Retinal Endovascular Surgery with Tissue Plasminogen Activator Injection for Central Retinal Artery Occlusion

Purpose: To report 2 cases of central retinal artery occlusion (CRAO) who underwent retinal endovascular surgery with injection of tissue plasminogen activator (tPA) into the retinal artery and showed a remarkable improvement in visual acuity and retinal circulation. Methods: Standard 25-G vitrectomy was performed under local anesthesia. Simultaneously, tPA (80,000 units/mL) solution was injected into the retinal artery of the optic disc for 2–3 min using a microneedle. Changes in visual acuity, fundus photography, optical coherence tomography (OCT), fluorescein angiography, and laser speckle flowgraphy (LSFG) results were examined. Results: Both cases could be treated within 12 h after the onset of CRAO. Case 1 was a 47-year-old woman. Her visual acuity improved from counting fingers before operation to 0.08 logMAR 1 month after the surgery. However, thinning of the retina at the macula was observed by OCT. Case 2 was a 70-year-old man. His visual acuity improved from counting fingers to 0.1 logMAR 2 months after the surgery. Both fluorescein angiography and LSFG showed improvement in retinal circulation after the surgery in case 2. Conclusions: Retinal endovascular surgery with injection of tPA into the retinal artery was feasible and may be a way to improve visual acuity and retinal circulation when performed in the acute phase of CRAO.
Case Rep Ophthalmol 2018;9:327–332

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Can Smartphones Promote Cancer Prevention Behaviours in Healthy Young Adults? A Prospective Study

Abstract

Cancer prevention should start as early as possible. Young adults would benefit largely from the use of a smartphone app aiming at promoting cancer prevention behaviours. The aims of the study described in this paper are to (1) examine the user participation and engagement with a cancer prevention app in real-life settings and (2) assess changes in the users' cancer prevention behaviours. A cancer prevention smartphone app called Happy was developed and released to the general population. Data from registered app users' (N = 3326) demographics and baseline cancer prevention behaviours was analysed. App engagement was measured and all behaviour data logged through the app was analysed to assess the effectiveness of the app in the promotion of cancer prevention behaviours. User demographics and baseline behaviour assessment show that the app reached its intended target population: young adults that generally do not comply with cancer prevention guidelines. Logged behavioural data showed an increased frequency in several cancer prevention behaviours and a significant increase in the overall putative cancer prevention level (p < 0.001). However, user engagement with the app was limited and might condition the long-term impact of such changes. Happy reached its intended population and seems to be an effective tool to promote cancer prevention. Further research is needed to fully assess its long-term persuasive potential.

https://ift.tt/2tqohUJ

A systematic review and meta-analysis of clinicopathologic factors linked to oncologic outcomes for renal cell carcinoma with tumor thrombus treated by radical nephrectomy with thrombectomy

Publication date: Available online 21 June 2018
Source:Cancer Treatment Reviews
Author(s): Liangyou Gu, Hongzhao Li, Zihuan Wang, Baojun Wang, Qingbo Huang, Xiangjun Lyu, Dan Shen, Yu Gao, Yang Fan, Xintao Li, Yongpeng Xie, Songliang Du, Kan Liu, Lu Tang, Cheng Peng, Xin Ma, Xu Zhang
BackgroundThere remain discrepancies over the factors that influence oncologic outcomes after radical nephrectomy with thrombectomy (RNTE). To assess significant predictors of oncologic outcomes after RNTE from a systematic review and meta-analysis.MethodsA comprehensive search of PubMed, Embase, Cochrane Library and Web of Science was performed to identify eligible studies. The endpoints included cancer-specific survival (CSS), overall survival (OS), and recurrence-free survival (RFS). A formal meta-analysis was performed for studies containing non-metastatic and metastatic tumors. Additionally, a sensitivity analysis including the subgroup of studies containing non-metastatic tumors only was conducted. Cumulative analyses of hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were conducted.ResultsOverall, 35 retrospective studies of low to moderate risk of bias including 11,929 patients were included. The results indicated that large tumor size, high Fuhrman grade, tumor necrosis, positive lymph node, and metastasis at surgery were adverse significant predictors for both CSS and OS. Also, IVC tumor thrombus, sarcomatoid differentiation, perinephretic fat invasion, and adrenal gland invasion were associated with poor CSS. In the subset of non-metastatic patients, the significant predictors were clinical symptom, thrombus level, Fuhrman grade and adrenal gland invasion for CSS; thrombus consistency, Fuhrman grade and tumor necrosis for OS; tumor size, Fuhrman grade and perinephretic fat invasion for RFS.ConclusionsA meta-analysis of available data identified significant prognostic factors of CSS, OS and RFS that should be systematically evaluated to propose a risk-adapted approach to postoperative patient counseling, risk stratification, and therapy selection.



https://ift.tt/2Igl4wa

Checkpoint Inhibitors as Treatment for Malignant Gliomas: “A Long Way To the Top”

Publication date: Available online 21 June 2018
Source:Cancer Treatment Reviews
Author(s): Matteo Simonelli, Pasquale Persico, Matteo Perrino, Paolo Andrea Zucali, Pierina Navarria, Federico Pessina, Marta Scorsetti, Lorenzo Bello, Armando Santoro
Glioblastoma is the most common and lethal malignant brain tumor in adults, with a very poor prognosis of less than two years despite surgical resection followed by radiotherapy and chemotherapy. To date, targeted agents and antiangiogenic therapy have failed to show survival benefits and novel treatment approaches are urgently needed.Immune checkpoint inhibitors have recently revolutionized the landscape of cancer immunotherapy achieving regulatory approvals for a number of other 'historically' resistant cancers. These exciting successes have generated great interest in investigating if these agents could be such effective also in brain tumors field. Moreover, the traditional dogma that considers the central nervous system (CNS) as an immune-privileged site lacking the potential for immunosurveillance has been challenged as it has become clear that the CNS is immunoactive. Critical barriers to an effective antitumor immunity in brain tumor patients are still represented by the peculiar CNS immunological milieu and the numerous systemic and local immunosuppressive forces exhibited by malignant gliomas to avoid immune recognition and cellular death.This review describes the current status of checkpoint modulation as treatment for malignant gliomas. We start illustrating the compelling molecular and immunological rationale, than we show striking preclinical evidence of activity and discuss available data from prospective clinical trials. Furthermore, we explore the role of predictive biomarkers of responsiveness to checkpoint blockade in the context of gliomas, along with the development of combinatorial and potentially synergistic approaches with other established anti-cancer treatments or complementary immunotherapeutic modalities.



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Cancers, Vol. 10, Pages 211: Immunosenescence and Immunotherapy in Elderly Acute Myeloid Leukemia Patients: Time for a Biology-Driven Approach

Cancers, Vol. 10, Pages 211: Immunosenescence and Immunotherapy in Elderly Acute Myeloid Leukemia Patients: Time for a Biology-Driven Approach

Cancers doi: 10.3390/cancers10070211

Authors: Alessandro Isidori Federica Loscocco Marilena Ciciarello Giulia Corradi Mariangela Lecciso Darina Ocadlikova Sarah Parisi Valentina Salvestrini Sergio Amadori Giuseppe Visani Antonio Curti

Acute myeloid leukemia (AML) is a disease, which mainly affects the elderly population. Unfortunately, the prognosis of patients aged &gt;65 years is dismal, with 1-year overall survival approaching 10% with conventional therapies. The hypothesis of harnessing the immune system against cancer, including leukemia, has been postulated for a long time, and several clinical attempts have been made in this field. In the last years, we increased our knowledge about the interplay between AML and immune cells, but no major improvement has been translated, up to now, from bench to bedside. However, the outstanding results coming from the modern immuno-oncology trials with new drugs have granted a new interest for immunotherapy in AML. Accordingly, the elderly population represents an ideal target, given the low percentage of patients eligible for allogeneic stem cell transplant. With that in mind, in the era of immunotherapy, we consider immunosenescence as the optimal background to start investigating a biology-driven approach to AML therapy in the elderly. By taking into account the physiological age-related changes of immune response, more personalized and tailored use of the new drugs and strategies harnessing the immune system against AML, has the potential to increase their efficacy and impact on clinical outcomes.

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Validation of multiple myeloma risk stratification indices in routine clinical practice: Analysis of data from the Czech Myeloma Group Registry of Monoclonal Gammopathies

Cancer Medicine, EarlyView.


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Bone marrow transplant-associated thrombotic microangiopathy without peripheral blood schistocytes: a case report and review of the literature

Abstract

Background

Bone marrow transplant-associated thrombotic microangiopathy (TA-TMA) is a relatively frequent but under-recognized and under-treated hematopoietic stem cell transplant (HSCT) complication that leads to significant post-transplant morbidity and mortality. Classic TMA-defining laboratory abnormalities appear at different times in the course of TA-TMA development, with schistocytes often appearing later in the disease course. In some severe TMA cases, schistocytes may be absent due to increased endothelial permeability. Unfortunately, many clinicians continue to perceive the presence of schistocytes as an absolute requirement for TA-TMA diagnosis, which leads to delayed recognition and treatment of this potentially fatal transplant complication.

Methods

Patient chart review and PubMed literature search using the term, "transplant-associated thrombotic microangiopathy".

Case presentation

A 54-year-old male IgG kappa multiple myeloma underwent a reduced intensity allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with fludarabine and melphalan. On day + 27, the patient developed acute kidney injury followed by repeated episodes of diarrhea and gastrointestinal bleeding attributed to graft versus host disease (GVHD) and cytomegalovirus (CMV) colitis. Repeated colonic biopsies suggested CMV infection and GVHD. Despite appropriate treatment with antiviral therapy and immunosuppressants, the patient's condition continued to deteriorate. He experienced concomitant anemia and thrombocytopenia as well as elevated lactate dehydrogenase and low haptoglobin levels, but a TA-TMA diagnosis was not made due to an absence of schistocytes on peripheral smear. The patient expired secondary to uncontrolled gastrointestinal bleeding. A post-mortem analysis of the resection specimen revealed extensive TMA involving numerous arteries and arterioles in the ileal and colonic submucosa as well as in the muscularis propria and deep lamina propria of the mucosa.

Conclusions

TA-TMA can occur in the absence of peripheral blood schistocytes. Our experience underscores the importance of considering the diagnosis of intestinal TA-TMA in patients with refractory post-transplant diarrhea and GI bleeding, even if all classic features are not present.

https://ift.tt/2Md8Gzu

Clinical trial on the effects of thalidomide on hemoglobin synthesis in patients with moderate thalassemia intermedia

Abstract

To investigate the efficacy and safety of thalidomide in patients with thalassemia intermedia (TI). Patients with a confirmed diagnosis of TI who met the trial criteria and signed consent forms were prescribed oral thalidomide 50 mg qn for 3 months from February 2017. Complete blood counts, Hb analysis, and liver and kidney functions were monitored monthly during treatment and any differences were compared before and after treatment. Patients with Hb increments > 2.0 g/dL were termed main responders (MaR), and those with Hb increments between 1.0 and 2.0 g/dL as minor responders (MiR), otherwise they were termed non-responders. Relevance analysis was performed to explore parameters predicting Hb increments after treatment. Adverse effects during treatment were carefully recorded. The overall response rate (ORR = MaR + MiR) and MaR rates were 78.6 and 50% after 1 month of treatment, respectively, and 85.7 and 71.4% after 3 months treatment. At the end of the treatment period, Hb and HbF increased by 2.5 ± 1.8 g/dL and 2.5 ± 1.6 g/dL, while bilirubin, lactate dehydrogenase, and the nucleated red blood cell count (NRBC) were significantly decreased, while the reticulocyte count significantly increased. Correlation analysis showed that the Hb increments correlated significantly with the ratio of HbF before treatment (r = 0.683, P = 0.007) rather than age, Hb, reticulocyte count, and NRBC before treatment. Adverse events during treatment were mild, and drug reduction or withdrawal from the trial was not required. Thalidomide had rapid and significant effects in patients with TI, and also, it is safe and convenient. But larger scale clinical trials will be required to confirm our conclusions. Trial Registration: NCT02995707, https://www.clinicaltrials.gov/ct2/show/NCT03184844?term=thalidomide+thalassemia&rank=1.

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The use of blue light flexible cystoscopy with hexaminolevulinate & the diagnosis of bladder cancer

Future Oncology, Ahead of Print.


https://ift.tt/2tj1dbl

Alkaline phosphatase in metastatic castration-resistant prostate cancer: reassessment of an older biomarker

Future Oncology, Ahead of Print.


https://ift.tt/2KaIFjY

Milestones over the development of SB3, a trastuzumab biosimilar

Future Oncology, Ahead of Print.


https://ift.tt/2MK8Mjg

Nivolumab and its use in the second-line treatment of metastatic urothelial cancer

Future Oncology, Ahead of Print.


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Clinical implication of changes in body composition and weight in patients with early-stage and metastatic breast cancer

Publication date: Available online 21 June 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Ilaria Trestini, Luisa Carbognin, Sara Monteverdi, Sara Zanelli, Alessandro De Toma, Clelia Bonaiuto, Rolando Nortilli, Elena Fiorio, Sara Pilotto, Massimo Di Maio, Antonio Gasbarrini, Giovanni Scambia, Giampaolo Tortora, Emilio Bria
Breast cancer represents the most frequent cancer among women in Western countries. Although physicians and patients have witnessed a significant evolution in both treatment strategies and personalized medicine (the identification of featured patients' subsets such as HER2-driven disease), the identification of additional prognostic clinical predictors referring to patients' dietary habits represents a research area aiming to further improve the overall management of this disease. In this regard, body composition (i.e. the relative proportion of fat and muscles) and its changes have recently generated growing interest. A large body of evidence supports the relationship between overweight or weight gain and poor outcome in patients with early-stage breast cancer during adjuvant, and more recently, also neoadjuvant therapy. Nevertheless, available data on post-diagnosis weight variations and mortality report controversial results. Indeed, the limited data produced in the metastatic setting do not indicate an impact of body size on the outcome of these patients. With these perspectives, this review aims to elucidate the complex association between weight, body composition and breast cancer outcome, across the different settings of such disease. The more recent and important findings are highlighted, emphasizing the potential role of body composition assessment to predict individualize chemotherapy dosing, toxicity and efficacy, in order to improve the overall health status and prognosis of such still to date growing patients' population.



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Accuracy of a Novel Handheld Wireless Platform for Detection of Cardiac Dysfunction in Anthracycline-Exposed Survivors of Childhood Cancer

Purpose: Childhood cancer survivors are at risk for anthracycline-related cardiac dysfunction, often developing at a time when they are least engaged in long-term survivorship care. New paradigms in survivorship care and chronic disease screening are needed in this population. We compared the accuracy of a novel handheld mHealth platform (Vivio) as well as echocardiography for assessment of cardiac function [left ventricular ejection fraction (EF)] in childhood cancer survivors with cardiac magnetic resonance (CMR) imaging (reference).

Experimental Design: Cross-sectional study design was used. Concurrent evaluation of EF was performed using Vivio, two-dimensional (2D) echocardiography, and CMR. Differences in mean EF (2D echocardiography vs. CMR; Vivio vs. CMR) were compared using Bland–Altman plots. Linear regression was used to evaluate proportional bias.

Results: A total of 191 consecutive survivors participated [50.7% female; median time from diagnosis: 15.8 years (2–44); median anthracycline dose: 225 mg/m² (25–642)]. Echocardiography overestimated mean EF by 4.9% (P < 0.001); linear regression analysis confirmed a proportional bias, when compared with CMR (t = 3.1, P < 0.001). There was no difference between mean EF derived from Vivio and from CMR (–0.2%, P = 0.68). The detection of cardiac dysfunction via echocardiography was poor when compared with CMR [Echo EF < 45% (sensitivity 14.3%), Echo EF < 50% (sensitivity 28.6%)]. Sensitivity was substantially better for Vivio-based measurements [EF < 45% or EF < 50% (sensitivity 85.7%)].

Conclusions: This accessible technology has the potential to change the day-to-day practice of clinicians caring for the large number of patients diagnosed with cardiac dysfunction and heart failure each year, allowing real-time monitoring and management of their disease without the lag-time between imaging and interpretation of results. Clin Cancer Res; 1–7. ©2018 AACR.

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Interplay between ShcA signaling and PGC-1{alpha} triggers targetable metabolic vulnerabilities in breast cancer

The ShcA adaptor protein transduces oncogenic signals downstream of receptor tyrosine kinases. We show here that breast tumors engage the ShcA pathway to increase their metabolism. ShcA signaling enhanced glucose catabolism through glycolysis and oxidative phosphorylation, rendering breast cancer cells critically dependent on glucose. ShcA signaling simultaneously increased the metabolic rate and flexibility of breast cancer cells by inducing the PGC-1α transcription factor, a central regulator of mitochondrial metabolism. Breast tumors that engaged ShcA signaling were critically dependent on PGC-1α to support their increased metabolic rate. PGC-1α deletion drastically delayed breast tumor onset in an orthotopic mouse model, highlighting a key role for PGC-1α in tumor initiation. Conversely, reduced ShcA signaling impaired both the metabolic rate and flexibility of breast cancer cells, rendering them reliant on mitochondrial oxidative phosphorylation. This metabolic reprogramming exposed a targetable metabolic vulnerability, leading to a sensitization of breast tumors to inhibitors of mitochondrial complex I (biguanides). Genetic inhibition of ShcA signaling in the Polyoma virus middle T (MT) breast cancer mouse model sensitized mammary tumors to biguanides during the earliest stages of breast cancer progression. Tumor initiation and growth were selectively and severely impaired in MT/ShcA-deficient animals. These data demonstrate that metabolic reprogramming is a key component of ShcA signaling and serves an unappreciated yet vital role during breast cancer initiation and progression. These data further unravel a novel interplay between ShcA and PGC-1α in the coordination of metabolic reprogramming and demonstrate the sensitivity of breast tumors to drugs targeting oxidative phosphorylation.

https://ift.tt/2tprPYj

CD271+ cells are diagnostic and prognostic and exhibit elevated MAPK activity in SHH medulloblastoma

The extensive heterogeneity both between and within the medulloblastoma (MB) subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH MB subgroup. Here we demonstrate the utility of CD271 as a novel diagnostic and prognostic marker for SHH MB using immunohistochemical analysis and transcriptome data across 763 primary tumors. RNA sequencing of CD271+ and CD271- cells revealed molecularly distinct, co-existing cellular subsets both in vitro and in vivo. MAPK/ERK signaling was upregulated in the CD271+ population, and inhibiting this pathway reduced endogenous CD271 levels, stem/progenitor cell proliferation, and cell survival as well as cell migration in vitro. Treatment with the MEK inhibitor selumetinib extended survival and reduced CD271 levels in vivo; whereas, treatment with vismodegib, a well-known smoothened (SMO) inhibitor currently in clinical trials for the treatment of recurrent SHH medulloblastoma, had no significant effect in our models. Our study demonstrates the clinical utility of CD271 as both a diagnostic and prognostic tool for SHH MB tumors and reveals a novel role for MEK inhibitors in targeting CD271+ SHH MB cells.

https://ift.tt/2K7l6by

Treponema denticola chymotrypsin-like protease as associated with HPV-negative oropharyngeal squamous cell carcinoma

Treponema denticola chymotrypsin-like protease as associated with HPV-negative oropharyngeal squamous cell carcinoma

<i>Treponema denticola</i> chymotrypsin-like protease as associated with HPV-negative oropharyngeal squamous cell carcinoma, Published online: 22 June 2018; doi:10.1038/s41416-018-0143-5

Treponema denticola chymotrypsin-like protease as associated with HPV-negative oropharyngeal squamous cell carcinoma

https://ift.tt/2Ke5giA

Correction: Genistein downregulates onco-miR-1260b and upregulates sFRP1 and Smad4 via demethylation and histone modification in prostate cancer cells

Correction: Genistein downregulates onco-miR-1260b and upregulates sFRP1 and Smad4 via demethylation and histone modification in prostate cancer cells

Correction: Genistein downregulates onco-miR-1260b and upregulates sFRP1 and Smad4 via demethylation and histone modification in prostate cancer cells, Published online: 22 June 2018; doi:10.1038/s41416-018-0146-2

Correction: Genistein downregulates onco-miR-1260b and upregulates sFRP1 and Smad4 via demethylation and histone modification in prostate cancer cells

https://ift.tt/2MewLGk

Normal vaginal delivery at term after expectant management of heterotopic caesarean scar pregnancy: a case report

Heterotopic pregnancy with a combination of a caesarean scar pregnancy and an intrauterine pregnancy is rare and has potentially life-threatening complications.

https://ift.tt/2McZvzj

Pronounced femur malunion after pathological bone fracture due to a simple bone cyst in the shaft of the femur, treated using Ilizarov fixation: a case report

Although a simple bone cyst carries the risk of pathological fractures, it rarely causes severe deformity. Here we report a case of severe femoral deformity after multiple pathological fractures due to simple ...

https://ift.tt/2JWiSQl

Treponema denticola chymotrypsin-like protease as associated with HPV-negative oropharyngeal squamous cell carcinoma

https://ift.tt/2lnynlI

Correction: Genistein downregulates onco-miR-1260b and upregulates sFRP1 and Smad4 via demethylation and histone modification in prostate cancer cells

https://ift.tt/2tt2yv9

Chronic Liver Injury Induces Conversion of Biliary Epithelial Cells into Hepatocytes

Publication date: Available online 21 June 2018
Source:Cell Stem Cell
Author(s): Xing Deng, Xin Zhang, Weiping Li, Ren-Xin Feng, Lu Li, Gui-Rong Yi, Xiao-Nan Zhang, Chuan Yin, Hong-Yu Yu, Jun-Ping Zhang, Bin Lu, Lijian Hui, Wei-Fen Xie
Chronic liver injury can cause cirrhosis and impaired liver regeneration, impairing organ function. Adult livers can regenerate in response to parenchymal insults, and multiple cellular sources have been reported to contribute to this response. In this study, we modeled human chronic liver injuries, in which such responses are blunted, without genetic manipulations, and assessed potential contributions of non-parenchymal cells (NPCs) to hepatocyte regeneration. We show that NPC-derived hepatocytes replenish a large fraction of the liver parenchyma following severe injuries induced by long-term thioacetamide (TAA) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) treatment. Through lineage tracing of biliary epithelial cells (BECs), we show that BECs are a source of new hepatocytes and gain an Hnf4α⁺CK19⁺ bi-phenotypic state in periportal regions and fibrotic septa. Bi-phenotypic cells were also detected in cirrhotic human livers. Together, these data provide further support for hepatocyte regeneration from BECs without genetic interventions and show their cellular plasticity during severe liver injury.

Graphical abstract

Teaser

Understanding cellular sources of hepatocyte regeneration is critical for developing effective therapies for chronic liver diseases. Xie and colleagues show that severe liver injuries can, without genetic interventions, induce biliary epithelial cells to significantly contribute to hepatocyte regeneration through direct lineage conversion.


https://ift.tt/2tiL0ms

Single-Cell RNA-Seq Reveals Dynamic Early Embryonic-like Programs during Chemical Reprogramming

Publication date: Available online 21 June 2018
Source:Cell Stem Cell
Author(s): Ting Zhao, Yao Fu, Jialiang Zhu, Yifang Liu, Qian Zhang, Zexuan Yi, Shi Chen, Zhonggang Jiao, Xiaochan Xu, Junquan Xu, Shuguang Duo, Yun Bai, Chao Tang, Cheng Li, Hongkui Deng
Chemical reprogramming provides a powerful platform for exploring the molecular dynamics that lead to pluripotency. Although previous studies have uncovered an intermediate extraembryonic endoderm (XEN)-like state during this process, the molecular underpinnings of pluripotency acquisition remain largely undefined. Here, we profile 36,199 single-cell transcriptomes at multiple time points throughout a highly efficient chemical reprogramming system using RNA-sequencing and reconstruct their progression trajectories. Through identifying sequential molecular events, we reveal that the dynamic early embryonic-like programs are key aspects of successful reprogramming from XEN-like state to pluripotency, including the concomitant transcriptomic signatures of two-cell (2C) embryonic-like and early pluripotency programs and the epigenetic signature of notable genome-wide DNA demethylation. Moreover, via enhancing the 2C-like program by fine-tuning chemical treatment, the reprogramming process is remarkably accelerated. Collectively, our findings offer a high-resolution dissection of cell fate dynamics during chemical reprogramming and shed light on mechanistic insights into the nature of induced pluripotency.

Graphical abstract

Teaser

Single-cell RNA sequencing analysis of chemical reprogramming depicts its trajectory and highlights dynamic intermediate cellular programs resembling early embryonic signatures. Zhao et al. apply these insights to develop a faster reprogramming system.


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hPSC Modeling Reveals that Fate Selection of Cortical Deep Projection Neurons Occurs in the Subplate

Publication date: Available online 21 June 2018
Source:Cell Stem Cell
Author(s): M. Zeeshan Ozair, Christoph Kirst, Bastiaan L. van den Berg, Albert Ruzo, Tiago Rito, Ali H. Brivanlou
Cortical deep projection neurons (DPNs) are implicated in neurodevelopmental disorders. Although recent findings emphasize post-mitotic programs in projection neuron fate selection, the establishment of primate DPN identity during layer formation is not well understood. The subplate lies underneath the developing cortex and is a post-mitotic compartment that is transiently and disproportionately enlarged in primates in the second trimester. The evolutionary significance of subplate expansion, the molecular identity of its neurons, and its contribution to primate corticogenesis remain open questions. By modeling subplate formation with human pluripotent stem cells (hPSCs), we show that all classes of cortical DPNs can be specified from subplate neurons (SPNs). Post-mitotic WNT signaling regulates DPN class selection, and DPNs in the caudal fetal cortex appear to exclusively derive from SPNs. Our findings indicate that SPNs have evolved in primates as an important source of DPNs that contribute to cortical lamination prior to their known role in circuit formation.

Graphical abstract

Teaser

Ozair et al. show that major classes of cortical DPNs can be specified from subplate neurons (SPNs) derived from hPSCs by modulating post-mitotic WNT signaling. The findings indicate that SPNs have evolved in primates as an important contributor to cortical lamination. These findings have implications for understanding neurodevelopmental disorders.


https://ift.tt/2JWFpfL

Too Much Carrot and Not Enough Stick in New Stem Cell Oversight Trends

Publication date: Available online 21 June 2018
Source:Cell Stem Cell
Author(s): Paul S. Knoepfler
Regulators are now more often distinguishing between perceived good citizens and "bad actors" in stem cell and regenerative medicine clinical research, resulting in relatively more polar, carrot-and-stick oversight approaches. Here, I discuss why there may be too much carrot and not enough stick by regulators for effective enforcement.

Teaser

Regulators are now more often distinguishing between perceived good citizens and "bad actors" in stem cell and regenerative medicine clinical research, resulting in relatively more polar, carrot-and-stick oversight approaches. Here, I discuss why there may be too much carrot and not enough stick by regulators for effective enforcement.


https://ift.tt/2MerY7P

Safety concerns regarding ablative radiotherapy for ventricular tachycardia

Dear Editor,

https://ift.tt/2ywyC7v

Harnessing drug/radiation interaction through daily routine practice: Leverage medical and methodological point of view (MORSE 02-17 study)

Safety profile of the interaction between anticancer drugs and radiation is a recurrent question. However, there are little data regarding the non-anticancer treatment (NACT)/radiation combinations. The aim of the present study was to investigate concomitant NACTs in patients undergoing radiotherapy in a French comprehensive cancer center.

https://ift.tt/2lqKjDj

Survival gain with re-Op/RT for recurred high-grade gliomas depends upon risk groups

A majority of high-grade gliomas relapse despite combined surgery, radiotherapy and chemotherapy. There is no consensus on standard treatment for recurrent high-grade gliomas, or defined efficacy of adjuvant re-RT after re-Op. This retrospective study evaluated the benefit and safety of re-RT after re-Op (re-Op/RT).

https://ift.tt/2tmFI8C

Proton therapy for pediatric malignancies: Fact, figures and costs. A joint consensus statement from the pediatric subcommittee of PTCOG, PROS and EPTN

Radiotherapy plays an important role in the management of childhood cancer, with the primary aim of achieving the highest likelihood of cure with the lowest risk of radiation-induced morbidity. Proton therapy (PT) provides an undisputable advantage by reducing the radiation 'bath' dose delivered to non-target structures/volume while optimally covering the tumor with tumoricidal dose. This treatment modality comes, however, with an additional costs compared to conventional radiotherapy that could put substantial financial pressure to the health care systems with societal implications.

https://ift.tt/2lnUtnW

Long term patient reported swallowing function following chemoradiotherapy for oropharyngeal carcinoma

Limited data are available to inform on long term swallowing outcomes following concurrent chemoradiotherapy for oropharyngeal carcinoma. The aims of this study are to determine long term patient-reported swallowing outcomes across two large UK centres in routine clinical practice and identify associated factors.

https://ift.tt/2tsD2Xf

Do fetuses need vasopressors just before their birth?

https://ift.tt/2IeZwjS

Apoptotic Cell-Derived Extracellular Vesicles Promote Malignancy of Glioblastoma Via Intercellular Transfer of Splicing Factors

Publication date: Available online 21 June 2018
Source:Cancer Cell
Author(s): Marat S. Pavlyukov, Hai Yu, Soniya Bastola, Mutsuko Minata, Victoria O. Shender, Yeri Lee, Suojun Zhang, Jia Wang, Svetlana Komarova, Jun Wang, Shinobu Yamaguchi, Heba Allah Alsheikh, Junfeng Shi, Dongquan Chen, Ahmed Mohyeldin, Sung-Hak Kim, Yong Jae Shin, Ksenia Anufrieva, Evgeniy G. Evtushenko, Nadezhda V. Antipova, Georgij P. Arapidi, Vadim Govorun, Nikolay B. Pestov, Mikhail I. Shakhparonov, L. James Lee, Do-Hyun Nam, Ichiro Nakano
Aggressive cancers such as glioblastoma (GBM) contain intermingled apoptotic cells adjacent to proliferating tumor cells. Nonetheless, intercellular signaling between apoptotic and surviving cancer cells remain elusive. In this study, we demonstrate that apoptotic GBM cells paradoxically promote proliferation and therapy resistance of surviving tumor cells by secreting apoptotic extracellular vesicles (apoEVs) enriched with various components of spliceosomes. apoEVs alter RNA splicing in recipient cells, thereby promoting their therapy resistance and aggressive migratory phenotype. Mechanistically, we identified RBM11 as a representative splicing factor that is upregulated in tumors after therapy and shed in extracellular vesicles upon induction of apoptosis. Once internalized in recipient cells, exogenous RBM11 switches splicing of MDM4 and Cyclin D1 toward the expression of more oncogenic isoforms.

Graphical abstract

Teaser

Pavlyukov et al. show that apoptotic GBM cells secrete vesicles enriched with components of spliceosomes to alter RNA splicing in surviving tumor cells and promote their aggressiveness. They identify RBM11 as one such factor that switches MDM4 and cyclinD1 toward the more oncogenic isoforms in recipient cells.


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Erratum

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Risk of high-grade serous ovarian cancer associated with pelvic inflammatory disease, parity and breast cancer

Publication date: August 2018
Source:Cancer Epidemiology, Volume 55
Author(s): Louise M. Stewart, Katrina Spilsbury, Susan Jordan, Colin Stewart, C. D'Arcy J. Holman, Aime Powell, Joanne Reekie, Paul Cohen
BackgroundOvarian carcinoma is not a single disease, but rather a collection of subtypes with differing molecular properties and risk profiles. The most common of these, and the subject of this work, is high-grade serous ovarian carcinoma (HGSC).MethodsIn this population-based study we identified a cohort of 441,382 women resident in Western Australia who had ever been admitted to hospital in the State. Of these, 454 were diagnosed with HGSC. We used Cox regression to derive hazard ratios (HRs) comparing the risk of disease in women who had each of a range of medical diagnoses and surgical procedures with women who did not.ResultsWe found an increased risk of HGSC associated with a diagnosis of pelvic inflammatory disease (PID) (HR 1.47, 95% CI 1.04–2.07) but not with a diagnosis of infertility or endometriosis with HRs of 1.12 (95% CI 0.73–1.71) and 0.82 (95% CI 0.55–1.22) respectively. A personal history of breast cancer was associated with a three-fold increase in the rate of HGSC. Increased parity was associated with a reduced risk of HGSC in women without a personal history of breast cancer (HR 0.57; 95% CI 0.44-0.73), but not in women with a personal history of breast cancer (HR 1.48; 95% CI 0.74–2.95).ConclusionsOur finding of an increased risk of HGSC associated with PID lends support to the hypothesis that inflammatory processes may be involved in the etiology of HGSC.



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The scientific impact and value of large, NCI-sponsored randomized phase III cancer chemoprevention trials

Publication date: August 2018
Source:Cancer Epidemiology, Volume 55
Author(s): Joseph M. Unger, William E. Barlow, Catherine M. Tangen, Scott D. Ramsey, Ian M. Thompson, Eric A. Klein, Michael LeBlanc, Charles D. Blanke, Phyllis J. Goodman, Lori M. Minasian, Van T. Nghiem, Dawn L. Hershman
BackgroundThe cancer research groups of the National Cancer Institute's National Clinical Trials Network have a history of successful conduct of large randomized phase III trials of chemoprevention for cancer. An important question for funding agencies is whether the conduct of large chemoprevention trials provides strong scientific return on investment.MethodsWe evaluated the scientific impact of four large chemoprevention trials – two for breast cancer and two for prostate cancer – using citation analysis, a bibliometric technique. The results were compared to the scientific impact of a series of treatment trials conducted over the same 20-year time period (1991–2010, inclusive). Average annual citation counts were compared using t-tests. Scientific impact was also assessed relative to trial costs.ResultsTwenty-seven treatment trials with 17,208 patients and four chemoprevention trials with 87,550 patients were examined. The mean annual citation rate for primary articles was higher for chemoprevention trials compared to treatment trials (188.1 vs. 40.4, p = .001). For both primary and secondary article publications, mean annual citations for articles associated with chemoprevention trials were also higher (483.9 vs. 69.0, p = .0003). Large chemoprevention trials were estimated to provide 50% more total citations from primary and secondary articles on a cost-adjusted basis.ConclusionBased on these criteria, the scientific impact of large phase III cancer chemoprevention trials was very high in absolute terms, and as good as or better than that of treatment trials after accounting for expenditure. For appropriate scientific questions, large chemoprevention trials provide a good scientific return on investment for federal funding agencies.

Graphical abstract

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Dietary Insulin Load and Cancer Recurrence and Survival in Patients With Stage III Colon Cancer: Findings From CALGB 89803 (Alliance)

Abstract

Background

Evidence suggests that diets inducing postprandial hyperinsulinemia may be associated with increased cancer-related mortality. The goal of this study was to assess the influence of postdiagnosis dietary insulin load and dietary insulin index on outcomes of stage III colon cancer patients.

Methods

We conducted a prospective observational study of 1023 patients with resected stage III colon cancer enrolled in an adjuvant chemotherapy trial who reported dietary intake halfway through and six months after chemotherapy. We evaluated the association of dietary insulin load and dietary insulin index with cancer recurrence and survival using Cox proportional hazards regression adjusted for potential confounders; statistical tests were two-sided.

Results

High dietary insulin load had a statistically significant association with worse disease-free survival (DFS), comparing the highest vs lowest quintile (adjusted hazard ratio [HR] = 2.77, 95% confidence interval [CI] = 1.90 to 4.02, P_trend < .001). High dietary insulin index was also associated with worse DFS (highest vs lowest quintile, HR = 1.75, 95% CI = 1.22 to 2.51, P_trend= .01). The association between higher dietary insulin load and worse DFS differed by body mass index and was strongest among patients with obesity (HR = 3.66, 95% CI = 1.88 to 7.12, P_interaction = .04). The influence of dietary insulin load on cancer outcomes did not differ by mutation status of KRAS, BRAF, PIK3CA, TP53, or microsatellite instability.

Conclusions

Patients with resected stage III colon cancer who consumed a high-insulinogenic diet were at increased risk of recurrence and mortality. These findings support the importance of dietary management following resection of colon cancer, and future research into underlying mechanisms of action is warranted.

https://ift.tt/2toFfmo

Too Early to Worry About Blueberries

Diet, the sum of all foods consumed by an individual or group, is widely accepted as an important lifestyle factor that mediates both cancer risk and prognosis (1). Diet can be dissected and analyzed in several ways—by nutrients, food groups, patterns, loads, indices, etc. An important goal of nutrition research in cancer survivors is to identify dietary factors that contribute to the risk for recurrence and mortality.

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Improved correlation of urinary cytology specimens using The Paris System in biopsy‐proven upper tract urothelial carcinomas

Cancer Cytopathology, EarlyView.


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Rhabdomyolysis: An Unusual Presentation of Mycoplasma pneumoniae Infection in an Adult—A Case Report and Literature Review

Mycoplasma pneumoniae is a common cause of community-acquired pneumonia, and many extrapulmonary manifestations have been described, but rhabdomyolysis is infrequently reported in adults. Of the few cases that have been reported in adults, it was almost exclusively seen when pneumonia was present. We report a case of a 30-year-old male who came in with complaints of fever and myalgia for three days. Immunoglobulin M antibodies for Mycoplasma pneumoniae were positive and trending up, despite having no radiographic evidence of pneumonia on chest X-ray or CT scan. He was treated successfully with levofloxacin and intravenous hydration. Later, his condition was clinically and biochemically improved, and he was discharged. Our patient did not present with typical respiratory tract symptoms of a mycoplasma infection. In addition, there was an absence of pneumonia on imaging, suggesting that rhabdomyolysis secondary to mycoplasma might be underdiagnosed and go untreated in the setting of low clinical suspicion. Upon review of the literature, there is only one other case of mycoplasma infection where rhabdomyolysis occurred in the absence of pneumonia. However, the degree of rhabdomyolysis in our case was much more severe. Although rare, when faced with rhabdomyolysis, Mycoplasma pneumoniae should be kept as a differential diagnosis even in the absence of pneumonia on radiological imaging.

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Cancers, Vol. 10, Pages 210: Genomic Landscapes of EBV-Associated Nasopharyngeal Carcinoma vs. HPV-Associated Head and Neck Cancer

Cancers, Vol. 10, Pages 210: Genomic Landscapes of EBV-Associated Nasopharyngeal Carcinoma vs. HPV-Associated Head and Neck Cancer

Cancers doi: 10.3390/cancers10070210

Authors: Hoi-Lam Ngan Lan Wang Kwok-Wai Lo Vivian Wai Yan Lui

: Epstein-Barr virus-positive nasopharyngeal carcinoma (EBV(+) NPC), and human papillomavirus-positive head and neck squamous cell carcinoma (HPV(+) HNSCC) are two distinct types of aggressive head and neck cancers with early age onsets. Their recently identified genomic landscapes by whole-exome sequencing (WES) clearly reveal critical roles of: (1) inflammation via NF-kB activation, (2) survival via PI3K aberrations, and perhaps (3) immune evasion via MHC loss in these cancers as summarized in this review. Immediate outcomes of these WES studies include the identification of potential prognostic biomarkers, and druggable events for these cancers. The impact of these genomic findings on the development of precision medicine and immunotherapies will be discussed. For both of these cancers, the main lethality comes from metastases and disease recurrences which may represent therapy resistance. Thus, potential curing of these cancers still relies on future identification of key genomic drivers and likely druggable events in recurrent and metastatic forms of these intrinsically aggressive cancers of the head and neck.

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A case of antiepiligrin cicatricial pemphigoid with extensive cutaneous erosions mimicking pemphigus vulgaris

Cicatricial pemphigoid (CP) is a chronic, autoimmune, subepidermal blistering disease with predominant mucosal involvement. In this article, we report a young patient with mucosal and extensive cutaneous involvement in the form of large erosions mimicking those of pemphigus vulgaris thus leading to diagnostic dilemma. We were unable to find any other previous reports with such extensive cutaneous erosions mimicking those of pemphigus vulgaris. Laminin 5 was the antigen found on knockout substrate testing. Antiepiligrin CP is a distinct subtype of CP with antibodies against laminin 5. This subtype is mostly associated with malignancy but no underlying malignancy was found in our case. Present report also highlights the importance of knockout substrate testing when immunoblot is not available.

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Usual suspects: the foreign bodies of the aerodigestive tract

This case series is about four different foreign bodies lodged in different locations of the aerodigestive tract. All four cases had delayed diagnosis due to inconspicuous history. Radiology in the form of computed tomography aided the appropriate diagnosis in most of these cases. Though all four patients have been successfully managed by removal of foreign body, not all of them have identical outcomes. A brief discussion about predictive factors in the fish bone foreign body has been included. The authors also discuss certain critical aspects of the management, which may aid in reducing the morbidity. We emphasise on the high index of suspicion in peculiar cases and on the low threshold for radiological investigation in doubtful clinical scenarios.

https://ift.tt/2MbVyLa

Numb chin syndrome as a presenting symptom of diffuse large B-cell lymphoma with secondary myelofibrosis

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma that classically presents with rapidly enlarging lymph nodes. We present a 59-year-old man with unusual clinical presentation of numb chin syndrome (NCS) as the first symptom of disease. On evaluation, he was found to have diffuse extranodal skeletal involvement in the form of lytic-sclerotic lesions and minimal lymphadenopathy. Bone marrow biopsy revealed a poorly differentiated tumour with infarction and extensive myelofibrosis. This was subsequently proven to be DLBCL of germinal centre type on immunohistochemical stain. NCS should alarm the clinician to investigate for an advanced underlying malignancy. Extensive myelofibrosis, though described in carcinomas and low grade lymphomas, may also be seen in high grade DLBCL.

https://ift.tt/2JSK8PA

Acute renal artery embolisation: role of local catheter-based intra-arterial thrombolysis

A 45-year-old man without previous comorbidity presented to us with acute onset right-sided flank pain for last 14 hours. His general physical and systemic examination was unremarkable, and there were no clinical signs of peritonitis. The ultrasonography did not reveal any evidence of nephrolithiasis or hydronephrosis. His contrast-enhanced CT scan revealed hypoattenuated areas of right kidney and evidence of right renal artery thrombosis. He was immediately shifted to cardiac catheterisation lab, and his renal angiography showed thrombotic occlusion of right renal artery. The bolus dose of streptokinase (250 000 IU) was given locally in renal artery by right judkins catheter followed by systemic infusion of streptokinase (100 000 IU/hour) for 24 hours. After that he was started on low molecular weight heparin. Repeat renal angiography done after 5 days showed completely normal right renal artery. His cardiac and thrombophilia work up was negative, and he was discharged on antiplatelets, oral anticoagulants and statins.

https://ift.tt/2IcbwCx

An unusual case of leptomeningeal carcinomatosis in a patient with primary adenocarcinoma of the lung

A 72-year-old man was brought to the emergency department with acute onset confusion and haemoptysis. Chest X-ray showed a possible lung mass, while CT head showed a fluid-filled, space-occupying lesion (SOL) in the right frontal lobe of the brain. MRI head indicated that this SOL had spilt its contents into the subarachnoid and intraventricular spaces. Due to a fluctuating Glasgow Coma Scale (GCS), the patient underwent emergency debulking. Macroscopically, a frail-walled cystic tumour filled with straw-coloured fluid was noted; histology confirmed metastasis from a primary lung adenocarcinoma. Whole brain radiotherapy was given, with a view to commence systemic therapy. The patient, however, deteriorated and unfortunately passed away a few weeks after completing radiotherapy. This patient presented with leptomeningeal metastasis as the first presentation of a lung adenocarcinoma, and had a highly unusual mechanism by which leptomeningeal spread had occurred, with metastatic brain tumour spilling its contents into the meningeal spaces.

https://ift.tt/2JYL6Kc

Necrotising fasciitis as a complication of primary varicella infection in an immunocompetent child

Necrotising fasciitis (NF) is an infrequent yet significant complication of primary varicella infection in immunocompetent children. We report a case of a 4-year-old girl who presented three days into her chicken pox illness, with a rapidly progressing, severely tender erythematous rash surrounding one chicken pox lesion on her thigh. She required intravenous antibiotics, two surgical debridements, a skin graft and a prolonged stay in the paediatric intensive care unit, but ultimately we were able to save her life and limb. NF is a rare complication of chicken pox that has high morbidity and mortality that requires prompt and specific treatment.

https://ift.tt/2IedpPi

Heart transplant recipient with mycophenolate mofetil-induced colitis: the great imitator

In this article, we report a case of a 55-year-old male heart transplant recipient who presented with diarrhoea. An extensive workup for infectious diseases was negative. The patient had a colonoscopy with biopsies showing colitis that mimicked graft-versus-host disease on histopathology. After excluding other potential causes and excluding acute cellular rejection, mycophenolate mofetil was discontinued, and the patient had significant clinical improvement with increased appetite and weight gain.

https://ift.tt/2JXZzWG

Abscess originating from osteomyelitis as a cause of lower urinary tract symptoms (LUTS) and acute urinary retention

Lower urinary tract symptoms (LUTS) are a common complaint in the general population with great impact on the quality of life. Besides the classical pathologies, there are less common causes that must be considered in the treatment approach for patients with LUTS. We present the case of a 30-year-old patient with multiple emergency department episodes with dysuria, urinary frequency, suprapubic pain and an episode of acute urinary retention. The blood and urine tests only revealed increased systemic inflammatory parameters. The ultrasound examination showed thickening of the bladder wall, and the CT scan revealed a retropubic abscess originating from a pubic symphysis osteomyelitis. A percutaneous drainage was performed and, after empirical antibiotic therapy, there was complete resolution of the clinical picture.

https://ift.tt/2I9XYqY

Unilateral pulmonary vein atresia: diagnostic dilemma unfolded on imaging

Unilateral pulmonary vein atresia is a rare entity, usually congenital in origin. It is thought to result from failure of incorporation of common pulmonary vein to left atrium. Patients often present with recurrent chest infections and haemoptysis during infancy or early childhood. Associated anomalies are commonly present in these cases. Pulmonary angiography is generally used for definitive diagnosis; however, characteristic imaging findings on latest multislice CT can be virtually diagnostic.

https://ift.tt/2thl76n

Influenza B-related meningoencephalitis in adults

We present a case involving an 85-year-old man with acute confusion and new onset seizure following a 1-week history of respiratory prodrome. This case report describes a case of influenza B-related meningoencephalitis supported by evidence of an influenza B infection and temporal relation of the neurological event and respiratory illness in the absence of other identifiable cause. Diagnosis is guided by cerebrospinal fluid profile and nasopharyngeal PCR. Treatment is largely supportive and the effect of vaccination on prevention of this neurological complication remains unclear.

https://ift.tt/2IcbdYp

Accidental aspiration of a solid tablet of sodium hydroxide

Sodium hydroxide is a corrosive, highly alkaline (PKa=14.8) household product. Ingestion of sodium hydroxide liquid is common, showing toxicity on the oesophagus and stomach. Nevertheless, cases of sodium hydroxide ingestions in pellet are rare and the management of them is unknown. We report the case of a 65-year-old man who accidentally swallowed a bleach tablet of 3.5 g. Six hours later, the patient developed an aphonia associated with dysponea stage IV, motivating a nasofibroscopy showing glottis and supraglottic necrosis and oedema for which the patient received intravenous steroids, was intubated and then underwent a tracheotomy. After 2 weeks under tracheotomy, local evolution was favourable allowing a removal of the cannula and a return back home.

https://ift.tt/2tdVe7k

Paraneoplastic cerebellar degeneration with bilateral facial palsy: a rare primary presentation of breast cancer

Paraneoplastic cerebellar degeneration is a rare dysfunction of the cerebellum associated with malignancy. Nevertheless, it is the most common paraneoplastic syndrome affecting the brain. A 50-year-old woman presented to the neurology outpatient department (OPD) with symptoms of cerebellar dysfunction since 4 months and complaints of a painless lump in the right breast and drooling from mouth since 1 month. Examination revealed classical signs of cerebellar dysfunction and a 5x5 cm lump in the right breast with a single right axillary lymph node. Serum anti-Yo antibody titre was strongly positive. The patient was referred to General Surgery OPD for opinion. After establishing the diagnosis of right breast carcinoma; she underwent a right modified radical mastectomy. She was referred to the oncologist for chemo/radiotherapy but because of poor performance status, only symptomatic treatment was pursued. Follow-up till now shows no improvement in the neurological dysfunction.

https://ift.tt/2MaZYSt

Oncocytoma of the adrenal gland in Birt-Hogg-Dube syndrome

A 32-year-old man was referred to our surgical unit with a left adrenal lesion. He was previously diagnosed with Birt-Hogg-Dube syndrome after presenting with a left pneumothorax and an incidental finding of a right apical lung mass. This syndrome is characterised commonly by benign skin hamartomas, recurrent pneumothoraces and an increased risk of renal tumours. He was unable to tolerate a biopsy of his lung lesion, however, this lung lesion was thought to be benign. Given the size of his adrenal lesion and radiological appearances, we performed a laparoscopic left adrenalectomy. Pathology confirmed that based on morphological appearances and immunohistochemical staining, this may represent an oncocytic tumour of the adrenal gland. This is only the third published case of an oncocytic tumour of the adrenal gland in a patient with Birt-Hogg-Dube syndrome.

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Wellens syndrome: a close call

We describe a case of a middle-aged man who presented to the emergency department with typical anginal chest pains and found to have new, deeply inverted T-waves on ECG consistent with Wellens' syndrome. Similar to the description by Wellens et al, a critical 99% stenosis of the proximal left anterior descending artery was indeed confirmed by coronary angiography and successfully treated with drug-eluting stent. It is very important that physicians recognise this ECG finding as a harbinger of a serious cardiovascular condition and the necessity for an early invasive cardiac catheterisation.

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Apprehension in patients mind: leading to myiasis

Description

A 65-year-old man had a history of acute urinary retention for which suprapubic catheterisation (SPC) was performed, following failed attempts at per urethral catheterisation by a local practitioner 3 months previously. He also had a history of hesitancy and intermittency for the past 1 year. He now presented with maggots discharging from the SPC site (figures 1 and 2). On taking a detailed history, he mentioned lack of local hygiene due to fear of dislodgement of SPC. There was no history of diabetes mellitus, surgical intervention or immune-compromised status.

Figure 1

Clinical photograph of the patient showing the suprapubic catheterisation site wound with maggots inside it.

Figure 2

Clinical photograph showing closer view of the suprapubic catheterisation site wound with maggots.

Per urethral catheterisation was attempted over a guide wire that was successful. Then his SPC was removed...

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Femoral nerve paralysis complicating a post-traumatic iliopsoas haematoma

Paralysis of the femoral nerve secondary to iliopsoas haematoma is a rare post-traumatic complication. Because of the large differential diagnosis, a high level of suspicion is required for its early recognition. Treatment modalities are controversial due to the rarity of this entity. An 18-year-old student presented with complete paralysis of the knee extensors and a sensory deficit on the anterior side of the thigh 5 weeks after a sport accident. MRI of the lesser pelvis showed an iliopsoas haematoma. Surgical decompression was performed and recovery was complete at 6 months of follow-up.

https://ift.tt/2IaiI23

DIPG-23. BRAINSTEM RADIATION EXPOSURE CONFERS SUBSTANTIAL RISK OF DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) IN MEDULLOBLASTOMA SURVIVORS: A REPORT FROM THE INTERNATIONAL DIPG REGISTRY

Abstract

With improved survivorship in medulloblastoma, there has been increasing recognition of the occurrence of secondary malignant brain tumors. To date, no studies have specifically addressed the risk of diffuse intrinsic pontine glioma (DIPG) in medulloblastoma survivors. We queried the International DIPG Registry and identified six cases of DIPG with prior medulloblastoma. Six additional cases were identified in reports from recent cooperative group medulloblastoma trials. Incidence of DIPG after medulloblastoma ranged from 0.3–3.9%. All 12 cases underwent surgical resection followed by craniospinal photon irradiation (range 18–36 Gy) and posterior fossa boost (range 19.8–36 Gy). Posterior fossa exposure was greater than 53 Gy in all cases. Median time to diagnosis of secondary DIPG was 7 years (range 2–11 years). Patients died of secondary DIPG a median of 8 months after diagnosis (range 4–17 months). Molecular subgroup of primary medulloblastomas with available tissue (n=5) revealed only non-WNT, non-SHH subgroups (group 3 or 4). Tumor/germline exome sequencing of three secondary DIPGs demonstrated tumors to be H3.3 wildtype and harbor higher mutational burden than radiation-naïve DIPGs. Mutational signature analysis of secondary DIPGs showed mutations consistent with radiation-induced DNA damage (e.g., insertional event in TP53), as well as mutations in other oncogenic drivers (e.g., NRAS, PI3KCA), suggestive of distinct mutational processes compared with primary DIPGs. In conclusion, we report for the first time that survivors of pediatric medulloblastoma are at risk for the development of secondary DIPG, likely consequent to radiation exposure. This risk highlights the importance of radiation field, volume, and modality in medulloblastoma treatment.

https://ift.tt/2lr9wxk

IMMU-09. OUTCOME OF PATIENTS WITH RECURRENT DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) TREATED WITH PEMBROLIZUMAB (ANTI-PD-1): A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY (PBTC045)

Abstract

INTRODUCTION

Children with diffuse intrinsic pontine glioma (DIPG) have a dismal prognosis. Checkpoint blockade has revolutionized treatment of some resistant cancers.

METHODS

Pembrolizumab, a PD-1 inhibitor, was administered to children with progressive DIPG (Stratum A) and results are reported here. Children aged 1-18yrs with progressive DIPG were eligible with functional scores >60 and physiologic or less steroid usage, among standard eligibility criteria. Pembrolizumab was administered at 2mg/kg IV every three weeks. Tumor tissue (if available), serum and MRI studies were collected for correlative analysis.

RESULTS

Five patients with progressive DIPG were enrolled from June-July 2015. The median age at diagnosis was 3.5yrs (range,2.8-6.9), and median time from diagnosis to study entry was 14.6 months (range,8.7-20.7). Progression-free survival (PFS) was 1.02 months (range,0.5-1.7); overall survival from initial treatment was 1.7 months (range,0.5-6.2). All patients clinically and/or radiographically worsened after one (n=1) or two (n=4) doses of pembrolizumab. Grade 3 or greater treatment-related adverse events included fatigue (n=2) and new or increased grade neurologic symptoms. Correlative analysis is ongoing.

CONCLUSIONS

Checkpoint inhibition holds potential for CNS cancer treatment; however, special consideration is required in the CNS with limited space and large disease burdens. In our study, patients rapidly deteriorated neurologically after initiation of checkpoint blockade, with a shorter median PFS than expected by analogous historical trials; pembrolizumab protocols were amended to exclude recurrent DIPG patients after these events. Our findings suggest caution when utilizing immunotherapy in actively progressing tumor in the brain stem.

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TBIO-19. MASS SPECTROMETRY OF COMMON CEREBELLAR TUMOURS IDENTIFIES DIFFERENCES IN METABOLISM

Abstract

Metabolic profiling by Magnetic Resonance Spectroscopy has shown the three most common paediatric cerebellar tumours are metabolically distinct; however, these techniques are limited by their sensitivity. Mass spectrometry is more sensitive and able to detect many more metabolites. In this study, metabolic phenotyping was performed to investigate the water-soluble metabolome and the lipidome of the three most common paediatric cerebellar tumours with the aim of informing a detailed metabolic pathway analysis. A discovery based experiment was performed on 60 surgically resected snap frozen pilocytic astrocytomas, ependymomas and medulloblastomas using UPLC-MS assays to detect water soluble and lipid metabolites. Principal component analysis demonstrates separation of the tumours based on the relative concentration of thousands of detected metabolites. The relative concentrations of glucose and glycolytic intermediates varied between the tumour types, as did metabolites involved in purine and pyrimidine metabolism. Key metabolites within the taurine metabolism pathway were found to be higher in medulloblastoma. Alterations were observed in lipid metabolism, with a wide range of relative concentration differences in di- and triacylglycerides, sphingolipids, ceramides, cardiolipins and glycerophospholipids. This study has shown that these tumours are metabolically distinct and offer the opportunities for stratified diagnosis and treatment. Some of the observed changes in relative concentration between the tumours reflect findings from spectroscopic studies, particularly with regards to taurine which is known to be higher in medulloblastoma. The ability of mass spectrometry to identify and measure lipid species and low concentration metabolites from tissue could allow targetable metabolic differences to be characterised and exploited.

https://ift.tt/2lohrLV

IMMU-10. NIVOLUMAB IN THE TREATMENT OF RECURRENT OR REFRACTORY PEDIATRIC BRAIN TUMORS: A SINGLE INSTITUTIONAL EXPERIENCE

Abstract

Tumor cells evade immune-mediated destruction through activation of checkpoints. Successful use of the immune checkpoint inhibitors in certain cancer types has generated interest in using this approach in pediatric brain tumors. Ten consecutive children (6 boys, 4 girls, mean age 11 years, range 2-17 years) with pediatric recurrent or refractory pediatric brain tumors (4 high grade glioma, 2 pineoblastoma, 1 disseminated low grade glioma, 1 medulloblastoma, 1 ependymoma, 1 primitive neuro-ectodermal tumor) were treated at Rady Children's Hospital San Diego from 2015-2017 with the immune checkpoint inhibitor nivolumab (3 mg/kg every 2 weeks). Eight had received prior chemotherapy and 9 received prior radiation therapy. Seven had radiographic progression of disease (total 36 doses, mean 3.6 doses) with mean time to progression of 5.4 weeks (range 1.6-13.7 weeks). One patient voluntarily discontinued treatment after stable disease at 24 weeks and 2 patients showed either transient stability or partial response of brain disease but worsening of metastatic disease. There were no dose limiting side effect observed, however there was a 10 % incidence of elevated ALT, hyperglycemia, pancreatitis and hypo-albuminemia. Although the tumor mutation burden (TMB) was low (mean 2, range 0-6.3), there was a trend between TMB and time to progression. PDL-1 immuno-histochemical analysis and next generation sequencing data on each tumor will be presented. Our findings suggest nivolumab is well tolerated in pediatric patients with recurrent brain tumors. Future randomized controlled studies stratifying for TMB may be necessary to demonstrate the efficacy of PD-L1 inhibitors in recurrent pediatric brain tumors.

https://ift.tt/2tq07d2

EPID-11. SYSTEMATIC REVIEW ON TREATMENT-RELATED HAEMATOLOGICAL ADVERSE EVENTS AFTER TEMOZOLOMIDE FOR A CNS TUMOUR

Abstract

BACKGROUND

Temozolomide is a widely used alkylating cytostatic drug for CNS tumours. Severe treatment-related haematological adverse events (tHAE) after the application of temozolomide are reported whilst the true incidence is elusive. The aim of this study is to determine the incidence, the risk-factors for, and course of secondary haematological adverse events after treatment with temozolomide in patients with CNS tumours.

METHODS

We reviewed the English literature between 1995-2016 on cases describing treatment-related haematological adverse events after temozolomide and set up a country-wide survey among (paediatric) neuro-oncologists in the Netherlands.

RESULTS

In 20 out of 199 manuscripts deriving from the literature search 26 cases (age 0-69, median 40,5 years) were found with a severe tHAE event after temozolomide: 5 aplastic anemia, 5 acute lymphoblastic leukemia, 9 acute myeloblastic leukemia, 1 diffuse large B-cell lymphoma, 6 myelodysplastic syndrome and 1 mixed lineage leukemia. Karyotype was detected in 17/26 cases, mainly monosomy 5&7. Quality check of the literature mainly showed missing data on predisposing family history. Seven additional cases of a t-HAE after TMZ in CNS a tumour were discovered via a clinical survey in the Netherlands. The median latency in developing a t-HAE was 14 months, the survival after t-HAE was median 4,5 months.

CONCLUSIONS

tHAE is rare and develops relatively early after treatment with temozolomide, while insufficient insight could be found for risk-factors for a t-HAE after temozolomide. Although most patients die from their secondary tHAE, its course differs substantially between individual cases.

https://ift.tt/2lmxIRn

IMMU-11. BRAINCHILD PIPELINE: LOCOREGIONAL IMMUNOTHERAPY WITH CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS FOR RECURRENT/REFRACTORY CENTRAL NERVOUS SYSTEM TUMORS

Abstract

Chimeric antigen receptor (CAR) T-cell therapy carries the promise of a broadly applicable, targeted, yet molecular pathway-independent, intervention for pediatric central nervous system (CNS) tumors. The BrainChild pipeline at Seattle Children's utilizes engineered CAR T-cells directed against the surface epitopes HER2, EGFR, B7-H3 and IL13Ralpha2, which are commonly expressed in pediatric CNS tumors including high-grade glioma, diffuse intrinsic pontine glioma, medulloblastoma, and ependymoma. Using in vitro and in vivo preclinical modeling, we have optimized the efficacy and specificity of the CAR constructs. The extracellular target-specific scFv domain for the HER2-specific and EGFR-specific CARs are derived from trastuzumab and an EGFR806 antibody, respectively. Third-generation CAR T-cells with medium-length (HER2-CAR) and short (EGFR806-CAR) spacers coupled to an intracellular 4-1BBζ domain result in complete and durable tumor eradication in mouse xenograft CNS tumor models. We now are poised to begin enrolling Phase 1 clinical trials for children and young adults with recurrent or refractory CNS tumors expressing the respective target epitopes. We will deliver locoregional adoptive therapy with autologous CD4 and CD8 T cells lentivirally transduced with the optimized CAR constructs. Using a dose-escalation regimen, CAR T-cells will be injected on a weekly schedule via indwelling catheters into the tumor resection cavity or the ventricular system. The primary objectives are safety and feasibility, along with secondary and exploratory objectives to define the CAR T-cell distribution in the CSF and peripheral circulation, target epitope expression across tumor populations, progression free and overall survival, and biomarkers of anti-tumor CAR T-cell activity.

https://ift.tt/2ts3OPp

CRAN-16. IMPORTANCE OF SURGICAL INTERVENTION IN RECOVERY OF VISUAL FUNCTION IN A TEENAGER WITH AN ACIDOPHILIC STEM CELL ADENOMA

Abstract

BACKGROUND

Prolactin-secreting macroadenomas are generally not life-threatening and often present with visual impairment. Medical management with a dopamine agonist is typically the treatment of choice, which significantly reduces the tumor size and improves symptoms without surgical morbidity. In this report, we present a case of an acidophilic stem cell adenoma (ASCA) that was slowly responsive to medical management, but exhibited marked visual recovery after surgical resection.

RESULTS

A 15 year-old previously healthy male presented with significantly decreased peripheral vision but no other neurologic or endocrinologic symptoms. Initial magnetic resonance imaging of the brain/spine revealed a mass in the suprasellar and sellar regions with extension into the cavernous sinus and a prolactin level of 644, leading to a presumptive diagnosis of macroprolactinoma. Medical management with cabergoline resulted in some decrease of the prolactin level, but no radiographic improvement or visual recovery after two months. He subsequently underwent endoscopic endonasal transsphenoidal resection with near-total restoration of his peripheral vision post-operatively and significant improvement of his prolactin level. Pathology was consistent with an ASCA (staining positively with prolactin, growth hormone (a-subunit), and pituitary-specific positive transcription factor 1), a rare pituitary adenoma that tends to be invasive and often requires more aggressive therapy; the patient thus underwent focal consolidative proton beam irradiation.

CONCLUSION

This case highlights the importance of considering acidophilic stem cell adenomas in the differential of medically-resistant pituitary macroadenomas and early consideration of resection in cases where significant visual or other symptoms exist, as timely intervention may substantially improve functional outcomes.

https://ift.tt/2lmxtFX

IMMU-12. T-CELL THERAPIES DEMONSTRATE EFFICACY WITHOUT TOXICITY IN IMMUNOCOMPETENT MODELS OF BRAINSTEM TUMORS

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a pediatric brainstem tumor with a dismal prognosis and no curative treatments. Immunotherapy has been considered as a treatment for these tumors because of its ability to provide specific and sustained tumor killing. By nature, this approach is inflammatory and remains controversial due to the potential for catastrophic inflammatory toxicity in the brainstem. In order to address whether this approach should be considered as a clinical option, we characterized the efficacy/toxicity profile of transgenic and chimeric antigen receptor (CAR) T-cell therapies in the brainstem using immunocompetent, syngeneic mouse models. We first adoptively transferred naïve transgenic T-cells recognizing the model tumor antigens gp100 or ovalbumin to treat established aggressive, transplantable murine tumors in the brainstem. Encouragingly, this therapy significantly extended median survival (16 to 32 days; p<.001) with no signs of therapeutic toxicity. We plan to expand these studies by incorporating hgp100 into a spontaneously-occurring, engineered model of DIPG, followed by transgenic T-cell treatment. Lastly and most clinically-relevant, we have used CAR T-cell therapy to treat B16 melanoma engineered to express EGFRvIII and implanted into the brainstem. This therapy extended median survival from 14 to 30 days (p<.001). We plan to evaluate whether combinatorial approaches using checkpoint inhibitors or oncolytic viruses can further enhance survival. Together these data from immunocompetent mouse models demonstrate that T-cell immunotherapies are well- tolerated and efficacious against tumors located in the brainstem, opening the door for future clinical trials.

https://ift.tt/2yv73eJ

EAPH-11. INTRAVENTRICULAR THERAPY ALTERNATING ETOPOSIDE, AQUEOUS CYTARABINE AND TOPOTECAN IS FEASIBLE AND SAFE: EXPERIENCE IN 26 PEDIATRIC PATIENTS WITH MALIGNANT BRAIN TUMORS

Abstract

BACKGROUND

Malignant brain tumors carry a high risk for leptomeningeal dissemination, but tumor cells floating in the CSF are often not affected by systemic and/or antiangiogenic chemotherapy. Since liposomal cytarabine was removed from the market, alternatives for intraventricular therapy are desperately needed. We report on our experience with an intraventricular therapy consisting of alternating cycles of etoposide, aqueous cytarabine and topotecan. PATIENTS AND

METHODS

Between 2008 and 2017, 26 patients aged 1 to 17 years (median 7 years) with various malignant brain tumors received intraventricular therapy via an Ommaya reservoir, consisting of alternating etoposide 0.5mg on five consecutive days (<1 year 0.25mg), topotecan 0.4mg twice a week (>1 and <2 years 0.25mg, >2 and <3 years 0.32mg) and aqueous cytarabin 30mg twice a week (<1 year 16mg, >1 and <2 years 20mg, >2 and <3 years 26mg).

RESULTS

1899 doses of etoposide (4–166/patient), corresponding to 2–36 five-day-cycles/patient (median 17), alternating with 307 doses of topotecan (1–49/patient, median 10), and 101 doses of aqueous cytarabine (1–28/patient, median 4) were administered. Treatment was given over a period of 1 – 115 months (median 12 months). Alternating intraventricular treatment was generally well tolerated. One boy with multiple recurrences of an ependymoma in the posterior fossa showed increased tremor after topotecan, another girl reported fatigue after topotecan.

CONCLUSION

Alternating intraventricular therapy with etoposide, aqueous cytarabine and topotecan is feasible and generally well tolerated, and can be an important addition for patients with malignant brain tumors.

https://ift.tt/2lqoBiO

IMMU-13. A FAILURE TO RESOLVE INFLAMMATION: ROLE OF RESOLVINS IN THE TREATMENT OF PEDIATRIC CNS TUMORS

Abstract

BACKGROUND

Current brain tumor therapies are focused on reducing tumor burden by inducing apoptotic and necrotic tumor cells. However, inflammation in the tumor microenvironment caused by this debris can accelerate tumor progression. Inflammation is endogenously regulated resolvins and protectins, molecules that are biosynthesized and act in the brain and cerebrospinal fluid. They clear cellular debris via local macrophages while reducing localized inflammatory cytokines. We hypothesized that control of inflammation through resolvins and protectins could represent a novel treatment modality by pharmacologically promoting the clearance of tumor cell debris by microglia, thereby depriving the surviving tumor cells of inflammatory stimuli. METHODS AND

RESULTS

We show that debris generated by killing of either medulloblastoma or glial tumors (using cisplatin chemotherapy, dabrafenib targeted therapy or the epigenetic inhibitors JQ1) stimulate residual live tumor cells to grow. This effect was inhibited by nanogram levels of resolvins/protectins and without toxicity in a variety of tumor types including orthotopic models. The effect was mediated via enhanced macrophage and microglial phagocytosis of tumor cell debris and counter-regulation the secretion of pro-inflammatory cytokines/chemokines, including CCL5, TNFα, CCL2, CXCL1, and CCL4.

CONCLUSIONS

We show that resolvins and protectins stimulate the clearance of tumor cell debris by stimulating macrophage and microglial phagocytosis and counter-regulating pro-inflammatory and pro-tumorigenic cytokines. This approach not only has relevance to our current approaches to cancer therapy (focused on maximal tumor cell kill), but may have an impact on the side effects of current immunotherapies where therapy induced inflammation in the tumor results in significant morbidity.

https://ift.tt/2tokmI1

HGG-36. NFκB AND FOXM1 MEDIATE ANTI-CANCER ACTIVITY OF DUAL HDAC AND PI3K INHIBITION IN PEDIATRIC HIGH GRADE GLIOMA AND DIPG

Abstract

Pediatric high-grade gliomas (pHGGs) and diffuse intrinsic pontine gliomas (DIPGs), portend a poor prognosis and are particularly recalcitrant to standard treatment. Aberrant chromatin remodeling and activation of the phosphatidylinositol 3-kinase (PI3K) pathway have been identified as important mediators of pHGG and DIPG pathogenesis. As inhibition of these pathways are promising therapeutic avenues and radiation is the only modality to prolong survival of DIPG patients, we sought to explore radiosensitizing functions of such inhibition and explore mechanisms of action of such agents. Here, we demonstrate that treatment with CUDC-907, a novel, first-in-class dual inhibitor of histone deacetylases (HDACs) and PI3K, in combination with radiotherapy evokes a synergistic cytotoxic response in pHGG and DIPG models in vitro and in vivo. We identify a novel mechanism of CUDC-907 in modulating DNA damage response by inhibiting radiation-induced DNA repair pathways, including homologous recombination and non-homologous end joining. The radiosensitizing effects of CUDC-907 were mediated by decreasing NFκB/Forkhead box M1 (FOXM1) recruitment to promoters of genes involved in the DNA damage response, and exogenous expression of NFκB/FOXM1 rescued CUDC-907-induced cytotoxicity. Together, these findings reveal CUDC-907 as a novel radiosensitizer with potent anti-tumor activity in pHGG and DIPG, and provide a preclinical rationale for the combination of CUDC-907 with radiotherapy as a novel therapeutic strategy for pHGG and DIPG. More globally, we have identified NFκB and FOXM1, and their downstream transcriptional elements, as critical targets for new treatments for pHGG and DIPG.

https://ift.tt/2lpZLzu

IMMU-14. KICKSTARTING THE CANCER IMMUNITY CYCLE BY INNATE CHECKPOINT INHIBITION TO TARGET PEDIATRIC BRAIN TUMORS

Abstract

Recently we published the effect of a humanized anti-CD47 antibody, on five aggressive and etiologically distinct pediatric brain tumors: Group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrates therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Disabling the inhibitory signals transduced by SIRPa by blocking anti- CD47 antibodies we promote phagocytic response driven by tumor-specific antibodies. These phagocytic innate cells are also professional antigen-presenting cells (APC), providing a link from innate to adaptive antitumor immunity. Consequently, we tested a number of approaches to augment immune checkpoint immunotherapy. We hypothesized that by activating immunogenic phagocytosis we could kickstart the cancer immunity cycle and hence augment adaptive checkpoint inhibitors against cold tumors such as medulloblastoma and pediatric glioma.

RESULTS

To determine the in vivo efficacy of combinatorial anti-CD47 and anti-PD1 therapies, spontaneous SHH medulloblastoma mouse models were treated by, i.p. injections with either PBS (control), anti-CD47, anti-PD1 or in combination. To test the cancer immunity hypothesis combination treatment was carried out either in sequence or simultaneously. Mice receiving anti-CD47 anti-PD1 duotherapy demonstrated increased survival when treated sequentially as compared to both monotherapies and control cohorts. Immunohistochemical and Flowcytometry analysis with the macrophage marker F4/80 and T-cell subset immune panel demonstrated varying patterns of macrophage and T-cell infiltration. Addition of anti-CTLA4 mAb did not enhance the efficacy of this effect suggesting the lack of infiltrating T-regulatory cells.

https://ift.tt/2yFfXGH

ATRT-22. SWI/SNF COMPLEX HETEROGENEITY RELATES WITH POLYPHENOTYPIC DIFFERENTIATION AND THE IMMUNE MICRO ENVIRONMENT IN RHABDOID TUMORS

Abstract

Malignant rhabdoid tumors (MRT), including central nervous system (CNS) Atypical Teratoid / Rhabdoid Tumors (AT/RT) and extra CNS (eCNS) MRT, are aggressive cancers characterized by loss of SMARCB1, a core component of the SWI/SNF chromatin-remodeling complex. Histopathologically, MRTs are characterized by polyphenotypic differentiation that varies from tumor to tumor. Because the SWI/SNF complex regulates differentiation we hypothesized that the SWI/SNF complex would exhibit heterogeneity in MRTs. We first characterized the SWI/SNF complex in developing human brain. SMARCB1 expression was highest in the cerebellum compared to hemispheric regions and remained so throughout development. In contrast, many subunits of the SWI/SNF complex were down regulated after cerebellar development. In MRTs we discovered that the SWI/SNF complex subunits showed marked differences between AT/RTs and eCNS MRTs. In eCNS MRTs high ACTL6A and ACTL6B expression was associated with neuronal differentiation while tumors with low ACTL6A and ACTL6B showed epithelial and mesenchymal differentiation. In AT/RTs there was marked heterogeneity in members of the PBAF complex including ARID2, BRD7 and PBRM1. Tumors with high PBAF expression were associated with worse prognosis, increased metastasis and cell cycle deregulation. Of the PBAF components, tumors with low PBRM1 showed a better prognosis and were associated with increased cytotoxic lymphocytes in their microenvironment. Our data demonstrate that MRTs exhibit heterogeneity in the SWI/SNF complex that may contribute to the polyphenotypic differentiation characteristic of these tumors, and which may have implications in understanding the biology, prognosis and development of immunotherapeutic approaches to these tumors.

https://ift.tt/2lpZLiY

IMMU-15. HIGH-RESOLUTION ANALYSIS OF THE T-CELL RECEPTOR REPERTOIRE AFTER ADOPTIVE CELLULAR THERAPY IN PEDIATRIC PATIENTS WITH CENTRAL PNETs (Re-MATCH TRIAL)

Abstract

Adoptive cellular therapy (ACT) using transfer of tumor-specific lymphocytes has emerged as a potent strategy for treatment of advanced and refractory malignancies. We have employed deep TCR repertoire sequencing approach to explore dynamics of T-cell immunity in the nine patients with recurrent medulloblastoma and PNETs undergoing adoptive cellular therapy (Re-MATCH protocol, FDA IND BB-14058). Total RNA was isolated from patient PBMC samples collected prior to adoptive cellular therapy and weekly for one month and then monthly following immunotherapy treatment. cDNA was generated with addition of a common adapter at 5' end of cDNA using RACE technology. Raw sequencing data were preprocessed using MiXCR software. Further TCR repertoire analysis was performed using tcR R-package and VDJtools software. We observed remarkable dynamic changes in the TCR repertoire in peripheral blood following ACT in all patients. The blood samples collected after adoptive cellular therapy revealed that certain T-cells were clonally expanded after ACT, with an increasing number of "hyper-expanded" TCR clones (comprising >1% of all TCR beta or alpha sequences). Hyper-expanded TCR clones and increased TCR diversity following ACT was associated with radiographic response to ACT and prolonged progression-free and overall survival. Limited TCR expansion and diversity following ACT was observed in patients with short overall and progression-free survival. These findings support further study of the use of TCR sequencing to monitor responses to adoptive cellular therapy and suggest that TCR clonal expansion and increasing TCR diversity following treatment may be associated with positive clinical responses.

https://ift.tt/2tls45E

DEV-09. ST. JUDE GLOBAL ACADEMY NEURO-ONCOLOGY SEMINAR: THE CREATION OF A TARGETED CURRICULUM FOR GLOBAL NEURO-ONCOLOGY

Abstract

The majority of the burden of pediatric patients with central nervous system (CNS) tumors resides in low- and middle-income countries (LMICs). The success of the treatment of this patient population relies on an effective multidisciplinary team, with updated knowledge and skills and, most importantly, awareness of the context in which they practice. The SJGANOS seeks to change the paradigm of educational interventions in pediatric oncology, by systematically creating a curriculum with directed educational interventions that will lead to improved patient outcomes. A targeted needs assessment (TNA) survey to evaluate the care team members, team dynamic, infrastructure, and patient outcomes was designed and distributed to 20 centers around the world. This TNA will describe the current state of neuro-oncology as a field in LMICs and define high-impact educational interventions. Since interdisciplinary competencies are best gained as a group, teams that treat patients with CNS tumors, including oncologists, neurosurgeons, pathologists, radio-oncologists, and radiologists from around the world will be invited to the SGNOS to be held in the summer of 2018. The Seminar will have two components, a distance-learning course and an onsite workshop, with the goal to provide higher-cognitive skills and provide the basis for a change in behavior. Ultimately, we wish to increase knowledge and skills, increase the multidisciplinary approach to care, and measurably increase the survival and quality of life of patients with CNS tumors around the world.

https://ift.tt/2ls5Aw5

IMMU-16. CHARACTERIZING TUMOR-IMMUNE INTERACTIONS IN DIFFUSE INTRINSIC PONTINE GLIOMA

Abstract

Diffuse Intrinsic Pontine Glioma (DIPG) is a universally fatal brain tumor diagnosed in approximately 300 children in the US each year. Radiation modestly extends patient survival and provides temporary relief from symptoms, however, surgical resection is impossible due to the tumor's location in the brainstem, and no chemotherapeutics have shown any efficacy; death generally occurs less than a year after diagnosis. Due to its ability to specifically eliminate tumor cells while leaving healthy tissue intact, immunotherapy could be a major breakthrough in the treatment of DIPG. As a first step towards the rational development of DIPG-specific cellular immunotherapy, we have characterized the immune microenvironment of DIPG tumors using IHC analysis of TMAs and Nanostring transcript analysis of frozen tumor samples. In contrast to pediatric and adult high-grade cortical gliomas (HGGs), DIPGs exhibit minimal infiltration with CD163+ myeloid cells or CD8+ T cells, consistent with their low mutational burden. Furthermore, unlike adult HGGs in particular, DIPG tumors had low levels of classical immunosuppressive factors including PD-L1, TGFβ, and IL-10. To directly examine the effects of DIPG cells on immune cells, we co-cultured primary tumor cells with immune cells from healthy donors. DIPG tumor cells did not polarize macrophages towards a pro-tumor phenotype, while U87 adult GBM cells did. Furthermore, DIPG cells did not slow T cell proliferation or prevent IFNγ production, while U87 cells did. Together, this suggests that although DIPG tumors are not inducing an immune response, adoptively transferred anti-tumor immune cells will not need to overcome an immunosuppressive microenvironment.

https://ift.tt/2trvsfs

DIPG-55. TARGETING SENESCENT CELLS WITH ABT-263 ENHANCES CELL DEATH INDUCED BY BMI1 INHIBITION AND IONIZING RADIATION IN DIPG

Abstract

Ionizing Radiation (IR) is a key treatment modality for DIPG, but it provides only temporary relief as the tumor cells develop resistance to radiation. Recently, we and others have shown that inhibition of BMI1 either alone or in combination with radiation attenuates DIPG cell proliferation in vitro. While we are demonstrating the in vivo efficacy of pharmacological inhibition of BMI1 and understanding the mechanism of anti-tumor effect of BMI1 inhibition in DIPG, the existence of treatment-resistant cells remains a major obstacle for a prolonged cure. Both IR and genetic or pharmacological inhibition of BMI1 induces cellular senescence as a mechanism to suppress tumor cell proliferation, implying that senescence can be considered as tumor suppressor. Paradoxically, recent studies have shown that accelerated senescence can mediate tumor recurrence due to the development of pro-oncogenic environment. In line with this, we are investigating whether clearance of treatment-induced senescent cells enhances treatment outcomes. DIPG cells exposed to different doses of radiation followed by treatment with ABT-263 (Navitoclax), a drug which selectively clears the senescent cells, resulted in increased radiosensitization. Treatment of pre-radiated DIPG cells with ABT-263 decreased the activity of senescence-associated beta-galactosidase and anti-apoptotic protein expression. Similarly, chemical inhibition of BMI1 in combination with ABT-263 showed synergistic killing of DIPG cells. The synergy was most pronounced in DIPG cells harboring wildtype p53. Our study highlights the importance of eliminating treatment-induced senescent cells while inhibiting proliferation of DIPG tumors, a combination which can immensely improve therapeutic efficacy in DIPG patients.

https://ift.tt/2lm92IC

IMMU-17. HEMATOPOIETIC STEM CELL-DERIVED DENDRITIC CELLS REPROGRAM THE BRAIN TUMOR MICROENVIRONMENT

Abstract

INTRODUCTION

Despite multimodality treatment, patients with malignant gliomas only achieve a median survival of 18 months. Our group has pioneered an adoptive T cell immunotherapy that utilizes total tumor RNA-pulsed dendritic cells to expand polyclonal tumor-reactive T cells ex-vivo. The strongest anti-tumor efficacy of adoptive T cell immunotherapy is achieved when combined with syngeneic hematopoietic stem and progenitor cell (HSPC) transplant. The inclusion of HSPCs leads to a doubling of median survival and 40% long-term cures in treatment-resistant murine malignant glioma, brainstem glioma, and medulloblastoma. In this study, we evaluated the HYPOTHESIS that adoptive T cell immunotherapy drives the differentiation of HSPCs into dendritic cells within the brain tumor microenvironment.

METHODS

We evaluated HSPC differentiation and function in the context of immunotherapy in tumor-bearing animals and HSPC proliferation and differentiation in-vitro using a T cell co-culture system.

RESULTS

The differentiation of HSPCs into CD11c⁺MHCII⁺CD86⁺ dendritic cells in the tumor microenvironment depended on tumor-reactive T cell-released IFN-γ. Additionally, HPSC-derived dendritic cells cross-presented tumor-derived antigens to tumor-reactive T cells, increasing T cell activation within the tumor. When evaluating the impact of HSPCs on host intratumoral immunity, we determined that HSPC transfer strongly supplants host myeloid-derived suppressor cells and downregulates suppressive genes.

CONCLUSIONS

We have made novel observations that HSPCs significantly enhance immunotherapy by supplanting host immunity and synergizing with T cells in the tumor microenvironment. A phase I trial evaluating the impact of HSPC transfer on adoptive immunotherapy in pediatric high-grade gliomas is on schedule to open this year (ACTION– FDA IND#BB-17298).

https://ift.tt/2yuFp1c

EPEN-11. ANALYSIS OF EXPRESSION OF YAP1, RELA, MAMLD1 AND FAM118B GENES IN PEDIATRIC EPENDYMOMA

Abstract

Ependymomas (EPN) are primary tumors in the central nervous system (CNS). In children, 90% of EPNs occur intracranial, with two-thirds being located in the posterior fossa (PF) and one-third within the supratentorial (ST) compartment. Despite the development of new molecular classifications and increasing understanding of the underlying EPN mechanisms, management and treatment remain challenging. We investigated the expression of genes involved in EPN molecular rearrangements (YAP1, RELA, MAMLD1 and FAM118B), in 27 EPN patients from Pediatric Oncology Institute - GRAACC, Brazil. Gene expression levels were quantified using qPCR. Molecular findings were correlated to clinicopathological characteristics of patients. Significant results were considered when p<0.005. Overall survival was significantly lower in patients with PF tumors than ST tumors (p=0.0109), and high YAP1 expression was related to worst overall survival (p=0.0488). ST tumors presented higher RELA expression than PF tumors (p=0.0089). Expression of YAP1 and FAM118B genes significantly correlated (r=0.917, p<0.0001). All investigated genes are partners in fusion genes recently described for EPN and the levels of expression observed were in agreement with findings in the literature. Additional studies are in progress to collaborate with the characterization of EPN genetics, once development of targeted therapies will require the understanding of tumor biology and its effect in the clinical outcomes. Based on recent molecular findings, and after the actualization of WHO classification of tumors of the CNS in 2016, it is becoming evident that, in the near future, histologic criteria alone might be insufficient to direct treatment, to predict outcomes and refine EPN treatment.

https://ift.tt/2lq025v

IMMU-18. PDL-1 EXPRESSION ON CIRCULATING CD68 (-) MONOCYTE-LIKE CELLS IN NF2 MENINGIOMA AS A BIOMARKER FOR TUMOR PROGRESSION

Abstract

Program cell death ligand-1 (PD-L1) membranous expression on >5% tumor cells (PD-L1 positive tumors) is an unfavorable prognostic marker in many solid tumors. We previously showed that approximately 40% of neurofibromatosis type 2 (NF2) meningiomas are PD-L1 positive tumors. However, due to the invasive nature of biopsies, collection of tumor tissue is not always feasible. Thus, a non-invasive alternative is needed to evaluate the status of tumor growth and confirm PD-L1 positive tumors before the consideration of immunotherapy. It has recently been revealed that expression of PD-L1 on tumor associated macrophages is also a strong prognostic indicator. We retrieved formalin-fixed paraffin-embedded (FFPE) tissue from 10 NF2 meningioma cases to identify PD-L1 expression on macrophages and/or monocytes. We found that 3 out of 4 PD-L1 positive tumors were associated with expression of PDL-1 on CD68 (-) monocyte-like cells located in the peri- and intravascular lumens. These cells were only observed in 1 out of 6 PD-L1 negative tumors. Compared to others, tumors with PD-L1 expression on monocyte-like cells presented a higher Ki-67 proliferative index that was above 10%. Our results suggest that PD-L1 positive circulating CD68 (-) monocyte-like cells are correlated with tumor cell PD-L1 expression and progression in NF2 meningiomas.

https://ift.tt/2yxzatE

Norcantharidin enhances antitumor immunity of GM‐CSF prostate cancer cells vaccine by inducing apoptosis of regulatory T cells

Cancer Science, EarlyView.


https://ift.tt/2K9cFj7

The role of radioactive iodine therapy in papillary thyroid cancer: an observational study based on SEER

https://ift.tt/2I9RvfQ

Curcumin suppresses the progression of laryngeal squamous cell carcinoma through the upregulation of miR-145 and inhibition of the PI3K/Akt/mTOR pathway

https://ift.tt/2JTbwNz

Combined small-cell lung carcinoma

https://ift.tt/2I9Rbh8

The prognosis for patients with newly diagnosed glioblastoma receiving bevacizumab combination therapy: a meta-analysis

https://ift.tt/2tkYsFq

Capabilities of the Monte Carlo Simulation Codes for Modeling of a Small Animal SPECT Camera

Abstract

Purpose

This study aims to compare Monte Carlo-based codes' characteristics in the determination of the basic parameters of a high-resolution single photon emission computed tomography (HiReSPECT) scanner.

Methods

The geometry of this dual-head gamma camera equipped with a pixelated CsI(Na) scintillator and lead hexagonal hole collimator were accurately described in the GEANT4 Application for the Tomographic Emission (GATE), Monte Carlo N-particle extended (MCNP-X), and simulation of imaging nuclear detectors (SIMIND) codes. We implemented simulation procedures similar to the experimental test for calculation of the energy spectra, spatial resolution, and sensitivity of HiReSPECT by using ^99mTc sources.

Results

The energy resolutions simulated by SIMIND, MCNP-X, and GATE were 17.53, 19.24, and 18.26%, respectively, while it was calculated at 19.15% in experimental test. The average spatial resolutions of the HiReSPECT camera at 2.5 cm from the collimator surface simulated by SIMIND, MCNP-X, and GATE were 3.18, 2.9, and 2.62 mm, respectively, while this parameter was reported at 2.82 mm in the experiment test. The sensitivities simulated by SIMIND, MCNP-X, and GATE were 1.44, 1.27, and 1.38 cps/μCi, respectively, on the collimator surface.

Conclusions

Comparison between simulation and experimental results showed that among these MC codes, GATE enabled to accurately model realistic SPECT system and electromagnetic physical processes, but it required more time and hardware facilities to run simulations. SIMIND was the most flexible and user-friendly code to simulate a SPECT camera, but it had limitations in defining the non-conventional imaging device. The most important characteristics like time and speed of simulation, preciseness of results, and user-friendliness should be considered during simulations.

https://ift.tt/2lpsJzk

Celastrol improves the therapeutic efficacy of EGFR-TKIs for non-small-cell lung cancer by overcoming EGFR T790M drug resistance

The development of resistance to therapy continues to be a serious clinical problem in lung cancer management. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is one of the most common chemotherapy drugs to treat non-small-cell lung cancer. However, almost all treatments fail after ∼1 year of treatment because of drug tolerance, probably occurring from the threonine 790 mutation (T790M) of the EGFR, resulting in overactivation of the EGFR. Celastrol is a natural compound that exhibits antiproliferative activity. In this study, we showed that celastrol combined with EGFR-TKIs significantly suppressed cell invasion of lung cancer cells with a T790M mutation by suppressing the EGFR pathway. Combined therapy with celastrol and EGFR-TKIs inhibited tumor growth in vivo. Together, these results suggested that combined therapy with EGFR-TKIs and celastrol may be a more effective treatment of patients with non-small-cell lung cancer with T790M mutations of the EGFR. * Ying Wang and Qiuyun Liu contributed equally to this article. Correspondence to Denghai Zhang, MD and Limin Xu, DSc, Sino-French Cooperative Central Lab, Shanghai Gongli Hospital, 219 Miao Pu Road, Pudong New District, Shanghai 200135, China Tel: +86 021 5885 9398; fax: +86 021 3882 1635; e-mails: shanghai_zhang@163.com; 13564378807@163.com Received December 22, 2017 Accepted April 24, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2lm21HV

The relationship between cancer‐related worry and posttraumatic growth in adolescent and young adult cancer survivors

Psycho-Oncology, EarlyView.


https://ift.tt/2MbmdaY

Prognostic value of miR-17-5p in cancers: a meta-analysis

https://ift.tt/2tpxVac

Diarrhoea in adult cancer patients: ESMO Clinical Practice Guidelines†

https://ift.tt/2yuHmLn

Interaction between anesthetic conditioning and ischemic preconditioning on metabolic function after hepatic ischemia–reperfusion in rabbits

Abstract

Background

Both anesthetic-induced and ischemic preconditioning are protective against hepatic ischemia–reperfusion injury. However, the effects of these preventive methods on the metabolic function remain to be elucidated. We investigated the anesthetic conditioning and ischemic preconditioning on the metabolic function of the rabbit model of hepatic ischemia–reperfusion.

Methods

After approval by the institutional animal care and use committee, 36 Japanese White rabbits underwent partial hepatic ischemia for 90 min either under sevoflurane or propofol anesthesia. All the rabbits underwent 90 min of hepatic ischemia, and half of the rabbits in each group underwent additional 10-min ischemia and 10-min reperfusion before index ischemia. Hepatic microvascular blood flow was intermittently measured during reperfusion period, and galactose clearance, serum aminotransferase activities, and lactate concentrations were determined 180 min after reperfusion.

Results

Neither anesthetic conditioning with sevoflurane nor ischemic preconditioning altered hepatic microvascular blood flow during reperfusion and serum transaminase activities after reperfusion. However, galactose clearance of reperfused liver was significantly higher under sevoflurane anesthesia than propofol (0.016 ± 0.005/min vs. 0.011 ± 0.004/min). Statistically significant interaction between anesthetic choice and application of ischemic preconditioning suggests that the ischemic preconditioning is selectively protective under propofol anesthesia. Increase of blood lactate concentration was significantly suppressed under sevoflurane anesthesia compared to propofol (1.5 ± 0.8 vs. 3.9 ± 1.4 mmol/l) without any statistically significant interaction with the application of ischemic preconditioning.

Conclusion

Sevoflurane attenuated the decrease of galactose clearance and increase of the blood lactate after reperfusion compared to propofol. Application of ischemic preconditioning was significantly protective under propofol anesthesia.

https://ift.tt/2M9nrmU