The role of surgical margins in chondrosarcoma

Publication date: Available online 8 June 2018
Source:European Journal of Surgical Oncology
Author(s): Jonathan D. Stevenson, Minna K. Laitinen, Michael C. Parry, Vaiyapuri Sumathi, Robert J. Grimer, Lee M. Jeys
IntroductionChondrosarcoma (CS) is the second most common primary bone sarcoma with no clear role for adjuvant therapy. The purpose of this study was to investigate (1) the relationship between surgical excision margins and local recurrence free survival (LRFS), and (2) the role of local recurrence (LR) in disease specific survival (DSS) in CS of the extremity and pelvis.Material and methods341 pelvic and extremity CS diagnosed between 2003 and 2015 were studied retrospectively.ResultsLR developed in 23% of cases. Pelvic location, pathologic fracture, margin and grade were significant factors for LR after univariate analysis. Multivariate analysis revealed surgical margin and pelvic location as positive factors for LR, and grade-1 and 2 CS as negative factors for LR. Pathologic fracture, central versus peripheral, grade, and LR were significant factors with univariate analysis for DSS; and grade was significant after multivariate analysis for all patients for DSS. After competing risk analysis, LR was statistically significant for DSS in grade-2 and grade-3 tumours.ConclusionSurgical margins determine LR in all CS grades, but LR affects DSS only in grade-2 and grade-3 tumours. Although narrow margins are acceptable in grade-1 tumours, since biopsy is unreliable in predicting final grade, a minimum 4-mm margin should be the aim in all cases.



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Prostate sparing cystectomy for bladder cancer: A two-center study

Publication date: Available online 8 June 2018
Source:European Journal of Surgical Oncology
Author(s): Charlotte S. Voskuilen, Elisabeth E. Fransen van de Putte, Jose I. Pérez-Reggeti, Erik van Werkhoven, Laura S. Mertens, Bas WG. van Rhijn, Mohamed Saad, Axel Bex, Xavier Cathelineau, Henk G. van der Poel, Simon Horenblas, Rafael Sanchez-Salas, Richard P. Meijer
PurposeTo assess long-term functional and oncologic outcomes of prostate sparing cystectomy (PSC) as a sexuality-preserving alternative to radical cystectomy in a selected group of bladder cancer (BC) patients.Materials and MethodsBetween 1995 and 2014, 185 BC patients underwent PSC according to one of two standardized procedures at two centers. All patients had received extensive evaluation to rule out prostate cancer and BC at the bladder neck and prostatic urethra (PU), including prostate specific antigen blood analysis, transrectal ultrasound and/or prostate biopsies, PU biopsies and/or PU frozen section analysis. All patients received an orthotopic ileal neobladder. Overall survival (OS) was assessed by Kaplan–Meier estimates. Cumulative incidence of cancer specific mortality, any recurrence and loco-regional recurrence were calculated using competing-risk methods. Finally, functional outcomes (voiding, continence and erectile function) were evaluated.Results185 patients (cTa-3N0M0) with a mean age of 57 years (SD: 9) were included. Median follow-up was 7.5 years (IQR: 5.6-10.8). Five-year OS was 71% and 5-year cumulative incidence of recurrence was 31%. Twenty patients (10.8%) had a loco-regional recurrence, two recurrences were in the PU. During follow-up, prostate cancer was detected in six patients (3.2%). Erectile function was preserved in 86.1% of patients, complete daytime and nighttime continence in 95.6% and 70.2%, respectively.ConclusionThis two-center study shows that in men with BC in whom the prostate and PU were proven free of malignancy, PSC would represent a valid treatment option with excellent functional outcome. Oncologic outcomes were comparable to what is known from radical cystoprostatectomy series.



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Reply to: Management of locally recurrent rectal cancer

Publication date: Available online 7 June 2018
Source:European Journal of Surgical Oncology
Author(s): Karin Westberg, Anna Martling




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18 F-FET-PET as a biomarker for therapy response in non-contrast enhancing glioma following chemotherapy

Abstract

Background

Monitoring treatment response after chemotherapy of gadolinium-(Gd)-negative gliomas is challenging as conventional MRI often indicates no radiological changes. We hypothesize that ¹⁸F-FET-PET can be used as a biomarker for response assessment in Gd-negative gliomas undergoing chemotherapy.

Methods

Sixty-one patients harboring Gd-negative WHO grade II or III glioma receiving alkylating agents (temozolomide or CCNU/procarbacine) were included. All patients underwent MRI and ¹⁸F-FET-PET before chemotherapy and 6 months later. We calculated T₂-volume, ¹⁸F-FET-PET based biological tumour volume (BTV) and maximal tumour-to-brain ratio (TBR_max). Moreover, dynamic PET acquisition was performed using time-activity-curves (TACs) analysis. For MRI-based response assessment, RANO criteria for low-grade glioma were used. For ¹⁸F-FET-PET, following classification scheme was tested: responsive disease (RD) when a decrease in either BTV ≥ 25% and/or TBR_max ≥ 10% occurred, an increase in BTV ≥ 25% and/or TBR_max increase > 10% characterized progressive disease (PD), minor changes ± 25% for BTV and ± 10% for TBR_max were regarded as stable disease (SD). Post-chemotherapy survival (PCS) and time-to-treatment failure (TTF) were calculated using the Kaplan–Meier method.

Results

¹⁸F-FET-PET based response has shown patients with RD to have the longest TTF time (78.5 vs 24.6 vs 24.1 months, p = 0.001), while there was no significant difference between patients with a SD and PD. A comparable pattern was observed for PCS (p < 0.001). T₂-volume based assessment was not associated with outcome.

Conclusion

¹⁸F-FET-PET is a promising biomarker for early response assessment in Gd-negative gliomas undergoing chemotherapy. It might be helpful for a timely adjustment of potentially ineffective treatment concepts and overcomes limitations of conventional structural imaging.

https://ift.tt/2kWUsXU

Cancers, Vol. 10, Pages 189: The Roles of p53 in Mitochondrial Dynamics and Cancer Metabolism: The Pendulum between Survival and Death in Breast Cancer?

Cancers, Vol. 10, Pages 189: The Roles of p53 in Mitochondrial Dynamics and Cancer Metabolism: The Pendulum between Survival and Death in Breast Cancer?

Cancers doi: 10.3390/cancers10060189

Authors: David E. Moulder Diana Hatoum Enoch Tay Yiguang Lin Eileen M. McGowan

Cancer research has been heavily geared towards genomic events in the development and progression of cancer. In contrast, metabolic regulation, such as aberrant metabolism in cancer, is poorly understood. Alteration in cellular metabolism was once regarded simply as a consequence of cancer rather than as playing a primary role in cancer promotion and maintenance. Resurgence of cancer metabolism research has identified critical metabolic reprogramming events within biosynthetic and bioenergetic pathways needed to fulfill the requirements of cancer cell growth and maintenance. The tumor suppressor protein p53 is emerging as a key regulator of metabolic processes and metabolic reprogramming in cancer cells&mdash;balancing the pendulum between cell death and survival. This review provides an overview of the classical and emerging non-classical tumor suppressor roles of p53 in regulating mitochondrial dynamics: mitochondrial engagement in cell death processes in the prevention of cancer. On the other hand, we discuss p53 as a key metabolic switch in cellular function and survival. The focus is then on the conceivable roles of p53 in breast cancer metabolism. Understanding the metabolic functions of p53 within breast cancer metabolism will, in due course, reveal critical metabolic hotspots that cancers advantageously re-engineer for sustenance. Illustration of these events will pave the way for finding novel therapeutics that target cancer metabolism and serve to overcome the breast cancer burden.

https://ift.tt/2sR5zFz

Cost–effectiveness of afatinib and erlotinib as second-line treatments for advanced squamous cell carcinoma of the lung

Future Oncology, Ahead of Print.


https://ift.tt/2kSyB3U

Evaluation of radiation-related invasion in primary patient-derived glioma cells and validation with established cell lines: impact of different radiation qualities with differing LET

Abstract

Purpose

Glioblastoma multiforme (GBM) is the most common primary brain tumor and has a very poor overall prognosis. Multimodal treatment is still inefficient and one main reason is the invasive nature of GBM cells, enabling the tumor cells to escape from the treatment area causing tumor progression. This experimental study describes the effect of low- and high-LET irradiation on the invasion of primary GBM cells with a validation in established cell systems.

Methods

Seven patient derived primary GBM as well as three established cell lines (LN229, LN18 and U87) were used in this study. Invasion was investigated using Matrigel® coated transwell chambers. Irradiation was performed with low- (X-ray) and high-LET (alpha particles) radiation. The colony formation assay was chosen to determine the corresponding alpha particle dose equivalent to the X-ray dose.

Results

4 Gy X-ray irradiation increased the invasive potential of six patient derived GBM cells as well as two of the established lines. In contrast, alpha particle irradiation with an equivalent dose of 1.3 Gy did not show any effect on the invasive behavior. The findings were validated with established cell lines.

Conclusion

Our results show that in contrast to low-LET irradiation high-LET irradiation does not enhance the invasion of established and primary glioblastoma cell lines. We therefore suggest that high-LET irradiation could become an alternative treatment option. To fully exploit the benefits of high-LET irradiation concerning the invasion of GBM further molecular studies should be performed.

https://ift.tt/2sDwEwI

Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3K{gamma} to promote pancreatic cancer metastasis

Exosomes are emerging as important mediators of the crosstalk between tumor cells and the microenvironment. However, the mechanisms by which exosomes modulate tumor development under hypoxia in pancreatic cancer (PC) remain largely unknown. Here we found that hypoxic exosomes derived from PC cells activate macrophages to the M2 phenotype in a HIF-1a or HIF-2a-dependent manner, which then facilitates the migration, invasion, and EMT of PC cells. Given that exosomes have been shown to transport miRNAs to alter cellular functions, we discovered that miR-301a-3p was highly expressed in hypoxic PC cells and enriched in hypoxic PC cells-derived exosomes. Circulating exosomal miR-301a-3p levels positively associated with depth of invasion, lymph node metastasis, late TNM stage, and poor prognosis of PC. Hypoxic exosomal miR-301a-3p induced the M2 polarization of macrophages via activation of the PTEN/PI3Kγ signaling pathway. Co-culturing of PC cells with macrophages in which miR-301a-3p was upregulated or treated with hypoxic exosomes enhanced their metastatic capacity. Collectively, these data indicate that PC cells generate miR-301a-3p-rich exosomes in a hypoxic microenvironment, which then polarize macrophages to promote malignant behaviors of PC cells. Targeting exosomal miR-301a-3p may provide a potential diagnosis and treatment strategy for PC.

https://ift.tt/2kT0U22

Macrophages Promote Circulating Tumor Cell-Mediated Local Recurrence Following Radiation Therapy in Immunosuppressed Patients

Although radiation therapy (RT) decreases the incidence of locoregional recurrence in breast cancer, patients with triple-negative breast cancer (TNBC) have increased risk of local recurrence following breast-conserving therapy (BCT). The relationship between RT and local recurrence is unknown. Here we tested the hypothesis that recurrence in some instances is due to the attraction of circulating tumor cells to irradiated tissues. To evaluate the effect of absolute lymphocyte count on local recurrence after RT in TNBC patients, we analyzed radiation effects on tumor and immune cell recruitment to tissues in an orthotopic breast cancer model. Recurrent patients exhibited a prolonged low absolute lymphocyte count when compared to non-recurrent patients following RT. Recruitment of tumor cells to irradiated normal tissues was enhanced in the absence of CD8+ T cells. Macrophages (CD11b+F480+) preceded tumor cell infiltration and were recruited to tissues following RT. Tumor cell recruitment was mitigated by inhibiting macrophage infiltration using maraviroc, an FDA-approved CCR5 receptor antagonist. Our work poses the intriguing possibility that excessive macrophage infiltration in the absence of lymphocytes promotes local recurrence after RT. This combination thus defines a high-risk group of TNBC patients.

https://ift.tt/2sOZwRF

Hexavalent Chromium-Induced Chromosome Instability Drives Permanent and Heritable Numerical and Structural Changes and a DNA Repair-Deficient Phenotype

A key hypothesis for how hexavalent chromium (Cr(VI)) causes cancer is that it drives chromosome instability (CIN), which leads to neoplastic transformation. Studies show chronic Cr(VI) can impact DNA repair and induce centrosome amplification, which can lead to structural and numerical CIN. However, no studies have considered whether these outcomes are transient or permanent. In this study, we exposed human lung cells to particulate Cr(VI) for three sequential 24-hour periods, each separated by about a month. After each treatment, cells were seeded at colony forming density, cloned, expanded and retreated, creating 3 generations of clonal cell lines. Each generation of clones was tested for chromium sensitivity, chromosome complement, DNA repair capacity, centrosome amplification, and the ability to grow in soft agar. After the first treatment, Cr(VI)-treated clones exhibited a normal chromosome complement, but some clones showed a repair-deficient phenotype and amplified centrosomes. After the second exposure, more than half of the treated clones acquired an abnormal karyotype including numerical and structural alterations, with many exhibiting deficient DNA double strand break repair and amplified centrosomes. The third treatment produced new abnormal clones, with previously abnormal clones acquiring additional abnormalities and most clones exhibiting repair deficiency. CIN, repair deficiency, and amplified centrosomes were all permanent and heritable phenotypes of repeated Cr(VI) exposure. These outcomes support the hypothesis that CIN is a key mechanism of Cr(VI)-induced carcinogenesis.

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Reciprocally Regulation of DUSP9 and DUSP16 Expression by HIF-1 Controls ERK and p38 MAP Kinase Activity and Mediates Chemotherapy-Induced Breast Cancer Stem Cell Enrichment

Triple-negative breast cancer (TNBC) has a poor prognosis due to its aggressive characteristics and lack of targeted therapies. Cytotoxic chemotherapy may reduce tumor bulk, but leaves residual disease due to the persistence of chemotherapy-resistant breast cancer stem cells (BCSCs), which are critical for tumor recurrence and metastasis. Here we demonstrate that hypoxia-inducible factor (HIF)-1-dependent regulation of mitogen-activated protein kinase (MAPK) signaling pathways contributes to chemotherapy-induced BCSC enrichment. Chemotherapy increased DUSP9 expression and decreased DUSP16 expression in a HIF-1-dependent manner, leading to inhibition of ERK and activation of p38 signaling pathways, respectively. Inhibition of ERK caused transcriptional induction of the pluripotency factor Nanog through decreased inactivating phosphorylation of FoxO3, while activation of p38 stabilized Nanog and Klf4 mRNA through increased inactivating phosphorylation of RNA binding protein ZFP36L1, both of which promoted specification of the BCSC phenotype. Inhibition of HIF-1 or p38 signaling blocked chemotherapy-induced pluripotency factor expression and BCSC enrichment. These surprising results delineate a mechanism by which a transcription factor switches cells from ERK to p38 signaling in response to chemotherapy and suggest that therapeutic targeting of HIF-1 or the p38 pathway in combination with chemotherapy will block BCSC enrichment and improve outcome in TNBC.

https://ift.tt/2xPgJQR

Ischaemic cardiomyopathy and embolic stroke in a young adult with suspected synthetic cannabinoid use

The incidence of cardiovascular disease is increasing in young adults. We are reporting a case of acute stroke in a young patient with severe ischaemic cardiomyopathy in the absence of traditional risk factors. After ruling out atherosclerotic disease, his presentation was attributed to synthetic cannabinoid use. We then discussed the typical barriers in early diagnosis and limitations of laboratory testing in this condition. Due to the increase in abuse of these synthetic drugs among young adults, there is a need for high clinical suspicion which can help with early recognition and improve morbidity and mortality associated with these chemicals.

https://ift.tt/2M6OMXC

Prognostic value of androgen receptor and FOXA1 co-expression in non-metastatic triple negative breast cancer and correlation with other biomarkers

Prognostic value of androgen receptor and FOXA1 co-expression in non-metastatic triple negative breast cancer and correlation with other biomarkers

Prognostic value of androgen receptor and FOXA1 co-expression in non-metastatic triple negative breast cancer and correlation with other biomarkers, Published online: 08 June 2018; doi:10.1038/s41416-018-0142-6

Prognostic value of androgen receptor and FOXA1 co-expression in non-metastatic triple negative breast cancer and correlation with other biomarkers

https://ift.tt/2LwhgsV

Toward Precision Medicine for Neurological and Neuropsychiatric Disorders

Publication date: Available online 7 June 2018
Source:Cell Stem Cell
Author(s): Rebecca M. Gibbs, Scott Lipnick, Joel W. Bateman, Lloyd Chen, Henry C. Cousins, Elizabeth G. Hubbard, Geraldine Jowett, Darren S. LaPointe, Maxine J. McGredy, Michelle N. Odonkor, Giuliana Repetti, Elizabeth Thomas, Lee L. Rubin
The genetic complexity, clinical variability, and inaccessibility of affected tissue in neurodegenerative and neuropsychiatric disorders have largely prevented the development of effective disease-modifying therapeutics. A precision medicine approach that integrates genomics, deep clinical phenotyping, and patient stem cell models may facilitate identification of underlying biological drivers and targeted drug development.

Teaser

The genetic complexity, clinical variability, and inaccessibility of affected tissue in neurodegenerative and neuropsychiatric disorders have largely prevented the development of effective disease-modifying therapeutics. A precision medicine approach that integrates genomics, deep clinical phenotyping, and patient stem cell models may facilitate identification of underlying biological drivers and targeted drug development.


https://ift.tt/2JDTnCi

Paneth Cell Multipotency Induced by Notch Activation following Injury

Publication date: Available online 7 June 2018
Source:Cell Stem Cell
Author(s): Shiyan Yu, Kevin Tong, Yanlin Zhao, Iyshwarya Balasubramanian, George S. Yap, Ronaldo P. Ferraris, Edward M. Bonder, Michael P. Verzi, Nan Gao
Paneth cells are post-mitotic intestinal epithelial cells supporting the stem cell niche and mucosal immunity. Paneth cell pathologies are observed in various gastrointestinal diseases, but their plasticity and response to genomic and environmental challenges remain unclear. Using a knockin allele engineered at the mouse Lyz1 locus, we performed detailed Paneth cell-lineage tracing. Irradiation induced a subset of Paneth cells to proliferate and differentiate into villus epithelial cells. RNA sequencing (RNA-seq) revealed that Paneth cells sorted from irradiated mice acquired a stem cell-like transcriptome; when cultured in vitro, these individual Paneth cells formed organoids. Irradiation activated Notch signaling, and forced expression of Notch intracellular domain (NICD) in Paneth cells, but not Wnt/β-catenin pathway activation, induced their dedifferentiation. This study documents Paneth cell plasticity, particularly their ability to participate in epithelial replenishment following stem cell loss, adding to a growing body of knowledge detailing the molecular pathways controlling injury-induced regeneration.

Graphical abstract

Teaser

Using a knockin allele engineered at the mouse Lyz1 locus, Yu et al. report that irradiation induces a subset of Paneth cells to dedifferentiate. This process can also be induced by expressing active Notch1 in this cell type. The study documents Paneth cell plasticity, expanding current understanding of intestinal regeneration.


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Prognostic value of androgen receptor and FOXA1 co-expression in non-metastatic triple negative breast cancer and correlation with other biomarkers

https://ift.tt/2sE9whh

Divergent dislocation of the carpometacarpal joints: a case report

Divergent carpometacarpal joint dislocations of the fingers are very rare. Due to severe swelling and overlapping of bones on a radiograph of the wrist and hand, dislocations are missed. The purpose of this cl...

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Lymphoblastic Lymphoma: Guidelines from the International Lymphoma Radiation Oncology Group (ILROG)

Publication date: Available online 7 June 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Bouthaina Shbib Dabaja, Lena Specht, Joachim Yahalom
Presentation with a large mediastinal mass is a hallmark of acute lymphoblastic lymphoma, a disease that is treated in the same way as acute lymphoblastic leukemia even in the absence of marrow involvement. The role of mediastinal radiation for patients who achieve complete remission after chemotherapy has been overlooked and controversial. This document presents current knowledge on the role of radiation for lymphoblastic lymphoma and best practices for addressing how to deliver mediastinal radiation with modern technology.



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A prospective comparison of computerized-tomography (CT) based with trans-rectal-ultrasonography (TRUS) assistance and magnetic-resonance imaging (MRI) based target-volume definition during image guided adaptive brachytherapy for cervical cancers

Publication date: Available online 7 June 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Umesh Mahantshetty, Pushpa Naga CH, Chira Ranjan Khadanga, Shivakumar Gudi, Supriya Chopra, Lavanya Gurram, Swamidas Jamema, Yogesh Ghadi, Shyamkishore Shrivastava
PurposeAlthough magnetic resonance imaging (MRI) represents the gold standard for image guided adaptive brachytherapy (IGABT) for cervical cancer, majority of brachytherapy (BT) continues to be guided by computerized tomography (CT). However, CT seems to overestimate the target volume definition while the potential of trans-rectal ultrasonography (TRUS) needs further evaluation. With an aim to evaluate CT-based target contouring with incorporation of TRUS during BT, we conducted this prospective comparative study.Materials and methodsPatients with locally advanced cervical cancer undergoing MR IGABT between January 2013 and March 2014 were included. During BT procedure, TRUS imaging with central tandem in situ was acquired at three representative levels. Reference points/dimensions (D1 to D4) of hypo-echoic region seen on TRUS images with respect to central tandem were recorded. CT and MR BT planning imaging was performed after BT application. High risk clinical target volume (HR-CTV) was contoured on CT with incorporation of clinical and TRUS imaging findings and compared with gold standard MR based target approach.ResultsImage sets belonging to 25 patients [FIGO IIB:11 (44%) and IIIB: 14 (56%)] were evaluable. The mean (±SD) volume of HR-CTV on CT and MR imaging were 39.1 (±20) cm³ and 39 (±19) cm³ respectively (r=0.92, p<0.001).Significant correlation was found between HR-CTV dimensions (width and thickness) between CT and MR at various levels (r=0.70 to 0.80, p<0.001).In addition, absolute differences in target dimensions between CT and MR were less than 0.5 cm. Also a strong correlation was seen for patients with medial and lateral parametrial invasion (p<0.05) between CT and MR imaging as compared to no parametrial disease at BT. Furthermore, the mean differences of HR-CTV width between CT and MR contours at various levels, irrespective of parametrial involvement was 0.1- 0.4 cm only.ConclusionsOur study suggests, CT based target and OAR delineation utilizing MR at diagnosis and real time TRUS information during BT seems comparable to the gold standard MR based approach in IGABT for cervical cancers.

Teaser

Target volume definition and delineation (high risk) at the time of brachytherapy (BT) is an important step in image guided adaptive brachytherapy for cervical cancers. We present the first prospective study comparing CT-based target delineation with incorporation of trans-rectal ultrasonography at BT and gold standard approach of MR-based target delineation and report comparable results. These findings have a potential impact on brachytherapy practice for cervical cancers across the globe.


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Volume of interest delineation techniques for 18 F-FDG PET-CT scans during neoadjuvant extremity soft tissue sarcoma treatment in adults: a feasibility study

Abstract

Background

This study explores various volume of interest (VOI) delineation techniques for fluorine-18-fluorodeoxyglucose positron emission tomography with computed tomography (¹⁸F-FDG PET-CT) scans during neoadjuvant extremity soft tissue sarcoma (ESTS) treatment.

Results

During neoadjuvant treatment, hyperthermic isolated limb perfusion (HILP) and preoperative external beam radiotherapy (EBRT), 11 patients underwent three ¹⁸F-FDG PET-CT scans. The first scan was made prior to the HILP, the second after the HILP but prior to the start of the EBRT, and the third prior to surgical resection. An automatically drawn VOI_auto, a manually drawn VOI_man, and two gradient-based semi-automatically drawn VOIs (VOI_grad and VOI_grad+) were obtained. Maximum standardized uptake value (SUV_max), SUV_peak, SUV_mean, metabolically active tumor volume (MATV), and total lesion glycolysis (TLG) were calculated from each VOI. The correlation and level of agreement between VOI delineation techniques was explored. Lastly, the changes in metabolic tumor activity were related to the histopathologic response. The strongest correlation and an acceptable level of agreement was found between the VOI_man and the VOI_grad+ delineation techniques. A decline (VOI_man) in SUVmax, SUVpeak, SUVmean, TLG, and MATV (all p < 0.05) was found between the three scans. A > 75% decline in TLG between scan 1 and scan 3 possibly identifies histopathologic response.

Conclusions

The VOI_grad+ delineation technique was identified as most reliable considering reproducibility when compared with the other VOI delineation techniques during the multimodality neoadjuvant treatment of locally advanced ESTS. A significant decline in metabolic tumor activity during the treatment was found. TLG deserves further exploration as predictor for histopathologic response after multimodality ESTS treatment.

https://ift.tt/2JDgoWa

MGMT promoter methylation is not correlated with integrin expression in malignant gliomas: clarifying recent clinical trial results

Abstract

Integrin alpha-v-beta-3 (α_vβ₃) is important for invasive tumor growth and angiogenesis in glioblastomas (GBM). However, recent clinical trials on inhibition of this integrin led to ambiguous results whether patients with methylated or unmethylated ⁶O-methylguanine methyltransferase (MGMT) promoter might profit from this kind of therapy. Therefore, we addressed the still unanswered question about a possible correlation between integrin α_vβ₃ expression and MGMT promoter methylation in GBM. For this purpose, tumor samples from newly diagnosed and untreated GBM patients with methylated (n = 22) or unmethylated (n = 17) MGMT promoter were simultaneously analyzed for integrin α_vβ₃ expression by an automated immunohistochemical staining platform. Interestingly, subsequent semi-quantitative analysis by a special imaging software did not show any difference in integrin expression between patients with methylated or unmethylated MGMT promoter status. Moreover, further analysis of the integrin subunits via ELISA from histologic sections revealed that there is no difference in integrin subunit expression between these patients. Hence, our results are important for designing future clinical trials with respect to treatment stratification, while it still has to be identified which other molecular factors determine differential responses to targeted anti-integrin α_vβ₃ treatment.

https://ift.tt/2kRG9Uy

Patterns of on-treatment cardiac adverse events within three clinical trials of adjuvant anthracycline-based chemotherapy

Abstract

Background

This study aims to assess the patterns of development of on-treatment cardiac side effects among patients with early breast cancer receiving anthracycline-based chemotherapy.

Methods

This is a pooled analysis of patient-level data of patients with early-stage breast cancer who were recruited into three clinical trials to receive different adjuvant chemotherapy regimens. Univariable and multivariable analyses of factors predicting the development of on-treatment cardiac adverse events were conducted through logistic regression analysis. The following factors were evaluated in the univariable analysis: age, menopausal status, body mass index, T stage, and type of chemotherapy protocol.

Results

Among the studied patients, 226 patients (6.7%) experienced 230 incidents of on-treatment cardiac toxicities. Cardiac ischemia was reported among 8 patients, cardiac dysfunction was reported among 19 patients, arrhythmias were reported in 161 patients and other non-specified forms of cardiac adverse events were reported in 42 patients. In univariable logistic regression, the following parameters were predictive of a higher probability of on-treatment cardiac adverse events (P < 0.05): higher age, higher body mass index and FAC chemotherapy protocol. When these factors were included in the multivariable logistic regression analysis, the following factors were predictive of a higher probability of cardiac adverse events: higher body mass index (P = 0.050) and FAC chemotherapy protocol (P = 0.001).

Conclusion

On-treatment cardiac events are not uncommon during adjuvant chemotherapy for early breast cancer. Higher dose of anthracyclines and higher body mass index are associated with a higher risk of on-treatment cardiac events.

https://ift.tt/2sEhAia

DZ-2384 has a superior preclinical profile to taxanes for the treatment of triple-negative breast cancer and is synergistic with anti-CTLA-4 immunotherapy

Triple-negative breast cancer (TNBC) is typically aggressive, difficult to treat, and commonly metastasizes to the visceral organs and soft tissues, including the lungs and the brain. Taxanes represent the most effective and widely used therapeutic class in metastatic TNBC but possess limiting adverse effects that often result in a delay, reduction, or cessation of their use. DZ-2384 is a candidate microtubule-targeting agent with a distinct mechanism of action and strong activity in several preclinical cancer models, with reduced toxicities. DZ-2384 is highly effective in patient-derived taxane-sensitive and taxane-resistant xenograft models of TNBC at lower doses and over a wider range relative to paclitaxel. When comparing compound exposure at minimum effective doses relative to safe exposure levels, the therapeutic window for DZ-2384 is 14–32 compared with 2.0 and less than 2.8 for paclitaxel and docetaxel, respectively. DZ-2384 is effective at reducing brain metastatic lesions when used at maximum tolerated doses and is equivalent to paclitaxel. Drug distribution experiments indicate that DZ-2384 is taken up more efficiently by tumor tissue but at equivalent levels in the brain compared with paclitaxel. Selective DZ-2384 uptake by tumor tissue may in part account for its wider therapeutic window compared with taxanes. In view of the current clinical efforts to combine chemotherapy with immune checkpoint inhibitors, we demonstrate that DZ-2384 acts synergistically with anti-CTLA-4 immunotherapy in a syngeneic murine model. These results demonstrate that DZ-2384 has a superior pharmacologic profile over currently used taxanes and is a promising therapeutic agent for the treatment of metastatic TNBC. *Cynthia Bernier and Ahmed Soliman contributed equally to the writing of this article. Correspondence to Anne Roulston, PhD, Room 915C, 3655 Promenade Sir William Osler, Montreal, Canada, QC H3G 1Y6 Tel: +1 514 398 5226; fax: +1 514 398 7384; e-mail: anne.roulston@mcgill.ca Received December 31, 2017 Accepted May 3, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2LxpqRV

Resveratrol inhibits STAT5 activation through the induction of SHP-1 and SHP-2 tyrosine phosphatases in chronic myelogenous leukemia cells

STAT5 is an important transcription factor that is constitutively activated in various types of malignancies, including chronic myelogenous leukemia (CML). Whether the antitumor effects of resveratrol (RES) are linked to its capability to inhibit STAT5 activation in CML cells was investigated. We found that RES inhibited STAT5 activation in K562 and KU812 cell lines; RES also reduced the STAT5 concentration in the nucleus of K562 and KU812 cells. Protein tyrosine phosphatase (PTP) inhibitor, sodium pervanadate, reversed the RES-induced downregulation of STAT5, suggesting the involvement of a PTP. Indeed, we observed that RES decreased the expression of tyrosine phosphatase SHP-1 and SHP-2; moreover, the deletion of SHP-1 and SHP-2 genes by siRNA abolished the ability of RES to inhibit STAT5 activation, which suggested the critical role of both SHP-1 and SHP-2 in its possible mechanism of action. RES downregulated the expression of STAT5-regulated gene products such as Bcl-xL, Bcl-2, Cyclin D1, and Mcl-1, and increased the expression of Bax. This correlated with the suppression of proliferation and induction of apoptosis. Overall, our results suggest that RES is a blocker of STAT5 activation and thus may be potentially useful for the treatment of CML. *Qing Li and Li Zhang contributed equally to the writing of this article. Correspondence to Tao Sui, MD, Department of Hematology, Tianjin First Center Hospital, Tianjin 300192, People's Republic of China Tel: +86 022 236 26946; fax: +86 022 236 26492; e-mail: taosui71@163.com Received September 23, 2017 Accepted March 23, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2JjEfe3

The potential failure risk of the cone-beam computed tomography-based planning target volume margin definition for prostate image-guided radiotherapy based on a prospective single-institutional hybrid analysis

The purpose of this study was to evaluate the impact of markerless on-board kilovoltage (kV) cone-beam computed tomography (CBCT)-based positioning uncertainty on determination of the planning target volume (P...

https://ift.tt/2kRmcx8

Fluorescent nuclear track detectors for alpha radiation microdosimetry

While alpha microdosimetry dates back a couple of decades, the effects of localized energy deposition of alpha particles are often still unclear since few comparative studies have been performed. Most modern a...

https://ift.tt/2sP5iTo

Quality of radiotherapy reporting in randomized controlled trials of prostate cancer

Good radiotherapy reporting in clinical trials of prostate radiotherapy is important because it will allow accurate reproducibility of radiotherapy treatment and minimize treatment variations that can affect p...

https://ift.tt/2kXnyGK

Lokoregionale Tiefenhyperthermie verbessert das krankheitsspezifische Gesamtüberleben in Kombination mit einer neoadjuvanten Chemotherapie bei Hochrisiko-Weichteilsarkomen

https://ift.tt/2HtooUu

Hygienic aspects of marker pens in radiation therapy

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Leading domestic community outreach as a radiation oncologist

Publication date: Available online 6 June 2018
Source:Practical Radiation Oncology
Author(s): Daniel M. Seible




https://ift.tt/2JBLhdr

Brain metastasis growth on pre-radiosurgical magnetic resonance imaging

Publication date: Available online 7 June 2018
Source:Practical Radiation Oncology
Author(s): Michael A. Garcia, Mekhail Anwar, Yao Yu, Sai Duriseti, Bryce Merritt, Jean Nakamura, Christopher Hess, Philip V. Theodosopoulos, Michael M. McDermott, Penny K. Sneed, Steve E. Braunstein
BackgroundA previous analysis showed that brain metastases treated with frameless stereotactic radiosurgery (SRS) planned with MRI >14 days before SRS had worse local control (LC). To evaluate if worse LC may be due to unaccounted interval metastasis growth and radiosurgical marginal miss, we quantified growth before SRS on pre-radiosurgical imaging.MethodsWe reviewed patients treated with fixed-frame SRS for brain metastases at our institution from 2010-2013 who had pretreatment diagnostic brain MRI and SRS-planning MRI scans available. Metastases were contoured on the pretreatment MRI and the day-of-treatment planning MRI for volumetric comparison. Growth rates were calculated. Serial volumetric contour expansions on the pretreatment MRI were used to determine the minimum margin necessary to encompass the entire metastasis on day of SRS. LC was estimated by Kaplan-Meier method.ResultsAmong 411 brain metastases in 165 patients, time between pretreatment and treatment MRI was associated with metastasis growth (p<0.001) with mean growth rate of 0.02 ml/day (95% CI 0.01-0.03), and 1.35-fold volume increase at 14 days. Time between MRI scans was associated with the amount of margin needed to target the entire brain metastasis volume on day of SRS (p<0.001), as were volume of metastasis on the pretreatment MRI (p<0.001) and melanoma histology (p<0.001). LC was not associated with growth rate among fixed-frame SRS patients.ConclusionTime between pretreatment MRI and SRS is associated with brain metastasis growth, but LC is not compromised when patients receive fixed-frame SRS with same-day MRI planning. Margins may be needed for metastases treated by frameless SRS to account for growth between planning MRI and SRS delivery.In this study we quantify brain metastasis growth over time by taking advantage of the availability of two pre-treatment MRI scans taken at two time points among patients treated with frame-fixed radiosurgery. We found metastasis growth is associated with time, initial metastasis size, melanoma histology, and concurrent chemotherapy. Performing serial margin expansions demonstrated factors that are associated with the amount of margin needed to target the entire metastasis on day of radiosurgery.



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Anatomical Look Into OnabotulinumtoxinA Injection for Chronic Migraine Headache

Background and Objectives While existing studies about onabotulinumtoxinA for chronic migraines have focused on injection location and appropriate dosing, little consideration has been given to patient body habitus and its potential impact on efficacy. We hypothesized that with increasing patient body mass index (BMI) there would be more subcutaneous fat separating targeted muscle groups from the skin surface, such that standard 0.5-inch needles used in existing protocols may not allow intramuscular injection. This may have implications for treatment planning. Methods Anatomically normal computed tomography scans of the head, neck, and face were randomly selected. Subjects were stratified into 4 groups based on BMI, with 30 patients in each group. Four standardized locations were chosen to obtain measurements from the skin surface to the underlying muscle fascia, including (1) frontalis, (2) temporalis, (3) semispinalis capitis, and (4) trapezius. Results Median depth for the temporalis was 12.65 mm (Q1 = 9.32 mm, Q3 = 15.08 mm) for the BMI greater than 35 kg/m2 group. Median depth for the semispinalis capitis was 13.77 mm (Q1 = 10.3 mm, Q3 = 15.7 mm) for the BMI 30 to 35 kg/m2 group, and 14.75 mm (Q1 = 11.00, Q3 = 17.00 mm) for the BMI greater than 35 kg/m2 group. Median depth for the trapezius was 13.95 mm (Q1 = 10.18 mm, Q3 = 19.00 mm) for the BMI greater than 35 kg/m2 group. These medians exceeded the length of the standard 0.5-inch (12.-mm) needle used in existing protocols. Conclusions Our study demonstrates that with increasing BMI there is a greater distance between the skin surface and the muscle fascia of muscles that are targeted for injection in standard chronic migraine botulinum toxin injection protocols. Because of this, patient body habitus may be an important factor in injection technique. Accepted for publication February 12, 2018. Address correspondence to: Ali Totonchi, MD, Department of Surgery, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH 44106 (e-mail: totonchia@yahoo.com). The authors declare no conflict of interest. Interim data from this work were presented at the 2017 Annual Meeting of the Ohio Valley Society of Plastic Surgeons in Pittsburgh, PA, on May 2 to 4, 2017. Copyright © 2018 by American Society of Regional Anesthesia and Pain Medicine.

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Post-gadolinium 3-dimensional spatial, surface, and structural characteristics of glioblastomas differentiate pseudoprogression from true tumor progression

Abstract

Purpose

Pseudoprogression is often indistinguishable from true tumor progression on conventional 2-dimensional (2D) MRI in glioblastoma multiforme (GBM) patients. The aim of this study was to determine the association between post-gadolinium 3-dimensional (3D) characteristics and clinical state in GBM patients.

Methods

Standardized 3D brain MRI studies were performed, and contrast enhancing portions of each tumor were segmented and analyzed, blinded to clinical state, using principal component analysis (PCA), medial axis transformation (MAT), and coverage analysis. Associations between the 3D characteristics of the post-gadolinium enhanced regions and the clinical status of patients were performed.

Results

A total of 15 GBM patients [male: 11 (73%); median age (range): 62 years (36–72)] with a median disease duration of 6 months (range 2–24 months) were studied cross-sectionally with 6 (40%) patients identified with tumor progression. Post-gadolinium features corresponding to the group with progressive disease exhibited a more spherical and symmetric shape relative to their stable counterparts (p = 0.005). The predictive value of a more uniformly full post-gadolinium enhanced shell to clinical progression was determined with a sensitivity of 66.7% (95% CI 29.9–92.5), specificity of 100% (54.1–100), and PPV of 100% (p = 0.028, 2-tailed Fisher's exact test). There did not appear to be an association between the thickness of the contrast enhanced shell to clinical state.

Conclusions

The application of 3D technology with post-gadolinium imaging data may inform healthcare providers with new insights into disease states based on spatial, surface, and structural patterns.

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Personalized Versus Protocolized Fluid Management Using Noninvasive Hemodynamic Monitoring (Clearsight System) in Patients Undergoing Moderate-Risk Abdominal Surgery

Advances in noninvasive hemodynamic monitoring systems allow delivery of goal-directed fluid therapy and could therefore be used in less-invasive surgical procedures. In this randomized controlled trial, we compared closed-loop–assisted goal-directed fluid therapy using a noninvasive cardiac output (Clearsight system) monitor (personalized approach) to a protocolized fluid therapy approach in 40 patients undergoing moderate-risk laparoscopic abdominal surgery. Cardiac output and stroke volume variations were not significantly different in both groups and remained within predefined target values >90% of the study time. Personalized fluid therapy does not seem to offer any hemodynamic advantage over a protocolized approach in this population. Accepted for publication May 8, 2018. Funding: Departmental. Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Trial Registry number: ClinicalTrials.gov (NCT03039946). Reprints will not be available from the authors. Address correspondence to Alexandre Joosten, MD, Department of Anesthesiology, Hospital Erasme, 808 Rt de Lennik, 1070 Brussels, Belgium. Address e-mail to Alexandre.Joosten@erasme.ulb.ac.be or joosten-alexandre@hottmail.com. © 2018 International Anesthesia Research Society

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Estimating the Risk of a Rare But Plausible Complication That Has Not Occurred After n Trials

No abstract available

https://ift.tt/2Jyc6iK

Barash’s Clinical Anesthesia, 8th ed

No abstract available

https://ift.tt/2Hs9DkK

More on Fatigue Mitigation for Anesthesiology Residents

No abstract available

https://ift.tt/2sDjCiN

Intraoperative Hemodynamic and Echocardiographic Measurements Associated With Severe Right Ventricular Failure After Left Ventricular Assist Device Implantation

BACKGROUND: Severe right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation increases morbidity and mortality. We investigated the association between intraoperative right heart hemodynamic data, echocardiographic parameters, and severe versus nonsevere RVF. METHODS: A review of LVAD patients between March 2013 and March 2016 was performed. Severe RVF was defined by the need for a right ventricular mechanical support device, inotropic, and/or inhaled pulmonary vasodilator requirements for >14 days. From a chart review, the right ventricular failure risk score was calculated and right heart hemodynamic data were collected. Pulmonary artery pulsatility index (PAPi) [(pulmonary artery systolic pressure − pulmonary artery diastolic pressure)/central venous pressure (CVP)] was calculated for 2 periods: (1) 30 minutes before cardiopulmonary bypass (CPB) and (2) after chest closure. Echocardiographic data were recorded pre-CPB and post-CPB by a blinded reviewer. Univariate logistic regression models were used to examine the performance of hemodynamic and echocardiographic metrics. RESULTS: A total of 110 LVAD patients were identified. Twenty-five did not meet criteria for RVF. Of the remaining 85 patients, 28 (33%) met criteria for severe RVF. Hemodynamic factors associated with severe RVF included: higher CVP values after chest closure (18 ± 9 vs 13 ± 5 mm Hg; P = .0008) in addition to lower PAPi pre-CPB (1.2 ± 0.6 vs 1.7 ± 1.0; P = .04) and after chest closure (0.9 ± 0.5 vs 1.5 ± 0.8; P = .0008). Post-CPB echocardiographic findings associated with severe RVF included: larger right atrial diameter major axis (5.4 ± 0.9 vs 4.9 ± 1.0 cm; P = .03), larger right ventricle end-systolic area (22.6 ± 8.4 vs 18.5 ± 7.9 cm2; P = .03), lower fractional area of change (20.2 ± 10.8 vs 25.9 ± 12.6; P = .04), and lower tricuspid annular plane systolic excursion (0.9 ± 0.2 vs 1.1 ± 0.3 cm; P = .008). Right ventricular failure risk score was not a significant predictor of severe RVF. Post-chest closure CVP and post-chest closure PAPi discriminated severe from nonsevere RVF better than other variables measured, each with an area under the curve of 0.75 (95% CI, 0.64–0.86). CONCLUSIONS: Post-chest closure values of CVP and PAPi were significantly associated with severe RVF. Echocardiographic assessment of RV function post-CPB was weakly associated with severe RVF. Accepted for publication April 30, 2018. Funding: This study was supported in part by the National Center for Advancing Translational Sciences, National Institutes of Health, Award Number UL1TR001064. Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). M. D. Gudejko and B. R. Gebhardt contributed equally and share first authorship. Reprints will not be available from the authors. Address correspondence to Frederick C. Cobey, MD, MPH, FASE, Department of Anesthesiology, Tufts Medical Center, 800 Washington St, Boston, MA 02111. Address e-mail to FCobey@tuftsmedicalcenter.org. © 2018 International Anesthesia Research Society

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Propofol and Remote Ischemic Preconditioning: Possible Implications for Studies of Clinical Myocardial Protection Using Volatile Anesthetics in Cardiac Surgery Patients?

No abstract available

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Risks and Benefits of Ultrasound, Nerve Stimulation, and Their Combination for Guiding Peripheral Nerve Blocks: A Retrospective Registry Analysis

BACKGROUND: Ultrasound, nerve stimulation, and their combination are all considered acceptable ways to guide peripheral nerve blocks. Which approach is most effective and associated with the fewest complications is unknown. We therefore used a large registry to analyze whether there are differences in vascular punctures, multiple skin punctures, and unintended paresthesia. METHODS: Twenty-six thousand seven hundred and thirty-three cases were extracted from the 25-center German Network for Regional Anesthesia registry between 2007 and 2016 and grouped into ultrasound-guided puncture (n = 10,380), ultrasound combined with nerve stimulation (n=8173), and nerve stimulation alone (n = 8180). The primary outcomes of vascular puncture, multiple skin punctures, and unintended paresthesia during insertion were compared with conditional logistic regression after 1:1:1 propensity score matching. Results are presented as odds ratios and 95% CIs. RESULTS: Propensity matching successfully paired 2508 patients with ultrasound alone (24% of 10,380 patients), 2508 patients with a combination of ultrasound/nerve stimulation (31% of 8173 patients), and 2508 patients with nerve stimulation alone (31% of 8180 patients). After matching, no variable was imbalanced (standardized differences

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Cardiac Structure and Function in Morbidly Obese Parturients: An Echocardiographic Study

BACKGROUND: The increasing prevalence of obesity worldwide is a major threat to global health. Cardiac structural and functional changes are well documented for obesity as well as for pregnancy, but there is limited literature on morbidly obese parturients. We hypothesized that there are both cardiac structural and functional differences between morbidly obese pregnant women and pregnant women of normal body mass index (BMI). METHODS: This prospective cross-sectional study was performed in 2 referral maternity units in Cape Town, South Africa, over a 3-month period. Forty morbidly obese pregnant women of BMI ≥40 kg·m−2 (group O) were compared to 45 pregnant women of BMI ≤30 kg·m−2 (group N). Cardiac structure and function were assessed by transthoracic echocardiography, according to the recommendations of the British Society of Echocardiography. The 2-sample t-test with unequal variances was used for the comparison of the mean values between the groups. RESULTS: Acceptable echocardiographic images were obtained in all obese women. Statistical significance was defined as P

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Decision Support Tool Improves Real and Perceived Anesthesiology Resident Relief Equity

BACKGROUND: The Accreditation Council of Graduate Medical Education requires monitoring of resident clinical and educational hours but does not require tracking daily work patterns or duty hour equity. Lack of such monitoring may allow for inequity that affects resident morale. No defined system for resident relief of weekday operating room (OR) clinical duties existed at our institution, leaving on-call residents to independently decide daily relief order. We developed an automated decision support tool (DST) to improve equitable decision making for clinical relief and assessed its impact on real and perceived relief equity. METHODS: The DST sent a daily e-mail to the senior resident responsible for relief decisions. It contained a prioritized relief list of noncall residents who worked in the OR beyond 5 PM the prior clinical day. We assessed actual relief equity using the number of times a resident worked in the OR past 5:30 PM on 2 consecutive weekdays as our outcome, adjusting for the mean number of open ORs each day between 5:00 PM and 6:59 PM in our main OR areas. We analyzed 14 months of data before implementation and 16 months of data after implementation. We assessed perceived relief equity before and after implementation using a questionnaire. RESULTS: After implementing the DST, the percentage of residents held 2 consecutive weekdays over the total of resident days worked decreased from 1.33% to 0.43%. The percentage of residents held beyond 5:30 PM on any given day decreased from 18.09% to 12.64%. Segmented regression analysis indicated that implementation of the DST was associated with a reduction in biweekly time series of residents kept late 2 days in a row, independent of the mean number of ORs in use. Surveyed residents reported the DST aided their ability to make equitable relief decisions (pre 60% vs post 94%; P = .0003). Eighty-five percent of residents strongly agreed that a prioritized relief list based on prior day work hours after 5 PM aided their decision making. After implementation, residents reported fewer instances of working past 5 PM within the past month (P

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Stoelting’s Anesthesia and Co-Existing Disease, 7th ed

No abstract available

https://ift.tt/2HsMRcn

Deep neuromuscular blockade and surgical conditions during laparoscopic ventral hernia repair: A randomised, blinded study

BACKGROUND Laparoscopic ventral hernia repair is a common surgical procedure. However, muscle contractions and general muscle tension may impair the surgical view and cause difficulties suturing the hernial defect. Deep neuromuscular blockade (NMB) paralyses the abdominal wall muscles and may help to create better surgical conditions. OBJECTIVES The current study investigated if deep compared with no NMB improved the surgical view during laparoscopic ventral hernia repair. DESIGN Crossover study. SETTING The study was carried out at Herlev and Gentofte Hospital, University of Copenhagen, Denmark and conducted from May 2015 until February 2017. PARTICIPANTS A total of 34 patients were randomised in an investigator-initiated, assessor-blinded crossover design of deep vs. no NMB during laparoscopic ventral hernia repair. INCLUSION CRITERIA Adults scheduled for elective laparoscopic ventral hernia repair. EXCLUSION CRITERIA Known allergy to any study medication, known homozygous variants in the butyrylcholinesterase gene, severe renal disease, neuromuscular disease, lactating or pregnant women, any indication for rapid sequence induction. INTERVENTIONS Deep NMB was established with rocuronium and reversed with sugammadex. Anaesthesia was conducted with propofol and remifentanil. MAIN OUTCOME MEASURES The primary outcome was evaluation of surgical view assessed on a five-point rating scale. Other outcomes included the surgical conditions during laparoscopic suturing of the hernia defect. RESULTS We found no difference in ratings for the surgical view when comparing deep with no NMB: mean −0.1 (95% confidence interval −0.4 to 0.2) (P = 0.521, paired t test). However, deep compared with no NMB improved the rating score for surgical conditions while suturing the hernia defect (P = 0.012, Mann–Whitney U test). No differences were found in either total length of surgery (P = 0.76) or hernia suturing time (P = 0.81). CONCLUSION Deep compared with no NMB did not change the rating score of the surgical view immediately after introduction of trocars during laparoscopic ventral hernia repair, but the surgical condition were improved during suturing of the hernia. TRIAL REGISTRATION ClinicalTrials.gov, NCT02247466. Correspondence to Matias V. Madsen, Department of Anaesthesiology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev Ringvej 75, Herlev, DK-2730, Denmark E-mail: matias.vested.madsen@regionh.dk © 2018 European Society of Anaesthesiology

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Isolated Left Ventricular Metastasis from Renal Cell Carcinoma: Diagnostic and Therapeutic Dilemma

Background: The treatment of metastatic renal cell carcinoma (RCC) has been radically changed by the advent of tyrosine kinase inhibitors (TKIs). However, few reports have described their role in cardiac metastases. We present a case of a left ventricular metastasis from RCC that was managed with pazopanib therapy. Case Report: A 74-year-old male with stage I RCC underwent right nephrectomy in 2004 and right lung metastasis resection in 2009. He was well till March 2016, when he presented with chest pain. Cardiac catheterization revealed a highly vascular mass in the apex. Cardiac magnetic resonance imaging revealed a left ventricular mass with full-thickness involvement of the myocardium, and the open cardiac biopsy was consistent with metastatic RCC. The patient was initially treated with pazopanib with response but later developed therapy-related side effects, and the dose was reduced. Due to tumor progression, he is currently on nivolumab instead and is stable. Conclusion: RCC with cardiac metastasis poses unique challenges with regard to diagnosis as well as treatment. The use of TKI therapy is associated with cardiotoxicity and has not been adequately studied in cardiac metastasis. Choosing the right treatment for this subgroup of patients continues to pose an ongoing dilemma.
Case Rep Oncol 2018;11:365–371

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Orbital Metastases from Breast Cancer with BRCA2 Mutation: A Case Report and Literature Review

Breast cancer is the second leading cause of cancer-related deaths in women in the United States. Of these women, 5–10% have an inherited form of breast cancer with a mutation in a major gene, such as the breast cancer susceptibility genes 1 or 2 (BRCA1 or BRCA2). Triple negative (the most common subtype of BRCA1-associated breast cancers) and Her2-positive breast cancer patients have more frequently been observed to develop central nervous system (CNS) metastases compared to other molecular subtypes of breast cancers. However, it remains an open question if BRCA2-associated breast cancers also have a higher propensity to develop CNS metastases. Here we report a rare case of recurrent BRCA2-associated breast cancer which manifested as orbital metastases. At the time of this publication, this is one of the first cases of BRCA2-associated breast cancer to present with orbital metastases. In this article, we discuss the diagnostic challenges and review the literature regarding this rare presentation.
Case Rep Oncol 2018;11:360–364

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Overexpression of CLEC3A promotes tumor progression and poor prognosis in breast invasive ductal cancer

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Novel quinazoline-based sulfonamide derivative (3D) induces apoptosis in colorectal cancer by inhibiting JAK2–STAT3 pathway

https://ift.tt/2M7nAbq

Ganglioglioma in children and young adults: single institution experience and review of the literature

Abstract

Background

Ganglioglioma (GG) is a rare mixed glial-neuronal neoplasm accounting for 0.5–5% of all pediatric central nervous system (CNS) tumors. Rarity of this tumor has precluded defining robust treatment guidelines. This retrospective study evaluates the prognostic factors and outcomes of this rare neoplasm.

Patients and methods

Retrospective analysis of 55 patients with GG was conducted to describe clinical findings, and outcomes. Kaplan–Meier survival and Cox-regression analyses were performed to assess the overall survival (OS) and progression-free survival (PFS).

Results

The mean age at diagnosis was 11.8 years (range 1–21 years) with a median follow-up period of 9.5 years. 53 patients (92.7%) had low grade GG and 2 patients had anaplastic GG. 25 patients had tumor progression, whose median PFS was 12 years. Six patients with low grade GG progressed to a higher grade, with median survival of 9.1 month after transformation. The 5 and 10 year PFS were 65 and 57%, respectively. The 5 and 10 year OS was 96 and 86% respectively. 8 of the 19 (42%) samples tested demonstrated positivity for the BRAF V600E mutation. Multivariate Cox regression analyses showed location and extent of resection were significant factors for PFS and presence of metastatsis attained significance for OS.

Conclusion

This is the one of the largest retrospective study of pediatric GG. Identifying clinical variables, which could stratify these tumors into low- and high-risk groups might help to profile a risk-based therapeutic strategy. Collaborative multiinstitutional prospective studies are warranted to delineate treatment consensus and investigate prognostic factors.

https://ift.tt/2LuNOmW

Red blood cells metabolome changes upon treatment with different X-ray irradiation doses

Abstract

The upholding of red blood cells (RBC) quality and the removal of leukocytes are two essential issues in transfusion therapy. Leukodepletion provides optimum results, nonetheless there are cases where irradiation is recommended for some groups of hematological patients such as the ones with chronic graft-vs-host disease, congenital cellular immunodeficiency, and hematopoietic stem cell transplant recipients. The European guidelines suggest irradiation doses from 25 to 50 Gray (Gγ). We evaluated the effect of different prescribed doses (15 to 50 Gγ) of X-ray irradiation on fresh leukodepleted RBCs bags using a novel protocol that provides a controlled irradiation. Biochemical assays integrated with RBCs metabolome profile, assessed by nuclear magnetic resonance spectroscopy, were performed on RBC units supernatant, during 14 days storage. Metabolome analysis evidenced a direct correlation between concentration increase of three metabolites, glycine, glutamine and creatine, and irradiation dose. Higher doses (35 and 50 Gγ) effect on RBC mean corpuscular volume, hemolysis, and ammonia concentration are considerable after 7 and 14 days of storage. Our data show that irradiation with 50 Gγ should be avoided and we suggest that 35 Gγ should be the upper limit. Moreover, we suggest for leukodepleted RBCs units the irradiation with the prescribed dose of 15 Gγ, value at center of bag, and ranging between 13.35–15 Gγ, measured over the entire bag volume, may guarantee the same benefits of a 25 Gγ dose assuring, in addition, a better quality of RBCs.

https://ift.tt/2sISwXB

Cancers, Vol. 10, Pages 188: Gain-of-Function (GOF) Mutant p53 as Actionable Therapeutic Target

Cancers, Vol. 10, Pages 188: Gain-of-Function (GOF) Mutant p53 as Actionable Therapeutic Target

Cancers doi: 10.3390/cancers10060188

Authors: Ramona Schulz-Heddergott Ute M. Moll

p53 missense mutant alleles are present in nearly 40% of all human tumors. Such mutated alleles generate aberrant proteins that not only lose their tumor-suppressive functions but also frequently act as driver oncogenes, which promote malignant progression, invasion, metastasis, and chemoresistance, leading to reduced survival in patients and mice. Notably, these oncogenic gain-of-function (GOF) missense mutant p53 proteins (mutp53) are constitutively and tumor-specific stabilised. This stabilisation is one key pre-requisite for their GOF and is largely due to mutp53 protection from the E3 ubiquitin ligases Mdm2 and CHIP by the HSP90/HDAC6 chaperone machinery. Recent mouse models provide convincing evidence that tumors with highly stabilized GOF mutp53 proteins depend on them for growth, maintenance, and metastasis, thus creating exploitable tumor-specific vulnerabilities that markedly increase lifespan if intercepted. This identifies mutp53 as a promising cancer-specific drug target. This review discusses direct mutp53 protein-targeting drug strategies that are currently being developed at various preclinical levels.

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