Soluble MICA is elevated in pancreatic cancer: results from a population based case-control study

Abstract

Objectives: Pancreatic cancer is diagnosed at a late stage and has one of the highest cancer mortality rates in the U.S., creating an urgent need for novel early detection tools. A candidate biomarker for use in early detection is the soluble MHC class I-related chain A (s-MICA) ligand, which pancreatic tumors shed to escape immune detection. The objective of this study was to define the association between s-MICA levels and pancreatic cancer, in a population-based case-control study.

Methods: S-MICA was measured in 163 pancreatic cancer cases and 542 controls. Unconditional logistic regression was used to calculate odds ratio (OR) for pancreatic cancer, and 95% confidence intervals (CI). Results: There was a positive association between increasing s-MICA levels and pancreatic cancer: compared to the lowest tertile, the ORs for pancreatic cancer were 1.25 (95% CI: 0.75 - 2.07) and 2.10 (95% CI: 1.29 -3.42) in the second and highest tertiles, respectively (p-trend=0.02).

Conclusions: Our study supports previous work demonstrating a positive association between plasma s-MICA levels and pancreatic cancer. This article is protected by copyright. All rights reserved

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Glyoxalase 2 drives tumorigenesis in human prostate cells in a mechanism involving androgen receptor and p53-p21 axis

Abstract

Glyoxalase 2 (Glo2), a metabolic enzyme, is overexpressed in some human cancers which suggests this enzyme may play a role in human tumorigenesis. In prostate cancer (PCa) the role of Glo2 has been scarcely investigated and there are no studies addressing a causative involvement of this protein in this neoplasia. Here we examined the immunohistochemical profile of Glo2 in human PCa and benign adjacent tissues and investigated Glo2 involvement in PCa development in human prostate cell lines. PCa and matched adjacent normal tissues were obtained from paraffin sections of primary PCa from 20 patients who had undergone radical prostatectomy. Histopathological diagnosis was confirmed for each sample. Glo2 expression analysis was performed by immunohistochemistry in prostate tissues, and by qRT-PCR and immunoblotting in prostate cell lines. The causative and mechanistic role of Glo2 in prostate tumorigenesis was demonstrated by Glo2 ectopic expression/silencing and employing specific activators/inhibitors. Our results showed that Glo2 was selectively expressed in PCa but not in the luminal compartment of the adjacent benign epithelium consistently in all the examined 20 cases. Glo2 expression in PCa was dependent on androgen receptor (AR) and was aimed at stimulating cell proliferation and eluding apoptosis through a mechanism involving the p53-p21 axis. Glo2 was intensely expressed in the basal cells of benign glands but was not involved in PCa genesis. Our results demonstrate for the first time that Glo2 drives prostate tumorigenesis and suggest that it may represent a novel adjuvant marker in the pathological diagnosis of early PCa. This article is protected by copyright. All rights reserved

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Cure rate of postpartum endometritis after different treatments in high produce dairy cows

Abstract

The main objective of this study was to compare the common treatment methods of clinical endometritis (CE) including injection of PGF2a and intrauterine infusion of cephapirin benzathine (CB) with intrauterine infusion of 50% dextrose solution (DEX) and intrauterine infusion of liquid paraffin (LP) in dairy cows. To this end, 188 lactating Holstein cows with clinical signs of endometritis were randomly assigned into five treatment groups and cytological smear was prepared. In group 1 (n = 37), cows were treated with intrauterine infusion of CB. In the second group (n = 53), the treatment protocol included intramuscular injection of 500-mg cloprostenol sodium in cows with corpus luteum (CL) in their ovaries. In group 3 (n = 43), cows were treated with intrauterine infusion of DEX solution. In group 4 (n = 35), cows were treated with intrauterine infusion of LP solution and 20 untreated cows were assigned into a control group (group 5). Clinical treatment rates were 62.2, 66, 60.5, 54.3, and 50% in CB, PG, DEX, LP, and control groups, respectively (P ≥ 0.05). In the cytological assessment, there was no significant difference in reduction in the neutrophil's number in the second examination after treatment (P ≥ 0.05). Percentage of cows with clean vaginal discharge in the second examination is higher in cows with CL than cows without CL in all five groups, but this difference was not significant (P ≥ 0.05). According to the result of this study, future large studies are required for assessment of DEX and LP as alternative therapies for the treatment of CE instead of antibiotics.

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Respiratory tract cadmium-induced injuries—poisoning via intake and water pH could influence their genesis? An experimental study in rats

Abstract

Cadmium exposure may result in a variety of pulmonary diseases. No studies have evaluated tracheal damage or even whether cadmium intake can damage the respiratory tract. We evaluated the possible injuries caused by cadmium poisoning via intake into the respiratory tract and the possible effects of water pH in their genesis. Ninety male Wistar rats were divided into six groups (n = 15): GC5—received CdCl2 (400 mg/l) in the drinking water at an acidic pH of 5; GC7 received CdCl2 (400 mg/l) in the drinking water at an acidic pH of 7.0; GC8—received CdCl2 (400 mg/l) in the drinking water at an acidic pH of 8.0; GW5—received water at an acidic pH of 5.0; GW7—received water at an acidic pH of 7.0; GW8—received water at an acidic pH of 8.0. Animals were euthanized after 6 months. Samples of the trachea and lung were removed for histopathologic analysis. The animals exposed to cadmium presented with goblet cells in the trachea at an average rate of 65.83 cells/6 high-power fields (HPF), whereas unexposed animals showed 85.16 cells/6HPF (p = 0.012). Further, pulmonary emphysema was demonstrated in 71.43 to 100% of exposed cases, whereas the unexposed animals presented emphysema in 6.66 to 15.38% of cases (p < 0.001). The respiratory tract is a target for cadmium-related injuries after intake; however, the pH of the water did not influence the development of these lesions.

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A novel physical colonoscopy simulator based on analysis of data from computed tomography colonography

Abstract

Purpose

Laparoscopic surgery is now practiced widely because of its lower postoperative morbidity. As flexible endoscopy during laparoscopic surgery minimizes surgical trauma further, training in endoscopy will become more important for surgeons. Thus, we designed a physical simulator, the Noda–Kitada–Suzuki (NKS) model, which could provide the more realistic insertion of a colonoscope.

Methods

We designed a colonoscopy simulator, based on information from computed tomography colonography scans of the anatomy and kinetic properties of the colon and rectum.

Results

The transparent skeleton body of the NKS model provides instant visual feedback to the operator and the trainer. Our novel colonoscopy simulator replicates the realistic and reproducible insertion of a colonoscope from the rectum to cecum, providing authentic views of the Houston's valves, the flexures, and mucosal folds. This was verified through an objective questionnaire, with 14 of 16 colonoscopists preferring the NKS model over the previous CM15 model for training purposes. Moreover, the Modified Colonoscopy Simulator Realism Questionnaire analysis confirmed that the NKS model was significantly more realistic than the CM15 for 7 (21.2%) of the 33 items when assessed by 12 colonoscopists.

Conclusion

The NKS model provides a realistic training platform and may improve the quality of training in colonoscopy.

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Erratum to: Osteosarcoma follow-up: chest X-ray or computed tomography?

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A novel physical colonoscopy simulator based on analysis of data from computed tomography colonography

Abstract

Purpose

Laparoscopic surgery is now practiced widely because of its lower postoperative morbidity. As flexible endoscopy during laparoscopic surgery minimizes surgical trauma further, training in endoscopy will become more important for surgeons. Thus, we designed a physical simulator, the Noda–Kitada–Suzuki (NKS) model, which could provide the more realistic insertion of a colonoscope.

Methods

We designed a colonoscopy simulator, based on information from computed tomography colonography scans of the anatomy and kinetic properties of the colon and rectum.

Results

The transparent skeleton body of the NKS model provides instant visual feedback to the operator and the trainer. Our novel colonoscopy simulator replicates the realistic and reproducible insertion of a colonoscope from the rectum to cecum, providing authentic views of the Houston's valves, the flexures, and mucosal folds. This was verified through an objective questionnaire, with 14 of 16 colonoscopists preferring the NKS model over the previous CM15 model for training purposes. Moreover, the Modified Colonoscopy Simulator Realism Questionnaire analysis confirmed that the NKS model was significantly more realistic than the CM15 for 7 (21.2%) of the 33 items when assessed by 12 colonoscopists.

Conclusion

The NKS model provides a realistic training platform and may improve the quality of training in colonoscopy.

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Erratum to: Osteosarcoma follow-up: chest X-ray or computed tomography?

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Screening for mismatch repair deficiency in colorectal cancer: data from three academic medical centers

Abstract

Reflex immunohistochemistry (rIHC) for mismatch repair (MMR) protein expression can be used as a screening tool to detect Lynch Syndrome (LS). Increasingly the mismatch repair-deficient (dMMR) phenotype has therapeutic implications. We investigated the pattern and consequence of testing for dMMR in three Irish Cancer Centres (CCs). CRC databases were analyzed from January 2005–December 2013. CC1 performs IHC upon physician request, CC2 implemented rIHC in November 2008, and CC3 has been performing rIHC since 2004. The number of eligible patients referred to clinical genetic services (CGS), and the number of LS patients per center was determined. 3906 patients were included over a 9-year period. dMMR CRCs were found in 32/153 (21%) of patients at CC1 and 55/536 (10%) at CC2, accounting for 3% and 5% of the CRC population, respectively. At CC3, 182/1737 patients (10%) had dMMR CRCs (P < 0.001). Additional testing for the BRAF V600E mutation, was performed in 49 patients at CC3 prior to CGS referral, of which 29 were positive and considered sporadic CRC. Referrals to CGS were made in 66%, 33%, and 30% of eligible patients at CC1, CC2, and CC3, respectively. LS accounted for CRC in eight patients (0.8%) at CC1, eight patients (0.7%) at CC2, and 20 patients (1.2%) at CC3. Cascade testing of patients with dMMR CRC was not completed in 56%. Universal screening increases the detection of dMMR tumors and LS kindreds. Successful implementation of this approach requires adequate resources for appropriate downstream management of these patients.

Universal screening for MMR deficiency using IHC has been recommended as a screening tool for Lynch Syndrome and is increasingly performed as a molecular predictor of response to immune checkpoint inhibition. Over half of patients in our study with dMMR colorectal cancer did not have downstream investigations for Lynch Syndrome. Successful implementation requires appropriate resourcing to ensure complete cascade testing.

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Screening for mismatch repair deficiency in colorectal cancer: data from three academic medical centers

Abstract

Reflex immunohistochemistry (rIHC) for mismatch repair (MMR) protein expression can be used as a screening tool to detect Lynch Syndrome (LS). Increasingly the mismatch repair-deficient (dMMR) phenotype has therapeutic implications. We investigated the pattern and consequence of testing for dMMR in three Irish Cancer Centres (CCs). CRC databases were analyzed from January 2005–December 2013. CC1 performs IHC upon physician request, CC2 implemented rIHC in November 2008, and CC3 has been performing rIHC since 2004. The number of eligible patients referred to clinical genetic services (CGS), and the number of LS patients per center was determined. 3906 patients were included over a 9-year period. dMMR CRCs were found in 32/153 (21%) of patients at CC1 and 55/536 (10%) at CC2, accounting for 3% and 5% of the CRC population, respectively. At CC3, 182/1737 patients (10%) had dMMR CRCs (P < 0.001). Additional testing for the BRAF V600E mutation, was performed in 49 patients at CC3 prior to CGS referral, of which 29 were positive and considered sporadic CRC. Referrals to CGS were made in 66%, 33%, and 30% of eligible patients at CC1, CC2, and CC3, respectively. LS accounted for CRC in eight patients (0.8%) at CC1, eight patients (0.7%) at CC2, and 20 patients (1.2%) at CC3. Cascade testing of patients with dMMR CRC was not completed in 56%. Universal screening increases the detection of dMMR tumors and LS kindreds. Successful implementation of this approach requires adequate resources for appropriate downstream management of these patients.

Universal screening for MMR deficiency using IHC has been recommended as a screening tool for Lynch Syndrome and is increasingly performed as a molecular predictor of response to immune checkpoint inhibition. Over half of patients in our study with dMMR colorectal cancer did not have downstream investigations for Lynch Syndrome. Successful implementation requires appropriate resourcing to ensure complete cascade testing.

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Cyclosporine is a potential curative treatment option for advanced thymoma

Abstract

Background

Thymectomy can effectively cure most thymoma patients; however, patients with advanced thymoma typically require chemotherapy, which is associated with limited efficacy in this context. Here we provide the first report of a patient with recurrent thymoma who achieved complete remission (CR) using cyclosporine therapy.

Case presentation

A 63-year-old woman who had undergone resection surgery for recurrent type B1 thymoma developed pure red cell aplasia (PRCA), and CT findings revealed thymoma recurrence. After the initiation of orally-administered cyclosporine, PRCA quickly resolved, and the thymoma disappeared without the administration of any anti-thymoma therapy. The patient has remained in CR for over 3 years using only cyclosporine.

Conclusions

This is the first report describing the curative potential of cyclosporine for the treatment of advanced thymoma. Although the mechanism underlying this effect remains unclear, cyclosporine can become a less toxic and more cost-effective treatment option for thymoma compared with conventional therapy. Clinical trials are needed to confirm the therapeutic potential of cyclosporine as a new treatment option for thymoma.

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Cyclosporine is a potential curative treatment option for advanced thymoma

Abstract

Background

Thymectomy can effectively cure most thymoma patients; however, patients with advanced thymoma typically require chemotherapy, which is associated with limited efficacy in this context. Here we provide the first report of a patient with recurrent thymoma who achieved complete remission (CR) using cyclosporine therapy.

Case presentation

A 63-year-old woman who had undergone resection surgery for recurrent type B1 thymoma developed pure red cell aplasia (PRCA), and CT findings revealed thymoma recurrence. After the initiation of orally-administered cyclosporine, PRCA quickly resolved, and the thymoma disappeared without the administration of any anti-thymoma therapy. The patient has remained in CR for over 3 years using only cyclosporine.

Conclusions

This is the first report describing the curative potential of cyclosporine for the treatment of advanced thymoma. Although the mechanism underlying this effect remains unclear, cyclosporine can become a less toxic and more cost-effective treatment option for thymoma compared with conventional therapy. Clinical trials are needed to confirm the therapeutic potential of cyclosporine as a new treatment option for thymoma.

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Association of Serum Trace Elements with Schizophrenia and Effects of Antipsychotic Treatment

Abstract

Variation of serum trace elements was previously reported in schizophrenia (SZ) patients; however, whether such variation is resulted from the antipsychotic treatment remains obscure. A case control study consist of 165 SZ inpatients and 614 healthy controls measured serum magnesium (Mg), Copper (Cu), calcium (Ca), phosphorus (Phos), iron (Fe), and zinc (Zn) to investigate the relationship of trace elements and SZ. The SZ patients were further followed up (average 3.8 weeks) to evaluate the effects of antipsychotic treatment on the trace element concentrations using repeated measures ANOVA analysis. The results showed that higher concentrations of Mg and Phos and lower concentrations of Ca, Fe, and Zn were significant in SZ patients than that of controls (P < 0.01). The age was positively correlated with Fe and Cu, and negatively correlated with Ca, Phos, and Zn in controls (P < 0.05). Fe in male SZ patients was significantly higher than in female (P < 0.001), as well as in paranoid SZ and acute SZ (P < 0.05). Phos significantly increased after risperidone, clozapine, and aripiprazole treatment (P < 0.05), while Cu was decreased after clozapine and aripiprazole treatment. Zn significantly decreased particularly in mixed type SZ, acute SZ, and schizotypal SZ after antipsychotic treatment. These results suggested that higher concentration of Phos and lower concentration of Fe and Zn have important implications for the risk of SZ and the antipsychotic treatment is likely to result in the decreased Fe and increased Phos in the clinical subtypes of SZ.

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Association of Serum Trace Elements with Schizophrenia and Effects of Antipsychotic Treatment

Abstract

Variation of serum trace elements was previously reported in schizophrenia (SZ) patients; however, whether such variation is resulted from the antipsychotic treatment remains obscure. A case control study consist of 165 SZ inpatients and 614 healthy controls measured serum magnesium (Mg), Copper (Cu), calcium (Ca), phosphorus (Phos), iron (Fe), and zinc (Zn) to investigate the relationship of trace elements and SZ. The SZ patients were further followed up (average 3.8 weeks) to evaluate the effects of antipsychotic treatment on the trace element concentrations using repeated measures ANOVA analysis. The results showed that higher concentrations of Mg and Phos and lower concentrations of Ca, Fe, and Zn were significant in SZ patients than that of controls (P < 0.01). The age was positively correlated with Fe and Cu, and negatively correlated with Ca, Phos, and Zn in controls (P < 0.05). Fe in male SZ patients was significantly higher than in female (P < 0.001), as well as in paranoid SZ and acute SZ (P < 0.05). Phos significantly increased after risperidone, clozapine, and aripiprazole treatment (P < 0.05), while Cu was decreased after clozapine and aripiprazole treatment. Zn significantly decreased particularly in mixed type SZ, acute SZ, and schizotypal SZ after antipsychotic treatment. These results suggested that higher concentration of Phos and lower concentration of Fe and Zn have important implications for the risk of SZ and the antipsychotic treatment is likely to result in the decreased Fe and increased Phos in the clinical subtypes of SZ.

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First clinical investigation of a 4D maximum likelihood reconstruction for 4D PET-based treatment verification in ion beam therapy

In clinical applications of Positron Emission Tomography (PET)-based treatment verification in ion beam therapy (PT-PET), detection and interpretation of inconsistencies between Measured PET and Expected PET are mostly limited by Measured PET noise, due to low count statistics, and by Expected PET bias, especially due to inaccurate washout modelling in off-line implementations. In this work, a recently proposed 4D Maximum Likelihood (ML) reconstruction algorithm which considers Measured PET and Expected PET as two different motion phases of a 4D dataset is assessed on clinical 4D PET-CT datasets acquired after carbon ion therapy.

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Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis

Inactivation of NF2/Merlin causes the autosomal dominant cancer predisposition syndrome Familial Neurofibromatosis Type 2 (NF2) and contributes to the development of malignant pleural mesothelioma (MPM). In order to develop a targeted therapy for NF2-mutant tumors, we have exploited the recent realization that Merlin loss drives tumorigenesis by activating the E3 ubiquitin ligase CRL4^DCAF1 - thereby inhibiting the Hippo pathway component Lats. Here, we show that MLN4924 - a NEDD8 activating enzyme (NAE) inhibitor - suppresses CRL4^DCAF1 and attenuates activation of YAP in NF2-mutant tumor cells. Additionally, MLN4924 sensitizes MPM to traditional chemotherapy, presumably as a result of collateral inhibition of cullin-RING ubiquitin ligases (CRLs) involved in DNA repair. However, even in combination with chemotherapy, MLN4924 does not exhibit significant preclinical activity. Further analysis revealed that depletion of DCAF1 or treatment with MLN4924 does not affect mTOR hyperactivation in NF2-mutant tumor cells, suggesting that loss of Merlin activates mTOR independently of CRL4^DCAF1. Intriguingly, combining MLN4924 with the mTOR/PI3K inhibitor GDC-0980 suppresses the growth of NF2-mutant tumor cells in vitro as well as in mouse and patient-derived xenografts. These results provide preclinical rationale for the use of NAE inhibitors in combination with mTOR/PI3K inhibitors in NF2-mutant tumors.

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Modeling of Patient Derived Xenografts in Colorectal Cancer

Developing realistic preclinical models using clinical samples that mirror complex tumor biology and behavior are vital to advancing cancer research. While cell-line cultures have been helpful in generating preclinical data, the genetic divergence between these and corresponding primary tumors has limited clinical translation. Conversely, patient derived xenografts (PDXs) in colorectal cancer (CRC) are highly representative of the genetic and phenotypic heterogeneity in the original tumor. Coupled with high-throughput analyses and bioinformatics, these PDXs represent robust preclinical tools for biomarkers, therapeutic target and drug discovery. <p>Successful PDX engraftment is hypothesized to be related to a series of anecdotal variables namely, tissue source, cancer stage, tumor grade, acquisition strategy, time to implantation, exposure to prior systemic therapy, and genomic heterogeneity of tumors. Although these factors at large can influence practices and patterns related to xenotransplantation, their relative significance in determining the success of establishing PDXs is uncertain. Accordingly, we systematically examined the predictive ability of these factors in establishing PDXs using 90 CRC patient specimens that were subcutaneously implanted into immunodeficient mice. Fifty (56%) PDXs were successfully established. Multivariate analyses showed tissue acquisition strategy [surgery 72.0% (95% confidence interval (CI): 58.2-82.6) vs. biopsy 35% (95%CI: 22.1-50.6%)] to be the key determinant for successful PDX engraftment.</p> <p>These findings contrast with current empiricism in generating PDXs and can serve to simplify or liberalize PDX modelling protocols. Better understanding the relative impact of these factors on efficiency of PDX formation will allow for pervasive integration of these models in care of CRC patients.  

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The multi-kinase inhibitor Debio 0617B reduces maintenance and self-renewal of primary human AML CD34+ stem/progenitor cells.

Acute myelogenous leukemia (AML) is initiated and maintained by leukemia stem cells (LSCs). LSCs are therapy-resistant, cause relapse and represent a major obstacle for the cure of AML. Resistance to therapy is often mediated by aberrant tyrosine kinase (TK) activation. These TKs primarily activate downstream signaling via STAT3/STAT5. In this study, we analyzed the potential to therapeutically target aberrant TK signaling and to eliminate LSCs via the multi-TK inhibitor Debio 0617B. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, SRC, ABL and class III/V receptor TKs. We demonstrate that expression of phospho-STAT3 (pSTAT3) in AML blasts is an independent prognostic factor for overall survival. Furthermore, phospho-STAT5 (pSTAT5) signaling is increased in primary CD34⁺ AML stem/progenitors. STAT3/STAT5 activation depends on tyrosine phosphorylation, mediated by several upstream TKs. Inhibition of single upstream TKs did not eliminate LSCs. In contrast, the multi-TK inhibitor Debio 0617B reduced maintenance and self-renewal of primary human AML CD34⁺ stem/progenitor cells in vitro and in xenotransplantation experiments resulting in long-term elimination of human LSCs and leukemia. Therefore, inhibition of multiple TKs upstream of STAT3/5 may result in sustained therapeutic efficacy of targeted therapy in AML and prevent relapses.

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Discovery and Characterization of Novel Non-substrate and Substrate NAMPT Inhibitors

Cancer cells are highly reliant on nicotinamide adenine dinucleotide (NAD⁺)-dependent processes including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD⁺ salvage from nicotinamide (NAM), has been investigated as a target for anti-cancer therapy. Known NAMPT inhibitors with potent cell activity are composed of a nitrogen-containing aromatic group, which is phosphoribosylated by the enzyme. Here, we identified two novel types of NAM competitive NAMPT inhibitors, only one of which contains a modifiable, aromatic nitrogen that could be a phosphoribosyl acceptor. Both types of compound effectively deplete cellular NAD⁺, and subsequently ATP, and produce cell death when NAMPT is inhibited in cultured cells for more than 48 hours. Careful characterization of the kinetics of NAMPT inhibition in vivo allowed us to optimize dosing to produce sufficient NAD⁺ depletion over time that resulted in efficacy in an HCT116 xenograft model. Our data demonstrate that direct phosphoribosylation of competitive inhibitors by the NAMPT enzyme is not required for potent in vitro cellular activity or in vivo anti-tumor efficacy.

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Vulnerability of small cell lung cancer to apoptosis induced by the combination of BET bromodomain proteins and BCL2 inhibitors

10% to 15% of all lung cancers are small cell lung cancer (SCLC). SCLC usually grows and metastasizes before it is diagnosed and relapses rapidly upon treatment. Unfortunately, no new targeted agent has been approved in the past 30 years for patients with SCLC. The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription initiation and elongation. BET proteins have been shown to regulate expression of key genes in oncogenesis such as MYC, CCND2, and BCL2L1. Here, we demonstrate that ~50% of SCLC cell lines are exquisitely sensitive to growth inhibition by the BET inhibitor, ABBV-075. The majority of these SCLC cell lines underwent apoptosis in response to ABBV-075 treatment via induction of caspase 3/7 activity. ABBV-075 enhanced the expression of proapoptotic protein BIM and down-regulated antiapoptotic proteins BCL2 and BCLxl to a lesser extent. Furthermore, BET inhibition increased BCL2-BIM complex, thus priming the cells for apoptosis. Indeed strong synergy was observed both in vitro and in vivo when co-treating the cells with BET inhibitor and the BH3-mimetic, BCL2 inhibitor venetoclax (ABT-199).  ABBV-075 interaction with venetoclax positively correlated with BCL2 expression.  Taken together, our studies provide a rationale for treating SCLC with BET and BCL2 inhibitors in tumors with high BCL2 protein expression.

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Synergy between androgen receptor antagonism and inhibition of mTOR and HER2 in breast cancer

The androgen receptor (AR) is widely expressed in breast cancer (BC) and evidence suggests dependence on AR signaling for growth and survival. AR antagonists such as enzalutamide and seviteronel have shown success in pre-clinical models and clinical trials of prostate cancer, and are currently being evaluated in BC. Reciprocal regulation between AR and the HER2/PI3K/mTOR pathway may contribute to resistance to HER2- and mTOR-targeted therapies; thus, dual inhibition of these pathways may synergistically inhibit BC growth. HER2+ and triple-negative BC cell lines were treated with AR antagonist plus anti-HER2 monoclonal antibody trastuzumab or mTOR inhibitor everolimus. Apoptosis, cell proliferation and drug synergy were measured in vitro. Pathway component genes and proteins were measured by qRT-PCR, western blot, and reverse phase protein array. In vivo, HER2+ BC xenografts were treated with enzalutamide, everolimus, trastuzumab, and combinations of these drugs. AR antagonists inhibited proliferation of both HER2+ and TNBC cell lines. Combining AR antagonist and either everolimus or trastuzumab resulted in synergistic inhibition of proliferation. Dihydrotestosterone caused increased phosphorylation of HER2 and/or HER3 that was attenuated by AR inhibition. Everolimus caused an increase in total AR, phosphorylation of HER2 and/or HER3, and these effects were abrogated by enzalutamide. Growth of trastuzumab-resistant HER2+ xenograft tumors was inhibited by enzalutamide, and combining enzalutamide with everolimus decreased tumor viability more than either single agent. AR antagonists synergize with FDA-approved BC therapies such as everolimus and trastuzumab through distinct mechanisms. Treatment combinations are effective in trastuzumab-resistant HER2+ BC cells in vivo.

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Targeting insulin receptor in breast cancer using small engineered protein scaffolds

Insulin receptor (InsR) and the type I insulin-like growth factor (IGF1R) are homologous receptors necessary for signal transduction by their cognate ligands insulin, insulin-like growth factor-I and -II (IGF-I and IGF-II). IGF1R monoclonal antibodies, intended to inhibit malignant phenotypic signaling, failed to show benefit in patients with endocrine-resistant tumors in phase III clinical trials. Our previous work showed that in tamoxifen-resistant cells IGF1R expression was lacking but InsR inhibition effectively blocked growth. In endocrine-sensitive breast cancer cells, insulin was not growth stimulatory, likely due to the presence of hybrid InsR/IGF1R, which has high affinity for IGF-I, but not insulin. Combination inhibition of InsR and IGF1R showed complete suppression of the system in endocrine-sensitive breast cancer cells. To develop InsR-binding agents, we employed a small protein scaffold, T7 phage Gene 2 Protein (Gp2) with the long-term goal of creating effective InsR inhibitors and diagnostics. Using yeast display and directed evolution, we identified three Gp2 variants (Gp2 #1, #5 and #10) with low nanomolar affinity and specific binding to cell-surface InsR. These Gp2 variants inhibited insulin-mediated monolayer proliferation in both endocrine-sensitive and -resistant breast cancer, but did not downregulate InsR expression. Gp2 #5 and Gp2#10 disrupted InsR function by inhibiting ligand-induced receptor activation. In contrast, Gp2 #1 did not block InsR phosphorylation. Notably, Gp2 #1 binding was enhanced by pre-treatment of cells with insulin suggesting a unique receptor-ligand binding mode. These Gp2 variants are the first non-immunoglobulin protein scaffolds to target insulin receptor and present compelling opportunity for modulation of InsR signaling.

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Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis

Inactivation of NF2/Merlin causes the autosomal dominant cancer predisposition syndrome Familial Neurofibromatosis Type 2 (NF2) and contributes to the development of malignant pleural mesothelioma (MPM). In order to develop a targeted therapy for NF2-mutant tumors, we have exploited the recent realization that Merlin loss drives tumorigenesis by activating the E3 ubiquitin ligase CRL4^DCAF1 - thereby inhibiting the Hippo pathway component Lats. Here, we show that MLN4924 - a NEDD8 activating enzyme (NAE) inhibitor - suppresses CRL4^DCAF1 and attenuates activation of YAP in NF2-mutant tumor cells. Additionally, MLN4924 sensitizes MPM to traditional chemotherapy, presumably as a result of collateral inhibition of cullin-RING ubiquitin ligases (CRLs) involved in DNA repair. However, even in combination with chemotherapy, MLN4924 does not exhibit significant preclinical activity. Further analysis revealed that depletion of DCAF1 or treatment with MLN4924 does not affect mTOR hyperactivation in NF2-mutant tumor cells, suggesting that loss of Merlin activates mTOR independently of CRL4^DCAF1. Intriguingly, combining MLN4924 with the mTOR/PI3K inhibitor GDC-0980 suppresses the growth of NF2-mutant tumor cells in vitro as well as in mouse and patient-derived xenografts. These results provide preclinical rationale for the use of NAE inhibitors in combination with mTOR/PI3K inhibitors in NF2-mutant tumors.

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Modeling of Patient Derived Xenografts in Colorectal Cancer

Developing realistic preclinical models using clinical samples that mirror complex tumor biology and behavior are vital to advancing cancer research. While cell-line cultures have been helpful in generating preclinical data, the genetic divergence between these and corresponding primary tumors has limited clinical translation. Conversely, patient derived xenografts (PDXs) in colorectal cancer (CRC) are highly representative of the genetic and phenotypic heterogeneity in the original tumor. Coupled with high-throughput analyses and bioinformatics, these PDXs represent robust preclinical tools for biomarkers, therapeutic target and drug discovery. <p>Successful PDX engraftment is hypothesized to be related to a series of anecdotal variables namely, tissue source, cancer stage, tumor grade, acquisition strategy, time to implantation, exposure to prior systemic therapy, and genomic heterogeneity of tumors. Although these factors at large can influence practices and patterns related to xenotransplantation, their relative significance in determining the success of establishing PDXs is uncertain. Accordingly, we systematically examined the predictive ability of these factors in establishing PDXs using 90 CRC patient specimens that were subcutaneously implanted into immunodeficient mice. Fifty (56%) PDXs were successfully established. Multivariate analyses showed tissue acquisition strategy [surgery 72.0% (95% confidence interval (CI): 58.2-82.6) vs. biopsy 35% (95%CI: 22.1-50.6%)] to be the key determinant for successful PDX engraftment.</p> <p>These findings contrast with current empiricism in generating PDXs and can serve to simplify or liberalize PDX modelling protocols. Better understanding the relative impact of these factors on efficiency of PDX formation will allow for pervasive integration of these models in care of CRC patients.  

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The multi-kinase inhibitor Debio 0617B reduces maintenance and self-renewal of primary human AML CD34+ stem/progenitor cells.

Acute myelogenous leukemia (AML) is initiated and maintained by leukemia stem cells (LSCs). LSCs are therapy-resistant, cause relapse and represent a major obstacle for the cure of AML. Resistance to therapy is often mediated by aberrant tyrosine kinase (TK) activation. These TKs primarily activate downstream signaling via STAT3/STAT5. In this study, we analyzed the potential to therapeutically target aberrant TK signaling and to eliminate LSCs via the multi-TK inhibitor Debio 0617B. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, SRC, ABL and class III/V receptor TKs. We demonstrate that expression of phospho-STAT3 (pSTAT3) in AML blasts is an independent prognostic factor for overall survival. Furthermore, phospho-STAT5 (pSTAT5) signaling is increased in primary CD34⁺ AML stem/progenitors. STAT3/STAT5 activation depends on tyrosine phosphorylation, mediated by several upstream TKs. Inhibition of single upstream TKs did not eliminate LSCs. In contrast, the multi-TK inhibitor Debio 0617B reduced maintenance and self-renewal of primary human AML CD34⁺ stem/progenitor cells in vitro and in xenotransplantation experiments resulting in long-term elimination of human LSCs and leukemia. Therefore, inhibition of multiple TKs upstream of STAT3/5 may result in sustained therapeutic efficacy of targeted therapy in AML and prevent relapses.

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Discovery and Characterization of Novel Non-substrate and Substrate NAMPT Inhibitors

Cancer cells are highly reliant on nicotinamide adenine dinucleotide (NAD⁺)-dependent processes including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD⁺ salvage from nicotinamide (NAM), has been investigated as a target for anti-cancer therapy. Known NAMPT inhibitors with potent cell activity are composed of a nitrogen-containing aromatic group, which is phosphoribosylated by the enzyme. Here, we identified two novel types of NAM competitive NAMPT inhibitors, only one of which contains a modifiable, aromatic nitrogen that could be a phosphoribosyl acceptor. Both types of compound effectively deplete cellular NAD⁺, and subsequently ATP, and produce cell death when NAMPT is inhibited in cultured cells for more than 48 hours. Careful characterization of the kinetics of NAMPT inhibition in vivo allowed us to optimize dosing to produce sufficient NAD⁺ depletion over time that resulted in efficacy in an HCT116 xenograft model. Our data demonstrate that direct phosphoribosylation of competitive inhibitors by the NAMPT enzyme is not required for potent in vitro cellular activity or in vivo anti-tumor efficacy.

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Vulnerability of small cell lung cancer to apoptosis induced by the combination of BET bromodomain proteins and BCL2 inhibitors

10% to 15% of all lung cancers are small cell lung cancer (SCLC). SCLC usually grows and metastasizes before it is diagnosed and relapses rapidly upon treatment. Unfortunately, no new targeted agent has been approved in the past 30 years for patients with SCLC. The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription initiation and elongation. BET proteins have been shown to regulate expression of key genes in oncogenesis such as MYC, CCND2, and BCL2L1. Here, we demonstrate that ~50% of SCLC cell lines are exquisitely sensitive to growth inhibition by the BET inhibitor, ABBV-075. The majority of these SCLC cell lines underwent apoptosis in response to ABBV-075 treatment via induction of caspase 3/7 activity. ABBV-075 enhanced the expression of proapoptotic protein BIM and down-regulated antiapoptotic proteins BCL2 and BCLxl to a lesser extent. Furthermore, BET inhibition increased BCL2-BIM complex, thus priming the cells for apoptosis. Indeed strong synergy was observed both in vitro and in vivo when co-treating the cells with BET inhibitor and the BH3-mimetic, BCL2 inhibitor venetoclax (ABT-199).  ABBV-075 interaction with venetoclax positively correlated with BCL2 expression.  Taken together, our studies provide a rationale for treating SCLC with BET and BCL2 inhibitors in tumors with high BCL2 protein expression.

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Synergy between androgen receptor antagonism and inhibition of mTOR and HER2 in breast cancer

The androgen receptor (AR) is widely expressed in breast cancer (BC) and evidence suggests dependence on AR signaling for growth and survival. AR antagonists such as enzalutamide and seviteronel have shown success in pre-clinical models and clinical trials of prostate cancer, and are currently being evaluated in BC. Reciprocal regulation between AR and the HER2/PI3K/mTOR pathway may contribute to resistance to HER2- and mTOR-targeted therapies; thus, dual inhibition of these pathways may synergistically inhibit BC growth. HER2+ and triple-negative BC cell lines were treated with AR antagonist plus anti-HER2 monoclonal antibody trastuzumab or mTOR inhibitor everolimus. Apoptosis, cell proliferation and drug synergy were measured in vitro. Pathway component genes and proteins were measured by qRT-PCR, western blot, and reverse phase protein array. In vivo, HER2+ BC xenografts were treated with enzalutamide, everolimus, trastuzumab, and combinations of these drugs. AR antagonists inhibited proliferation of both HER2+ and TNBC cell lines. Combining AR antagonist and either everolimus or trastuzumab resulted in synergistic inhibition of proliferation. Dihydrotestosterone caused increased phosphorylation of HER2 and/or HER3 that was attenuated by AR inhibition. Everolimus caused an increase in total AR, phosphorylation of HER2 and/or HER3, and these effects were abrogated by enzalutamide. Growth of trastuzumab-resistant HER2+ xenograft tumors was inhibited by enzalutamide, and combining enzalutamide with everolimus decreased tumor viability more than either single agent. AR antagonists synergize with FDA-approved BC therapies such as everolimus and trastuzumab through distinct mechanisms. Treatment combinations are effective in trastuzumab-resistant HER2+ BC cells in vivo.

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Targeting insulin receptor in breast cancer using small engineered protein scaffolds

Insulin receptor (InsR) and the type I insulin-like growth factor (IGF1R) are homologous receptors necessary for signal transduction by their cognate ligands insulin, insulin-like growth factor-I and -II (IGF-I and IGF-II). IGF1R monoclonal antibodies, intended to inhibit malignant phenotypic signaling, failed to show benefit in patients with endocrine-resistant tumors in phase III clinical trials. Our previous work showed that in tamoxifen-resistant cells IGF1R expression was lacking but InsR inhibition effectively blocked growth. In endocrine-sensitive breast cancer cells, insulin was not growth stimulatory, likely due to the presence of hybrid InsR/IGF1R, which has high affinity for IGF-I, but not insulin. Combination inhibition of InsR and IGF1R showed complete suppression of the system in endocrine-sensitive breast cancer cells. To develop InsR-binding agents, we employed a small protein scaffold, T7 phage Gene 2 Protein (Gp2) with the long-term goal of creating effective InsR inhibitors and diagnostics. Using yeast display and directed evolution, we identified three Gp2 variants (Gp2 #1, #5 and #10) with low nanomolar affinity and specific binding to cell-surface InsR. These Gp2 variants inhibited insulin-mediated monolayer proliferation in both endocrine-sensitive and -resistant breast cancer, but did not downregulate InsR expression. Gp2 #5 and Gp2#10 disrupted InsR function by inhibiting ligand-induced receptor activation. In contrast, Gp2 #1 did not block InsR phosphorylation. Notably, Gp2 #1 binding was enhanced by pre-treatment of cells with insulin suggesting a unique receptor-ligand binding mode. These Gp2 variants are the first non-immunoglobulin protein scaffolds to target insulin receptor and present compelling opportunity for modulation of InsR signaling.

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Retraction Note: MicroRNA-203 suppresses gastric cancer growth by targeting PIBF1/Akt signaling

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Antibiotic Stewardship im Alltag – „Fragen Sie Ihren Arzt und Apotheker!“

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 274-286
DOI: 10.1055/s-0042-122109

Antibiotic Stewardship (ABS) lässt sich nicht alleine praktizieren. Ein gut etabliertes, interdisziplinäres ABS-Team mit Mandat und Deputat durch die Geschäftsführung kann den Anforderungen im Alltag und bei Ausnahmesituationen wie z. B. einem Ausbruch durch einen multiresistenten Erreger gerecht werden. Klinisch-infektiologische Kompetenz ist dabei für alle Teammitglieder grundlegend. Die Rollen des ABS-Teams bei einem Ausbruchsgeschehen wie dem hier beschriebenen durch einen 4MRGN A. baumannii sind vielfältig. Der rationale Einsatz von Reserveantibiotika und Dosisoptimierung von Antiinfektiva, z. B. durch therapeutisches Drug Monitoring (TDM), stehen dabei im Vordergrund. Durch restriktiven Einsatz von Antibiotika kann der antibiotische Selektionsdruck gesenkt und damit der Bildung weiterer Resistenzen entgegengewirkt werden. Der Einsatz von Reserveantibiotika im Rahmen eines Ausbruchsgeschehens führt zu erheblichen Kostensteigerungen bei gleichzeitig sinkenden Patientenzahlen. Interdisziplinarität zwischen der Hygiene, dem ABS-Team und den verschiedenen Kliniken sowie Unterstützung durch die Geschäftsführung sind wichtig für die Prävention und auch das Management von Ausbrüchen durch multiresistente Erreger.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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Schnellübersicht der Anästhesie und Notfallmedizin

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 245-245
DOI: 10.1055/s-0042-120975

Georg Thieme Verlag KG Stuttgart · New York

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Beatmung mit reinem Sauerstoff verbessert nicht Ergebnisse bei der Reanimation

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 238-239
DOI: 10.1055/s-0043-106424

Georg Thieme Verlag KG Stuttgart · New York

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Stets aktueller Klassiker

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 244-244
DOI: 10.1055/s-0042-106750

Georg Thieme Verlag KG Stuttgart · New York

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Intravenöse Eisengabe: keine signifikante Einsparung von Transfusionen

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 238-238
DOI: 10.1055/s-0043-106426

Georg Thieme Verlag KG Stuttgart · New York

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Antibiotic Stewardship und Hygiene – 2 Seiten einer Medaille

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 248-259
DOI: 10.1055/s-0042-122129

In der öffentlichen Wahrnehmung werden hohe Raten von multiresistenten Erregern in medizinischen Einrichtungen vor allem mit zwei Begriffen assoziiert: erstens „Krankenhaus" und zweitens „Hygieneproblem". Wahrscheinlich mindestens ebenso wichtig oder sogar wichtiger ist jedoch der Antibiotikaeinsatz im ambulanten und stationären Bereich. Antibiotika selektionieren multiresistente Erreger (MRE). Durch die Mikrobiomforschung werden wir diese Zusammenhänge in der Zukunft besser verstehen. Wahrscheinlich bieten sich dadurch auch neue Ansatzpunkte für die Prävention der Ausbreitung von multiresistenten Erregern. Die vorliegenden Daten unterstreichen die Notwendigkeit der engen Interaktion zwischen Krankenhaushygiene und einer rationalen Antiinfektiva-Verordnung (Antibiotic Stewardship).
[...]

Georg Thieme Verlag KG Stuttgart · New York

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Subduralhämatom nach PDA häufiger als angenommen

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 239-240
DOI: 10.1055/s-0043-106425

Georg Thieme Verlag KG Stuttgart · New York

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Quiz intensiv – Stellen Sie die Diagnose!

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 298-302
DOI: 10.1055/s-0043-103259

Georg Thieme Verlag KG Stuttgart · New York

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Gabapentin – wenig analgetische Effekte in der Akutschmerztherapie

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 240-241
DOI: 10.1055/s-0043-102203

Georg Thieme Verlag KG Stuttgart · New York

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Alle Aspekte der modernen Schmerzmedizin auf einen Blick

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 244-244
DOI: 10.1055/s-0042-120976

Georg Thieme Verlag KG Stuttgart · New York

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Patienten erinnern sich an schmerzhafte Maßnahmen auf der ITS

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 241-241
DOI: 10.1055/s-0042-122656

Georg Thieme Verlag KG Stuttgart · New York

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Antibiotic Stewardship: Es ist fünf vor zwölf!

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 246-247
DOI: 10.1055/s-0043-104571

Georg Thieme Verlag KG Stuttgart · New York

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Fit für die Prüfung „Spezielle Schmerztherapie“

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 243-243
DOI: 10.1055/s-0042-104433

Georg Thieme Verlag KG Stuttgart · New York

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Antibiotic Stewardship – From Bench to Bedside

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 260-273
DOI: 10.1055/s-0043-100499

Der Artikel erläutert die praktische Umsetzung eines Antibiotic Stewardship (ABS) in der Klinik. Bei steigender Prävalenz von resistenten Bakterien ist die Ärzteschaft aufgefordert, Antibiotikaverordnungen kritisch zu hinterfragen und zu reduzieren. ABS-Programme sollen dies unterstützen. Hierbei muss insbesondere das Engagement der Klinikleitungen im ABS besser werden. Das Problembewusstsein für den Antibiotikaverbrauch muss besser werden und die Daten darüber intern transparent kommuniziert werden. Jedoch auch in der Ärzteschaft gibt es Schulungsbedarf. Das pathophysiologische Verständnis sowie die akkurate Diagnostik von Infektionserkrankungen müssen verbessert werden. Ärzte brauchen den Mut, auf Antibiotika zu verzichten. Der Konsens innerhalb einer Abteilung und eines Krankenhauses zur Vorenthaltung von Antibiotika muss gestärkt werden. Dabei muss jedoch auch das Bewusstsein steigen, die Sepsis als Notfall zu behandeln und dabei primär die Fokussanierung anzustreben und nicht nur die schnelle Antibiotikatherapie. Die mikrobiologische Präanalytik ist von entscheidender Bedeutung. Hier müssen weniger Abstriche, sondern mehr aussagekräftige Analysemethoden wie Blutkulturen oder invasive Proben angestrebt werden. Schließlich kommt der Interaktionen zwischen Klinikern, Mikrobiologen und Krankenhaushygienikern ein hoher Stellenwert zu.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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Ein praxisorientierter Survival-Guide für den Intensivalltag

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 243-244
DOI: 10.1055/s-0042-105826

Georg Thieme Verlag KG Stuttgart · New York

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Management des massiven intraoperativen Blutverlusts anhand eines Fallbeispiels

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 288-296
DOI: 10.1055/s-0042-102821

Der massive intraoperative Blutverlust stellt eine potenziell lebensbedrohliche Komplikation während eines operativen Eingriffs dar. Die letale Trias aus schockbedingter Azidose, Hypothermie und Koagulopathie verstärkt die Blutungsneigung zusätzlich. Um diesen circulus vitiosus zu vermeiden, erfordert das Management einer intraoperativen Massivblutung ein strukturiertes und standardisiertes Vorgehen. Vorrangige Behandlungsziele sind dabei die Aufrechterhaltung einer adäquaten Gewebeoxygenierung, die Wiederherstellung einer suffizienten Gerinnungsfunktion, sowie Normothermie und die Homöostase des Säure-Basen- und Elektrolythaushaltes. Der vorliegende Artikel veranschaulicht diese Therapieziele und ihre pathophysiologischen Hintergründe anhand eines Fallbeispiels.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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Vermeidung von Feuer/Brand/Explosion im OP

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 303-309
DOI: 10.1055/s-0042-116688

Die offene Sauerstoffgabe bei Patienten unter Sedierung und die Anwendung von Elektrokoagulation führen die Hitliste im Risikoprofil von Feuer, Brand, oder gar einer Explosion (FBE) in der Nähe von Menschen im OP. Das wesentliche Risiko ist das Dreieck „Oxidation – Zündenergie – entzündbares Material" (OZE). Ein hohes Risiko haben Eingriffe innerhalb oder in der Nähe des Luftwegs bei Anwendung von Laserenergie. Insgesamt treffen diese Ereignisse selten, aber mit steigender Tendenz und meist vollkommen unerwartet ein. Die verheerenden Konsequenzen sowie – bei sachgerechter Durchführung – die mögliche Vermeidung unterstreichen die Frage, mit welchen Maßnahmen das Risiko reduziert oder das Ereignis gar verhindert werden kann.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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Intubation fehlgeschlagen – und dann?

Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 237-238
DOI: 10.1055/s-0043-106427

Georg Thieme Verlag KG Stuttgart · New York

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Tumor cell expression of immune inhibitory molecules and tumor-infiltrating lymphocyte count predict cancer-specific survival in pancreatic and ampullary cancer

Abstract

Understanding the mechanisms of immune resistance in pancreatic and ampullary cancers is crucial for the development of suitable biomarkers and effective immunotherapeutics. Our aim was to examine the expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM, IDO and HLA-G, as well as CD8+ and FoxP3+ tumor infiltrating lymphocytes (TIL), in pancreatic and ampullary cancers, and to relate their individual, as well as their combined expression, to cancer survival. Tumor tissue from 224 patients with resected pancreatic (n=148) and ampullary (n=76) cancer was used to construct tissue-microarrays. Expression of immune inhibitory molecules and TIL was examined by immunohistochemistry. We show that immune inhibitory molecules are prevalently expressed. Moreover, high tumor expression of PD-L1 (p=.002), Gal-9 (p=.003), HVEM (p=.001), IDO (p=.049), HLA-G (p=.004) and high CD8/FoxP3 TIL ratio (p=.006) were associated with improved cancer-specific survival. All immune biomarkers, with the exception of IDO, were individually predictive of cancer-specific survival when adjusted for clinicopathologic characteristics. For every additional immune biomarker present survival was almost two-fold prolonged (HR 0.57 95%CI 0.47-0.69, p<.0001). When patients with pancreatic and ampullary cancer were analyzed separately the results were similar. We conclude that pancreas and ampullary cancers are rich in expression of immune-inhibitory molecules. These molecules can be targets for future immunotherapeutics, as well as form powerful immunological biomarkers. We propose that such immune biomarker panels be included in future prospective immunotherapy trials. This article is protected by copyright. All rights reserved.

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Long-distance interaction of the integrated HPV fragment with MYC gene and 8q24.22 region up-regulating the allele-specific MYC expression in HeLa cells

Abstract

Human papillomavirus (HPV) infection is the most important risk factor for cervical cancer development. In HeLa cell line, the HPV viral genome is integrated at 8q24 in one allele of chromosome 8. It has been reported that the HPV fragment integrated in HeLa genome can cis-activate the expression of proto-oncogene MYC, which is located at 500 kb downstream of the integrated site. However, the underlying molecular mechanism of this regulation is unknown. A recent study reported that MYC was highly expressed exclusively from the HPV-integrated haplotype, and a long-range chromatin interaction between the integrated HPV fragment and MYC gene has been hypothesized. In this study, we provided the experimental evidences supporting this long-range chromatin interaction in HeLa cells by using Chromosome Conformation Capture (3C) method. We found that the integrated HPV fragment, MYC and 8q24.22 was close to each other and might form a trimer in spatial location. When knocking out the integrated HPV fragment or 8q24.22 region from chromosome 8 by CRISPR/Cas9 system, the expression of MYC reduced dramatically in HeLa cells. Interestingly, decreased expression was only observed in three from eight cell clones, when only one 8q24.22 allele was knocked out. Functionally, HPV knockout caused senescence-associated acidic β-gal activity in HeLa cells. These data indicate a long-distance interaction of the integrated HPV fragment with MYC gene and 8q24.22 region, providing an alternative mechanism relevant to the carcinogenicity of HPV integration. This article is protected by copyright. All rights reserved.

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Genetic polymorphisms associated with pancreatic cancer survival: A genome-wide association study

Abstract

Previous findings on the association of genetic factors and pancreatic cancer survival are limited and inconsistent. In a two-stage study, we analyzed the existing genome-wide association study dataset of 868 pancreatic cancer patients from MD Anderson Cancer Center in relation to overall survival using Cox regression. Top hits were selected for replication in another 820 patients from the same institution using the Taqman genotyping method. Functional annotation, pathway analysis, and gene expression analysis were conducted using existing software and databases. We discovered genome-wide significant associations of patient survival with three imputed SNPs which, in complete LD (r²=1), were intronic SNPs of the PAIP2B (rs113988120) and DYSF genes (rs112493246 and rs138529893) located on chromosome 2. The variant alleles were associated with a 3.06-fold higher risk of death (95% confidence interval [CI]=2.10-4.47, P = 6.4 × 10^-9) after adjusting for clinical factors. Eleven SNPs were tested in the replication study and the association of rs113988120 with survival was confirmed (HR: 1.57, 95% CI: 1.13-2.20,P = 0.008). In silico analysis found rs1139988120 might lead to altered motif. This locus is in LD (D'=0.77) with 3 eQTL SNPs near or belong to the NAGK and MCEE genes. According to The Cancer Genome Atlas data and our previous RNA-sequencing data, the mRNA expression level of PAIP2B but not NAGK, MCEE or DYSF was significantly lower in pancreatic tumors than in normal adjacent tissues. Additional validation efforts and functional studies are warranted to demonstrate whether PAIP2B is a novel tumor suppressor gene and a potential therapeutic target for pancreatic cancer. This article is protected by copyright. All rights reserved.

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Human papillomavirus E7 protein detection as a method of triage to colposcopy of HPV positive women, in comparison to genotyping and cytology. Final results of the PIPAVIR study

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Patient monitoring through liquid biopsies using circulating tumor DNA

Abstract

Tumors release components such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and tumor-derived extracellular vesicles into the circulation. Multiple studies have demonstrated that molecular information about tumors and metastases can be extracted from these factors, which are therefore frequently referred to as "liquid biopsies". Liquid biopsies allow the longitudinal monitoring of tumor genomes non-invasively and may hence ensure that patients receive appropriate treatments that target the molecular features of their disease. Accordingly, the number of studies employing liquid biopsy based assays has been skyrocketing in the last few years. Here, we focus on three important issues, which are of high relevance for monitoring tumor genomes. First, we analyze the relation between the allele frequency of somatic tumor-specific mutations and the tumor fraction within plasma DNA. Second, we ask how well current tumor evolution models correlate with findings in longitudinal liquid biopsy studies. And, finally, as sensitivity is one of the key challenges of mutation detection, we address the challenge of detecting mutations occurring at very low allele frequencies in plasma DNA. This article is protected by copyright. All rights reserved.

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Benefit-to-harm ratio of the Danish breast cancer screening programme

ABSTRACT

The primary aim of breast cancer screening is to reduce breast cancer mortality, but screening also has negative side-effects as overdiagnosis. To evaluate a screening programme, both benefits and harms should be considered. Published estimates of the benefit-to-harm ratio, the number of breast cancer deaths prevented divided by the number of overdiagnosed breast cancer cases, varied considerably. The objective of the study was to estimate the benefit-to-harm ratio of breast cancer screening in Denmark. The numbers of breast cancer deaths prevented and overdiagnosed cases (invasive and ductal carcinoma in situ (DCIS)) were estimated per 1,000 women aged 50-79, using national published estimates for breast cancer mortality and overdiagnosis, and national incidence and mortality rates. Estimations were made for both invited and screened women. Among 1,000 women invited to screening from age 50 to age 69 and followed until age 79, we estimated that 5.4 breast cancer deaths would be prevented and 2.1 cases overdiagnosed, under the observed scenario in Denmark of a breast cancer mortality reduction of 23.4% and 2.3% of the breast cancer cases being overdiagnosed. The estimated benefit-to-harm ratio was 2.6 for invited women and 2.5 for screened women. Hence, 2-3 women would be prevented from dying from breast cancer for every woman overdiagnosed with invasive breast cancer or DCIS. The difference between the previous published ratios and 2.6 for Denmark is probably more a reflection of the accuracy of the underlying estimates than of the actual screening programmes. Therefore, benefit-to-harm ratios should be used cautiously. This article is protected by copyright. All rights reserved.

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Tumor cell expression of immune inhibitory molecules and tumor-infiltrating lymphocyte count predict cancer-specific survival in pancreatic and ampullary cancer

Abstract

Understanding the mechanisms of immune resistance in pancreatic and ampullary cancers is crucial for the development of suitable biomarkers and effective immunotherapeutics. Our aim was to examine the expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM, IDO and HLA-G, as well as CD8+ and FoxP3+ tumor infiltrating lymphocytes (TIL), in pancreatic and ampullary cancers, and to relate their individual, as well as their combined expression, to cancer survival. Tumor tissue from 224 patients with resected pancreatic (n=148) and ampullary (n=76) cancer was used to construct tissue-microarrays. Expression of immune inhibitory molecules and TIL was examined by immunohistochemistry. We show that immune inhibitory molecules are prevalently expressed. Moreover, high tumor expression of PD-L1 (p=.002), Gal-9 (p=.003), HVEM (p=.001), IDO (p=.049), HLA-G (p=.004) and high CD8/FoxP3 TIL ratio (p=.006) were associated with improved cancer-specific survival. All immune biomarkers, with the exception of IDO, were individually predictive of cancer-specific survival when adjusted for clinicopathologic characteristics. For every additional immune biomarker present survival was almost two-fold prolonged (HR 0.57 95%CI 0.47-0.69, p<.0001). When patients with pancreatic and ampullary cancer were analyzed separately the results were similar. We conclude that pancreas and ampullary cancers are rich in expression of immune-inhibitory molecules. These molecules can be targets for future immunotherapeutics, as well as form powerful immunological biomarkers. We propose that such immune biomarker panels be included in future prospective immunotherapy trials. This article is protected by copyright. All rights reserved.

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Long-distance interaction of the integrated HPV fragment with MYC gene and 8q24.22 region up-regulating the allele-specific MYC expression in HeLa cells

Abstract

Human papillomavirus (HPV) infection is the most important risk factor for cervical cancer development. In HeLa cell line, the HPV viral genome is integrated at 8q24 in one allele of chromosome 8. It has been reported that the HPV fragment integrated in HeLa genome can cis-activate the expression of proto-oncogene MYC, which is located at 500 kb downstream of the integrated site. However, the underlying molecular mechanism of this regulation is unknown. A recent study reported that MYC was highly expressed exclusively from the HPV-integrated haplotype, and a long-range chromatin interaction between the integrated HPV fragment and MYC gene has been hypothesized. In this study, we provided the experimental evidences supporting this long-range chromatin interaction in HeLa cells by using Chromosome Conformation Capture (3C) method. We found that the integrated HPV fragment, MYC and 8q24.22 was close to each other and might form a trimer in spatial location. When knocking out the integrated HPV fragment or 8q24.22 region from chromosome 8 by CRISPR/Cas9 system, the expression of MYC reduced dramatically in HeLa cells. Interestingly, decreased expression was only observed in three from eight cell clones, when only one 8q24.22 allele was knocked out. Functionally, HPV knockout caused senescence-associated acidic β-gal activity in HeLa cells. These data indicate a long-distance interaction of the integrated HPV fragment with MYC gene and 8q24.22 region, providing an alternative mechanism relevant to the carcinogenicity of HPV integration. This article is protected by copyright. All rights reserved.

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Genetic polymorphisms associated with pancreatic cancer survival: A genome-wide association study

Abstract

Previous findings on the association of genetic factors and pancreatic cancer survival are limited and inconsistent. In a two-stage study, we analyzed the existing genome-wide association study dataset of 868 pancreatic cancer patients from MD Anderson Cancer Center in relation to overall survival using Cox regression. Top hits were selected for replication in another 820 patients from the same institution using the Taqman genotyping method. Functional annotation, pathway analysis, and gene expression analysis were conducted using existing software and databases. We discovered genome-wide significant associations of patient survival with three imputed SNPs which, in complete LD (r²=1), were intronic SNPs of the PAIP2B (rs113988120) and DYSF genes (rs112493246 and rs138529893) located on chromosome 2. The variant alleles were associated with a 3.06-fold higher risk of death (95% confidence interval [CI]=2.10-4.47, P = 6.4 × 10^-9) after adjusting for clinical factors. Eleven SNPs were tested in the replication study and the association of rs113988120 with survival was confirmed (HR: 1.57, 95% CI: 1.13-2.20,P = 0.008). In silico analysis found rs1139988120 might lead to altered motif. This locus is in LD (D'=0.77) with 3 eQTL SNPs near or belong to the NAGK and MCEE genes. According to The Cancer Genome Atlas data and our previous RNA-sequencing data, the mRNA expression level of PAIP2B but not NAGK, MCEE or DYSF was significantly lower in pancreatic tumors than in normal adjacent tissues. Additional validation efforts and functional studies are warranted to demonstrate whether PAIP2B is a novel tumor suppressor gene and a potential therapeutic target for pancreatic cancer. This article is protected by copyright. All rights reserved.

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Human papillomavirus E7 protein detection as a method of triage to colposcopy of HPV positive women, in comparison to genotyping and cytology. Final results of the PIPAVIR study

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Patient monitoring through liquid biopsies using circulating tumor DNA

Abstract

Tumors release components such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and tumor-derived extracellular vesicles into the circulation. Multiple studies have demonstrated that molecular information about tumors and metastases can be extracted from these factors, which are therefore frequently referred to as "liquid biopsies". Liquid biopsies allow the longitudinal monitoring of tumor genomes non-invasively and may hence ensure that patients receive appropriate treatments that target the molecular features of their disease. Accordingly, the number of studies employing liquid biopsy based assays has been skyrocketing in the last few years. Here, we focus on three important issues, which are of high relevance for monitoring tumor genomes. First, we analyze the relation between the allele frequency of somatic tumor-specific mutations and the tumor fraction within plasma DNA. Second, we ask how well current tumor evolution models correlate with findings in longitudinal liquid biopsy studies. And, finally, as sensitivity is one of the key challenges of mutation detection, we address the challenge of detecting mutations occurring at very low allele frequencies in plasma DNA. This article is protected by copyright. All rights reserved.

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Benefit-to-harm ratio of the Danish breast cancer screening programme

ABSTRACT

The primary aim of breast cancer screening is to reduce breast cancer mortality, but screening also has negative side-effects as overdiagnosis. To evaluate a screening programme, both benefits and harms should be considered. Published estimates of the benefit-to-harm ratio, the number of breast cancer deaths prevented divided by the number of overdiagnosed breast cancer cases, varied considerably. The objective of the study was to estimate the benefit-to-harm ratio of breast cancer screening in Denmark. The numbers of breast cancer deaths prevented and overdiagnosed cases (invasive and ductal carcinoma in situ (DCIS)) were estimated per 1,000 women aged 50-79, using national published estimates for breast cancer mortality and overdiagnosis, and national incidence and mortality rates. Estimations were made for both invited and screened women. Among 1,000 women invited to screening from age 50 to age 69 and followed until age 79, we estimated that 5.4 breast cancer deaths would be prevented and 2.1 cases overdiagnosed, under the observed scenario in Denmark of a breast cancer mortality reduction of 23.4% and 2.3% of the breast cancer cases being overdiagnosed. The estimated benefit-to-harm ratio was 2.6 for invited women and 2.5 for screened women. Hence, 2-3 women would be prevented from dying from breast cancer for every woman overdiagnosed with invasive breast cancer or DCIS. The difference between the previous published ratios and 2.6 for Denmark is probably more a reflection of the accuracy of the underlying estimates than of the actual screening programmes. Therefore, benefit-to-harm ratios should be used cautiously. This article is protected by copyright. All rights reserved.

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Reduced intensity conditioning of allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia in patients older than 50 years of age: a systematic review and meta-analysis

Abstract

Purpose

A systematic review and meta-analysis were performed to explore the efficacy and safety of allogeneic hematopoietic stem cell transplantation with a reduced intensity conditioning regimen in elderly patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

Methods

Overall survival (OS) and event-free survival (EFS) were established as the primary endpoints for directly assessing the efficacy, and non-relapse mortality (NRM) for safety. The eligible patients were at or above 50 years of age, and the outcomes of the typical elderly patients (≥60 years) were analyzed individually.

Results

The pooled estimates (95% confidence interval (CI)) for 1-year OS, EFS and NRM were 65 (55–74)  %, 50 (44–55)  % and 26 (21–30)  %, respectively; as for the patients ≥60 years of age, these were 63 (53–72) %, 46 (41–50)  % and 28 (23–32) %, respectively. No significantly statistical difference achieved between MDS and AML patients in 1-year EFS and NRM [relative risk (RR) 0.91, 95% CI 0.80–1.04; P = 0.172 and RR 1.18, 95% CI 0.82–1.69; P = 0.365]. The patients with lower diseases risk had the possibility of higher OS rate at ≥ 3 years than those with higher diseases risk (RR 1.37, 95% CI 0.95–1.97; P = 0.088). The patients had significantly higher 2-year OS and EFS rates in complete remission (CR, CR1 and CR2) at transplantation compared to those with advanced diseases (P < 0.05).

Conclusions

RIC-alloHSCT is a feasible treatment option for the patients older than 50 year of age with MDS and AML. Advanced diseases status and higher diseases risk may be the poor factors for prognosis.

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Impact of intra-tumoral IL17A and IL32 gene expression on T-cell responses and lymph node status in breast cancer patients

Abstract

Purpose

Pro-inflammatory cytokines such as Interleukin-17A (IL17A) and Interleukin-32 (IL32), known to enhance natural killer and T cell responses, are also elevated in human malignancies and linked to poor clinical outcomes. To address this paradox, we evaluated relation between IL17A and IL32 expression and other inflammation- and T cell response-associated genes in breast tumors.

Methods

TaqMan-based gene expression analysis was carried out in seventy-eight breast tumors. The association between IL17A and IL32 transcript levels and T cell response genes, ER status as well as lymph node status was also examined in breast tumors from TCGA dataset.

Results

IL17A expression was detected in 32.7% ER-positive and 84.6% ER-negative tumors, with higher expression in the latter group (26.2 vs 7.1-fold, p < 0.01). ER-negative tumors also showed higher expression of IL32 as opposed to ER-positive tumors (8.7 vs 2.5-fold, p < 0.01). Expression of both IL17A and IL32 genes positively correlated with CCL5, GNLY, TBX21, IL21 and IL23 transcript levels (p < 0.01). Amongst ER-positive tumors, higher IL32 expression significantly correlated with lymph node metastases (p < 0.05). Conversely, in ER-negative subtype, high IL17A and IL32 expression was seen in patients with negative lymph node status (p < 0.05). Tumors with high IL32 and IL17A expression showed higher expression of TH1 response genes studied, an observation validated by similar analysis in the TCGA breast tumors (n=1041). Of note, these tumors were characterized by low expression of a potentially immunosuppressive isoform of IL32 (IL32γ).

Conclusion

These results suggest that high expression of both IL17A and IL32 leads to enhancement of T cell responses. Our study, thus, provides basis for the emergence of strong T cell responses in an inflammatory milieu that have been shown to be associated with better prognosis in ER-negative breast cancer.

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Reduced intensity conditioning of allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia in patients older than 50 years of age: a systematic review and meta-analysis

Abstract

Purpose

A systematic review and meta-analysis were performed to explore the efficacy and safety of allogeneic hematopoietic stem cell transplantation with a reduced intensity conditioning regimen in elderly patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

Methods

Overall survival (OS) and event-free survival (EFS) were established as the primary endpoints for directly assessing the efficacy, and non-relapse mortality (NRM) for safety. The eligible patients were at or above 50 years of age, and the outcomes of the typical elderly patients (≥60 years) were analyzed individually.

Results

The pooled estimates (95% confidence interval (CI)) for 1-year OS, EFS and NRM were 65 (55–74)  %, 50 (44–55)  % and 26 (21–30)  %, respectively; as for the patients ≥60 years of age, these were 63 (53–72) %, 46 (41–50)  % and 28 (23–32) %, respectively. No significantly statistical difference achieved between MDS and AML patients in 1-year EFS and NRM [relative risk (RR) 0.91, 95% CI 0.80–1.04; P = 0.172 and RR 1.18, 95% CI 0.82–1.69; P = 0.365]. The patients with lower diseases risk had the possibility of higher OS rate at ≥ 3 years than those with higher diseases risk (RR 1.37, 95% CI 0.95–1.97; P = 0.088). The patients had significantly higher 2-year OS and EFS rates in complete remission (CR, CR1 and CR2) at transplantation compared to those with advanced diseases (P < 0.05).

Conclusions

RIC-alloHSCT is a feasible treatment option for the patients older than 50 year of age with MDS and AML. Advanced diseases status and higher diseases risk may be the poor factors for prognosis.

http://ift.tt/2p78q9o

Impact of intra-tumoral IL17A and IL32 gene expression on T-cell responses and lymph node status in breast cancer patients

Abstract

Purpose

Pro-inflammatory cytokines such as Interleukin-17A (IL17A) and Interleukin-32 (IL32), known to enhance natural killer and T cell responses, are also elevated in human malignancies and linked to poor clinical outcomes. To address this paradox, we evaluated relation between IL17A and IL32 expression and other inflammation- and T cell response-associated genes in breast tumors.

Methods

TaqMan-based gene expression analysis was carried out in seventy-eight breast tumors. The association between IL17A and IL32 transcript levels and T cell response genes, ER status as well as lymph node status was also examined in breast tumors from TCGA dataset.

Results

IL17A expression was detected in 32.7% ER-positive and 84.6% ER-negative tumors, with higher expression in the latter group (26.2 vs 7.1-fold, p < 0.01). ER-negative tumors also showed higher expression of IL32 as opposed to ER-positive tumors (8.7 vs 2.5-fold, p < 0.01). Expression of both IL17A and IL32 genes positively correlated with CCL5, GNLY, TBX21, IL21 and IL23 transcript levels (p < 0.01). Amongst ER-positive tumors, higher IL32 expression significantly correlated with lymph node metastases (p < 0.05). Conversely, in ER-negative subtype, high IL17A and IL32 expression was seen in patients with negative lymph node status (p < 0.05). Tumors with high IL32 and IL17A expression showed higher expression of TH1 response genes studied, an observation validated by similar analysis in the TCGA breast tumors (n=1041). Of note, these tumors were characterized by low expression of a potentially immunosuppressive isoform of IL32 (IL32γ).

Conclusion

These results suggest that high expression of both IL17A and IL32 leads to enhancement of T cell responses. Our study, thus, provides basis for the emergence of strong T cell responses in an inflammatory milieu that have been shown to be associated with better prognosis in ER-negative breast cancer.

http://ift.tt/2pJg3qG

Neonatal imaging using an on-site small footprint MR scanner

Abstract

With its soft-tissue definition, multiplanar capabilities and advanced imaging techniques, magnetic resonance imaging (MRI) for neonatal care can provide better understanding of pathology, allowing for improved care and counseling to families. However, MR imaging in neonates is often difficult due to patient instability and the complex support necessary for survival. In our institution, we have installed a small footprint magnet in the neonatal intensive care unit (NICU) to minimize patient risks and provide the ability to perform MR imaging safely in this population. With this system, we have been able to provide more information with regard to central nervous system disorders, abdominal pathology, and pulmonary and airway abnormalities, and have performed postmortem imaging as an alternative or supplement to pathological autopsy. In our experience, an MR scanner situated within the NICU has allowed for safer and more expedited imaging of this vulnerable population.

http://ift.tt/2pJd1Ti

Clinical association analysis of ependymomas and pilocytic astrocytomas reveals elevated FGFR3 and FGFR1 expression in aggressive ependymomas

Abstract

Background

Fibroblast growth factor receptors (FGFRs) are well-known proto-oncogenes in several human malignancies and are currently therapeutically targeted in clinical trials. Among glioma subtypes, activating FGFR1 alterations have been observed in a subpopulation of pilocytic astrocytomas while FGFR3 fusions occur in IDH wild-type diffuse gliomas, resulting in high FGFR3 protein expression. The purpose of this study was to associate FGFR1 and FGFR3 protein levels with clinical features and genetic alterations in ependymoma and pilocytic astrocytoma.

Methods

FGFR1 and FGFR3 expression levels were detected in ependymoma and pilocytic astrocytoma tissues using immunohistochemistry. Selected cases were further analyzed using targeted sequencing.

Results

Expression of both FGFR1 and FGFR3 varied within all tumor types. In ependymomas, increased FGFR3 or FGFR1 expression was associated with high tumor grade, cerebral location, young patient age, and poor prognosis. Moderate-to-strong expression of FGFR1 and/or FGFR3 was observed in 76% of cerebral ependymomas. Cases with moderate-to-strong expression of both proteins had poor clinical prognosis. In pilocytic astrocytomas, moderate-to-strong FGFR3 expression was detected predominantly in non-pediatric patients. Targeted sequencing of 12 tumors found no protein-altering mutations or fusions in FGFR1 or FGFR3.

Conclusions

Elevated FGFR3 and FGFR1 protein expression is common in aggressive ependymomas but likely not driven by genetic alterations. Further studies are warranted to evaluate whether ependymoma patients with high FGFR3 and/or FGFR1 expression could benefit from treatment with FGFR inhibitor based therapeutic approaches currently under evaluation in clinical trials.

http://ift.tt/2qtfJgc

Neonatal imaging using an on-site small footprint MR scanner

Abstract

With its soft-tissue definition, multiplanar capabilities and advanced imaging techniques, magnetic resonance imaging (MRI) for neonatal care can provide better understanding of pathology, allowing for improved care and counseling to families. However, MR imaging in neonates is often difficult due to patient instability and the complex support necessary for survival. In our institution, we have installed a small footprint magnet in the neonatal intensive care unit (NICU) to minimize patient risks and provide the ability to perform MR imaging safely in this population. With this system, we have been able to provide more information with regard to central nervous system disorders, abdominal pathology, and pulmonary and airway abnormalities, and have performed postmortem imaging as an alternative or supplement to pathological autopsy. In our experience, an MR scanner situated within the NICU has allowed for safer and more expedited imaging of this vulnerable population.

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Clinical association analysis of ependymomas and pilocytic astrocytomas reveals elevated FGFR3 and FGFR1 expression in aggressive ependymomas

Abstract

Background

Fibroblast growth factor receptors (FGFRs) are well-known proto-oncogenes in several human malignancies and are currently therapeutically targeted in clinical trials. Among glioma subtypes, activating FGFR1 alterations have been observed in a subpopulation of pilocytic astrocytomas while FGFR3 fusions occur in IDH wild-type diffuse gliomas, resulting in high FGFR3 protein expression. The purpose of this study was to associate FGFR1 and FGFR3 protein levels with clinical features and genetic alterations in ependymoma and pilocytic astrocytoma.

Methods

FGFR1 and FGFR3 expression levels were detected in ependymoma and pilocytic astrocytoma tissues using immunohistochemistry. Selected cases were further analyzed using targeted sequencing.

Results

Expression of both FGFR1 and FGFR3 varied within all tumor types. In ependymomas, increased FGFR3 or FGFR1 expression was associated with high tumor grade, cerebral location, young patient age, and poor prognosis. Moderate-to-strong expression of FGFR1 and/or FGFR3 was observed in 76% of cerebral ependymomas. Cases with moderate-to-strong expression of both proteins had poor clinical prognosis. In pilocytic astrocytomas, moderate-to-strong FGFR3 expression was detected predominantly in non-pediatric patients. Targeted sequencing of 12 tumors found no protein-altering mutations or fusions in FGFR1 or FGFR3.

Conclusions

Elevated FGFR3 and FGFR1 protein expression is common in aggressive ependymomas but likely not driven by genetic alterations. Further studies are warranted to evaluate whether ependymoma patients with high FGFR3 and/or FGFR1 expression could benefit from treatment with FGFR inhibitor based therapeutic approaches currently under evaluation in clinical trials.

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Identification of a novel the ITG{alpha}v{beta}6-binding peptide using protein separation and phage display

Purpose: Targeted therapies are regarded as promising approaches to increase 5-year survival rate of head and neck squamous cell carcinoma (HNSCC) patients. Experimental design: For the selection of carcinoma-specific peptides membrane proteome of HNO97 tumor cells fractionated by the ProteomeLab™ PF2D system and corresponding HNO97 cells were deployed for an alternating biopanning using a sunflower trypsin inhibitor1-based phage display (SFTI8Ph) library. Stability, binding properties and affinity of novel candidates were assessed in vitro using radio-HPLC, binding experiments and surface plasmon resonance assay (SPR), respectively. Subsequently, the affinity of the peptide was verified in situ by using peptide histochemistry, in vitro using flow cytometry, and in vivo by positron emissions tomography (PET/CT). Results: We identified a novel ITGαvβ6 binding peptide (SFITGv6) containing the amino acid sequence FRGDLMQL. SFITGv6 provides stability over a period of 24 hours and demonstrates high affinity (KD = 14.8 nM) for ITGαvβ6. In HNO97 cells, a maximal uptake and internalization of up to 37.3% and 37.5%, respectively, was measured. Small-animal PET imaging and biodistribution studies of HNO97 xenografted Balb/c nu/nu mice showed tumor-specific accumulation of 68Ga- and 177Lu-labeled DOTA-SFITGv6, respectively, 30-60 min after injection. Moreover, peptide histochemistry revealed a strong and homogenous binding of biotin-labeled SFITGv6 to HNSCC tumors and breast- and lung cancer-derived brain metastases. Finally, first PET/CT scans of HNSCC and NSCLC patients displayed SFITGv6 accumulation specifically in tumors, but not in inflammatory lesions. Conclusion: Thus, SFITGv6 represents a novel powerful tracer for imaging and possibly for endoradiotherapy of ITGαvβ6-positive carcinoma.

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Phase I trial of intratumoral injection of CCL21 gene modified dendritic cells in lung cancer elicits tumor-specific immune responses and CD8+ T cell infiltration

Purpose: A phase I study was conducted to determine safety, clinical efficacy, and anti-tumor immune responses in patients with advanced non-small cell lung carcinoma (NSCLC) following intratumoral (IT) administration of autologous dendritic cells (DC) transduced with an adenoviral (Ad) vector expressing the CCL21 gene (Ad-CCL21-DC). We evaluated safety and tumor antigen-specific immune responses following in situ vaccination (ClinicalTrials.gov: NCT01574222). Experimental Design: Sixteen stage IIIB/IV NSCLC subjects received two vaccinations (1 x 106, 5 x 106, 1 x 107, or 3 x 107 dendritic cells/injection) by CT- or bronchoscopic-guided IT injections (days 0 and 7). Immune responses were assessed by tumor antigen-specific peripheral blood lymphocyte induction of IFN-gamma in ELISPOT assays. Tumor biopsies were evaluated for CD8+ T cells by immunohistochemistry (IHC) and for PD-L1 expression by IHC and real-time PCR (RT-PCR). Results: Twenty-five percent (4/16) of patients had stable disease at day 56. Median survival was 3.9 months. ELISPOT assays revealed 6 of 16 patients had systemic responses against tumor associated antigens (TAA). Tumor CD8+ T cell infiltration was induced in 54% of subjects (7/13; 3.4-fold average increase in the number of CD8+ T cells per mm2). Patients with increased CD8+ T cells following vaccination showed significantly increased PD-L1 mRNA expression. Conclusions:Intratumoral vaccination with Ad-CCL21-DC resulted in 1) induction of systemic tumor antigen-specific immune responses, 2) enhanced tumor CD8+ T cell infiltration, and 3) increased tumor PD-L1 expression. Future studies will evaluate the role of combination therapies with PD-1/PD-L1 checkpoint inhibition combined with DC-CCL21 in situ vaccination.

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The "tricky business" of identifying mechanisms of resistance to anti-PD-1.

<span style="margin: 0px; font-family: 'Times New Roman','serif';">Resistance to immune checkpoint inhibitors can vary between patients and amongst metastases. Understanding the genomic, transcriptomic and microenvironmental factors that contribute to this variability will reveal the mechanisms that tumors utilize to evade the therapeutic effects of checkpoint inhibitor immunotherapies and will enable us to develop strategies to overcome them. </span>

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Identification of a novel the ITG{alpha}v{beta}6-binding peptide using protein separation and phage display

Purpose: Targeted therapies are regarded as promising approaches to increase 5-year survival rate of head and neck squamous cell carcinoma (HNSCC) patients. Experimental design: For the selection of carcinoma-specific peptides membrane proteome of HNO97 tumor cells fractionated by the ProteomeLab™ PF2D system and corresponding HNO97 cells were deployed for an alternating biopanning using a sunflower trypsin inhibitor1-based phage display (SFTI8Ph) library. Stability, binding properties and affinity of novel candidates were assessed in vitro using radio-HPLC, binding experiments and surface plasmon resonance assay (SPR), respectively. Subsequently, the affinity of the peptide was verified in situ by using peptide histochemistry, in vitro using flow cytometry, and in vivo by positron emissions tomography (PET/CT). Results: We identified a novel ITGαvβ6 binding peptide (SFITGv6) containing the amino acid sequence FRGDLMQL. SFITGv6 provides stability over a period of 24 hours and demonstrates high affinity (KD = 14.8 nM) for ITGαvβ6. In HNO97 cells, a maximal uptake and internalization of up to 37.3% and 37.5%, respectively, was measured. Small-animal PET imaging and biodistribution studies of HNO97 xenografted Balb/c nu/nu mice showed tumor-specific accumulation of 68Ga- and 177Lu-labeled DOTA-SFITGv6, respectively, 30-60 min after injection. Moreover, peptide histochemistry revealed a strong and homogenous binding of biotin-labeled SFITGv6 to HNSCC tumors and breast- and lung cancer-derived brain metastases. Finally, first PET/CT scans of HNSCC and NSCLC patients displayed SFITGv6 accumulation specifically in tumors, but not in inflammatory lesions. Conclusion: Thus, SFITGv6 represents a novel powerful tracer for imaging and possibly for endoradiotherapy of ITGαvβ6-positive carcinoma.

http://ift.tt/2pZVHud

Phase I trial of intratumoral injection of CCL21 gene modified dendritic cells in lung cancer elicits tumor-specific immune responses and CD8+ T cell infiltration

Purpose: A phase I study was conducted to determine safety, clinical efficacy, and anti-tumor immune responses in patients with advanced non-small cell lung carcinoma (NSCLC) following intratumoral (IT) administration of autologous dendritic cells (DC) transduced with an adenoviral (Ad) vector expressing the CCL21 gene (Ad-CCL21-DC). We evaluated safety and tumor antigen-specific immune responses following in situ vaccination (ClinicalTrials.gov: NCT01574222). Experimental Design: Sixteen stage IIIB/IV NSCLC subjects received two vaccinations (1 x 106, 5 x 106, 1 x 107, or 3 x 107 dendritic cells/injection) by CT- or bronchoscopic-guided IT injections (days 0 and 7). Immune responses were assessed by tumor antigen-specific peripheral blood lymphocyte induction of IFN-gamma in ELISPOT assays. Tumor biopsies were evaluated for CD8+ T cells by immunohistochemistry (IHC) and for PD-L1 expression by IHC and real-time PCR (RT-PCR). Results: Twenty-five percent (4/16) of patients had stable disease at day 56. Median survival was 3.9 months. ELISPOT assays revealed 6 of 16 patients had systemic responses against tumor associated antigens (TAA). Tumor CD8+ T cell infiltration was induced in 54% of subjects (7/13; 3.4-fold average increase in the number of CD8+ T cells per mm2). Patients with increased CD8+ T cells following vaccination showed significantly increased PD-L1 mRNA expression. Conclusions:Intratumoral vaccination with Ad-CCL21-DC resulted in 1) induction of systemic tumor antigen-specific immune responses, 2) enhanced tumor CD8+ T cell infiltration, and 3) increased tumor PD-L1 expression. Future studies will evaluate the role of combination therapies with PD-1/PD-L1 checkpoint inhibition combined with DC-CCL21 in situ vaccination.

http://ift.tt/2qGB3eB

The "tricky business" of identifying mechanisms of resistance to anti-PD-1.

<span style="margin: 0px; font-family: 'Times New Roman','serif';">Resistance to immune checkpoint inhibitors can vary between patients and amongst metastases. Understanding the genomic, transcriptomic and microenvironmental factors that contribute to this variability will reveal the mechanisms that tumors utilize to evade the therapeutic effects of checkpoint inhibitor immunotherapies and will enable us to develop strategies to overcome them. </span>

http://ift.tt/2pZXJuk

The impact of perioperative fluid therapy on short-term outcomes and 5-year survival among patients undergoing colorectal cancer surgery-a prospective cohort study within an ERAS protocol

Publication date: Available online 3 May 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Daniel Asklid, Josefin Segelman, Claes Gedda, Fredrik Hjern, Klas Pekkari, Ulf O. Gustafsson
BackgroundRestricted perioperative fluid therapy is one of several interventions in the enhanced recovery after surgery (ERAS) protocol, designed to reduce morbidity and hospital stay after surgery. The impact of this single intervention on short and long term outcome after colorectal surgery is unknown.Patients and MethodsThis cohort study includes all consecutive patients operated with abdominal resection of colorectal cancer 2002-2007 at Ersta Hospital, Stockholm, Sweden. All patients were treated within an ERAS protocol and registered in the ERAS-database. Compliance to interventions in the ERAS protocol was analysed. The impact of a restrictive perioperative fluid therapy (≤3000 ml on the day of surgery) protocol on short-term outcomes as well as 5-year survival was assessed with multivariable analysis adjusted for confounding factors.ResultsNine hundred and eleven patients were included. Patients receiving ≤ 3000 ml of intravenous fluids on the day of surgery had a lower risk of complications OR 0.44 (95% C I 0.28-0.71), symptoms delaying discharge OR 0.47(95% C I 0.32-0.70) and shorter length of stay compared with patients receiving >3000 ml. In cox regression analysis, the risk of cancer specific death was reduced with 55% HR 0.45(95% C I 0.25-0.81) for patients receiving ≤ 3000 ml compared with patients receiving >3000 ml.ConclusionA restrictive compared with a non-restrictive perioperative fluid therapy on the day of surgery may be associated with lower short-term complication rates, faster recovery, shorter length of stay and improved 5-year survival.



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Selective use of radioactive iodine (RAI) in thyroid cancer: no longer “one size fits all”

Publication date: Available online 3 May 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Jennifer L. Marti, Luc G.T. Morris, Allen S. Ho
A remarkable, evidence-based trend toward de-escalation has reformed the practice of radioactive iodine (RAI) administration for thyroid cancer patients. Updated guidelines have supported both decreased RAI doses for select populations, as well as expanded definitions of low-risk and intermediate-risk patients that may not require RAI. Correspondingly, there is now increased flexibility for hemithyroidectomy without need for RAI, and relaxed TSH suppression targets for low-risk thyroidectomy patients. Clinical judgment remains indispensable where multiple risk factors co-exist that individually are not indications for RAI. This is especially salient in intermediate-risk patients with a less than excellent response to therapy, determined through thyroglobulin and ultrasound surveillance. Such judgement, however, may lead to patterns of inappropriate RAI practices or overuse with little benefit to the patient and unnecessary harm. A multidisciplinary, risk-adapted approach is ever more important and obliges the surgeon to understand the likelihood that their patients will receive RAI. The risks and benefits of RAI, its evolved role in contemporary guidelines, and current patterns of use among endocrinologists are reviewed, as well as the practical implications for thyroid surgeons.



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