Upregulation of insulin-like growth factor II mRNA-binding protein 3 (IMP3) has negative prognostic impact on early invasive (pT1) adenocarcinoma of the esophagus

Abstract

Purpose

Therapeutic decisions in esophageal adenocarcinomas (EAC) restricted to mucosa (pT1a) or submucosa (pT1b) depend mainly on classic histomorphology-based criteria like tumor grading or lymphovascular invasion with limited success. There is a strong need for reliable pre-therapeutical biomarker-based evaluation also applicable on endoscopically obtained biopsies.

Methods

Patients who underwent esophagectomy due to EAC in a high volume center between 1999 and 2016 were included. Tissue microarrays (TMA) were retrospectively established from the formalin-fixed and paraffin-embedded material of the resected specimens and immunohistochemically stained using a monoclonal primary antibody specific for IMP3. IMP3 staining intensity was scored manually according to a 3-tier-scoring system (negative, weak and strong).

Results

371 EACs were interpretable for analysis. 109 patients (29%) had early invasive (pT1a/pT1b) and 262 patients (71%) locally advanced EAC (> pT2). 259 EACs (70%) revealed positive immunostaining for IMP3 including 167 strongly and 92 weakly positive. Early EAC had significantly lower IMP3 expression compared to advanced tumor stages (p < 0.0001). IMP3 positive pT1 EAC revealed higher levels of lymph node metastases (LNM) (p = 0.0001) and pT1b tumors showed higher rates of IMP3 positivity compared to pT1a (p = 0.007). Subdividing the submucosa in thirds, there was a significant trend for higher IMP3 expression with deeper tumor infiltration from pT1a to pT1b (sm3) (p = 0.0001). There was an association between IMP3 expression and shortened survival in pT1 EAC (p = 0.038).

Conclusions

IMP3 expression correlates with depth of tumor infiltration, rate of LNM and is associated with worse outcome. Thus, IMP3 might be useful for therapeutic decisions in early-invasive EAC.

https://ift.tt/2KGOkSd

Identification of gene expression levels in primary melanoma associated with clinically meaningful characteristics

Factors influencing melanoma survival include sex, age, clinical stage, lymph node involvement, as well as Breslow thickness, presence of tumor-infiltrating lymphocytes based on histological analysis of primary melanoma, mitotic rate, and ulceration. Identification of genes whose expression in primary tumors is associated with these key tumor/patient characteristics can shed light on molecular mechanisms of melanoma survival. Here, we show results from a gene expression analysis of formalin-fixed paraffin-embedded primary melanomas with extensive clinical annotation. The Cancer Genome Atlas data on primary melanomas were used for validation of nominally significant associations. We identified five genes that were significantly associated with the presence of tumor-infiltrating lymphocytes in the joint analysis after adjustment for multiple testing: IL1R2, PPL, PLA2G3, RASAL1, and SGK2. We also identified two genes significantly associated with melanoma metastasis to the regional lymph nodes (PIK3CG and IL2RA), and two genes significantly associated with sex (KDM5C and KDM6A). We found that LEF1 was significantly associated with Breslow thickness and CCNA2 and UBE2T with mitosis. RAD50 was the gene most significantly associated with survival, with a higher level of expression associated with worse survival. *Marianne Berwickh and Christopher Amos contributed equally to the writing of this article. Correspondence to Marianne Berwick, MD, Department of Internal Medicine and Dermatology, MSC10-5550, 1 University of New Mexico, Albuquerque, NM 87131, USA Tel: +1 203 464 4117; fax: +1 505 272 2579; e-mail: mberwick@salud.unm.edu or Correspondence to Christopher Amos, PhD, Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA Tel: +1 713 798 2102; fax: +1 713 798 3658; e-mail: christopher.i.amos@dartmouth.edu Received February 19, 2018 Accepted May 15, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2KsjbCN

Skeletal muscle and solitary bone metastases from malignant melanoma: multimodality imaging and oncological outcome

Malignant melanoma solitary metastases to bone or skeletal muscle occur in 0.8% of patients. The aim of this study was to evaluate features of skeleton and muscle metastases with multimodality imaging and review the oncological outcome. Thirteen patients with melanoma metastases from January 2006 to February 2016 were included. Histologic confirmation was obtained. Imaging studies included computed tomography (CT), MRI, and/or positron emission tomography/CT. Treatment received and BRAF status were recorded. Differences in BRAF status and overall survival (OS) were analyzed using the χ2-test. Associations between OS and metastases were analyzed using Cox proportional models. Nine (69%) patients showed osseous involvement. Lower extremity bones were affected in three (23%) patients: first toe, right calcaneal spurs, and knee. The spine was involved in three (23%) patients. In two (15%) patients, the pelvic bones were involved. In one (8%) patient, the temporal bone was affected. Nine (70%) patients had a history of malignant melanoma, with a median time to progression of 28 months. The median OS was 18 months: 24 months in patients with a history of melanoma and 3 months in patients with metastases at first diagnosis. The median follow-up duration was 28 months. BRAF mutant versus wild-type tumors showed significant differences in OS (P=0.03). The hazard ratio for death in the metastatic group at diagnosis was 6.83, 95% confidence interval: 1.060–144.072 (P=0.04). Solitary metastases from melanoma to the skeleton and muscle are rare. CT, MRI, and positron emission tomography/CT are useful for the evaluation of musculoskeletal findings. Image findings are not definitive for diagnosing a malignant solitary lesion; thus, a pathologic confirmation with a biopsy is recommended. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. https://ift.tt/1hexVwJ *Vilma Pacheco-Barcia and Nieves Gómez-Léon contributed equally to the writing of this article. Correspondance to Vilma Pacheco-Barcia, MD, Department of Medical Oncology, Hospital Universitario La Princesa, C/Diego de León 62, 28006 Madrid, Spain Tel: +34 9152 2200; fax: +34 914 021 169; e-mail: vilmapbarcia@yahoo.es Received February 3, 2018 Accepted May 29, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Dynamic Angiogenic Switch as Predictor of Response to Chemotherapy-Bevacizumab in Patients With Metastatic Colorectal Cancer

Background: Previous studies have shown that metastatic colorectal carcinoma (mCRC) patients treated with bevacizumab, experience variation in the plasma levels of angiogenesis growth factors and related cytokines, called angiogenic switch (AS). The aim of the present study was to analyze the relationship between AS and the clinical response during standard chemotherapy-bevacizumab treatment. Patients and Methods: Patients with Eastern Cooperative Oncology Group 0-1 mCRC were eligible. Patients received treatment with standard dose capecitabine plus either oxaliplatin or irinotecan and bevacizumab for 6 cycles. Initial treatment was followed by maintenance therapy with bevacizumab plus capecitabine until progression. Plasma levels of angiogenic-related cytokines (hepatocyte growth factor, placental growth factor, macrophage chemoattractant protein-3, MM-9, eotaxin, basic fibroblast growth factor, and interleukin 18) were prospectively analyzed at baseline and every 8 weeks. Progression-free survival (PFS) was calculated using the Kaplan-Meier method. Results: A total of 71 patients were enrolled. AS was observed in 45 patients (63.4%), 28 of whom experienced AS at the first evaluation after treatment start. Disease control, which includes partial/complete response and stable disease, was seen in 96% of AS patients (43/45), but only in 15/26 (58%) for the remaining patients without evidence of AS (P

https://ift.tt/2u0MPnz

Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer

Ann Oncol 2018; 29: i28–i37 (doi:10.1093/annonc/mdx705)

https://ift.tt/2z4Gxce

Phase II study of nab-paclitaxel in refractory small bowel adenocarcinoma and CpG island methylator phenotype (CIMP)-high colorectal cancer

Ann Oncol 2018; 29: 139–144 (doi:10.1093/annonc/mdx688)

https://ift.tt/2lRU6lS

Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium

Ann Oncol 2017; 28: 2517–2525 (doi:10.1093/annonc/mdx352)

https://ift.tt/2z8Z0EJ

Potentiation of PD-L1 blockade with a potency-matched dual cytokine–antibody fusion protein leads to cancer eradication in BALB/c-derived tumors but not in other mouse strains

Abstract

We have recently described a novel therapeutic antibody product (IL2–F8–TNF^mut), featuring the simultaneous fusion of murine IL2 and of a TNF mutant with scFv(F8), an antibody specific to the alternatively-spliced extra domain A of fibronectin (EDA). Here, we report on the in vivo characterization of the anti-cancer activity of IL2–F8–TNF^mut in four immunocompetent murine models of cancer, CT26, WEHI-164, F9 teratocarcinoma and Lewis lung carcinoma (LLC), using the product alone or in combination with a monoclonal antibody specific to murine PD-L1. All four models exhibited a strong expression of EDA-fibronectin, which was confined to vascular structures for F9 tumors, while the other three malignancies exhibited a more stromal pattern of staining. A complete and long-lasting tumor eradication of CT26 and WEHI-164 tumors was observed in BALB/c mice when IL2–F8–TNF^mut was used in combination with PD-L1 blockade. The combination treatment led to improved tumor growth inhibition in 129/SvEv mice bearing murine teratocarcinoma or in C57BL/6 mice bearing murine LLC, but those cancer cures were difficult to achieve in those models. A microscopic analysis of tumor sections, obtained 24 h after pharmacological treatment, revealed that the PD-L1 antibody had homogenously reached tumor cells in vivo and that the combination of PD-L1 blockade with IL2–F8–TNF^mut stimulated an influx of NK cells and of T cells into the neoplastic mass. These data indicate that potency-matched dual-cytokine fusion proteins may be ideally suited to potentiate the therapeutic activity of immune check-point inhibitors.

https://ift.tt/2Kylt39

Systemic-inflammation-based score can predict prognosis in metastatic gastric cancer patients before first-line chemotherapy

Future Oncology, Ahead of Print.


https://ift.tt/2KIrVE0

Effect of daily and every other day stereotactic body radiotherapy (SBRT) schedules on treatment-related fatigue in patients with Hepatocellular Carcinoma (HCC)

Publication date: Available online 3 July 2018
Source:Practical Radiation Oncology
Author(s): Shaakir Hasan, Paul Renz, Matthew Packard, Sean Horrigan, Steven Gresswell, Alexander V. Kirichenko
PurposeWe compared the rate and severity of fatigue in patients who completed stereotactic body radiotherapy (SBRT) to the liver daily(QD) compared with every other day(QOD)Methods and MaterialsFrom 2010 to 2017, 91 patients with Child Pugh(CP) A(n=57) or CP-B (34) cirrhosis who completed 100 SBRT sessions to 110 HCC lesions were analyzed in this study. Confounding variables with fatigue such as CP-C cirrhosis, ECOG over 2, or a history of ascites/encephalopathy were excluded. Fatigue was assessed against several treatment/patient related variables with univariate and propensity score-matched multivariate analysis. Median follow-up was 18 months.ResultsHCC patients with BCLC stages 0(n=10), A(n=32), and B(n=58) and a median age of 62 were analyzed. Median tumor diameter was 3 cm (1.1-11 cm). ECOG performance status was 0(n=44), 1(n=43), or 2(n=13). The median dose was 45 Gy in 5 fractions. 65 treatments were QD and 45 were QOD.Grade 1 and 2 fatigue developed in 49% and 14% of treatments, respectively. Among those treated daily, 78% developed G1/G2 fatigue compared to 44% treated QOD (OR=4.52, P=0.001). Grade 2 fatigue occurred in 22% compared to 7.3% for QD and QOD treatment, respectively (OR=3.83, P=0.048). There was no difference in fatigue rate for time of treatment(morning/afternoon), dose, treated volume, CP score, BCLC stage, or performance status were not associated with any level of fatigue. There were no difference in local control between QD and QOD treatments.ConclusionsCompared to traditional daily treatment fractions, SBRT delivered QOD to cirrhotic patients with HCC may reduce the risk of fatigue.



https://ift.tt/2tXS9bg

Incidence and patterns of locoregional failure following stereotactic body radiation therapy (SBRT) for pancreatic adenocarcinoma.

Publication date: Available online 3 July 2018
Source:Practical Radiation Oncology
Author(s): Michael J. Baine, Richard Sleightholm, Chi Lin
PurposeStereotactic body radiation therapy (SBRT) is increasingly utilized in the neoadjuvant and definitive settings for pancreatic adenocarcinoma. Risk of local and regional recurrence following this treatment remains largely unknown. Due to lack of elective nodal treatment and high fractional dose, we hypothesized that the incidence of regional out-of-field recurrence would predominate following SBRT.Methods and MaterialsElectronic medical records of all patients treated in our department with SBRT for pancreatic adenocarcinoma were retrospectively reviewed. Patients were separated into those who converted or did not convert to surgical resectability. Demographic, treatment, and outcome data were collected and analyzed. Recurrence was assessed based on RECIST 1.1 criteria. Treatment plans were reviewed to determine locations of failure with respect to treatment volume. Statistical comparisons were made using Mann-Whitney U testing for continuous variables and Chi-squared testing for dichotomous variables.ResultsData on 69 patients was available for analysis. Following treatment, 26.1% (18/69) of patients suffered in-field recurrence and 15.9% (11/69) of patients recurred regionally out-of-field. Median time to in-field and out-of-field failures were similar at 120.5 and 108.0 days, respectively (p=0.65). Of those who failed out-of-field, 36.4% (4/11) were without in-field failure prior to death. In-field failure rates were less in those who subsequently underwent surgical resection than in those who did not (9.1% (2/22) vs 34.0% (16/47), p=0.028), while out-of-field recurrence was unaffected by subsequent surgical resection (13.6% (3/22) vs 17.0% (8/47), p=0.720). All out-of-field failures occurred in areas receiving < 2600 cGy.ConclusionsThe incidence of out-of-field failure remains acceptable following SBRT for pancreatic adenocarcinoma. Despite the high BED allowed by SBRT in-field control remains problematic, continuing to signal relative radiation resistance associated with bulky disease.



https://ift.tt/2lRLMCE

Consensus on Molecular Subtypes of High-grade Serous Ovarian Carcinoma

Purpose: The majority of ovarian carcinomas are of high-grade serous histology, which is associated with poor prognosis. Surgery and chemotherapy are the mainstay of treatment, and molecular characterization is necessary to lead the way to targeted therapeutic options. To this end, various computational methods for gene expression-based subtyping of high-grade serous ovarian carcinoma (HGSOC) have been proposed, but their overlap and robustness remain unknown. Experimental Design: We assess three major subtype classifiers by meta-analysis of publicly available expression data, and assess statistical criteria of subtype robustness and classifier concordance. We develop a consensus classifier that represents the subtype classifications of tumors based on the consensus of multiple methods, and outputs a confidence score. Using our compendium of expression data, we examine the possibility that a subset of tumors are unclassifiable based on currently proposed subtypes. Results: HGSOC subtyping classifiers exhibit moderate pairwise concordance across our data compendium (58.9%-70.9%, p < 10-5) and are associated with overall survival in a meta-analysis across datasets (p < 10-5). Current subtypes do not meet statistical criteria for robustness to re-clustering across multiple datasets (Prediction Strength < 0.6). A new subtype classifier is trained on concordantly classified samples to yield a consensus classification of patient tumors that correlates with patient age, survival, tumor purity, and lymphocyte infiltration. Conclusion: A new consensus ovarian subtype classifier represents the consensus of methods, and demonstrates the importance of classification approaches for cancer that do not require all tumors to be assigned to a distinct subtype.

https://ift.tt/2MMUuNU

Final Report of a Phase I Trial of Olaparib with Cetuximab and Radiation for Heavy Smoker Patients with Locally Advanced Head and Neck Cancer.

Purpose: Our goal was to evaluate the safety and toxicity of combining a PARP inhibitor, olaparib with cetuximab and fractionated intensity modulated radiation therapy for patients with locally advanced head and neck cancer and heavy smoking histories. Experimental Design: Patients with ≥10 pack/year history of smoking were treated with olaparib at doses ranging from 25 mg-200 mg orally twice daily (BID) beginning ~10 days prior to initiation of and with concurrent radiation (69.3 Gy in 33 fractions) using a TITE-CRM model. Cetuximab was administered starting ~5 days prior to radiation per standard of care. Results: A total of 16 patients were entered onto the study with 15 evaluable for acute toxicity. The most common treatment-related Grade 3-4 side effects were radiation dermatitis and mucositis (38% and 69%, respectively). The maximum tolerated dose was determined to be 50 mg PO BID, but the RP2D was deemed to be 25 mg PO BID. At a median follow up of 26 months, the actuarial median overall survival was 37 months but was not reached for other endpoints. Two-year overall survival, progression free survival, local control, and distant control rates were 72%, 63%, 72%, 79%, respectively. Patients who continued to smoke during therapy experienced higher recurrence rates. MYCand KMT2Awere identified as potential correlatives of response on gene amplification and mutational analysis. Conclusion: Olaparib at 25 mg oral BID with concurrent cetuximab and radiation was well tolerated with reduced dermatitis within the radiation field. Responses rates were promising for this high-risk population.

https://ift.tt/2KrzGii

Parallel Accumulation of Tumor Hyaluronan, Collagen and Other Drivers of Tumor Progression

Purpose:The tumor microenvironment (TME) evolves to support tumor progression. One marker of more aggressive malignancy is hyaluronan (HA) accumulation. Here we characterize biological and physical changes associated with HA accumulating (HA-high) tumors. Experimental Design:We used immunohistochemistry, in vivo imaging of tumor pH, and microdialysis to characterize the TME of HA-high tumors, including tumor interstitial pressure (tIP), vascular structure, hypoxia, tumor perfusion by doxorubicin, pH, content of collagen and smooth muscle actin (α-SMA). A novel method was developed to measure real-time tumor-associated soluble cytokines and growth factors. We also evaluated biopsies of murine and pancreatic cancer patients to investigate HA and collagen content, important contributors to drug resistance. Results:In immunodeficient and immunocompetent mice, increasing tumor HA content is accompanied by increasing collagen content, tIP, vascular collapse, hypoxia, and increased metastatic potential, as reflected by increased α-SMA. In vivo treatment of HA-high tumors with PEGylated recombinant human hyaluronidase (PEGPH20) dramatically reversed these changes and depleted stores of VEGF-A165, suggesting that PEGPH20 may also diminish the angiogenic potential of the TME. Finally, we observed in xenografts and in pancreatic cancer patients a coordinated increase in HA and collagen tumor content. Conclusions: The accumulation of HA in tumors is associated with high tIP, vascular collapse, hypoxia, and drug resistance. These findings may partially explain why more aggressive malignancy is observed in the HA-high phenotype. We have shown that degradation of HA by PEGPH20 partially reverses this phenotype and leads to depletion of tumor-associated VEGF-A165. These results encourage further clinical investigation of PEGPH20.

https://ift.tt/2MOntkH

Combined CDK4/6 and pan-mTOR inhibition is synergistic against intrahepatic cholangiocarcinoma

Purpose: Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer type, lacking effective therapies and associated with a dismal prognosis. Palbociclib is a selective CDK4/6 inhibitor, which has been shown to suppress cell proliferation in many experimental cancer models. Recently, we demonstrated that pan-mTOR inhibitors, such as MLN0128, effectively induce apoptosis, while having limited efficacy in restraining proliferation of ICC cells. Here, we tested the hypothesis that Palbociclib, due to its ant-proliferative properties in many cancer types, might synergize with MLN0128 to impair ICC growth. Experimental Design: Human ICC cell lines and the AKT/YapS127A ICC mouse model were used to test the therapeutic efficacy of Palbociclib and MLN0128, either alone or in combination. Results: Administration of Palbociclib suppressed in vitro ICC cell growth by inhibiting cell cycle progression. Concomitant administration of Palbociclib and MLN0128 led to a pronounced, synergistic growth constraint of ICC cell lines. Furthermore, while treatment with Palbociclib or MLN0128 alone resulted in tumor growth reduction in AKT/YapS127A mice, a remarkable tumor regression was achieved when the two drugs were administered simultaneously. Mechanistically, Palbociclib was found to potentiate MLN0128 mTOR inhibition activity, whereas MLN0128 prevented the upregulation of cyclin D1 induced by Pa1bociclib treatment. Conclusions:Our study indicates the synergistic activity of Palbociclib and MLN0128 in inhibiting ICC cell proliferation. Thus, combination of CDK4/6 and mTOR inhibitors might represent a novel, promising, and effective therapeutic approach against human ICC.

https://ift.tt/2KGO5qk

Mast cell activation and KSHV infection in Kaposi sarcoma

Purpose: Kaposi sarcoma (KS) is a vascular tumor initiated by infection of endothelial cells (ECs) with KS-associated herpesvirus (KSHV). KS is dependent on sustained pro-inflammatory signals provided by intra-lesional leukocytes and continued infection of new ECs. However, the sources of these cytokines and infectious virus within lesions are not fully understood. Here, mast cells (MCs) are identified as pro-inflammatory cells within KS lesions that are permissive for, and activated by, infection with KSHV. Experimental Design: Three MC lines were used to assess permissivity to infection and to evaluate MC activation following infection. Biopsies from 31 AIDS-KS cases and 11 AIDS controls were evaluated by immunohistochemistry for the presence of MCs in KS lesions, assessment of activation state, and KSHV infection. Plasma samples from 26 AIDS-KS, 13 classic KS, and 13 healthy adults were evaluated for levels of MC granule contents tryptase and histamine. Results: In culture, MCs supported KSHV infection and infection induced MC degranulation. Within KS lesions MCs were closely associated with spindle cells. MC activation was extensive within KS patients, reflected by elevated circulating levels of tryptase and N-methylhistamine. One patient with clinical signs of extensive MC activation was treated with antagonists of MC-derived pro-inflammatory mediators, which resulted in rapid and durable regression of AIDS-KS lesions. Conclusions: Using complimentary in vitro and in vivo studies we identify MCs as a potential long-lived reservoir for KSHV and a source of pro-inflammatory mediators within the lesion microenvironment. Additionally, we identify MC antagonists as a promising novel therapeutic approach for KS.

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The epigenomic landscape of pituitary adenomas reveals specific alterations and differentiates among acromegaly, Cushing's disease and endocrine-inactive subtypes

Purpose Pituitary adenomas (PAs) are one of the most common benign neoplasms of the central nervous system. Although emerging evidence suggests roles for both genetic and epigenetic factors in tumorigenesis, the degree to which these factors contribute to disease remains poorly understood. Experimental Design A multi-platform analysis was performed to identify the genomic and epigenomic underpinnings of disease among the three major subtypes of surgically-resected PAs in 48 patients: growth hormone (GH)-secreting (n=17), adrenocorticotropic hormone (ACTH)-secreting (n=13, including 3 silent-ACTH adenomas), and endocrine-inactive (n=18). Whole-exome sequencing was used to profile the somatic mutational landscape, whole-transcriptome sequencing was used to identify disease specific patterns of gene expression, and array-based DNA methylation profiling was used to examine genome-wide patterns of DNA methylation. Results Recurrent single nucleotide and small indel somatic mutations were infrequent among the three adenoma subtypes. However, somatic copy number alterations (SCNAs) were identified in all three PA subtypes. Methylation analysis revealed adenoma subtype-specific DNA methylation profiles, with GH-secreting adenomas being dominated by hypomethylated sites. Likewise, gene expression patterns revealed adenoma subtype-specific profiles. Integrating DNA methylation and gene expression data revealed that hypomethylation of promoter regions are related with increased expression of GH1 and SSTR5 genes in GH-secreting adenomas and POMCgene in ACTH-secreting adenomas. Finally, multispectral IHC staining of immune-related proteins showed abundant expression of PD-L1among all three adenoma subtypes. Conclusions Taken together, these data stress the contribution of epigenomic alterations to disease specific etiology among adenoma subtypes and highlight potential targets for future immunotherapy-based treatments.

https://ift.tt/2KKhuQi

Paclitaxel Sensitivity of Ovarian Cancer can be enhanced by knocking down Pairs of Kinases that regulate MAP4 Phosphorylation and Microtubule Stability

Purpose: Most ovarian cancer patients receive paclitaxel chemotherapy, but less than half respond. Pre-treatment microtubule stability correlates with paclitaxel response in ovarian cancer cell lines. Microtubule stability can be increased by depletion of individual kinases. As microtubule stability can be regulated by phosphorylation of microtubule associated proteins (MAPs), we reasoned that depletion of pairs of kinases that regulate phosphorylation of MAPs could induce microtubule stabilization and paclitaxel sensitization. Experimental Design: Fourteen kinases known to regulate paclitaxel sensitivity were depleted individually in 12 well-characterized ovarian cancer cell lines before measuring proliferation in the presence or absence of paclitaxel. Similar studies were performed by depleting all possible pairs of kinases in 6 ovarian cancer cell lines. Pairs that enhanced paclitaxel sensitivity across multiple cell lines were studied in depth in cell culture and two xenograft models. Results: Transfection of siRNA against 10 of the 14 kinases enhanced paclitaxel sensitivity in at least 6 of 12 cell lines. Dual knockdown of IKBKB/STK39 or EDN2/TBK1 enhanced paclitaxel sensitivity more than silencing single kinases. Sequential knockdown was superior to concurrent knockdown. Dual silencing of IKBKB/STK39 or EDN2/TBK1 stabilized microtubules by inhibiting phosphorylation of p38 and MAP4, inducing apoptosis and blocking cell cycle more effectively than silencing individual kinases. Knockdown of IKBKB/STK39 or EDN2/TBK1 enhanced paclitaxel sensitivity in two ovarian xenograft models. Conclusions: Sequential knockdown of dual kinases increased microtubule stability by decreasing p38-mediated phosphorylation of MAP4 and enhanced response to paclitaxel in ovarian cancer cell lines and xenografts, suggesting a strategy to improve primary therapy.

https://ift.tt/2MIRbr4

Comparison of longitudinal CA125 algorithms as a first line screen for ovarian cancer in the general population

Purpose: In the United Kingdom Collaborative Trial of Ovarian Cancer Screening(UKCTOCS) women in the multimodal (MMS) arm had a serum CA125 test (first-line), with those at increased risk, having repeat CA125/ultrasound (second-line test). CA125 was interpreted using the 'Risk of Ovarian Cancer Algorithm'(ROCA). We report on performance of other serial algorithms and a single CA125 threshold as a first line screen in the UKCTOCS dataset. Experimental Design: 50,083 post-menopausal women who attended 346,806 MMS screens were randomly split into training and validation sets, following stratification into cases (ovarian/tubal/peritoneal cancers) and controls. The two longitudinal algorithms, a new serial algorithm, method of mean trends (MMT) and the parametric empirical Bayes (PEB) were trained in the training set and tested in the blinded validation set and the performance characteristics, including that of a single CA125 threshold, were compared. Results The area under receiver operator curve (AUC) was significantly higher (p=0.01) for MMT (0.921) compared to CA125 single threshold (0.884). At a specificity of 89.5%, sensitivities for MMT (86.5%;95%CI:78.4-91.9) and PEB (88.5%;95%CI:80.6-93.4) were similar to that reported for ROCA (sensitivity 87.1%; specificity 87.6%; AUC 0.915) and significantly higher than the single CA125 threshold (73.1%;95%CI:63.6-80.8). Conclusions: These findings from the largest available serial CA125 data set in the general population provide definitive evidence that longitudinal algorithms are significantly superior to simple cut-offs for ovarian cancer screening. Use of these newer algorithms requires incorporation into a multimodal strategy. The results highlight the importance of incorporating serial change in biomarker levels in cancer screening/early detection strategies.

https://ift.tt/2KGO2e8

Drug sensitivity screening and genomic characterization of 45 HPV-negative head and neck carcinoma cell lines for novel biomarkers of drug efficacy

There is an unmet need for effective targeted therapies for patients with advanced head and neck squamous cell carcinoma (HNSCC). We correlated gene expression, gene copy numbers and point mutations in 45 human papillomavirus negative HNSCC cell lines with the sensitivity to 220 anticancer drugs to discover predictive associations to genetic alterations. The drug response profiles revealed diverse efficacy of the tested drugs across the cell lines. Several genomic abnormalities and gene expression differences were associated with response to mTOR, MEK and EGFR inhibitors. NOTCH1 and FAT1 were the most commonly mutated genes after TP53 and also showed some association with response to MEK and/or EGFR inhibitors. MYC amplification and FAM83H overexpression associated with sensitivity to EGFR inhibitors, and PTPRD deletion with poor sensitivity to MEK inhibitors. The connection between high FAM83H expression and responsiveness to EGFR inhibitor erlotinib was validated by gene silencing and from the dataset at the Cancer Cell Line Encyclopedia. The data provide several novel genomic alterations that associated to the efficacy of targeted drugs in HNSCC. These findings require further validation in experimental models and clinical series.

https://ift.tt/2KHZqq4

A Chemosensitivity Study of Colorectal Cancer Using Xenografts of Patient-Derived Tumor Initiating Cells

Current genomic and gene expression analyses provide versatile tools to improve cancer chemotherapy. However, it is still difficult to predict whether each patient responds to a particular regimen or not. To predict chemosensitivity in each colorectal cancer patient, we developed an evaluation method using the primary tumor initiating cells (TIC, aka cancer stem cells) xenografted in nude mice subcutaneously (patient-derived spheroid xenografts; PDSXs). Simultaneously, we also prepared the conventional patient-derived xenografts (PDXs) from the same patients' tumors, and compared the dosing results with those of PDSXs. We further compared the chemosensitivities of PDSXs with those of seven patients who had been given regimens such as FOLFOX and FOLFIRI to treat their metastatic lesions. As the results, the PDSX method provided much more precise and predictable tumor growth with less variance than conventional PDX, although both retained the epithelial characteristics of the primary tumors. Likewise, drug-dosing tests showed essentially the same results in PDXs and PDSXs, with stronger statistical power in PDSXs. Notably, the cancer chemosensitivity in each patient was precisely reflected in that of the PDSX mice along the clinical course until the resistance emerged at the terminal stage. This "paraclinical" xenograft trials using PDSXs may help selection of chemotherapy regimens efficacious for each patient, and more importantly, avoiding inefficient ones by which the patient can lose precious time and QOL. Furthermore, the PDSX method may be employed for evaluations of off-label uses of cancer chemotherapeutics and compassionate uses of yet-unapproved new drugs in personalized therapies.

https://ift.tt/2MMQX26

Inhibition of Parp1 by BMN673 effectively sensitizes cells to radiotherapy by upsetting the balance of repair pathways processing DNA double-strand breaks

Parp inhibitors (Parpi) are commonly used as single agents for the management of tumors with homologous recombination repair (HRR) deficiencies, but combination with radiotherapy is not widely considered due to the modest radiosensitization typically observed. BMN673 is one of the most recently developed Parpi and has been shown to mediate strong cell sensitization to methylating agents. Here we explore the mechanisms of BMN673 radiosensitization to killing, aiming to combine it with radiotherapy (RT). We demonstrate markedly stronger radiosensitization by BMN673 at concentrations substantially lower (50nM) than Olaparib (3µM) or AG14361 (0.4µM) and dramatically lower as compared to second generation inhibitors such as PJ34 (5µM). Notably, BMN673 radiosensitization peaks after surprisingly short contact times (~1h) and at pharmacologically achievable concentrations in vivo. BMN673 exerts a complex set of effects on DNA-double strand break (DSB) processing including inhibition of classical non-homologous end joining (cNHEJ) and alternative end joining pathway (altEJ) at high doses of ionizing radiation (IR). BMN673 enhances resection at DSB and favors HRR and altEJ at low clinically relevant IR doses. The combined outcome of these effects is an abrogation in the inherent balance of DSB processing culminating in the formation of chromosomal translocations that underpin radiosensitization. Our observations pave the way to clinical trials exploring inherent benefits in combining BMN673 with RT for the treatment of various forms of cancer.

https://ift.tt/2KHZiqA

Role of EphB3 receptor in mediating head and neck tumor growth, cell migration, and response to PI3K inhibitor

Eph proteins have emerged as critical drivers affecting tumor growth and progression in human malignancies. Our TCGA data analysis showed that EphB3, a receptor tyrosine kinase, is frequently co-amplified with PIK3CA in head and neck squamous cell carcinoma (HNSCC). We therefore hypothesized that EphB3 amplification plays a pro-tumorigenic role in HNSCC and that EphB3 and PIK3CA are co-operating oncogenes that contribute toward its pathogenesis. This hypothesis was not experimentally supported since EphB3 knockdown failed to alter HNSCC tumor cell growth in vitro or in vivo with an orthotopic model. However, responsiveness of EphB3 knockdown tumors to the PI3K inhibitor, BKM120, was significantly decreased in terms of both tumor growth delay and survival. This is correlated with an increase in pro-survival proteins, S6 and Bcl-XL in the EphB3 shRNA tumors treated with BKM120 compared to controls. We further observed that EphB3 knockdown resulted in increased migration in vitro and increased EMT gene signature in vivo. To explain these results, we examined EphB3 phosphorylation levels in HNSCC at baseline. While total EphB3 levels were high, we found low phospho-EphB3 levels in HNSCCs. Forced EphB3 phosphorylation with an ephrin-B2-Fc fusion protein resulted in decreased HNSCC migration and cell growth and enhanced response to BKM120 in vitro. These data collectively indicate that progression of HNSCC selects for low/inhibited EphB3 activity to enhance their survival and migratory abilities and decrease response to PI3K signaling. Therefore, strategies focused on activating EphB3 might be helpful to inhibit tumor growth and enhance sensitivity to PI3K inhibitors in HNSCC.

https://ift.tt/2MMQOf4

Efficacy of the MDM2 inhibitor SAR405838 in glioblastoma is limited by poor distribution across the blood-brain barrier

Controversy exists surrounding whether heterogeneous disruption of the blood-brain barrier (BBB), as seen in glioblastoma (GBM), leads to adequate drug delivery sufficient for efficacy in GBM. This question is especially important when using potent, targeted agents that have a poor penetration across an intact BBB. Efficacy of the murine double minute-2 (MDM2) inhibitor SAR405838 was tested in patient-derived xenograft (PDX) models of GBM. In vitro efficacy of SAR405838 was evaluated in PDX models with varying MDM2-expression and those with high (GBM108) and low (GBM102) expression were evaluated for flank and orthotopic efficacy. BBB permeability, evaluated using TexasRed-3kDa dextran, was significantly increased in GBM108 through VEGFA over-expression. Drug delivery, magnetic resonance imaging (MRI), and orthotopic survival were compared between BBB-intact (GBM108-vector) and BBB-disrupted (GBM108-VEGFA) models. MDM2-amplified PDX lines with high MDM2 expression were sensitive to SAR405838 in comparison to MDM2 control lines in both in vitro and heterotopic models. In contrast to profound efficacy observed in flank xenografts, SAR405838 was ineffective in orthotopic tumors. Although both GBM108-vector and GBM108-VEGFA readily imaged on MRI following gadolinium contrast administration, GBM108-VEGFA tumors had a significantly enhanced drug and gadolinium accumulation, as determined by MALDI-MSI. Enhanced drug delivery in GBM108-VEGFA translated into a marked improvement in orthotopic efficacy. This study clearly shows that limited drug distribution across a partially intact BBB may limit the efficacy of targeted agents in GBM. Brain penetration of targeted agents is a critical consideration in any precision medicine strategy for GBM.

https://ift.tt/2KE7po2

Predictors for poor cosmetic outcome in patients with early stage breast cancer treated with breast conserving therapy: Results of the Young boost trial

In the Young Boost trial (YBT), breast cancer patients ≤50 years of age, treated with breast conserving therapy (BCT) were randomized between a 26 Gy boost dose and a 16 Gy boost dose, with local recurrence as primary and cosmetic outcome (CO) as secondary endpoint. Data of the YBT was used to investigate which factors are related with worse cosmetic outcome after BCT.

https://ift.tt/2lTOckk

The central nervous system manifestations of localized craniofacial scleroderma: a study of 10 cases and literature review

Abstract

Background

Localized craniofacial scleroderma is a rare pediatric disease that involves a spectrum of discoloration, fibrosis and hemiatrophy of the face and scalp. Children with localized craniofacial scleroderma may have neurological symptoms, and in this context often undergo diagnostic imaging of the brain.

Objective

To catalogue neuroimaging abnormalities in patients with localized craniofacial scleroderma treated at our institution, review their clinical courses and compare this data with prior studies.

Materials and methods

Following Institutional Review Board approval, an imaging database search identified 10 patients with localized craniofacial scleroderma and neuroimaging abnormalities treated at our institution. Neuroimaging exams and the electronic medical record were reviewed for each case.

Results

The most common indications for neuroimaging were headache or seizure (80% of cases). The most common neuroimaging abnormalities were T2-hyperintense, subcortical white matter lesions ipsilateral to the cutaneous lesion (90% of cases) on magnetic resonance imaging (MRI). Calcifications or blood products (50%), cysts (40%) and abnormal enhancement (20%) were also observed. A positron emission tomography (PET) scan obtained for a single case demonstrated diminished ¹⁸F-fluorodeoxyglucose (FDG) avidity corresponding to the dominant focus of signal abnormality on MRI. Progressive neuroimaging abnormalities were present in 30% of cases. There was no consistent relationship between changes in neurological symptoms following treatment and neuroimaging findings.

Conclusion

Our results are similar to previously published data. In the absence of new or worsening neurological symptoms, the role of neuroimaging for follow-up of localized craniofacial scleroderma is unclear. Knowledge of intracranial neuroimaging abnormalities that are commonly associated with localized craniofacial scleroderma helps to distinguish these lesions from others that have similar appearance.

https://ift.tt/2z9bmg3

Presentation and diagnosis of patients with type 3 von Willebrand disease in resources-limited laboratory

Publication date: Available online 3 July 2018
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Abbas Hashim Abdulsalam, Yusra Ghiath, Nidhal Alrahal
Von Willebrand disease (VWD) is a bleeding disorder that results from decreased von Willebrand factor (VWF) activity < 0.30 iu/mL. Therefore, the diagnosis of type 3 VWD in patients with bleeding requires finding a VWF:Ag and/or VWF:platelet ristocetin cofactor (RiCof) < 0.03 iu/mL, no further testing is usually necessary. This is a cohort study that included 64 patients with type 3 VWD who were presented and diagnosed at the National Center of Hematology (NCH) from October 2014 to October 2016. In this study the sensitivity of VWF:Ag is only 78%, the sensitivity of VWF:RiCof is 92% of diagnosed cases. From our results it can be concluded that patients with type 3 VWD are usually presented with moderate/severe mucocutaneous bleeding that is associated with prolonged bleeding time test of > 10 minutes and a family history of similar type of bleeding. This fact was frequently utilized to provisionally diagnose several members of the same family, forming a cohort of patients that is larger than the number of objectively-diagnosed patients included in this study, when they cannot afford to be all tested with VWF:Ag/VWF:RiCof.



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Catumaxomab with Activated T-cells Efficiently Lyses Chemoresistant EpCAM-positive Triple-negative Breast Cancer Cell Lines

Background/Aim: Epithelial cell adhesion molecule (EpCAM) is expressed in various types of cancer, including breast cancer, and is correlated with metastasis, invasion, therapeutic resistance and prognosis. Moreover, several cell surface markers, such as CD44 and EpCAM, are molecular targets on cancer stem-like cells of breast cancer. The aim of this study was to investigate whether catumaxomab, a clinical-grade bispecific antibody that binds to both EpCAM on tumor cells and CD3 on T-cells, combined with activated T-cells can eliminate chemoresistant triple-negative breast cancer (TNBC) cells in vitro. Materials and Methods: First, a cell line (MUK-BC1) was established from human breast carcinoma cells derived from a patient with chemoresistant and disseminated breast cancer. These EpCAM-positive TNBC cells were almost completely resistant to various drug-mediated cytotoxicities up to a concentration of 10 μg/ml. Results: Pre-treatment with catumaxomab and subsequent addition of interleukin-2/OKT3-activated autologous T-cells eliminated EpCAM-positive TNBC cells. Conclusion: Catumaxomab combined with activated T-cells may be a potent therapeutic modality to overcome chemoresistant EpCAM-positive TNBC cells.

https://ift.tt/2MHilyD

Lung Cancer Stem Cells and Cancer Stem Cell-targeting Natural Compounds

The novel information regarding molecular and translational research have created a paradigm shift in the understanding of lung cancer biology, revealing the more precise target for anti-cancer drug discovery. Lung cancer is a leading cause of cancer death worldwide accounting for approximately 1 in 5 of all cancer-related deaths. The most important causes of death in such a cancer involves the treatment failure as well as the spreading of cancer cells to distant sites which the cancer stem cell (CSC) within the tumor is accepted as a key driver. CSC is a rare special population of cancer cells exhibiting high tumorigenic properties together with self-renewal and differentiation capability. CSC is not only linked with high tumor-initiating activity, but is also implicated in chemotherapeutic resistance, metastasis, epithelial to mesenchymal transition, and recurrence. Thereafter, novel therapeutic strategies targeting these CSCs are considered in order to improve long-term clinical outcome. Here, we provide sufficient data regarding the biology of CSC in lung cancer, known CSC markers and cellular signals, and promising compounds targeting the stem cell signals in lung cancer that may benefit the development of novel anti-cancer treatment.

https://ift.tt/2KGQ3ag

The Impact of Immune Interaction on the Metastatic Infiltration of Colorectal Carcinoma to Lymph Nodes

Background/Aim: Tumour-infiltrating lymphocytes (TILs) and Granzyme B play crucial roles in immune reactions against colorectal carcinoma (CRCa). The inhibitor of Granzyme B is Serpin B9. The aim of this study was to evaluate the effect of immunohistological parameters of TILs on the prognosis of CRCa and presence of lymph node metastasis. Patients and Methods: A total of 152 patients who underwent surgery for CRCa were analyzed, including 63 patients in cohort stage II, according to the Union for International Cancer Control (UICC), and 89 patients in cohort UICC stage III. The TIL pattern was classified as peritumoural (PTL), intratumoural (ITL), intrastromal (ISL) or Crohn-like, and immunohistological staining of TIL and cancer cells was also performed. Results: A significantly higher density of CD8⁺ and CD4⁺ TILs was observed in the UICC II group, and significantly higher densities of CD4⁺ TILs were observed in the UICC II group in all distinguished patterns. In the same cohort, higher numbers of CD57⁺ cells and FoxP3⁺ TILs and Granzyme B levels were observed. In cohort UICC III, there was a higher density of ISL, PTL CD8⁺, CD25⁺ TILs and cancer cells showed staining for Serpin B9. CD57, Granzyme B and CD8 were demonstrated as positive prognostic factors of overall survival, and CD57 and CD4⁺ TILs were demonstrated as positive prognostic factors of recurrence. Conclusion: TILs and CD57 are promising prognostic factors of CRCa. The association of Serpin B9 with lymph node metastasis reveals a potential mechanism for tumour resistance to immune reaction.

https://ift.tt/2MIKTI6

Severe Defects in the Macrophage Barrier to Gut Microflora in Inflammatory Bowel Disease and Colon Cancer

The continuity of the subepithelial band of lamina propria-indigenous macrophages (SBLP-M) discourages commensal gut bacteria from invading the host. In this Review we analyzed the impact of a disintegrating SBLP-M in inflammatory bowel disease (IBD), which results in microbiota inflow, inadequate immune responses and IBD-associated colon cancer. In previous work, we analyzed endoscopic biopsies taken from normal-looking descending colon in 247 patients with IBD, and 167 from control patients without IBD. Sections immunostained for cluster of differentiation 68 (CD68) protein showed no inflammatory changes. In IBD, the band of CD68+ SBLP-M was fragmented or minute in 59% (47/80) and absent in 9% (7/80). In contrast, only 31% (51/167) of the biopsies from control patients had a fragmented/minute band of CD68+ SBLP-M and this band was not absent in any (p<0.05). The finding that the band of CD68+ SBLP-M was fragmented to totally lost in IBD suggests a long-lasting defect in the barrier against the gut microbiome in IBD. The lack of ongoing inflammation in colonic biopsies should rule-out the participation of bone marrow-derived inflammation-elicited macrophages in loss of the barrier. Today, it is widely accepted that dysbiosis and inappropriate immune response to microbial flora play a pivotal role in the pathogenesis and development of IBD-associated colon cancer. Based on present knowledge, it is submitted that defects in the SBLP-M barrier in IBD encourage the trespassing of the gut microflora into the host, thereby destabilizing host immunity. These events in concert may play the ultimate pivotal role in the evolution of colon cancer in patients with IBD.

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Efficacy and Safety of Bi-weekly Pegfilgrastim for Dose-dense Chemotherapy-induced Neutropenia in Breast Cancer Patients

Background/Aim: The dose-dense doxorubicin and cyclophosphamide (ddAC) for patients with HER-2-negative breast cancer is recommended by the National Comprehensive Cancer Network guideline in US. However, there are little data on serum G-CSF concentrations in patients undergoing bi-weekly dose-dense therapy with pegfilgrastim. The objective of this study was to compare the serum G-CSF concentrations in patients receiving pegfilgrastim in bi- or tri-weekly regimens. Patients and Methods: This study included 26 patients who received ddAC or docetaxel and cyclophosphamide (TC) for primary breast cancer. Serum G-CSF concentrations were measured by ELISA. Results: Serum G-CSF concentrations peaked in the second week of ddAC cases and in the ninth week of TC cases. Neutrophils gradually increased until the sixth week in ddAC cases, while they were slightly decreased during the first three weeks in TC cases. Treatments were completed without febrile neutropenia or treatment delays. Conclusion: Primary prophylactic pegfilgrastim administrations increased serum G-CSF concentrations, helping to maintain the absolute neutrophil counts that are required to undergo chemotherapy. The treatment of ddAC with 3.6 mg pegfilgrastim is completely safe for female Japanese patients.

https://ift.tt/2MHJbXt

The Role of Histone Deacetylase Inhibitors in Uveal Melanoma: Current Evidence

Uveal melanoma is the most common intraocular malignancy in adults, representing approximately 3% of all melanoma cases. Despite progress in chemotherapy, radiation and surgical treatment options, the prognosis and survival rates remain poor. Acetylation of histone proteins causes transcription of genes involved in cell growth, DNA replication and progression of cell cycle. Overexpression of histone deacetylases occurs in a wide spectrum of malignancies. Histone deacetylase inhibitors block the action of histone deacetylases, leading to inhibition of tumor cell proliferation. This article reviewed the potential therapeutic effects of histone deacetylase inhibitors on uveal melanoma. MEDLINE database was used under the key words/phrases: histone deacetylase, inhibitors, uveal melanoma and targeted therapies for uveal melanoma. A total of 47, English articles, not only referring to uveal melanoma, published up to February 2018 were used. Valproic acid, trichostatin A, tenovin-6, depsipeptide, panobinostat (LBH-589), vorinostat (suberanilohydroxamic acid) entinostat (MS-275), quisinostat, NaB, JSL-1, MC1568 and MC1575 are histone deacetylase inhibitors that have demonstrated promising antitumor effects against uveal melanoma. Histone deacetylase inhibitors represent a promising therapeutic approach for the treatment of uveal melanoma.

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Skin Reaction to Cetuximab as a Criterion for Treatment Selection in Head and Neck Cancer

Background/Aim: It can be hypothesized that in patients with locally advanced head and neck cancer and prominent cetuximab (CMb)-induced skin rash, immunoradiotherapy would result in a survival advantage over chemoradiotherapy with cisplatin (CP). Patients and Methods: After a loading dose of CMb, one weekly cycle of CMb and CP concurrently with RT, patients who developed a grade ≥2 rash proceeded with immunoradiotherapy, and those with a grade 0-1 rash had chemoradiotherapy. Results: A grade 3-4 allergic reaction to CMb developed in 11/39 (28.2%) patients and further recruitment was stopped. These patients proceeded treatment with CP. In early assessment of skin rash 10/28 patients qualified for chemoradiotherapy and 18/28 patients for immunoradiotherapy. There was no difference in survival between the two groups. Conclusion: Rate of serious CMb-induced hypersensitivity reactions was unacceptably high. Even though immunoradiotherapy was administered only to the prognostically most favorable group of patients, it resulted in no advantage over chemoradiotherapy.

https://ift.tt/2MNFcsb

Contribution of Computed Tomographic Angiography to Pretreatment Planning of Radio-embolization of Liver Tumors

Transarterial radio-embolization (TARE) using yttrium-90 microspheres is a promising method based on the brachytherapeutic effect of radionuclide with beta-minus decay dissolved in solid microparticles applied directly to tumor-supplying arteries. This treatment is complex, as well as logistically and technically extremely demanding and must be planned in detail. The visualization of the vascular supply of the liver and the possible parasitic supply of the tumor is essential not only for indication of the procedure and correct identification of the arteries to which the microspheres will be applied, but also for prevention of non-target deposition of radioactive material. This review addresses the use of computed tomographic angiography in the preparatory phase of TARE.

https://ift.tt/2KK20vE

Possible Application of Ascites-infiltrating Gamma-delta T Cells for Adoptive Immunotherapy

Background/Aim: Malignant ascites contain many tumour-infiltrating lymphocytes. T cells with antitumour activity have attracted attention as effector cells in cancer immunotherapy. V₂⁺ T cells were cultured from peripheral blood mononuclear cells (PBMCs) and ascites-infiltrating lymphocytes (AILs) to compare the differences in response to 2-methyl-3-butenyl-1-pyrophosphate (2M3B1-PP) and zoledronate (Zol) as antigens in vitro. Materials and Methods: To expand V₂⁺ T cells from PBMCs and AILs from 29 patients with cancer, these cells were cultured and subjected to analysis. Results: The proliferation rate of V₂⁺ T cells was higher in both PBMCs and AILs when cultured with Zol than with 2M3B1-PP. Although V₂⁺ T cells show a higher rate of expansion in AILs compared to PBMCs, the number of mixed tumour cells in ascites was decreased when cultured with Zol. Conclusion: V₂⁺ T cells in AILs are cytotoxic to tumour cells in ascites and may be considered in adoptive immunotherapy.

https://ift.tt/2MLkCZH

High ANXA7 Potentiates Eucalyptol Toxicity in Hormone-refractory Prostate Cancer

Background/Aim: Our studies showed that ANXA7 is a novel tumor suppressor gene that is lost in various aggressive forms of prostate cancer. However, little is known about the role of ANXA7 in the anticancer drug treatment towards different cancers. Materials and Methods: The expression of ANXA7 was measured in the 60 cancer cell lines of the NCI-60 ADS project and correlated with the enhanced sensitivity to over 30,000 natural and synthetic compounds. Results: Eucalyptol showed a high positive correlation with ANXA7 expression and castration-resistant prostate cancer cell death occurred very effectively in response to the combination of eucalyptol and overexpressed wt-ANXA7 than either agent alone. The synergistic effects of ANXA7 and eucalyptol resulted in concordant changes in gene expression profiles particularly of Ras family members, MDM4, NF-ĸB and VEGF. Conclusion: Overexpression of ANXA7 enhances eucalyptol cytotoxicity in prostate cancer cell lines.

https://ift.tt/2KMnZC6

Heterogeneity of PD-L1 Expression and Relationship with Biology of NSCLC

Immunotherapy with monoclonal antibodies against programmed cell death (PD-1), such as nivolumab and pembrolizumab, has significantly improved the survival of patients with metastatic non-small cell lung cancer (NSCLC). In order to determine the subset of patients that can benefit most from these therapies, biomarkers such as programmed death ligand-1 (PD-L1) have been proposed. However, the predictive and prognostic role of the use of PD-L1 is controversial. Anti-PD-L1 immunohistochemistry may not represent the actual status of the tumour because of individual variability and tumour heterogeneity. Additionally, there may be analytical variability due to the use of different assays and antibodies to detect PD-L1. Moreover PD-L1 expression is also regulated by oncogenic drivers in NSCLC, such as epidermal growth factor receptor (EGFR), echinoderm microtubule-associated protein-like 4 (EML4) fusion with anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS). Preclinical studies have shown the potential role of targeted therapy in immune escape mechanisms in NSCLC cells. This review summarizes current literature data on the heterogeneity of PD-L1 expression and the relationship with such factors and with clinicopathological features of NSCLC.

https://ift.tt/2MNF63N

Hydrogen Sulfide Is Increased in Oral Squamous Cell Carcinoma Compared to Adjacent Benign Oral Mucosae

Background/Aim: Hydrogen sulfide (H₂S) and the enzymes that synthesize it, cystathionine-b-synthase, cystathionine -lyase, and 3-mercaptopyruvate, are increased in different human malignancies. Due to its short half-life, H₂S concentrations have not been directly measured in a human malignancy. Here we directly measured in vivo H₂S levels within oral squamous cell carcinoma (OSCC). Patients and Methods: Punch biopsies of OSCC and benign mucosae from 15 patients were analyzed by HPLC, western blotting, and tissue microarray analyses. Results: H₂S concentrations were significantly higher in OSCC compared to adjacent benign oral mucosae. Western blot and tissue microarray studies revealed significantly increased cystathionine-b-synthase, cystathionine -lyase, and 3-mercaptopyruvate, phopho-Stat3, mitoNEET, hTERT, and MAPK protein levels in OSCC. Conclusion: H₂S concentrations and the enzymes that synthesize it are significantly increased in OSCC. Here, for the first time H₂S concentrations within a living human malignancy were measured and compared to adjacent counterpart benign tissue.

https://ift.tt/2KvmBED

Neoadjuvant Radiotherapy with Capecitabine Plus Bevacizumab for Locally Advanced Lower Rectal Cancer: Results of a Single-institute Phase II Study

Background/Aim: A single-arm phase II clinical trial was conducted to evaluate the safety and efficacy of adding bevacizumab to standard capecitabine-based neoadjuvant chemoradiotherapy (CRT) for the treatment of locally advanced rectal cancer (LARC). Patients and Methods: Twenty-five patients were enrolled. Patients received capecitabine-based CRT for 5 weeks and 3 days. Bevacizumab was administered every 2 weeks during CRT. Within 6-10 weeks after completion of CRT, surgery was performed. Results: With regard to CRT-related acute toxicities, most of the adverse events were limited to grade 1. A pathological complete response was obtained in four (16%) patients. In total, six patients (24%) developed postoperative complications. Six out of five (83%) patients healed without the need for surgical intervention. Conclusion: Although acute toxicity during CRT with bevacizumab was minimal and postoperative complications do not seem to increase, the addition of bevacizumab apparently offers no clinically-significant benefit for patients with LARC.

https://ift.tt/2MNESJZ

Analysis of Anticancer Activity and Chemical Sensitization Effects of Dendropanax morbifera and Commersonia bartramia Extracts

Background/Aim: Dendropanax morbifera (DM) and Commersonia bartramia (CB) are possible candidates for immunotherapy. In this study, the cytotoxicity and chemical sensitization of DM and CB extracts on gynecologic and colon cancers were evaluated. Materials and Methods: The malignant cell lines were cultured and analyzed for cytotoxicity and chemical sensitization. A mouse model was also constructed to make the condition similar to in vivo. Reverse transcription-polymerase chain reaction was conducted to determine alterations in drug-resistant genes. Results: The extracts from DM and CB showed specific cytotoxicity to malignant cell lines. DM increased chemical sensitivity to cervical and ovarian cancer, while CB showed improved sensitization to endometrial cancer. The effects of the extracts were confirmed using a mouse model. The extracts induced differences in the expression levels of a number of genes related to drug resistance. Conclusion: DM and CB extracts could be novel agents for immunotherapy and chemical sensitization in gynecologic and colon cancers.

https://ift.tt/2KriM3k

Structure-associated Functional Control of TX-1877 Series by Glyco-conjugation

Background/Aim: Sugar molecules are often used as a tool to structurally modify chemical compounds. The features of synthesized sugar-conjugated TX-1877 derivatives were herein examined. Materials and Methods: The molecular stabilities (reactivity) and hydrophobicities of sugar (e.g., monosaccharide and tetra-O-acetylated monosaccharide)-conjugated TXs were analyzed using a molecular simulation (e.g. molecular mechanics (MM) and molecular orbital (MO) analysis). Results: The hydrophobicities of TX-1877 derivatives were increased by tetra-O-acetylation, and TX-2244 exhibited the most potent radiosensitizing activity (enhancement ratio: ER=2.30). Conclusion: The conformations and hydrophobicities of chemical compounds may be controlled by adding monosaccharide- and tetra-O-acetyl-conjugated sugars to TX-1877.

https://ift.tt/2MO1OZV

Immunohistochemical Study of Mitosis-regulatory Proteins in Gastroenteropancreatic Neuroendocrine Neoplasms

Background/Aim: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare and heterogeneous tumors. Therapeutic targets remain to be identified and apart from the proliferation marker Ki-67, useful prognostic markers are rare. Mitotic proteins, such as forkheadbox protein M1 (FOXM1), survivin and aurora kinases, play a role in GEP-NEN progression. In this study, immunohistochemistry was used to analyze how this protein network is expressed in different subgroups of GEP-NENs and determine potential expression patterns that could be useful as tumor markers. Materials and Methods: Tumor tissues from 75 patients were studied immunohistochemically with antibodies against aurora B, survivin and FOXM1. The expression pattern was correlated with clinicopathological data such as tumor grading, metastatic state and prognosis. Results: The immunohistochemical analysis of nuclear aurora kinase B revealed a positive correlation with nuclear survivin and FOXM1 staining patterns. Furthermore, aurora B was positively related to grading and tumor size and negatively to differentiation and functionality. Conclusion: The expression of aurora kinase B is associated with differentiation, progression and the aggressiveness of GEP-NENs. In the context of tumor progression, aurora B is strongly associated with markers of the mitosis regulatory network, survivin, FOXM1 and Ki-67. A shift of the intracellular localization of aurora B might be useful for the subclassification of intermediate-grade intestinal NET and NEC (20%<Ki-67<55%), since detailed Ki-67-based guidelines only exist for the pancreatic tumors. Most importantly, nuclear abundance of aurora B was found to be strictly limited to high-grade tumors, which is important for the consideration of aurora inhibitors for therapy of NENs.

https://ift.tt/2KyaxTr

Concentration-dependent Activation of Inflammatory/Anti-inflammatory Functions of Macrophages by Hydrolyzed Whey Protein

Background/Aim: Whey protein is a mixture of globulins isolated from whey and mainly composed of β-lactoglobulin, α-lactoalbumin, and lactoferrin. In this study, whey protein was hydrolyzed using various proteases, and the macrophage activation was evaluated. Materials and Methods: Hydrolyzed whey protein was prepared using various proteases to evaluate phagocytic activity and cytokine productivity. Results: The results of SDS-PAGE and gel permeation chromatography (GPC) analysis indicated that the molecular weight of whey protein was reduced using various proteases. The hydrolyzed whey protein showed a concentration-dependent induction of macrophage phagocytic activity. In addition, the hydrolyzed whey protein significantly enhanced the production of the inflammatory cytokine, TNF-α. Production of the anti-inflammatory cytokine, IL-10, was not observed at concentrations up to 1 μg, but significant production was confirmed at 100 μg. Conclusion: Hydrolyzed whey protein can induce the phagocytic activity of macrophages and activation of the inflammatory/anti-inflammatory functions of the macrophages depends on the concentration of the hydrolyzed whey protein.

https://ift.tt/2MLqy53

Polymorphisms in TWIST1 and ZEB1 Are Associated with Prognosis of Gastric Cancer Patients

Background/Aim: Epithelial–mesenchymal transition (EMT) program has been linked as a driver of metastatic dissemination by conferring migratory and invasive capacity to cancer cells. Gastric cancer (GC) patients with tumors expressing altered levels of EMT markers have low survival. This study aimed to assess if polymorphisms of CDH1, TWIST1, SNAIL2, ZEB1 and ZEB2 genes are associated with survival in GC patients. Patients and Methods: A total of 153 individuals with diagnosis of GC were recruited in Santiago, Chile. All patients were genotyped using Infinium Global Screening Array (GSA). Twenty Tag SNPs of the studied genes were retrieved. Results: Three SNPs were associated with survival: rs2526614 (TWIST1) (genotype CA + AA, adjusted HR=0.58, 95%CI=0.37-0.93), rs6953766 (TWIST1) (genotype GG, crude HR=2.02, 95%CI=1.06-3.82, adjusted HR=2.14, 95%CI=1.07-4.25), and rs431073 (ZEB1) (genotype AC + CC, crude HR=1.62, 95%CI=1.01-2.59, adjusted HR=1.96, 95%CI=1.18-3.25). Conclusion: To the best of our knowledge, this is the first study proposing a role of these SNPs in cancer prognosis. Their use as prognostic markers of GC survival warrants further investigation.

https://ift.tt/2KvmIA3

Prognostic Factors for Pancreatic Cancer Patients Treated with Immune-cell Therapy

Background/Aim: The past 17 years, immune-cell therapy has been administered to 990 patients with advanced or recurrent pancreatic adenocarcinoma and 50 patients with curatively resected pancreatic adenocarcinoma. Materials and Methods: The correlation between overall survival (OS) and various factors including sex, age, performance status (PS), distant metastasis, chemotherapy, radiotherapy, and type of immune-cell therapy were evaluated by univariate and multivariate analyses. Results: The median OS of advanced or recurrent pancreatic cancer was 5.8 months, and the prognosis was improved in pancreatic cancer patients who received immune-cell therapy with PS scores of 0-1 [hazard risk (HR)=0.56; 95% confidence interval (CI)=0.46-0.68; p<0.0001], chemotherapy (HR=0.68; 95%CI=0.54-0.87; p=0.002), or radiotherapy (HR=0.76; 95%CI=0.63-0.93; p=0.006). Multivariate analysis demonstrated that distant metastasis indicated a poor prognosis for pancreatic cancer patients that were administered immune-cell therapy (HR=1.62; 95%CI=1.37-1.93; p<0.0001). Additionally, the combined immune-cell therapy with αβ T cell and dendritic cell (DC) vaccine provided a survival benefit in advanced or recurrent pancreatic cancer patients (HR=0.69; 95%CI=0.57-0.83; p<0.0001). Conclusion: A survival benefit could be potentially obtained with better PS by the combination of αβ T cell therapy, DC vaccine therapy, and chemotherapy at an early stage in pancreatic cancer.

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MART-10, a 1{alpha},25(OH)2D3 Analog, Potently Represses Metastasis of ER+ Breast Cancer Cells with VEGF-A Overexpression

Background: Breast cancer ranks second in the list of cancer-related deaths for women. Even under multidisciplinary treatment, 25-50% of patients with breast cancer still ultimately develop metastasis, leading to poor prognosis. In addition to inducing angiogenesis, vascular endothelial growth factor-A (VEGF-A) is believed to directly increase cancer cell metastatic potential and overexpression of VEGF-A is associated with higher invasiveness of breast cancer. 1α,25(OH)₂D₃, the active form of vitamin D, and its analogs have been widely applied as anticancer agents in the past. Material and Methods: Western blot, migration and invasion assays, enzyme-linked immunosorbent assay, and immunofluorescent stain were applied in this study. Result: VEGF-A increased cell migration and invasion in estrogen receptor-positive (ER+) breast cancer MCF-7 cells. VEGF-A induced an autocrine loop in MCF-7 cells as VEGF-A treatment increased both VEGF-A expression and secretion. The expression of VEGF receptor type 2 (VEGFR2) and neuropilin 1 was also up-regulated by VEGF-A in MCF-7 cells. In addition, F-actin synthesis and LIM domain kinase 1 (LIMK-1) phosphorylation were increased by VEGF-A. VEGF-A also increased β-catenin expression and nuclear translocation of both β-catenin and nuclear factor-ĸB (NF-ĸB), indicating increased β-catenin and NF-ĸB activity. 1α,25(OH)₂D₃ and MART-10, an analog of 1α,25(OH)₂D₃, effectively repressed VEGF-A-induced MCF-7 cell migration and invasion and other VEGF-A-induced effects on MCF-7 cells, with MART-10 being more potent than 1α,25(OH)₂D₃. Conclusion: MART-10 can be deemed as a promising agent for prevention and treatment of metastasis of ER+ breast cancer with VEGF-A overexpression.

https://ift.tt/2KsPy45

Glycemic dysregulation in a patient with type 2 diabetes treated with 5-azacitidine: a case report

Diabetes and myelodysplastic syndrome are two conditions that may coexist in a single patient, since both diseases are prevalent in the elderly. The pathophysiology of myelodysplastic syndrome involves recurre...

https://ift.tt/2KuCrQ0

Sub-acute intestinal obstruction – a rare complication of Plasmodium falciparum malaria in an adult: a case report

Malaria remains a major public health problem in most tropical countries. It occasionally presents with both typical and atypical signs and symptoms. Gastrointestinal manifestations are common in malaria endem...

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Differentiating pseudoprogression from true progression: analysis of radiographic, biologic, and clinical clues in GBM

Abstract

Introduction

Pseudoprogression (PsP) is a diagnostic dilemma in glioblastoma (GBM) after chemoradiotherapy (CRT). Magnetic resonance imaging (MRI) features may fail to distinguish PsP from early true progression (eTP), however clinical findings may aid in their distinction.

Methods

Sixty-seven patients received CRT for GBM between 2003 and 2016, and had pre- and post-treatment imaging suitable for retrospective evaluation using RANO criteria. Patients with signs of progression within the first 12-weeks post-radiation (P-12) were selected. Lesions that improved or stabilized were defined as PsP, and lesions that progressed were defined as eTP.

Results

The median follow up for all patients was 17.6 months. Signs of progression developed in 35/67 (52.2%) patients within P-12. Of these, 20/35 (57.1%) were subsequently defined as eTP and 15/35 (42.9%) as PsP. MRI demonstrated increased contrast enhancement in 84.2% of eTP and 100% of PsP, and elevated CBV in 73.7% for eTP and 93.3% for PsP. A decrease in FLAIR was not seen in eTP patients, but was seen in 26.7% PsP patients. Patients with eTP were significantly more likely to require increased steroid doses or suffer clinical decline than PsP patients (OR 4.89, 95% CI 1.003–19.27; p = 0.046). KPS declined in 25% with eTP and none of the PsP patients.

Conclusions

MRI imaging did not differentiate eTP from PsP, however, KPS decline or need for increased steroids was significantly more common in eTP versus PsP. Investigation and standardization of clinical assessments in response criteria may help address the diagnostic dilemma of pseudoprogression after frontline treatment for GBM.

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Neuroimaging classification of progression patterns in glioblastoma: a systematic review

Abstract

Background

Our primary objective was to report the current neuroimaging classification systems of spatial patterns of progression in glioblastoma. In addition, we aimed to report the terminology used to describe 'progression' and to assess the compliance with the Response Assessment in Neuro-Oncology (RANO) Criteria.

Methods

We conducted a systematic review to identify all neuroimaging studies of glioblastoma that have employed a categorical classification system of spatial progression patterns. Our review was registered with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) registry.

Results

From the included 157 results, we identified 129 studies that used labels of spatial progression patterns that were not based on radiation volumes (Group 1) and 50 studies that used labels that were based on radiation volumes (Group 2). In Group 1, we found 113 individual labels and the most frequent were: local/localised (58%), distant/distal (51%), diffuse (20%), multifocal (15%) and subependymal/subventricular zone (15%). We identified 13 different labels used to refer to 'progression', of which the most frequent were 'recurrence' (99%) and 'progression' (92%). We identified that 37% (n = 33/90) of the studies published following the release of the RANO classification were adherent compliant with the RANO criteria.

Conclusions

Our review reports significant heterogeneity in the published systems used to classify glioblastoma spatial progression patterns. Standardization of terminology and classification systems used in studying progression would increase the efficiency of our research in our attempts to more successfully treat glioblastoma.

https://ift.tt/2tXI9P6

Diagnostic performance of apparent diffusion coefficient parameters for glioma grading

Abstract

This study was to evaluate the diagnostic performance of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) parameters derived from diffusion tensor imaging in the differentiation between grade II and III gliomas. The records of 60 patients (30 women, 30 men; mean age, 45.4 years) suspected of having gliomas who underwent an ADC image-guided stereotactic biopsy were retrospectively reviewed. The values of FA and ADC were measured, and the sensitivity, specificity, accuracy and area under the curve (AUC) of those parameters were calculated based on the receiver operating characteristic curve analysis. A predictive diagnostic equation was also constructed and evaluated. Significant differences in minimum ADC values were found in the quantitative analysis between the grade III and II glioma groups. The sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV), accuracy and AUC for identifying grade III and II gliomas at the optimum cut-off value of 0.895 × 10⁻³ mm²/s of minimum ADC were 81.0, 89.1, 77.3, 91.1, 86.6 and 0.87, respectively. The predictive diagnostic equation was superior to the single minimum ADC indicator with a sensitivity of 90.5%, a specificity of 84.8%, a PPV of 73.1%, an NPV of 95.1%, and an accuracy of 86.6%, respectively. The study provides evidence that minimum ADC values have a superior diagnostic performance in differentiating grade III and II gliomas, and the predictive diagnostic equation may be helpful in the differentiation.

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Identification of miR-379/miR-656 (C14MC) cluster downregulation and associated epigenetic and transcription regulatory mechanism in oligodendrogliomas

Abstract

Introduction

Although role of individual microRNAs (miRNAs) in the pathogenesis of gliomas has been well studied, their role as a clustered remains unexplored in gliomas.

Methods

In this study, we performed the expression analysis of miR-379/miR-656 miRNA-cluster (C14MC) in oligodendrogliomas (ODGs) and also investigated the mechanism underlying modulation of this cluster.

Results

We identified significant downregulation of majority of the miRNAs from this cluster in ODGs. Further data from The Cancer Genome Atlas (TCGA) also confirmed the global downregulation of C14MC. Furthermore, we observed that its regulation is maintained by transcription factor MEF2. In addition, epigenetic machinery involving DNA and histone-methylation are also involved in its regulation, which is acting independently or in synergy. The post- transcriptionally regulatory network of this cluster showed enrichment of key cancer-related biological processes such as cell adhesion and migration. Also, there was enrichment of several cancer related pathways viz PIK3 signaling pathway and glioma pathways. Survival analysis demonstrated association of C14MC (miR-487b and miR-409-3p) with poor progression free survival in ODGs.

Conclusion

Our work demonstrates tumor-suppressive role of C14MC and its role in pathogenesis of ODGs and therefore could be relevant for the development of new therapeutic strategies.

https://ift.tt/2u2hjFM

Reduced hydroxymethylation characterizes medulloblastoma while TET and IDH genes are differentially expressed within molecular subgroups

Abstract

Introduction

Medulloblastoma (MB) is an embryonal tumour that originates from genetic deregulation of cerebellar developmental pathways and is classified into 4 molecular subgroups: SHH, WNT, group 3, and group 4. Hydroxymethylation levels progressively increases during cerebellum development suggesting a possibility of deregulation in MB pathogenesis. The aim of this study was to investigate global hydroxymethylation levels and changes in TET and IDH gene expression in MB samples compared to control cerebellum samples.

Methods

The methods utilized were qRT-PCR for gene expression, dot-blot and immunohistochemistry for global hydroxymethylation levels and sequencing for the investigation of IDH mutations.

Results

Our results show that global hydroxymethylation level was decreased in MB, and low 5hmC level was associated with the presence of metastasis. TET1 expression levels were decreased in the WNT subgroup, while TET3 expression levels were decreased in the SHH subgroup. Reduced TET3 expression levels were associated with the presence of events such as relapse and death. Higher expression of IDH1 was observed in MB group 3 samples, whereas no mutations were detected in exon 4 of IDH1 and IDH2.

Conclusion

These findings suggest that reduction of global hydroxymethylation levels, an epigenetic event, may be important for MB development and/or maintenance, representing a possible target in this tumour and indicating a possible interaction of TET and IDH genes with the developmental pathways specifically activated in the MB subgroups. These genes could be specific targets and markers for each subgroup.

https://ift.tt/2lSmEMj

Tumor-related epilepsy: epidemiology, pathogenesis and management

Abstract

Introduction

Seizure is a common comorbidity in patients with brain tumor. It may be the presenting symptom or develop after the tumor diagnosis. The underlying pathophysiology of brain tumor-related epilepsy remains poorly understood.

Methods

A comprehensive literature review of Pubmed English articles from 1980–2017 was performed to summarize current knowledge and treatment options of brain tumor-related epilepsy.

Results

Multiple factors have been found to contribute to tumor-related epilepsy, including tumor type, speed of tumor growth, location, and tumor burden. The underlying pathogenesis of epilepsy is not clear but perturbations in the peri-tumoral regions, both structural and cellular communications, have been implicated.

Conclusions

Surgical and medical treatments of tumor-related epilepsy remain challenging as additional factors such as the extent of surgical resection, interactions with tumor-related oncological treatments and anti-epileptic medication related side effects need to be considered.

https://ift.tt/2u1L35I

Benzene exposure at workplace and risk of colorectal cancer in four Nordic countries

Publication date: August 2018
Source:Cancer Epidemiology, Volume 55
Author(s): Madar Talibov, Jorma Sormunen, Johnni Hansen, Kristina Kjaerheim, Jan-Ivar Martinsen, Per Sparen, Laufey Tryggvadottir, Elisabete Weiderpass, Eero Pukkala
ObjectiveThe aim of this case-control study was to assess the effect of occupational benzene exposure on the risk of colorectal cancer, including its subtypes.MethodsThe study included 181,709 colon cancer and 109,227 rectal cancer cases diagnosed between 1961 and 2005 in Finland, Iceland, Norway and Sweden. Cases were identified from the Nordic Occupational Cancer Study (NOCCA) cohort. Five controls per case were selected from the same cohort, matched for country, birth year, and sex. Occupational benzene exposure for each study participant was estimated by linking their job titles to country specific job-exposure matrices. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by using conditional logistic regression models. The results were adjusted for physical strain at work, formaldehyde, ionizing radiation and wood dust.ResultsIncreased risk was observed for all colorectal cancer (OR = 1.12, 95% CI 1.05–1.18) for the high decile of cumulative benzene exposure, indicating a statistically significant dose-response relationship. This excess risk was mainly seen in ascending colon (OR = 1.27, 95% CI 1.13–1.43), and transversal colon (OR = 1.21, 95% CI 1.01–1.41). The ORs in the highest exposure category were markedly higher in women than in men in all subsites of colon and rectum.ConclusionThis study showed an association between workplace benzene exposure and colorectal cancer. The risk was restricted to ascending and transversal colon, and was the strongest among women.



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Hormonal contraceptive use and smoking as risk factors for high-grade cervical intraepithelial neoplasia in unvaccinated women aged 30–44 years: A case-control study in New South Wales, Australia

Publication date: August 2018
Source:Cancer Epidemiology, Volume 55
Author(s): Huilan Xu, Sam Egger, Louiza S Velentzis, Dianne L O'Connell, Emily Banks, Jessica Darlington-Brown, Karen Canfell, Freddy Sitas
BackgroundHuman papillomavirus (HPV) vaccines protect against HPV types 16/18, but do not eliminate the need to detect pre-cancerous lesions. Australian women vaccinated as teenage girls are now entering their mid-thirties. Since other oncogenic HPV types have been shown to be more prevalent in women ≥30 years old, understanding high grade cervical lesions in older women is still important. Hormonal contraceptives (HC) and smoking are recognised cofactors for the development of pre-malignant lesions.Methods886 cases with cervical intraepithelial neoplasia (CIN) 2/3 and 3636 controls with normal cytology were recruited from the Pap Test Register of NSW, Australia. All women were aged 30–44 years. Conditional logistic regression was used to quantify the relationship of HC and smoking to CIN 2/3 adjusted for various factors.ResultsCurrent-users of HC were at higher risk for CIN 2/3 than never-users [odds ratio (OR) = 1.50, 95%CI = 1.03–2.17] and risk increased with increasing duration of use [ORs:1.13 (0.73–1.75), 1.51 (1.00–2.72), 1.82 (1.22–2.72) for <10, 10–14, ≥15 years of use; p-trend = 0.04]. Ex-users had risks similar to never-users (OR 1.08, 95%CI = 0.75–1.57) regardless of duration of use. Current smoking was significantly associated with CIN 2/3 (OR = 1.43, 95%CI = 1.14–1.80) and risk increased with increasing number of cigarettes/day (p-trend = 0.02). Among ex-smokers, the risk of CIN 2/3 decreased with increasing time since quitting (p-trend = 0.04).ConclusionsIn this benchmark study, current, long term users of HC and current smokers of ≥5 cigarettes/day were each at increased risk of developing CIN 2/3. Findings support smoking cessation in relation to decreasing the risk of pre-cancerous lesions and reinforce the continuing need for cervical screening for cancer prevention in vaccinated and unvaccinated populations.



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Proton versus photon deep inspiration breath hold technique in patients with hodgkin lymphoma and mediastinal radiation

The benefits of proton therapy in the treatment of patients with Hodgkin lymphoma (HL) are controversially discussed. Therefore we compared intensitiy modulated proton therapy (IMPT) with intensity modulated r...

https://ift.tt/2Not423

Postoperative (chemo) radiation in patients with squamous cell cancers of the head and neck – clinical results from the cohort of the clinical cooperation group “Personalized Radiotherapy in Head and Neck Cancer”

Postoperative (chemo) radiation improves tumor control and survival in high-risk patients with head and neck squamous cell carcinoma based on established risk factors. The clinical cooperation group "Personali...

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Self- and informant-rated apathy in patients with childhood-onset craniopharyngioma

Abstract

Introduction

The current study aimed to assess whether childhood-onset craniopharyngioma patients suffer from symptoms of apathy, as assessed by patients themselves and their close others. We further analyzed whether apathy scores are related to symptoms of depression.

Methods

Childhood-onset craniopharyngioma patients (n = 35, 16 female, median age = 22) and matched healthy controls (n = 35, 19 female, median age = 21) were asked to complete self-ratings of the Apathy Evaluation Scale, whereas informant-ratings were obtained from their close others. Depression was assessed by self-ratings using the German version of the Center for Epidemiological Studies Depression Scale. As primary outcome measures, self- and informant-rated apathy scores were compared between patients and healthy controls. As secondary outcome measures, differences between self- and informant-rated apathy within the single groups and associations between apathy and depression were analyzed.

Results

Compared to healthy controls, patients displayed significantly higher apathy levels in informant-ratings (median_patients = 18, median_controls = 12, p = .021), but not in self-ratings (median_patients = 11, median_controls =12, p = .68). In patients, there was a significant discrepancy between self- and informant-rated apathy and self-rated apathy was related to symptoms of depression.

Conclusions

This is the first study to show that childhood-onset craniopharyngioma patients may be at high risk for apathy. Noteworthy, apathy levels in the patient group were judged to be high by their close others but not by the patients themselves, indicating that many patients were not fully aware of their impairments. As apathy is associated with numerous adverse outcomes affecting everyday life and vocational opportunities, future investigations are needed to identify specific risk factors for apathy.

Clinical Trial Registration No: NCT00258453.

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In vitro leishmanicidal effects of the anti-fungal drug natamycin are mediated through disruption of calcium homeostasis and mitochondrial dysfunction

Abstract

Natamycin, a Food and Drug Administration approved anti-fungal drug, and also used as a food additive was evaluated for anti-leishmanial activity since it is known to specifically bind to ergosterol, which is essential to these parasites but absent in mammals. Promising anti-proliferative activity was observed in both promastigote and amastigote forms of the parasite with IC₅₀ values of 15 and 8 µM respectively and a selective index of 12.5. The ultrastructural effects of natamycin on both forms of the parasite and physiological effects on promastigotes were studied in detail for the first time. Electron microscopic observations in treated cells revealed sub-cellular changes like plasma membrane alterations, accumulation of vesicles in the flagellar pocket and extensive mitochondrial damage. Natamycin treatment in promastigotes resulted in elevation of cytosolic calcium (Ca²⁺) levels which caused irreversible loss of mitochondrial membrane potential. This resulted in depletion of cellular ATP levels along with ROS generation finally leading to apoptosis-like and necrotic cell death. In view of our observations along with the safety profile of an existing anti-fungal drug, natamycin may be further investigated for repurposing it as a promising drug candidate against Leishmaniasis.

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Optimisation of treatment with lenvatinib in radioactive iodine-refractory differentiated thyroid cancer

Publication date: Available online 2 July 2018
Source:Cancer Treatment Reviews
Author(s): Jaume Capdevila, Kate Newbold, Lisa Licitra, Aron Popovtzer, Francesc Josep Moreso Mateo, José Zamorano, Michael Kreissl, Javier Aller, Enrique Grande
Lenvatinib has been approved for the treatment of advanced differentiated thyroid cancer (DTC) refractory to radioactive iodine (RAI) following the results of the SELECT trial which demonstrated a significant increase in progression-free survival and a high response rates. The data reported for lenvatinib in RAI-refractory DTC (RAI-R DTC) are the most significant to date in this patient population, with a RECIST objective response rate above 60% and almost 80% reduction in the risk of disease progression. Because the first indication in oncology for lenvatinib is specifically in RAI-R DTC, a period of familiarisation with its safety and efficacy profile is required.This review includes a series of specific recommendations for optimising the management of RAI-R DTC with lenvatinib, as well as specific guidelines for minimising the incidence and severity of adverse events (AEs), which enable dose intensity to be increased and this way maximise the benefits of the drug in the patient population treated. These recommendations were defined at a meeting of experts of different specialities, reviewing available scientific evidence on the drug, as well as their own direct personal experience in daily clinical practice.For toxicity to be properly managed, a multidisciplinary approach is required in which the different medical services, nursing staff and the patient and their careers are all involved. It is essential to assess the suitability of patients who are candidates for lenvatinib, as well as their clinical and physiological status prior to treatment. They must then be closely monitored to prevent and detect possible AEs. The main objective should be to maintain the dose that obtains the maximum therapeutic effect, discontinuing the treatment only if the toxicity becomes unmanageable or there is no clinical benefit.



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Non-invasive kinetic modelling of PET tracers with radiometabolites using a constrained simultaneous estimation method: evaluation with 11 C-SB201745

Abstract

Background

Kinetic analysis of dynamic PET data requires an accurate knowledge of available PET tracer concentration within blood plasma over time, known as the arterial input function (AIF). The gold standard method used to measure the AIF requires serial arterial blood sampling over the course of the PET scan, which is an invasive procedure and makes this method less practical in clinical settings. Traditional image-derived methods are limited to specific tracers and are not accurate if metabolites are present in the plasma.

Results

In this work, we utilise an image-derived whole blood curve measurement to reduce the computational complexity of the simultaneous estimation method (SIME), which is capable of estimating the AIF directly from tissue time activity curves (TACs). This method was applied to data obtained from a serotonin receptor study (¹¹C-SB207145) and estimated parameter results are compared to results obtained using the original SIME and gold standard AIFs derived from arterial samples. Reproducibility of the method was assessed using test-retest data. It was shown that the incorporation of image-derived information increased the accuracy of total volume of distribution (V _T) estimates, averaged across all regions, by 40% and non-displaceable binding potential (BP _ND) estimates by 16% compared to the original SIME. Particular improvements were observed in K₁ parameter estimates. BP _ND estimates, based on the proposed method and the gold standard arterial sample-derived AIF, were not significantly different (P=0.7).

Conclusions

The results of this work indicate that the proposed method with prior AIF information obtained from a partial volume corrected image-derived whole blood curve, and modelled parent fraction, has the potential to be used as an alternative non-invasive method to perform kinetic analysis of tracers with metabolite products.

https://ift.tt/2lRTRHJ

Clinical evaluation of two consecutive UroVysion fluorescence in situ hybridization tests to detect intravesical recurrence of bladder cancer: a prospective blinded comparative study in Japan

Abstract

Background

We evaluated the use of UroVysion fluorescence in situ hybridization tests to detect the intravesical recurrence of bladder cancer during follow-up after a transurethral resection of bladder tumor (TURBT).

Methods

In this prospective, blinded, comparative study, 486 patients treated by TURBT within the prior 2 years were registered at 12 centers. Urine cytology and UroVysion tests were performed once or twice at a central testing laboratory. For the patients with no suspicious findings of bladder cancer in the first analysis, the same examination set was repeated 3 months later as the second analysis. Totals of 468 and 399 patients were eligible for the first and second analyses, respectively. We determined the sensitivity and specificity of two consecutive UroVysion tests.

Results

Bladder cancers were identified in 44 patients at the first analysis. The UroVysion test had 50.0% (95% CI 35.2–64.8%) sensitivity and 72.4% (68.3–76.8%). Urine cytology had 4.5% (0.0–10.7%) sensitivity and 99.8% (99.3–100.0%) specificity. The concordant rate of the first and second UroVysion test results was 72% (kappa coefficient 0.157). Interestingly, the patients with two consecutive positive UroVysion test results had the highest cancer detection rate (14.8%), which is greater than those of the patients with a positive result in either (7.2%) or neither (1.2%) of the two tests at the 3-month follow-up.

Conclusions

The UroVysion test provided higher sensitivity than urine cytology to detect bladder cancer during post-TURBT follow-up. Two consecutive UroVysion tests might be a better indicator to predict intravesical recurrence.

https://ift.tt/2Nnk6SO

Usefulness of 11C-Methionine Positron Emission Tomography for Monitoring of Treatment Response and Recurrence in a Glioblastoma Patient on Bevacizumab Therapy: A Case Report

Recently developed molecular targeted therapies such as bevacizumab (BEV; Avastin) therapy have therapeutic efficacy for glioblastoma. However, it is difficult to distinguish between a tumor response and nonenhancing tumor progression with conventional magnetic resonance imaging (MRI) after BEV administration. Here we present a recurrent glioblastoma case in which ¹¹C-methionine positron emission tomography (MET-PET) provided useful information for detecting tumor recurrence after complete remission, as assessed by the Response Assessment in Neuro-Oncology criteria. A 47-year-old male with a left frontal lobe glioblastoma experienced recurrence 6 months postoperatively. We administered BEV concomitantly with temozolomide, subsequent to gamma knife surgery. Two months after starting BEV, complete remission was obtained. MET uptake on PET gradually decreased and had nearly disappeared 4 months after initiating BEV. No enhanced area was seen on MRI for 17 months after BEV initiation. Nevertheless, MET-PET revealed recurrence, visualized as nonenhancing tumor progression. MET-PET provides useful information for detecting glioblastoma recurrence, which lacks contrast enhancement on MRI after BEV therapy.
Case Rep Oncol 2018;11:442–449

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Impact of external cooling with icepacks on 68 Ga-PSMA uptake in salivary glands

Abstract

Background

External cooling of the salivary glands is advised to prevent xerostomia in lutetium-177-PSMA treatment for advanced prostate cancer. Since evidence addressing this subject is sparse, this study aims to determine impact of icepacks application on uptake in salivary glands. Eighty-nine patients referred for gallium-68-PSMA PET/CT for (re)staging of prostate cancer were prospectively included. Twenty-four patients were scanned with unilateral (solely left-sided) icepacks; 20 with bilateral icepacks; 45 without icepacks. Icepacks were applied approximately 30 minutes prior to tracer injection. PET/CT acquisition started 1 hour postinjection. Radiotracer uptake was measured in the parotid- and submandibular glands.

Results

When comparing the intervention group with the control group, uptake in the left parotid gland significantly differed: SUV_max: 11.07 ± 3.53 versus 12.95 ± 4.16; p = 0.02. SUV_peak: 9.91 ± 3.14 versus 11.45 ± 3.61; p = 0.04. SUV_max and SUV_peak were reduced with 14.52% and 13.45%. All other SUV values did not significantly differ. Patients with bilateral icepacks showed no significant differences in PSMA uptake compared to the control group (all: p > 0.05). Intra-patient analysis revealed some significant differences in SUV_max and SUV_peak between the cooled and non-cooled parotid gland (SUV_max: 11.12 ± 3.71 versus 12.69 ± 3.75; p = 0.00. SUV_peak: 9.93 ± 3.32 versus 11.25 ± 3.25; p = 0.00).

Conclusions

Impact of icepacks on PSMA uptake seems to be limited to the parotid glands. As clinical relevance of these findings is debatable, structural application of icepacks in the setting of lutetium-177 PSMA therapy needs careful consideration.

https://ift.tt/2Ktex7A

PET radioligand binding to translocator protein (TSPO) is increased in unmedicated depressed subjects

Abstract

Background

Inflammation is associated with major depressive disorder (MDD). Translocator protein 18 kDa (TSPO), a putative biomarker of neuroinflammation, is quantified using positron emission tomography (PET) and ¹¹C-PBR28, a TSPO tracer. We sought to (1) investigate TSPO binding in MDD subjects currently experiencing a major depressive episode, (2) investigate the effects of antidepressants on TSPO binding, and (3) determine the relationship of peripheral and central inflammatory markers to cerebral TSPO binding. Twenty-eight depressed MDD subjects (unmedicated (n = 12) or medicated (n = 16)) and 20 healthy controls (HC) underwent PET imaging using ¹¹C-PBR28. Total distribution volume (V_T, proportional to Bmax/Kd) was measured and corrected with the free fraction in plasma (fp). The subgenual prefrontal cortex (sgPFC) and anterior cingulate cortex (ACC) were the primary regions of interest. Peripheral blood samples and cerebrospinal fluid were analyzed to investigate the relationship between TSPO binding and peripheral and central inflammatory markers, including interleukins and neurotrophic factors previously linked to depression.

Results

TSPO binding was higher in MDD versus HC in the sgPFC (Cohen's d = 0.64, p = .038, 95% CI 0.04–1.24) and ACC (d = 0.60, p = .049, 95% CI 0.001–1.21), though these comparisons missed the corrected threshold for statistical significance (α = .025). Exploratory analyses demonstrated that unmedicated MDD subjects had the highest level of TSPO binding, followed by medicated MDD subjects, who did not differ from HC. TSPO binding correlated with interleukin-5 in cerebrospinal fluid but with no other central inflammatory markers.

Conclusions

This study found a trend towards increased TSPO binding in the brains of MDD subjects, and post hoc analysis extended these findings by demonstrating that this abnormality is significant in unmedicated (but not medicated) MDD subjects.

https://ift.tt/2MKZEdn

An Unusual Presentation of Kawasaki Disease: Gallbladder Hydrops and Acute Cholestatic Hepatitis

Kawasaki disease is the most common vasculitis of childhood. In its classical form, at least four of five diagnostic criteria including cervical lymphadenopathy (1.5 cm or more), nonsuppurative conjunctivitis, intraoral mucosal changes, edema in hands and feet, and maculopapular rash are required with prolonged fever over 5 days. Atypical cases which are different from the classical type or incomplete cases which does not include all the diagnostic criteria can be seen. The typical Kawasaki disease is a self-limiting disease with fever lasting for an average of two weeks. In such patients who have not been diagnosed and whose treatment has been delayed, coronary artery aneurysm, myocardial depression, arrhythmia, and vascular complications may increase morbidity and mortality. We would like to present a rare case of an atypical patient with gallbladder hydrops and acute cholestatic hepatitis.

https://ift.tt/2Nj59RE

Cancers, Vol. 10, Pages 222: Radiation Pneumonitis: Old Problem, New Tricks

Cancers, Vol. 10, Pages 222: Radiation Pneumonitis: Old Problem, New Tricks

Cancers doi: 10.3390/cancers10070222

Authors: Varsha Jain Abigail T. Berman

Radiation therapy is a major treatment modality for management of non-small cell lung cancer. Radiation pneumonitis is a dose limiting toxicity of radiotherapy, affecting its therapeutic ratio. This review presents patient and treatment related factors associated with the development of radiation pneumonitis. Research focusing on reducing the incidence of radiation pneumonitis by using information about lung ventilation, imaging-based biomarkers as well as normal tissue complication models is discussed. Recent advances in our understanding of molecular mechanisms underlying lung injury has led to the development of several targeted interventions, which are also explored in this review.

https://ift.tt/2KKWZjc