabetes mellitus caused by treatment with low-dose interferon-α in a melanoma patient

Interferon-α (INF-α) is used as an adjuvant treatment for high-risk cutaneous melanoma. It has a large variety of potentially severe and irreversible side effects and can contribute toward the development of autoimmune disease. We report a case of a 59-year-old woman who developed type 1 diabetes following the use of low-dose IFN-α for the adjuvant treatment of stage IIB melanoma. Fifteen months after initiating IFN-α, she presented with blood glucose of 1126 mg/dl, hyponatremia, and microalbuminuria. Antibodies to glutamic acid decarboxylase and islet antigen-2 were negative and C-peptide was markedly reduced. There was no personal or family history of any autoimmune conditions. Reinforced insulin treatment and volume substitution with saline and glucose as a counter-regulation was started. To the best of our knowledge, this is the first reported case of low-dose IFN-α-induced type 1 diabetes. Clinicians should closely evaluate the pros and cons of IFN-α treatment in an adjuvant setting and remain mindful of the possibility of drug-induced autoimmune disease.

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Risk factors for development of melanoma brain metastasis and disease progression: a single-center retrospective analysis

imageMelanoma metastasis to the brain is associated with a poor prognosis. We sought to determine patient demographics and primary tumor factors associated with the development of brain metastasis (BM) and survival. We also investigated whether the BM detection setting (routine screening vs. symptomatic presentation) affected clinical outcomes. A database of melanoma patients seen from 1999 to 2015 at our institution was reviewed to identify patients who developed BM. Patients with BM were matched by initial stage with patients who did not develop BM as a control group. Patient demographics, primary tumor characteristics, and clinical outcomes were analyzed. A total of 123 patients with BM were matched by initial presenting stage to 237 patients without BM. The characteristics of the primary melanoma tumor associated with BM development included location on the scalp (P=0.030), nodular histologic type (P=0.020), and Breslow depth more than 4 mm (P=0.048), whereas location on the leg was associated with decreased BM risk (P=0.006). In patients with BM, time to first recurrence for melanomas of the scalp was significantly shorter (10.8 vs. 24.8 months, P=0.007) than nonscalp head and neck tumors. Patient stage, tumor depth, nodular type, and ulceration were also associated with worse clinical outcomes. There were no differences in the clinical outcomes between patients whose BM were detected upon routine screening versus those detected upon symptomatic presentation. In summary, factors predictive of development of BM included primary scalp location, nodular type, and depth. In BM patients, scalp location, stage, tumor depth, nodular type, and ulceration, but not detection setting, were associated with worse clinical outcomes.

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Fulminant type 1 diabetes after adjuvant ipilimumab therapy in cutaneous melanoma

No abstract available

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Inverse relationship between Ki67 and survival in early luminal breast cancer: confirmation in a multivariate analysis

Abstract

Introduction

Ki67 is a prognostic marker in early breast cancer, but its real usefulness remains controversial. The standard cut-off values for Ki67 have not been universally accepted and different values may be used depending on the type of biopsy (fine needle biopsy versus surgical specimen biopsy). The objective of this study was to evaluate the prognostic significance of Ki67 and to determine the most accurate prognostic cut-off.

Materials and methods

495 tissue samples from patients with luminal tumours who underwent breast surgery between 2005 and 2011 were collected from the Department of Pathology at Hospital de la Santa Creu i Sant Pau, Barcelona. Patients with stage IV, HER2-positive tumours or triple-negative breast carcinoma were excluded from the study. Pathology data including tumour grading and ki67 percentage were obtained retrospectively from clinical records. In all cases, the percentage of ki67 was evaluated in fine needle biopsies.

Results

In the multivariate analysis, Ki67 as a continuous variable was associated with poor overall survival (OS) and cancer-specific survival (CSS) (OS p = 0.0001, HR 1.037, CI 1.014–1.059; CSS p = 0.0001, HR 1.063, CI 1.031–1.096) (Cox regression model). CSS was poor when associated with a KI67 cut-off point >14% (p = 0.013, HR 14.85; CI 1.074–120.53) (Cox regression model). Disease-free survival (DFS) was not associated with Ki67

Conclusions

Prognosis of luminal breast carcinoma can be predicted using Ki67 as a continuous variable and a standard cut-off value of 14%. Information about the specimen type used to determine ki67 should be recorded in the pathological report.



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New on NCI’s Websites for September 2017

NCI periodically provides updates on new websites and other online content of interest to the cancer community.



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Correlation of early PET findings with tumor response to molecular targeted agents in patients with advanced driver-mutated non-small cell lung cancer

Abstract

Recent advances in positron emission tomography with fluorine-18-fluorodeoxyglucose (FDG-PET) have facilitated not only the diagnosis and staging of lung cancer, but also the prediction of treatment outcome. The present study was designed to assess the usefulness of early FDG-PET examination for predicting subsequent tumor size reduction in response to molecular targeted agents in metastatic non-small cell lung cancer (NSCLC) with sensitive gene anomalies. I. In 29 targeted lesions of 10 NSCLC patients, changes in FDG uptake before and on day 7 after the initiation of molecular targeted therapy (gefitinib, n = 7; crizotinib, n = 3) were compared with subsequent radiographic tumor size reduction by RECIST. FDG uptake was evaluated as the maximum standardized uptake value (SUVmax) of each targeted lesion. SUVmax decreased in all lesions after therapy (mean SUVmax 8.3 ± 3.4 before to 3.7 ± 1.8 after therapy, p < 0.05). The % decrease in SUVmax of each lesion was significantly correlated with the % tumor size reduction (r = 0.44). In addition, the reduction rate of SUVmax in metastatic bone lesions after initiation of molecular targeted therapy was significantly lower than that in targeted organs (27.1 ± 27.5 vs. 51.2 ± 21.3%, respectively, p < 0.05). Early reduction in FDG-PET uptake after initiation of molecular targeted agents was able to predict subsequent tumor reduction in patients harboring EGFR-mutated or ALK-positive NSCLC. In addition, nontargeted bone metastasis may have different glucose metabolism after TKI treatment compared with other involved organs.



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Checkpoint inhibitors: the new treatment paradigm for urothelial bladder cancer

Abstract

Bladder cancer is the most common malignancy involving the genitourinary system (Siegel et al. in CA Cancer J Clin, 66:7–30, 2016). In the USA, it is the fifth most common cancer and approximately 79,000 new cases will be diagnosed in 2017 (Siegel et al. in CA Cancer J Clin, 66:7–30, 2016). The mortality from bladder cancer is approximately 17,000 deaths each year (Siegel et al. in CA Cancer J Clin, 66:7–30, 2016). The incidence rate for bladder cancer is higher in men compared to women. Risk factors are predominantly related to tobacco smoking, although infection with Schistosoma haematobium is another risk factor in selected populations (Antoni et al. in Eur Urol, 71:96–108, 2017). Cisplatin-based systemic chemotherapy regimens remain the standard of care in both the neoadjuvant and metastatic setting for muscle-invasive bladder cancer (Gupta et al. in Cancer, 9(15):1–14, 2017; Von der Maase et al. in J Clin Oncol, 23:4602–4608, 2005; De Santis et al. in J Clin Oncol, 30:191–199, 2012; Bellmunt et al. in J Clin Oncol, 27: 4454–4461, 2009). There is an estimated overall survival of 9–15 months in metastatic bladder cancer in those who receive the standard of care platinum-based chemotherapy (Von der Maase et al. in J Clin Oncol, 23:4602–4608, 2005; De Santis et al. in J Clin Oncol, 30:191–199, 2012). The median survival, however, is significantly reduced after relapse in patient treated with platinum chemotherapy to less than 7 months (Bellmunt et al. in J Clin Oncol, 27: 4454–4461, 2009). Thus, this approach is preferred for patients who can tolerate this treatment as first-line chemotherapy (Gupta et al. in Cancer, 9(15):1–14, 2017). Until recently, there were few treatment options for those patients with poor performance status who are ineligible to receive cisplatin including renal insufficiency and multiple comorbidities or had disease progression after receiving platinum-based chemotherapy (Gupta et al. in Cancer, 9(15):1–14, 2017). With further understanding of tumor immune evasion, systemic immunotherapy which utilizes the patient's own immune system directly to eradicate and target neoplastic cells, has now been approved for urothelial bladder cancer. Monoclonal antibodies that target programmed cell death protein 1 (PD-1), including Nivolumab and Pembrolizumab, and its ligand, PD-L1, including Atezolizumab, Durvalumab, Avelumab, have all been investigated and approved in the setting of metastatic refractory urothelial cancer (Gupta et al. in Cancer, 9(15):1–14, 2017; Von der Maase et al. in J Clin Oncol, 23:4602–4608, 2005; Zilchi et al. in BioMed Res Int, 2017, 2017, doi:10.1155/2017/5618174). Atezolizumab and Pembrolizumab have also been approved as first-line therapy in the setting of cisplatin-ineligible metastatic bladder cancer (Gupta et al. in Cancer, 9(15):1–14, 2017; Zilchi et al. in BioMed Res Int, 2017, 2017, doi:10.1155/2017/5618174). Those that target cytotoxic T-lymphocyte-associated protein 4, including Ipilimumab and Tremelimumab, have also been investigated and further studies are being performed (Gupta et al. in Cancer, 9(15):1–14, 2017; Zilchi et al. in BioMed Res Int, 2017, 2017, doi:10.1155/2017/5618174). This review outlines the systemic immunotherapies that have been approved or are currently being investigated.



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Induction of antitumor response to fibrosarcoma by Newcastle disease virus-infected tumor vaccine

Abstract

Fibrosarcoma is a locally aggressive malignant tumor with a high recurrence rate, so that wide excisional surgery is necessary for treatment. However, it is often difficult to resect with a sufficient margin of excision at the site of tumor infiltration. Recombinant tumor vaccine therapy is a useful method to induce specific immunity. In this study, we have shown its utility as a candidate for therapy by applying a recombinant Newcastle disease virus (rNDV) tumor vaccine (rNDV-TV). Although the therapeutic effect of similar viruses has been examined in several tumors, the vaccination efficacy against fibrosarcoma has not been demonstrated until now. In this study, we showed the induction of an antitumor response by rNDV-TV against murine fibrosarcoma and investigated the role of lymphocytes in tumor elimination. Intraperitoneal inoculation of murine fibrosarcoma (WEHI164) cells showed increased lethality in C.B.17scid/scid (scid) mice within 2 weeks of inoculation. The survival rate increased to 80% when the mice were transfused with CD3+ cells from BALB/c mice previously immunized with rNDV-TV. However, all mice died from tumor growth after inoculation with non-immunized CD3+ cells. Although the survival rate was around 50% in mice receiving only immunized CD4+ and CD8+ cells, the survival rate was not decreased in mice receiving CD3+CD4CD8 (natural killer T; NKT) cells together with immunized CD4+ and CD8+ cells. This study showed rNDV-TV induced an antitumor T cell response to WEHI164 cells, and major subsets of cells involved in tumor exclusion were CD4+ and CD8+ cells, together with NKT cells.



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20(S)-25-methoxyl-dammarane-3β, 12β, 20-triol negatively regulates activation of STAT3 and ERK pathways and exhibits anti-cancer effects in HepG2 cells

Abstract

The pro-inflammatory cytokine interleukin 6 (IL-6), via activating its downstream JAK/STAT3 and Ras/ERK signaling pathways, is involved in cell growth, proliferation and anti-apoptotic activities in various malignancies. To screen inhibitors of IL-6 signaling, we constructed a STAT3 and ERK dual-pathway responsive luciferase reporter vector (Co.RE). Among several candidates, the natural compound 20(S)-25-methoxyl-dammarane-3β, 12β, 20-triol (25-OCH3-PPD, GS25) was identified to clearly inhibit the luciferase activity of Co.RE. GS25 was confirmed to indeed inhibit activation of both STAT3 and ERK pathways and expression of downstream target genes of IL-6, and to predominantly decrease the viability of HepG2 cells via induction of cell cycle arrest and apoptosis. Interestingly, GS25 showed preferential inhibition of HepG2 cell viability relative to normal liver L02 cells. Further investigation showed that GS25 could not induce apoptosis and block activation of STAT3 and ERK pathways in L02 cells as efficiently as in HepG2 cells, which may result in differential effects of GS25 on malignant and normal liver cells. In addition, GS25 was found to potently suppress the expression of endogenous STAT3 at a higher concentration and dramatically induce p38 phosphorylation in HepG2 cells, which could mediate its anti-cancer effects. Finally, we demonstrated that GS25 also inhibited tumor growth in HepG2 xenograft mice. Taken together, these findings indicate that GS25 elicits its anti-cancer effects on HepG2 cells through multiple mechanisms and has the potential to be used as an inhibitor of IL-6 signaling. Thus, GS25 may be developed as a treatment for hepatocarcinoma with low toxicity on normal liver tissues as well as other inflammation-associated diseases.



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Retraction: Abstract 408: ACP-196, An Orally Bioavailable Covalent Selective Inhibitor of Btk, Modulates the Innate Tumor Microenvironment, Exhibits Antitumor Efficacy and Enhances Gemcitabine Activity in Pancreatic Cancer



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Targeting Adenosine in BRAF-Mutant Melanoma Reduces Tumor Growth and Metastasis

Increasing evidence exists for the role of immunosuppressive adenosine in promoting tumor growth and spread in a number of cancer types, resulting in poor clinical outcomes. In this study, we assessed whether the CD73-adenosinergic pathway is active in melanoma patients and whether adenosine restricts the efficacy of clinically approved targeted therapies for commonly mutated BRAFV600E melanoma. In AJCC stage III melanoma patients, CD73 expression (the enzyme that generates adenosine) correlated significantly with patients presenting nodal metastatic melanoma, suggesting that targeting this pathway may be effective in advanced stage disease. In addition, dabrafenib and trametinib treatment of CD73+ BRAFV600E-mutant melanomas caused profound CD73 downregulation in tumor cells. Inhibition of BRAF and MEK in combination with the A2A adenosine receptor provided significant protection against tumor initiation and metastasis formation in mice. Our results suggest that targeting adenosine may enhance therapeutic responses for melanoma patients receiving targeted or immune-based therapies. Cancer Res; 77(17); 4684–96. ©2017 AACR.

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Resistance to the Antibody-Drug Conȷugate T-DM1 Is Based in a Reduction in Lysosomal Proteolytic Activity

Trastuzumab-emtansine (T-DM1) is an antibody–drug conjugate (ADC) that was approved recently to treat HER2+ breast cancers. Despite its impressive clinical efficacy in many patients, intrinsic and acquired resistance to T-DM1 has emerged as a challenge. To identify mechanisms of T-DM1 resistance, we isolated several resistant HER2+ clones exhibiting stable drug refractoriness in vitro and in vivo. Genomic comparisons showed substantial differences among three of the isolated clones, indicating several potential mechanisms of resistance to T-DM1. However, we observed no differences in HER2 levels and signaling among the resistant models and parental HER2+ cells. Bioinformatics studies suggested that intracellular trafficking of T-DM1 could underlie resistance to T-DM1, and systematic analysis of the path followed by T-DM1 showed that the early steps in the internalization of the drug were unaltered. However, in some of the resistant clones, T-DM1 accumulated in lysosomes. In these clones, lysosomal pH was increased and the proteolytic activity of these organelles was deranged. These results were confirmed in T-DM1–resistant cells from patient-derived HER2+ samples. We postulate that resistance to T-DM1 occurs through multiple mechanisms, one of which is impaired lysosomal proteolytic activity. Because other ADC may use the same internalization-degradation pathway to deliver active payloads, strategies aimed at restoring lysosomal functionality might overcome resistance to ADC-based therapies and improve their effectiveness. Cancer Res; 77(17); 4639–51. ©2017 AACR.

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Charting the Future of Cancer Health Disparities Research: A Position Statement from the American Association for Cancer Research, the American Cancer Society, the American Society of Clinical Oncology, and the National Cancer Institute



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Transglutaminase 2 Is a Direct Target Gene of YAP/TAZ—Letter



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Epithelial-to-Mesenchymal and Mesenchymal-to-Epithelial Transition in Mesenchymal Tumors: A Paradox in Sarcomas?

The epithelial-to-mesenchymal transition (EMT) is a reversible process comprised of various subprograms via which epithelial cells reduce their intercellular adhesions and proliferative capacity while gaining a mesenchymal phenotype with increased migratory and invasive properties. This process has been well described in several carcinomas, which are cancers of epithelial origin, and is crucial to metastatic tumor cell dissemination and drug resistance. In contrast, the precise role of EMT-related processes in tumors originating from mesenchymal tissues, such as bone and soft-tissues sarcomas, is still largely unclear. In fact, although the existence of the EMT in sarcomas appears paradoxical because these cancers are, by definition, mesenchymal ab initio, accumulating evidence suggests that many sarcomas can undergo EMT-related processes, which may be associated with aggressive clinical behavior. These processes may be especially operative in certain sarcoma subtypes, such as carcinosarcomas displaying a biphenotypic morphology with characteristics of both mesenchymal and epithelial tumors. In this review, we discuss findings regarding the potential existence of EMT-related processes in sarcomas and propose that sarcomas can reside in a metastable state, enabling them to become either more mesenchymal or epithelial under specific conditions, which likely has important clinical implications. Cancer Res; 77(17); 4556–61. ©2017 AACR.

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WEE1 Kinase Inhibitor AZD1775 Has Preclinical Efficacy in LKB1-Deficient Non-Small Cell Lung Cancer

G1–S checkpoint loss contributes to carcinogenesis and increases reliance upon the G2–M checkpoint for adaptation to stress and DNA repair, making G2–M checkpoint inhibition a target for novel therapeutic development. AZD1775, an inhibitor against the critical G2–M checkpoint protein WEE1, is currently in clinical trials across a number of tumor types. AZD1775 and DNA-damaging agents have displayed favorable activity in several preclinical tumor models, often in the molecular context of TP53 loss. Whether AZD1775 efficacy is modulated by other molecular contexts remains poorly understood. The tumor suppressor serine/threonine kinase 11 (LKB1/STK11) is one of the most frequently mutated genes in non–small cell lung cancer (NSCLC) and is commonly comutated with oncogenic KRAS mutations. We investigated the preclinical effects of AZD1775 in the context of KRAS/LKB1 in NSCLC. Using NSCLC cell lines, we found that AZD1775 alone and in combination with DNA-damaging agents (e.g., cisplatin and radiation) decreased tumor cell viability in LKB1-deficient NSCLC cells. In vitro, LKB1 deficiency enhanced DNA damage and apoptosis in response to AZD1775 exposure compared with wild-type LKB1 cells. In a genetically engineered mouse model of mutant Kras with concomitant loss of Lkb1, combined AZD1775 and cisplatin extended overall survival compared with cisplatin alone. Our data suggest that lack of phosphorylation of LKB1 by ATM was involved in AZD1775-mediated cytotoxicity. Collectively, these findings provide a clinical application for AZD1775 with DNA-damaging agents in KRAS/LKB1 NSCLC. Cancer Res; 77(17); 4663–72. ©2017 AACR.

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Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFN{gamma} Signaling

Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell–based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFNγ signaling, led to impaired recognition by tumor-specific CD8+ T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I–related APM. Loss of target antigens or impaired IFNγ signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted. Cancer Res; 77(17); 4562–6. ©2017 AACR.

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SPIN90 Depletion and Microtubule Acetylation Mediate Stromal Fibroblast Activation in Breast Cancer Progression

Biomechanical remodeling of stroma by cancer-associated fibroblasts (CAF) in early stages of cancer is critical for cancer progression, and mechanical cues such as extracellular matrix stiffness control cell differentiation and malignant progression. However, the mechanism by which CAF activation occurs in low stiffness stroma in early stages of cancer is unclear. Here, we investigated the molecular mechanism underlying CAF regulation by SPIN90 and microtubule acetylation under conditions of mechanically soft matrices corresponding to normal stromal rigidity. SPIN90 was downregulated in breast cancer stroma but not tumor, and this low stromal expression correlated with decreased survival in breast cancer patients. Spin90 deficiency facilitated recruitment of mDia2 and APC complex to microtubules, resulting in increased microtubule acetylation. This increased acetylation promoted nuclear localization of YAP, which upregulated expression of myofibroblast marker genes on soft matrices. Spin90 depletion enhanced tumor progression, and blockade of microtubule acetylation in CAF significantly inhibited tumor growth in mice. Together, our data demonstrate that loss of SPIN90-mediated microtubule acetylation is a key step in CAF activation in low stiffness stroma. Moreover, correlation among these factors in human breast cancer tissue supports the clinical relevance of SPIN90 and microtubule acetylation in tumor development. Cancer Res; 77(17); 4710–22. ©2017 AACR.

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APOBEC3A and APOBEC3B Activities Render Cancer Cells Susceptible to ATR Inhibition

The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like APOBEC3A and APOBEC3B have emerged as key mutation drivers in cancer. Here, we show that APOBEC3A and APOBEC3B activities impose a unique type of replication stress by inducing abasic sites at replication forks. In contrast to cells under other types of replication stress, APOBEC3A-expressing cells were selectively sensitive to ATR inhibitors (ATRi), but not to a variety of DNA replication inhibitors and DNA-damaging drugs. In proliferating cells, APOBEC3A modestly elicited ATR but not ATM. ATR inhibition in APOBEC3A-expressing cells resulted in a surge of abasic sites at replication forks, revealing an ATR-mediated negative feedback loop during replication. The surge of abasic sites upon ATR inhibition associated with increased accumulation of single-stranded DNA, a substrate of APOBEC3A, triggering an APOBEC3A-driven feed-forward loop that ultimately drove cells into replication catastrophe. In a panel of cancer cell lines, ATRi selectively induced replication catastrophe in those harboring high APOBEC3A and/or APOBEC3B activities, showing that APOBEC3A and APOBEC3B activities conferred susceptibility to ATRi. Our results define an APOBEC-driven replication stress in cancer cells that may offer an opportunity for ATR-targeted therapy. Cancer Res; 77(17); 4567–78. ©2017 AACR.

http://ift.tt/2vw79AJ

Targeting Histone Demethylases in MYC-Driven Neuroblastomas with Ciclopirox

Histone lysine demethylases facilitate the activity of oncogenic transcription factors, including possibly MYC. Here we show that multiple histone demethylases influence the viability and poor prognosis of neuroblastoma cells, where MYC is often overexpressed. We also identified the approved small-molecule antifungal agent ciclopirox as a novel pan-histone demethylase inhibitor. Ciclopirox targeted several histone demethylases, including KDM4B implicated in MYC function. Accordingly, ciclopirox inhibited Myc signaling in parallel with mitochondrial oxidative phosphorylation, resulting in suppression of neuroblastoma cell viability and inhibition of tumor growth associated with an induction of differentiation. Our findings provide new insights into epigenetic regulation of MYC function and suggest a novel pharmacologic basis to target histone demethylases as an indirect MYC-targeting approach for cancer therapy. Cancer Res; 77(17); 4626–38. ©2017 AACR.

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Cytosine Deaminase APOBEC3A Sensitizes Leukemia Cells to Inhibition of the DNA Replication Checkpoint

Mutational signatures in cancer genomes have implicated the APOBEC3 cytosine deaminases in oncogenesis, possibly offering a therapeutic vulnerability. Elevated APOBEC3B expression has been detected in solid tumors, but expression of APOBEC3A (A3A) in cancer has not been described to date. Here, we report that A3A is highly expressed in subsets of pediatric and adult acute myelogenous leukemia (AML). We modeled A3A expression in the THP1 AML cell line by introducing an inducible A3A gene. A3A expression caused ATR-dependent phosphorylation of Chk1 and cell-cycle arrest, consistent with replication checkpoint activation. Further, replication checkpoint blockade via small-molecule inhibition of ATR kinase in cells expressing A3A led to apoptosis and cell death. Although DNA damage checkpoints are broadly activated in response to A3A activity, synthetic lethality was specific to ATR signaling via Chk1 and did not occur with ATM inhibition. Our findings identify elevation of A3A expression in AML cells, enabling apoptotic sensitivity to inhibitors of the DNA replication checkpoint and suggesting it as a candidate biomarker for ATR inhibitor therapy. Cancer Res; 77(17); 4579–88. ©2017 AACR.

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LSD1 Inhibitor T-3775440 Inhibits SCLC Cell Proliferation by Disrupting LSD1 Interactions with SNAG Domain Proteins INSM1 and GFI1B

T-3775440 is an irreversible inhibitor of the chromatin demethylase LSD1, which exerts antiproliferative effects by disrupting the interaction between LSD1 and GFI1B, a SNAG domain transcription factor, inducing leukemia cell transdifferentiation. Here, we describe the anticancer effects and mechanism of action of T-3775440 in small-cell lung cancer (SCLC). T-3775440 inhibited proliferation of SCLC cells in vitro and retarded SCLC tumor growth in vivo. T-3775440 disrupted the interaction between LSD1 and the transcriptional repressor INSM1, thereby inhibiting expression of neuroendocrine-associated genes, such as ASCL1. INSM1 silencing phenocopied the effects of T-3775440 on gene expression and cell proliferation, consistent with the likelihood T-3775440 mediated its effects in SCLC by inhibiting INSM1. T-3775440 also inhibited proliferation of an SCLC cell line that overexpressed GFI1B, rather than INSM1, by disrupting the interaction between LSD1 and GFI1B. Taken together, our results argue that LSD1 plays an important role in neuroendocrine-associated transcription and cell proliferation of SCLC via interactions with the SNAG domain proteins INSM1 and GFI1B. Targeting these critical interactions with LSD1 inhibitors offers a novel rational strategy to therapeutically manage SCLC. Cancer Res; 77(17); 4652–62. ©2017 AACR.

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Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma

Glycerophosphodiesterase EDI3 (GPCPD1; GDE5; GDPD6) has been suggested to promote cell migration, adhesion, and spreading, but its mechanisms of action remain uncertain. In this study, we targeted the glycerol-3-phosphate acyltransferase GPAM along with choline kinase-α (CHKA), the enzymes that catabolize the products of EDI3 to determine which downstream pathway is relevant for migration. Our results clearly showed that GPAM influenced cell migration via the signaling lipid lysophosphatidic acid (LPA), linking it with GPAM to cell migration. Analysis of GPAM expression in different cancer types revealed a significant association between high GPAM expression and reduced overall survival in ovarian cancer. Silencing GPAM in ovarian cancer cells decreased cell migration and reduced the growth of tumor xenografts. In contrast to these observations, manipulating CHKA did not influence cell migration in the same set of cell lines. Overall, our findings show how GPAM influences intracellular LPA levels to promote cell migration and tumor growth. Cancer Res; 77(17); 4589–601. ©2017 AACR.

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Identification of Interacting Stromal Axes in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a molecularly heterogeneous cancer that is difficult to treat. Despite the role it may play in tumor progression and response to therapy, microenvironmental (stromal) heterogeneity in TNBC has not been well characterized. To address this challenge, we investigated the transcriptome of tumor-associated stroma isolated from TNBC (n = 57). We identified four stromal axes enriched for T cells (T), B cells (B), epithelial markers (E), or desmoplasia (D). Our analysis method (STROMA4) assigns a score along each stromal axis for each patient and then combined the axis scores to subtype patients. Analysis of these subtypes revealed that prognostic capacity of the B, T, and E scores was governed by the D score. When compared with a previously published TNBC subtyping scheme, the STROMA4 method better captured tumor heterogeneity and predicted patient benefit from therapy with increased sensitivity. This approach produces a simple ontology that captures TNBC heterogeneity and informs how tumor-associated properties interact to affect prognosis. Cancer Res; 77(17); 4673–83. ©2017 AACR.

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TP53INP1 Downregulation Activates a p73-Dependent DUSP10/ERK Signaling Pathway to Promote Metastasis of Hepatocellular Carcinoma

Identifying critical factors involved in the metastatic progression of hepatocellular carcinoma (HCC) may offer important therapeutic opportunities. Here, we report that the proapoptotic stress response factor TP53INP1 is often selectively downregulated in advanced stage IV and metastatic human HCC tumors. Mechanistic investigations revealed that TP53INP1 downregulation in early-stage HCC cells promoted metastasis via DUSP10 phosphatase-mediated activation of the ERK pathway. The DUSP10 promoter included putative binding sites for p73 directly implicated in modulation by TP53INP1. Overall, our findings show how TP53INP1 plays a critical role in limiting the progression of early-stage HCC, with implications for developing new therapeutic strategies to attack metastatic HCC. Cancer Res; 77(17); 4602–12. ©2017 AACR.

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MAPK Signaling and Inflammation Link Melanoma Phenotype Switching to Induction of CD73 during Immunotherapy

Evolution of tumor cell phenotypes promotes heterogeneity and therapy resistance. Here we found that induction of CD73, the enzyme that generates immunosuppressive adenosine, is linked to melanoma phenotype switching. Activating MAPK mutations and growth factors drove CD73 expression, which marked both nascent and full activation of a mesenchymal-like melanoma cell state program. Proinflammatory cytokines like TNFα cooperated with MAPK signaling through the c-Jun/AP-1 transcription factor complex to activate CD73 transcription by binding to an intronic enhancer. In a mouse model of T-cell immunotherapy, CD73 was induced in relapse melanomas, which acquired a mesenchymal-like phenotype. We also detected CD73 upregulation in melanoma patients progressing under adoptive T-cell transfer or immune checkpoint blockade, arguing for an adaptive resistance mechanism. Our work substantiates CD73 as a target to combine with current immunotherapies, but its dynamic regulation suggests limited value of CD73 pretreatment expression as a biomarker to stratify melanoma patients. Cancer Res; 77(17); 4697–709. ©2017 AACR.

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PRMT1-Mediated Translation Regulation Is a Crucial Vulnerability of Cancer

Through an shRNA screen, we identified the protein arginine methyltransferase Prmt1 as a vulnerable intervention point in murine p53/Rb-null osteosarcomas, the human counterpart of which lacks effective therapeutic options. Depletion of Prmt1 in p53-deficient cells impaired tumor initiation and maintenance in vitro and in vivo. Mechanistic studies reveal that translation-associated pathways were enriched for Prmt1 downstream targets, implicating Prmt1 in translation control. In particular, loss of Prmt1 led to a decrease in arginine methylation of the translation initiation complex, thereby disrupting its assembly and inhibiting translation. p53/Rb-null cells were sensitive to p53-induced translation stress, and analysis of human cancer cell line data from Project Achilles further revealed that Prmt1 and translation-associated pathways converged on the same functional networks. We propose that targeted therapy against Prmt1 and its associated translation-related pathways offer a mechanistic rationale for treatment of osteosarcomas and other cancers that exhibit dependencies on translation stress response. Cancer Res; 77(17); 4613–25. ©2017 AACR.

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Pharmacokinetics and Pharmacodynamics-Based Mathematical Modeling Identifies an Optimal Protocol for Metronomic Chemotherapy

Metronomic chemotherapy is usually associated with better tolerance than conventional chemotherapy, and encouraging response rates have been reported in various settings. However, clinical development of metronomic chemotherapy has been hampered by a number of limitations, including the vagueness of its definition and the resulting empiricism in protocol design. In this study, we developed a pharmacokinetic/pharmacodynamic mathematical model that identifies in silico the most effective administration schedule for gemcitabine monotherapy. This model is based upon four biological assumptions regarding the mechanisms of action of metronomic chemotherapy, resulting in a set of 6 minimally parameterized differential equations. Simulations identified daily 0.5–1 mg/kg gemcitabine as an optimal protocol to maximize antitumor efficacy. Both metronomic protocols (0.5 and 1 mg/kg/day for 28 days) were evaluated in chemoresistant neuroblastoma-bearing mice and compared with the standard MTD protocol (100 mg/kg once a week for 4 weeks). Systemic exposure to gemcitabine was 14 times lower in the metronomic groups compared with the standard group. Despite this, metronomic gemcitabine significantly inhibited tumor angiogenesis and reduced tumor perfusion and inflammation in vivo, while standard gemcitabine did not. Furthermore, metronomic gemcitabine yielded a 40%–50% decrease in tumor mass at the end of treatment as compared with control mice (P = 0.002; ANOVA on ranks with Dunn test), while standard gemcitabine failed to significantly reduce tumor growth. Stable disease was maintained in the metronomic groups for up to 2 months after treatment completion (67%–72% reduction in tumor growth at study conclusion, P < 0.001; ANOVA on ranks with Dunn test). Collectively, our results confirmed the superiority of metronomic protocols in chemoresistant tumors in vivo. Cancer Res; 77(17); 4723–33. ©2017 AACR.

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Transglutaminase 2 Is a Direct Target Gene of YAP-TAZ—Response



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Impact of multiple malignancies on surgical outcomes in patients with 1 cm or smaller non-small cell lung cancer

Abstract

Background

Because most patients with small-sized non-small cell lung cancer (NSCLC) are asymptomatic, their lesions are detected by cancer screenings or routine checkups for other diseases. Incidences of multiple malignancies have been reported to be 27% in patients with stage I–III NSCLC. Some patients have treatment histories for other malignancies, and their small-sized NSCLC was incidentally detected during follow-up. There is no established report regarding the influence of multiple malignancies on small-sized NSCLC prognosis. Therefore, we investigated the correlation between multiple malignancies and surgical outcomes in patients with small-sized NSCLC.

Methods

In total, 44 patients underwent definitive pulmonary resection for NSCLC of 1 cm or smaller between January 2003 and December 2012. Tumor size was measured by macroscopic findings of the resected specimens, and we then retrospectively investigated their clinical courses.

Results

One patient had hemoptysis symptoms, whereas 43 patients were asymptomatic; among them, NSCLC was detected by examinations for other diseases in 31 patients and by cancer screening in 12 patients. In total, 20 patients (45%) had multiple malignancies. The median follow-up period was 68 months. One patient had a recurrence from current NSCLC. No patients died of current NSCLC. The overall 5-year survival rate was 90% for all patients. Patients with multiple malignancies had significantly poorer prognoses compared with those without multiple malignancies (P = 0.016). However, patients with treatment intervals of more than 5 years had prognoses equivalent to those of patients without multiple malignancies (P = 0.829). Only the presence of multiple malignancies was a significantly poor prognostic factor in univariate and multivariate analyses.

Conclusion

NSCLC of 1 cm or smaller showed good prognoses. The presence of multiple malignancies was a significantly poor prognostic factor, and short treatment intervals also correlated with poor prognosis.



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Downregulation of GPR155 as a prognostic factor after curative resection of hepatocellular carcinoma

Abstract

Background

Molecular biomarkers capable of predicting recurrence patterns and prognosis are helpful for risk stratification and providing appropriate treatment to patients with hepatocellular carcinoma (HCC). In this study, we focused on G protein-coupled receptor 155 (GPR155), a cell surface signaling protein, as a candidate biomarker.

Methods

We analyzed GPR155 expression, DNA methylation, and copy number in HCC cell lines. The clinical significance of GPR155 expression was evaluated using 144 pairs of surgically resected liver and normal tissues with subgroup analysis based on hepatitis virus infection.

Results

GPR155 mRNA expression levels were differential and were decreased in 89% of HCC cell lines. No DNA methylation was detected, whereas copy number alterations were present in five (56%) HCC cell lines. GPR155 mRNA expression level was independent of background liver status and significantly lower in HCC tissues than corresponding normal liver tissues. The expression patterns of GPR155 protein by immunohistochemical staining were significantly associated with those of GPR155 mRNA. Downregulation of GPR155 was significantly associated with more aggressive HCC phenotypes including high preoperative α-fetoprotein, poor differentiation, serosal infiltration, vascular invasion, and advanced disease stage. Patients with downregulation of GPR155 were more likely to have worse prognosis after curative resection irrespective of hepatitis virus infection. Patients who experienced extrahepatic (distant) recurrences had significantly lower GPR155 expression than those with intrahepatic (liver confined) recurrences.

Conclusions

Downregulation of GPR155 may serve as a prognosticator that also predicts initial recurrence sites independent of hepatitis virus infection.



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Effectiveness of PIVKA-II in the detection of hepatocellular carcinoma based on real-world clinical data

Abstract

Background

Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) is an efficient biomarker specific for hepatocellular carcinoma (HCC). Some researchers have proved that levels of PIVKA-II reflect HCC oncogenesis and progression. However, the effectiveness of PIVKA-II based on real-world clnical data has barely been studied.

Methods

A total of 14,861 samples were tested in Southwest Hospital in over 2 years' time. Among them, 4073 samples were PIVKA-II positive. Finally, a total of 2070 patients with at least two image examinations were enrolled in this study. Levels of AFP and PIVKA-II were measured by chemiluminescence enzyme immunoassay (CLEIA) and chemiluminescent microparticle Immunoassay (CMIA), respectively.

Results

A total of 1016 patients with HCC were detected by PIVKA-II in a real-world application. In all these cases, 88.7% cases primarily occurred and patients with advanced HCC covered 61.3%. Levels of PIVKA-II were significantly higher in advanced group (4650.0 mAU/ml, 667.0–33,438.0 mAU/ml) than early-stage group (104.5 mAU/ml, 61.0–348.8 mAU/ml; P < 0.001). Levels of PIVKA-II elevated significantly in recurrence and residual group than recovery group (P < 0.001). A total of 1054 PIVKA-II positive patients were non-HCC cases. Among them, cirrhosis took the largest part (46.3%), followed by hepatitis (20.6%) and benign nodules (15.3%). High-levels of PIVKA-II in at-risk patients is an indicator of HCC development in two-year time.

Conclusions

Our data showed that PIVKA-II effectively increases the detection rate of HCC was a valid complement to AFP and image examination in HCC surveillance.



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A change in the study evaluation paradigm reveals that larynx preservation compromises survival in T4 laryngeal cancer patients

Abstract

Background

Larynx preservation (LP) is recommended for up to low-volume T4 laryngeal cancer as an evidence-based treatment option that does not compromise survival. However, a reevaluation of the current literature raises questions regarding whether there is indeed reliable evidence to support larynx preservation for T4 tumor patients.

Methods

In an observational cohort study of 810 laryngeal cancer patients, we evaluated the outcomes of all T4 tumor patients treated with primary chemo-radiotherapy (CRT) or primary radiotherapy alone (RT) compared with upfront total laryngectomy followed by adjuvant (chemo)radiotherapy (TL + a[C]RT). Additionally, we reevaluated the studies that form the evidence base for the recommendation of LP for patients with up to T4 tumors (Pfister et al., J Clin Oncol 24:3693–704, 2006).

Results

The evaluation of all 288 stage III and IV patients together did not show a significant difference in overall survival (OS) between CRT-LP and TL + a(C)RT (hazard ratio (HR) 1.23; 95% confidence interval (CI): 0.82–1.86; p = 0.31) using a multivariate proportional hazard model. However, a subgroup analysis of T4 tumor patients alone (N = 107; 13.9%) revealed significantly worse OS after CRT compared with TL + a(C)RT (HR 2.0; 95% CI: 1.04–3.7; p = 0.0369). A reevaluation of the subgroup of T4 patients in the 5 LP studies that led to the ASCO clinical practice guidelines revealed that only 21–45 T4 patients had differential data on survival outcome. These data, however, showed a markedly worse outcome for T4 patients after LP.

Conclusions

T4 laryngeal cancer patients who reject TL as a treatment option should be informed that their chance of organ preservation with primary conservative treatment is likely to result in a significantly worse outcome in terms of OS. Significant loss of survival in T4 patients after LP is also confirmed in recent literature.



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Down-regulation of miRNA-148a and miRNA-625-3p in colorectal cancer is associated with tumor budding

Abstract

Background

MiRNAs are often deregulated in colorectal cancer and might function as tumor suppressors or as oncogenes. They participate in controlling key signaling pathways involved in proliferation, invasion and apoptosis and may serve as prognostic and predictive markers. In this study we aimed to evaluate the role of miRNA-148a and miRNA-625-3p in metastatic colorectal cancer.

Methods

Fifty-four patients with a first-time diagnosed CRC receiving FOLFOX ± Bevacizumab were involved in the study. Tumor samples underwent routine pathology examination including evaluation for tumor budding and KRAS. MiRNA-148a and miRNA-625-3p expression analysis was done by RT-PCR. Associations between expression of both miRNAs and clinico-pathological factors, treatment outcomes and survival were analyzed.

Results

Both miRNA-148a and miRNA-625-3p were down-regulated in the tumors compared to normal colonic mucosa. Significantly lower expression of both miRNAs was noticed in tumors with budding phenomenon compared to tumors without it (median values of miRNA-148a were 0.314 and 0.753 respectively, p = 0.011, and 0.404 and 0.620 respectively for miRNA-625-3p, p = 0.036). Significantly lower expression of miRNA-625-3p was detected in rectal tumors, compared to tumors in the colon (median 0.390 and 0.665 respectively, p = 0.037). Progression free survival was significantly lower in patients with high miRNA-148a expression (6 and 9 months respectively, p = 0.033), but there were no significant differences in PFS for miRNA-625-3p and in overall survival for both miRNAs.

Conclusions

There was a significant relationship between low miRNA-148a and miRNA-625-3p expression and tumor budding, which is thought to represent epithelial-mesenchymal transition. Both studied miRNAs may be associated with a more aggressive phenotype and could be the potential prognostic and predictive biomarkers in CRC. Further investigation is needed to confirm miRNAs involvement in EMT, and their prognostic and predictive value.



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Reimbursement of radiotherapy in Germany

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Publication date: Available online 1 September 2017
Source:Cancer/Radiothérapie
Author(s): H. Schmidberger
Reimbursement of radiotherapy in Germany is mainly based on a certain fixed fee for treatment planning and patient set up in addition to payment per fraction. This applies to outpatient care for patients with public health insurance or private health insurance. Payment per fraction has a considerable influence on reimbursement of inpatients as well. The advantage of payment per fraction is the simplicity and transparency. The disadvantage is an inadequate reimbursement for new treatment modalities like hypofractionation or stereotactic body radiotherapy.



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Présentation de l’étude Gortec 2017-03 : radiothérapie en conditions stéréotaxiques postopératoire des cancers localisés de l’oropharynx et de la cavité buccale avec marges à risque (PHRC-K-16-164)

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Publication date: Available online 31 August 2017
Source:Cancer/Radiothérapie
Author(s): J. Biau, J. Miroir, C. Millardet, N. Saroul, N. Pham-Dang, S. Racadot, F. Huguet, F. Kwiatkowski, B. Pereira, J. Bourhis, M. Lapeyre
L'étude du groupe d'oncologie radiothérapie tête et cou (Gortec) 2017-03-Stereo-post est de phase 2, multicentrique, nationale, financée dans le cadre d'un programme hospitalier de recherche clinique (PHRC). La promotion est assurée par le centre Jean-Perrin à Clermont-Ferrand, en partenariat avec le Gortec. Les investigateurs principaux sont le Dr J Biau et le Dr M Lapeyre. L'objectif principal est d'étudier la toxicité sévère tardive d'une radiothérapie stéréotaxique postopératoire de 36Gy en six fractions des cancers localisés de l'oropharynx et la cavité buccale avec marges à risque. Les objectifs secondaires comprennent la toxicité aiguë, l'efficacité, l'impact nutritionnel et la qualité de vie. La population concernera des patients adultes atteints de carcinome épidermoïde de stade pT1 ou pT2, de l'oropharynx ou la cavité buccale (hors lèvres), sans indication d'irradiation ganglionnaire ni de chimiothérapie concomitante, avec marges à risque (R1, inférieure à 5mm ou incertaine). Quatre-vingt-dix patients seront inclus sur deux ans ; le calcul a été réalisé en limitant le taux d'effet tardif sévère à 5–15 % à 2 ans, avec un taux de contrôle local d'au moins 80 à 90 % à 2 ans. En cas de positivité de cette étude, la radiothérapie stéréotaxique postopératoire de 36Gy en six fractions pourrait devenir une troisième option thérapeutique en alternative à la curiethérapie ou à la radiothérapie conformationnelle avec modulation d'intensité (RCMI) normofractionnée, pour les irradiations postopératoires des cancers localisés avec marges à risque.The GORTEC 2017-03-Stereo-postop study is a phase 2, multicentric, nationwide study, funded by the hospital clinical research program (PHRC). The sponsor is Centre Jean-Perrin in Clermont-Ferrand, in partnership with the GORTEC. The principal investigators are Dr J Biau and Dr M Lapeyre. The main objective is to study severe late toxicity of postoperative stereotactic radiotherapy (6×6Gy) for early stage oropharyngeal and oral cavity cancer with high risk margins. The secondary objectives include acute toxicity, efficacy, nutritional impact and quality of life. The population is adult patients, with pT1 or pT2 squamous cell carcinoma of the oropharynx or oral cavity (except lips), without indication of neck irradiation or concomitant chemotherapy, with at risk margin (R1, less than 5mm or uncertain). Ninety patients will be included over a 2-year period; this was calculated to limit the rate of 2-year severe toxicity at 5 to 15%, with a 2-year local control of at least 80 to 90%. If this study is considered as positive, stereotactic radiotherapy (6×6Gy) could become the third therapeutic option, with brachytherapy and normofractionated intensity-modulated radiotherapy (IMRT), for postoperative irradiation of oropharyngeal and oral cavity cancer with high risk margins.



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Association de radiothérapie externe et de curiethérapie pour les cancers de la prostate

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Publication date: Available online 31 August 2017
Source:Cancer/Radiothérapie
Author(s): O. Chapet, A. Bossi, S. Horn, G. Créhange
La curiethérapie exclusive est un traitement standard des cancers de prostate de bas risque selon la classification de D'Amico. Pour les cancers de risque intermédiaire à haut risque, il est proposé de l'associer à une radiothérapie externe afin de mieux prendre en compte le risque d'effraction capsulaire et/ou d'atteinte des vésicules séminales. Trois études randomisées ont montré que cette association améliorait la probabilité de survie sans récidive, par rapport à une radiothérapie externe exclusive. Ce bénéfice n'a pas été retrouvé en termes de survie globale. L'association d'une hormonothérapie est certainement nécessaire pour les cancers à haut risque. Sa place reste clairement à définir pour les cancers de prostate de risque intermédiaire pris en charge par cette association de radiothérapie externe et de curiethérapie. Les techniques de curiethérapie de haut ou de bas débit de dose sont adaptées, avec des résultats similaires en termes de contrôle biochimique. Le haut débit semble avoir un profil de tolérance urinaire meilleur. Le bas débit a l'avantage de l'expertise d'un plus grand nombre de centres et de la simplicité.Brachytherapy as sole treatment is standard of care for D'Amico classification low-risk prostate cancer. For intermediate and high-risk patients, brachytherapy can be associated to external beam radiation therapy to better take into account the risk of extracapsular effraction and/or seminal vesicle involvement. Three randomized studies have shown that this association increases freedom from relapse survival compared to exclusive external beam radiation therapy. This benefit is not shown for overall survival. The addition of a hormonal therapy to this association is most likely mandatory for high-risk patients, and needs to be confirmed for intermediate risk patients. Both high-dose rate and low-dose rate brachytherapy are suitable with similar biochemical disease free survival rates. High-dose rate brachytherapy seems to have a better genitourinary tolerance profile, while low-dose rate brachytherapy is an easier process and has a more widespread expertise.



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De qui peut-on se passer dans la prise en charge du cancer du rectum ?

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Publication date: Available online 31 August 2017
Source:Cancer/Radiothérapie
Author(s): P. Rouanet
Des avancées spectaculaires ont bouleversé la prise en charge des cancers du rectum. La personnalisation de leur prise en charge a permis de sélectionner les intervenants en fonction des caractéristiques pronostiques initiales (oncologue radiothérapeute) ou de la réponse tumorale (chirurgien). Aujourd'hui, la prise en charge de ces tumeurs doit tenir compte du stade tumoral, du pronostic au diagnostic, de la réponse tumorale et des caractéristiques du patient, ainsi que de ses motivations. Le résultat de la prise en charge de ces tumeurs est plus qu'oncologique, il est aussi fonctionnel.Dramatic progress has deeply moved rectal cancer management. Tailoring of treatment allow to select participants according to initial prognostic factors (radiotherapist) or tumoral response (surgeon). Today, this management must keep in mind tumoral initial staging, prognostic at the time of diagnosis, tumoral response and characteristic, and patient's motivation. The result of this patient care is more than oncologic, it is also functional.



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Imagerie médicale computationnelle (radiomique) et potentiel en immuno-oncologie

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Publication date: Available online 31 August 2017
Source:Cancer/Radiothérapie
Author(s): R. Sun, E.J. Limkin, L. Dercle, S. Reuzé, E.I. Zacharaki, C. Chargari, A. Schernberg, A.S. Dirand, A. Alexis, N. Paragios, É. Deutsch, C. Ferté, C. Robert
L'arrivée de l'immunothérapie a profondément modifié la prise en charge de multiples cancers, permettant des réponses tumorales jusqu'alors inespérées, même si une majorité des cancers ne répondent pas à ces nouveaux traitements. L'identification de biomarqueurs permettant de cibler les cancers répondeurs est un enjeu majeur. L'imagerie médicale computationnelle (ou radiomique) est une discipline récente et extrêmement prometteuse. Elle consiste en l'analyse informatique d'images médicales et les traduit en données quantitatives complexes. Ces données de haute dimension permettent une caractérisation et une analyse plus en profondeur du phénotype tumoral. L'imagerie médicale computationnelle présente l'avantage d'être non invasive, de pouvoir évaluer la maladie tumorale dans sa globalité, et de pouvoir être répétée dans le temps pour suivre l'évolution tumorale au cours du temps. L'imagerie médicale computationnelle a pour objectif final de déterminer des biomarqueurs d'imagerie apportant une aide à la décision médicale et permettant aussi de mieux comprendre la biologie du cancer. Cette revue développe le processus de l'analyse en imagerie computationnelle et présente le potentiel de son utilisation en immuno-oncologie.The arrival of immunotherapy has profoundly changed the management of multiple cancers, obtaining unexpected tumour responses. However, until now, the majority of patients do not respond to these new treatments. The identification of biomarkers to determine precociously responding patients is a major challenge. Computational medical imaging (also known as radiomics) is a promising and rapidly growing discipline. This new approach consists in the analysis of high-dimensional data extracted from medical imaging, to further describe tumour phenotypes. This approach has the advantages of being non-invasive, capable of evaluating the tumour and its microenvironment in their entirety, thus characterising spatial heterogeneity, and being easily repeatable over time. The end goal of radiomics is to determine imaging biomarkers as decision support tools for clinical practice and to facilitate better understanding of cancer biology, allowing the assessment of the changes throughout the evolution of the disease and the therapeutic sequence. This review will develop the process of computational imaging analysis and present its potential in immuno-oncology.



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