Cancer by Sfakianakis Alexandros: 03/19/18

Δευτέρα 19 Μαρτίου 2018

Primary mucinous carcinoma of thyroid gland with prominent signet-ring-cell differentiation: a case report and review of the literature

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STK39 blockage by RNA interference inhibits the proliferation and induces the apoptosis of renal cell carcinoma

http://ift.tt/2tYCX0E

Economic Burden of HR+/HER2- Metastatic Breast Cancer Among Adult Premenopausal Women

Abstract

Introduction

Premenopausal women with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) have complex treatment needs and may receive sequential combinations of endocrine therapy (ET) or chemotherapy. This study describes healthcare utilization (HRU) and costs among premenopausal women with HR+/HER2- mBC in real-world settings from a payer's perspective.

Methods

In this retrospective cohort study, premenopausal women with HR+/HER2- mBC who received ET or chemotherapy were identified from the Truven Health Analytics MarketScan database (1 January 2006–31 December 2015). The main HRU outcomes per patient per 6 months (PPP6 M) were measured during each line of therapy and included number of days in inpatient (IP) and outpatient (OP) services. Healthcare costs per patient per month (PPPM) included medical and pharmacy costs.

Results

A total of 3203 patients received first-line, 2194 received second-line, and 1242 received third-line therapy for mBC. Mean number of IP days PPP6 M were 1.6, 1.3, and 1.5 days in the first, second, and third lines, respectively. Mean number of days with OP services PPP6 M was 31.4, 30.9, and 23.3 in the first, second, and third lines, respectively. Among patients receiving ET, mean total healthcare costs were $6521, $4440, and $4555 PPPM in the first, second, and third line, respectively. Among patients receiving chemotherapy, mean total healthcare costs were $16,842, $12,868, and $16,129 PPPM in the first, second, and third line, respectively. These costs were mainly driven by treatment and OP costs.

Conclusion

Real-world HRU and costs among premenopausal women with HR+/HER2- mBC are extensive. Patients who received chemotherapy incurred approximately twice the costs of patients treated with ET.

Funding

Novartis Pharmaceutical Corp.

http://ift.tt/2prbUWy

Economic Burden of HR+/HER2- Metastatic Breast Cancer Among Adult Premenopausal Women

Abstract

Introduction

Methods

Results

Conclusion

Real-world HRU and costs among premenopausal women with HR+/HER2- mBC are extensive. Patients who received chemotherapy incurred approximately twice the costs of patients treated with ET.

Funding

Novartis Pharmaceutical Corp.

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Novel biomarker-based model for the prediction of sorafenib response and overall survival in advanced hepatocellular carcinoma: a prospective cohort study

Abstract

Background

Prediction of the outcome of sorafenib therapy using biomarkers is an unmet clinical need in patients with advanced hepatocellular carcinoma (HCC). The aim was to develop and validate a biomarker-based model for predicting sorafenib response and overall survival (OS).

Methods

This prospective cohort study included 124 consecutive HCC patients (44 with disease control, 80 with progression) with Child-Pugh class A liver function, who received sorafenib. Potential serum biomarkers (namely, hepatocyte growth factor [HGF], fibroblast growth factor [FGF], vascular endothelial growth factor receptor-1, CD117, and angiopoietin-2) were tested. After identifying independent predictors of tumor response, a risk scoring system for predicting OS was developed and 3-fold internal validation was conducted.

Results

A risk scoring system was developed with six covariates: etiology, platelet count, Barcelona Clinic Liver Cancer stage, protein induced by vitamin K absence-II, HGF, and FGF. When patients were stratified into low-risk (score ≤ 5), intermediate-risk (score 6), and high-risk (score ≥ 7) groups, the model provided good discriminant functions on tumor response (concordance [c]-index, 0.884) and 12-month survival (area under the curve [AUC], 0.825). The median OS was 19.0, 11.2, and 6.1 months in the low-, intermediate-, and high-risk group, respectively (P < 0.001). In internal validation, the model maintained good discriminant functions on tumor response (c-index, 0.825) and 12-month survival (AUC, 0.803), and good calibration functions (all P > 0.05 between expected and observed values).

Conclusions

This new model including serum FGF and HGF showed good performance in predicting the response to sorafenib and survival in patients with advanced HCC.

http://ift.tt/2G6d4RI

Novel biomarker-based model for the prediction of sorafenib response and overall survival in advanced hepatocellular carcinoma: a prospective cohort study

Abstract

Background

Methods

Results

Conclusions

This new model including serum FGF and HGF showed good performance in predicting the response to sorafenib and survival in patients with advanced HCC.

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Prognostic value of metformin for non-small cell lung cancer patients with diabetes

Abstract

Background

The anti-cancer role of metformin has been reported in many different kinds of solid tumors, but how it affects non-small cell lung cancer (NSCLC) is currently elusive. The aim of this study was to investigate the influence of metformin treatment on diabetic NSCLC.

Methods

Two hundred fifty-five patients of diabetic NSCLC receiving therapy in our hospital from 2014 to 2016 were enrolled in our study. The information on clinical diagnosis, pathology, and prognosis as well as the influence of metformin in diabetic NSCLC were collected and assessed. Univariate and multivariate analytical techniques were applied to explore how metformin affect the survival of NSCLC.

Results

One hundred fifty of the 255 diabetic NSCLC patients took metformin. The median overall survival time (OST) and disease-free survival time (DFST) were significantly prolonged with metformin treatment compared to without metformin treatment (OST 25.0 vs 11.5 months, p = 0.005; DFST 15.6 vs 8.5 months, p = 0.010). Multivariate analysis indicated that metformin treatment could be used to predict the long-term outcome of diabetic NSCLC independently (HR = 0.588, 95% CI 0.466–0.895, p = 0.035).

Conclusion

Our study revealed that the metformin could help in improving the final outcome of NSCLC patients with diabetes in the long term and thus could be applied to treat NSCLC.

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Prognostic value of metformin for non-small cell lung cancer patients with diabetes

Abstract

Background

Methods

Results

Conclusion

Our study revealed that the metformin could help in improving the final outcome of NSCLC patients with diabetes in the long term and thus could be applied to treat NSCLC.

http://ift.tt/2G4IoAd

Perioperative Management of Patients with Inflammatory Rheumatic Diseases Undergoing Major Orthopaedic Surgery: A Practical Overview

Abstract

Patients with inflammatory rheumatic diseases often need orthopaedic surgery due to joint involvement. Total hip replacement and total knee replacement are frequent surgical procedures in these patients. Due to the complexity of the inflammatory rheumatic diseases, the perioperative management of these patients must envisage a multidisciplinary approach. The frequent association with extraarticular comorbidities must be considered when evaluating perioperative risk of the patient and should guide the clinician in the decision-making process. However, guidelines of different medical societies may vary and are sometimes contradictory. Orthopaedics should collaborate with rheumatologists, anaesthesiologists and, when needed, cardiologists and haematologists with the common aim of minimising perioperative risk in patients with inflammatory rheumatic diseases. The aim of this review is to provide the reader with simple practical recommendations regarding perioperative management of drugs such as disease-modifying anti-rheumatic drugs, corticosteroids, non-steroidal anti-inflammatory drugs and tools for a risk stratification for cardiovascular and thromboembolic risk based on current evidence for patients with inflammatory rheumatic diseases.

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Perioperative Management of Patients with Inflammatory Rheumatic Diseases Undergoing Major Orthopaedic Surgery: A Practical Overview

Abstract

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Myxoid liposarcoma: local relapse and metastatic pattern in 43 patients

Abstract

Background

Liposarcomas are the second most common type of soft tissue sarcomas, 30–50% of these are of myxoid subtype. The aim of this retrospective study was to analyze the local control rate, the metastatic pattern and survival of patients in a consecutive single-institution series.

Methods

From 1983 to 2015, 43 patients with myxoid liposarcoma of the extremities and trunk wall underwent resections. The margin was defined as R0 (wide) or R1 (marginal). Patients were followed for evidence of local recurrence or distant metastasis. Overall and recurrence-free survival was calculated.

Results

The mean age was 48.6 years. The lower extremity was involved in 40 cases, the mean tumour size was 12 cm. In 31 cases a wide and in 12 cases a marginal resection was performed. Grading was G1 in 14, G2 in 25 and G3 in 4 cases.

Nine patient died in follow-up, 4 of them with metastatic disease, all nonpulmonary. 5-year local recurrence (LR) free survival was 82%. 4 (9.3%) patients developed LR (all R1). Overall survival (OS) was 81% after 5 and 72% after 10 years. In multivariate analysis age and Grading proved to be significant on OS. According to univariate analysis, only age over 48 years and distant metastasis had a significant impact on overall survival.

Conclusions

Patients with myxoid liposarcomas have a good prognosis. Myxoid liposarcoma has a distinct pattern of nonpulmonary metastatic disease. Therefore, patients with high-risk extremity myxoid liposarcoma should undergo imaging studies of the chest, abdomen, spine and pelvis as part of their staging and follow-up examinations preferably with whole body MRI, or CT scans and MRI of the spine and pelvic region for detection of suspected metastatic disease.

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Myxoid liposarcoma: local relapse and metastatic pattern in 43 patients

Abstract

Background

Methods

Results

Conclusions

http://ift.tt/2G8toRW

Pretreatment prognostic factors of survival and late toxicities for patients with nasopharyngeal carcinoma treated by simultaneous integrated boost intensity-modulated radiotherapy

Abstract

Background

To scrutinize the pretreatment prognosticators on survival and late toxicities in a homogenous cohort of nasopharyngeal carcinoma (NPC) patients treated by simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT).

Methods

A total of 219 non-distant metastatic NPC patients consecutively treated by SIB-IMRT at a single institute were collected. The pretreatment factors including the socio-demographic variables, TNM stages, gross tumor volume (GTV), Epstein-Barr virus (EBV)-DNA, and hematologic inflammatory markers were analyzed. Cox model was used to screen the prognostic factors of late toxicities and four survival outcomes including locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), failure-free survival (FFS), and overall survival (OS).

Results

Statistically significant inter-correlations were observed between the values of EBV-DNA, some hematologic inflammatory markers, GTV, and N classification. The 5-year LRRFS, DMFS, FFS, and OS rates were 87.9%, 89.4%, 79.4%, and 81.3%, respectively. Multivariate analysis revealed that advanced N classification (N2–3 vs. N0–1) remained the only significant negative prognosticator for all the four survival outcomes. An increased monocyte percentage and a decreased lymphocyte-to-monocyte ratio were significantly associated with poorer FFS and OS, respectively. Larger GTV was observed to be predictive of poorer LRRFS. Patients with T3–4 (HR: 3.5, 95% CI: 1.0–12.1, p = 0.048) or higher GTV (HR: 1.006, 95% CI: 1.001–1.011, p = 0.027) were associated with higher incidence of radiation neuropathy.

Conclusion

N classification remains the most significant survival predictor for NPC patients treated by SIB-IMRT after adjusting these biomarkers. GTV impacts not only on locoregional control but also radiation neuropathy.

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Pretreatment prognostic factors of survival and late toxicities for patients with nasopharyngeal carcinoma treated by simultaneous integrated boost intensity-modulated radiotherapy

Abstract

Background

Methods

Results

Conclusion

http://ift.tt/2G8B2vu

Underutilization and disparities in access to EGFR testing among Medicare patients with lung cancer from 2010 – 2013

Abstract

Background

Tumor testing for mutations in the epidermal growth factor receptor (EGFR) gene is indicated for all newly diagnosed, metastatic lung cancer patients, who may be candidates for first-line treatment with an EGFR tyrosine kinase inhibitor. Few studies have analyzed population-level testing.

Methods

We identified clinical, demographic, and regional predictors of EGFR & KRAS testing among Medicare beneficiaries with a new diagnosis of lung cancer in 2011–2013 claims. The outcome variable was whether the patient underwent molecular, EGFR and KRAS testing. Independent variables included: patient demographics, Medicaid status, clinical characteristics, and region where the patient lived. We performed multivariate logistic regression to identify factors that predicted testing.

Results

From 2011 to 2013, there was a 19.7% increase in the rate of EGFR testing. Patient zip code had the greatest impact on odds to undergo testing; for example, patients who lived in the Boston, Massachusetts hospital referral region were the most likely to be tested (odds ratio (OR) of 4.94, with a 95% confidence interval (CI) of 1.67–14.62). Patient demographics also impacted odds to be tested. Asian/Pacific Islanders were most likely to be tested (OR 1.63, CI 1.53–1.79). Minorities and Medicaid patients were less likely to be tested. Medicaid recipients had an OR of 0.74 (CI 0.72–0.77). Hispanics and Blacks were also less likely to be tested (OR 0.97, CI 0.78–0.99 and 0.95, CI 0.92–0.99), respectively. Clinical procedures were also correlated with testing. Patients who underwent transcatheter biopsies were 2.54 times more likely to be tested (CI 2.49–2.60) than those who did not undergo this type of biopsy.

Conclusions

Despite an overall increase in EGFR testing, there is widespread underutilization of guideline-recommended testing. We observed racial, income, and regional disparities in testing. Precision medicine has increased the complexity of cancer diagnosis and treatment. Targeted interventions and clinical decision support tools are needed to ensure that all patients are benefitting from advances in precision medicine. Without such interventions, precision medicine may exacerbate racial disparities in cancer care and health outcomes.

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Relationship between time elapsed since completion of radiotherapy and quality of life of patients with breast cancer

Abstract

Background

To investigate the relationship between time elapsed since completion of radiotherapy (RT) and quality of life (QOL) of patients with breast cancer.

Methods

A total of 300 patients with breast cancer were treated at the First Affiliated Hospital of Anhui Medical University between January 2013 and April 2016. Of these, 212 patients were included in the study. Patients were divided into 4 groups based on the time elapsed since completion of RT. The generic cancer questionnaire, EORTC QLQ-30, and the breast cancer-specific questionnaire, QLQ-BR23, were used to assess the QOL.

Results

Analysis of time elapsed since completion of RT and QOL revealed changes in the scores for role function with passage of time; the third year's scores were the highest. Pain symptoms during the 3rd and 4th years after RT were lower than those during the 1st and 2nd years after RT; scores for financial difficulties fluctuated with passage of time; perception of own body scores improved within first 3 years; sexual activity and enjoyment of sexual activity showed a significant decrease during the 2nd to 4th year post RT. Scores pertaining to concerns about future state of health showed a significant increase during the 2nd to 4th year after RT, while breast symptoms score showed fluctuations with passage of time.

Conclusions

Social function, pain symptoms, and concerns about future state of health tended to improve with passage of time after RT. Other scales showed no correlation with time elapsed since completion of RT.

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Underutilization and disparities in access to EGFR testing among Medicare patients with lung cancer from 2010 – 2013

Abstract

Background

Methods

Results

Conclusions

http://ift.tt/2G9LGlA

Relationship between time elapsed since completion of radiotherapy and quality of life of patients with breast cancer

Abstract

Background

To investigate the relationship between time elapsed since completion of radiotherapy (RT) and quality of life (QOL) of patients with breast cancer.

Methods

Results

Conclusions

Social function, pain symptoms, and concerns about future state of health tended to improve with passage of time after RT. Other scales showed no correlation with time elapsed since completion of RT.

http://ift.tt/2FXKezo

Recent advances in medical therapy for metastatic urothelial cancer

Abstract

Cytotoxic chemotherapy has been the mainstay of medical therapy for metastatic urothelial cancer. Currently, the gemcitabine/cisplatin regimen is widely used worldwide as the standard first-line medical treatment. Very recently, in 2017, pembrolizumab, a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1, was approved as a second-line treatment to be used after platina-based chemotherapy for metastatic urothelial cancer in Japan. Based on its promising anti-tumor efficacy and manageable safety profile as demonstrated in the phase III KEYNOTE-045 trial, pembrolizumab therapy is expected to be rapidly introduced for treating metastatic urothelial cancer in clinical practice. The paradigm of medical treatment for patients with metastatic UC is dramatically changing through the introduction of this and other immune-checkpoint inhibitors. In this article, we provide a brief overview of these immune-checkpoint inhibitors and a comprehensive summary of the use of cytotoxic chemotherapy for metastatic urothelial cancer, including ongoing clinical trials.

http://ift.tt/2u4hDqM

Recent advances in medical therapy for metastatic urothelial cancer

Abstract

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Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways

Abstract

Background

Metformin is a commonly used drug for the treatment of diabetes. Accumulating evidence suggests that it exerts anti-tumor effects in many cancers, including multiple myeloma (MM); however, the underlying molecular mechanisms have not been clearly elucidated.

Methods

The anti-myeloma effects of metformin were evaluated using human MM cell lines (RPMI8226 and U266) in vitro and in vivo NOD-SCID murine xenograft MM model. Cell viability was assessed with CCK8 and cell proliferation was measured by EdU incorporation assay. Cell cycle distribution and apoptosis were examined by flow cytometry. Transmission electron microscopy was used to visualized autophagosomes. Activation of AMPK and inhibition of mTORC1/C2 pathways was assessed by Western blot analysis. RPMI8226 cells and U266 cell lines with AMPK knockdown were generated by transfection with small interfering RNA targeting the AMPK-α1 and α2 subunits using Lipofectamine 2000 reagent.

Results

Metformin effectively inhibited the proliferation of MM cell lines, an effect that was associated with the induction of autophagy and G0/G1 cell cycle arrest, but not apoptosis. Metformin activated AMPK and repressed both mTORC1 and mTORC2 signaling pathways in myeloma cells as well as downstream molecular signaling pathways, such as p-4EBP1 and p-AKT. AMPK activation resulted in direct phosphorylation and activation of tuberous sclerosis complex 2 (TSC2), leading to inhibition of the mammalian target of rapamycin (mTOR). In addition, metformin inhibited myeloma cell growth in an AMPK-dependent manner. The xenograft mouse model further confirmed that metformin inhibited tumor growth by upregulation of AMPK and downregulation of mTOR.

Conclusions

Metformin inhibits the proliferation of myeloma cells by inducing autophagy and cell-cycle arrest. Our results suggest that the molecular mechanism involves dual repression of mTORC1 and mTORC2 pathways via AMPK activation. Our study provides a theoretical basis for the development of novel strategies for the treatment of MM using metformin as an already approved and safe drug.

http://ift.tt/2pnEmt4

Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways

Abstract

Background

Methods

Results

Conclusions

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Induction of apoptosis in imatinib sensitive and resistant chronic myeloid leukemia cells by efficient disruption of bcr-abl oncogene with zinc finger nucleases

Abstract

Background

The bcr-abl fusion gene is the pathological origin of chronic myeloid leukemia (CML) and plays a critical role in the resistance of imatinib. Thus, bcr-abl disruption-based novel therapeutic strategy may warrant exploration. In our study, we were surprised to find that the characteristics of bcr-abl sequences met the design requirements of zinc finger nucleases (ZFNs).

Methods

We constructed the ZFNs targeting bcr-abl with high specificity through simple modular assembly approach. Western blotting was conducted to detect the expression of BCR-ABL and phosphorylation of its downstream STAT5, ERK and CRKL in CML cells. CCK8 assay, colony-forming assay and flow cytometry (FCM) were used to evaluate the effect of the ZFNs on the viablity and apoptosis of CML cells and CML CD34⁺ cells. Moreover, mice model was used to determine the ability of ZFNs in disrupting the leukemogenesis of bcr-abl in vivo.

Results

The ZFNs skillfully mediated 8-base NotI enzyme cutting site addition in bcr-abl gene of imatinib sensitive and resistant CML cells by homology-directed repair (HDR), which led to a stop codon and terminated the translation of BCR-ABL protein. As expected, the disruption of bcr-abl gene induced cell apoptosis and inhibited cell proliferation. Notably, we obtained similar result in CD34⁺ cells from CML patients. Moreover, the ZFNs significantly reduced the oncogenicity of CML cells in mice.

Conclusion

These results reveal that the bcr-abl gene disruption based on ZFNs may provide a treatment choice for imatinib resistant or intolerant CML patients.

http://ift.tt/2FM25gB

Induction of apoptosis in imatinib sensitive and resistant chronic myeloid leukemia cells by efficient disruption of bcr-abl oncogene with zinc finger nucleases

Abstract

Background

Methods

Results

Conclusion

These results reveal that the bcr-abl gene disruption based on ZFNs may provide a treatment choice for imatinib resistant or intolerant CML patients.

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Modified Cervicography and Visual Inspection With Acetic Acid as an Alternative Screening Method for Cervical Precancerous Lesions.

https:--www.ncbi.nlm.nih.gov-corehtml-pm

Modified Cervicography and Visual Inspection With Acetic Acid as an Alternative Screening Method for Cervical Precancerous Lesions.

J Cancer Prev. 2017 Dec;22(4):254-259

Authors: Purwoto G, Dianika HD, Putra A, Purbadi S, Nuranna L

Abstract
Background: We compared the diagnostic accuracy between visual inspection with acetic acid (VIA) and modified cervicography as an alternative screening method for cervical precancerous lesions.
Methods: A diagnostic cross-sectional study was performed at the outpatient clinic at an Indonesian national referral hospital from February until April 2015. We collected samples from patients who sequentially underwent VIA examination, modified cervicography, and colposcopy.
Results: A total of 185 patients were included in this study. Modified cervicography showed positive results in 7.6% of patients, while 7.0% of patients had a VIA positive result. This is compared to 5.4% of patients showing abnormal colposcopy results. From those results, we obtained that sensitivity and specificity of VIA were 96.0% and 90.9%. Meanwhile, sensitivity and specificity of modified cervicography were 97.7% and 90.9%, respectively, compared to colposcopy as a gold standard.
Conclusions: Modified cervicography and VIA are reliable tools for cervical cancer screening, with comparable sensitivity and specificity. Modified cervicography can be used as a supplementary tool to improve the documentation of VIA and as an alternative to VIA alone.

PMID: 29302584 [PubMed]

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Erratum: Analysis of Gastric Body Microbiota by Pyrosequencing: Possible Role of Bacteria Other Than Helicobacter pylori in the Gastric Carcinogenesis.

Erratum: Analysis of Gastric Body Microbiota by Pyrosequencing: Possible Role of Bacteria Other Than Helicobacter pylori in the Gastric Carcinogenesis.

J Cancer Prev. 2017 Dec;22(4):267

Authors: Sohn SH, Kim N, Jo HJ, Kim J, Park JH, Nam RH, Seok YJ, Kim YR, Lee DH

Abstract
[This corrects the article on p. 115 in vol. 22, PMID: 28698866.].

PMID: 29302586 [PubMed - in process]

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High Intensity Interval Training Increases Natural Killer Cell Number and Function in Obese Breast Cancer-challenged Mice and Obese Women.

High Intensity Interval Training Increases Natural Killer Cell Number and Function in Obese Breast Cancer-challenged Mice and Obese Women.

J Cancer Prev. 2017 Dec;22(4):260-266

Authors: Barra NG, Fan IY, Gillen JB, Chew M, Marcinko K, Steinberg GR, Gibala MJ, Ashkar AA

Abstract
High intensity interval training (HIIT) boosts natural killer (NK) cell number and activity in normal weight breast cancer patients; however, whether this occurs in obese individuals is not well established. The goal of this study was to determine whether HIIT effectively boosts NK cells as a therapeutic strategy against breast cancer in an obese mouse model and in overweight/obese women. Diet induced female C57Bl/6 obese mice were assigned to undergo HIIT for four weeks or remain sedentary. Female participants were subjected to a six weeks HIIT protocol. HIIT mice acclimatized to treadmill running were subsequently injected with 5 × 105 polyoma middle T (MT) breast cancer cells intravenously. NK cell number and activation were monitored using flow cytometry, and tumor burden or lipid content evaluated from histological lung and liver tissues, respectively. In both mice and humans, circulating NK cell number and activation (CD3-NK1.1+CD27+ and CD3-CD56+, respectively) markedly increased immediately after HIIT. HIIT obese mice had reduced lung tumor burden compared to controls following MT challenge, and had diminished hepatic lipid deposition despite minimal body weight loss. Our findings demonstrate that HIIT can benefit obese individuals by enhancing NK cell number and activity, reducing tumor burden, and enhancing metabolic health.

PMID: 29302585 [PubMed]

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TP53 R72P Polymorphism and Susceptibility to Human Papillomavirus Infection Among Women With Human Immunodeficiency Virus in Morocco: A Case-control Study.

TP53 R72P Polymorphism and Susceptibility to Human Papillomavirus Infection Among Women With Human Immunodeficiency Virus in Morocco: A Case-control Study.

J Cancer Prev. 2017 Dec;22(4):248-253

Authors: Lahsen AO, Baba H, Bensghir R, Fayssel N, Sodqi M, Marih L, Nadifi S, Wakrim L, El Filali KM, Ezzikouri S

Abstract
Background: Human papillomavirus (HPV) is the most common sexually transmitted agent worldwide. HPV is the main causative agent for cervical cancer. The HPV oncoprotein E6 binds to the tumor suppressor gene product p53, promoting its degradation; the Arg allele of TP53 R72P polymorphism binds more ardently with HPV E6 than the Pro variant. Here, we investigated whether TP53 R72P gene variant, rs104252, was associated with susceptibility to HPV infection in women with human immunodeficiency virus (HIV).
Methods: We analyzed 200 HPV-positive and 68 uninfected women with HIV. Genomic DNA was isolated from cervical swab. The TP53 R72P polymorphism was genotyped by PCR-RFLP. Unconditional logistic regression was used to assess the association between polymorphism and the clinical, lifestyle, and behavioral data.
Results: The genotype and allele frequencies of rs104252 variant did not differ between women without or with HPV infection (P > 0.05). Moreover, the p53 polymorphism was not associated with cervical cytology. In contrast, when we analyzed according to behavior factors, the P72P genotype was more frequent among HPV-positive smoker women. However, no significant relationship was found between alcohol, contraceptive use, and number of partners with TP53 R72P genotype distributions among HPV-positive cases (P > 0.05).
Conclusions: The R72 variant of p53 R72P is not associated with HPV infection and progression of lesions. There was no association between this variant and behavior factors in HPV-positive cases. The P72P genotype may be more frequent among HPV-positive smoker women.

PMID: 29302583 [PubMed]

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Secondary Primary Prostate Cancer after Colorectal Cancer: A Nationwide Population-based Cohort Study in Korea.

Secondary Primary Prostate Cancer after Colorectal Cancer: A Nationwide Population-based Cohort Study in Korea.

J Cancer Prev. 2017 Dec;22(4):241-247

Authors: Kim HS, Choi YJ, Shin DW, Han KD, Yoon H, Shin CM, Park YS, Kim N, Lee DH

Abstract
Background: Colorectal cancer (CRC) and prostate cancer frequently occur in developed countries. There are several reports on the association between CRC and prostate cancer; however, the conclusions are inconsistent to investigate the association of the development of secondary primary prostate cancer among patients with prior primary CRC using a nationwide population-based dataset.
Methods: Patients registered in the Republic of Korea National Health Insurance System database who were diagnosed with CRC between 2007 and 2012 were followed-up until the end of 2015, and we investigated the new diagnosis secondary primary prostate cancer. We compared the incidence of prostate cancer in age-matched controls using the Cox proportional hazards models.
Results: We analyzed a total of 85,455 first primary CRC survivors. During the follow-up period of 494,222 person-years, 2,005 patients (2.30%) developed secondary primary prostate cancer (incidence rate 4.06/1,000 person-years). The median duration of follow-up was 5.78 years. Compared with the general population, CRC patients had a significantly increased risk of secondary primary prostate cancer (HR = 2.30, 95% CI = 2.18-2.43; P < 0.001). Multivariate analysis (including age, sex, body mass index, hypertension, diabetes mellitus, dyslipidemia, and income) showed that age < 55 years (HR = 20.74, 95% CI = 11.81-36.41; P < 0.001) is a significant independent predictor of secondary primary prostate cancer development.
Conclusions: Men diagnosed with colorectal cancer are at an increased risk of secondary primary prostate cancer, particularly those aged < 55 years. The data suggests that colorectal cancer patients aged < 55 years require regular screening for prostate cancer.

PMID: 29302582 [PubMed]

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Novel Genetic Associations Between Lung Cancer and Indoor Radon Exposure.

Novel Genetic Associations Between Lung Cancer and Indoor Radon Exposure.

J Cancer Prev. 2017 Dec;22(4):234-240

Authors: Choi JR, Koh SB, Park SY, Kim HR, Lee H, Kang DR

Abstract
Background: Lung cancer is the leading cause of cancer-related death worldwide, for which smoking is considered as the primary risk factor. The present study was conducted to determine whether genetic alterations induced by radon exposure are associated with the susceptible risk of lung cancer in never smokers.
Methods: To accurately identify mutations within individual tumors, next generation sequencing was conduct for 19 pairs of lung cancer tissue. The associations of germline and somatic variations with radon exposure were visualized using OncoPrint and heatmap graphs. Bioinformatic analysis was performed using various tools.
Results: Alterations in several genes were implicated in lung cancer resulting from exposure to radon indoors, namely those in epidermal growth factor receptor (EGFR), tumor protein p53 (TP53), NK2 homeobox 1 (NKX2.1), phosphatase and tensin homolog (PTEN), chromodomain helicase DNA binding protein 7 (CHD7), discoidin domain receptor tyrosine kinase 2 (DDR2), lysine methyltransferase 2C (MLL3), chromodomain helicase DNA binding protein 5 (CHD5), FAT atypical cadherin 1 (FAT1), and dual specificity phosphatase 27 (putative) (DUSP27).
Conclusions: While these genes might regulate the carcinogenic pathways of radioactivity, further analysis is needed to determine whether the genes are indeed completely responsible for causing lung cancer in never smokers exposed to residential radon.

PMID: 29302581 [PubMed]

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Protective Effect of Allium tuberosum Extract on Vascular Inflammation in Tumor Necrosis Factor-α-induced Human Vascular Endothelial Cells.

Protective Effect of Allium tuberosum Extract on Vascular Inflammation in Tumor Necrosis Factor-α-induced Human Vascular Endothelial Cells.

J Cancer Prev. 2017 Dec;22(4):228-233

Authors: Hur HJ, Lee AS

Abstract
Background: Endothelial adhesion molecule expression induced by pro-inflammatory cytokine plays an important role in vascular endothelial cell injury, leading to vascular disease. Allium tuberosum (AT), which is used as a functional food, has a thrombolytic effect. It contains vitamin A, vitamin C, carbohydrate, calcium, iron, and phosphorus. There are many carotenes that turn into vitamin A in the body. Also, it helps blood circulation and stimulates metabolism. The purpose of the this study was to estimate the anti-inflammatory effects of the AT extract.
Methods: Human vascular endothelial cells were pre-treated with 100 μg/mL AT extract for 30 minutes and subsequently co-treated with TNF-α (10 ng/mL) and AT extract (100 μg/mL) for 1, 4, and 6 hours. After treatment, the cells were lysed and used for quantitative reverse transcription PCR, Western blot analysis, and monocyte adhesion assay.
Results: We examined the effect of the AT extract on inflammatory gene expression in TNF-α-induced human umbilical vein endothelial cells (HUVECs). The extract reduced the expression levels of mRNA and protein of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in TNF-α-stimulated HUVECs. It also inhibited the TNF-α-induced phosphorylation of the NF-κB p65 subunit and degradation of IκBα. Furthermore, the AT extract prevented the increased adhesion capacity of monocyte to TNF-α-stimulated vascular endothelial cells by reducing ICAM-1 and VCAM-1 expression.
Conclusions: The AT extract has preventive and anti-inflammatory effect against vascular disease and has potential for supporting prevention against the early process of atherosclerosis.

PMID: 29302580 [PubMed]

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Myricetin Inhibits Angiogenesis by Inducing Apoptosis and Suppressing PI3K/Akt/mTOR Signaling in Endothelial Cells.

Myricetin Inhibits Angiogenesis by Inducing Apoptosis and Suppressing PI3K/Akt/mTOR Signaling in Endothelial Cells.

J Cancer Prev. 2017 Dec;22(4):219-227

Authors: Kim GD

Abstract
Background: Myricetin has been shown to possess potential antiangiogenic effects in endothelial cells. However, the underlying mechanisms are not fully understood. Therefore, we evaluated its antiangiogenic effects in human umbilical vascular endothelial cells (HUVECs).
Methods: HUVECs were cultured in endothelial cell growth medium-2 to induce proliferation and angiogenesis and treated with different doses of myricetin (0.25, 0.5, and 1 μM) for 24 hours. Cell proliferation was analyzed by the MTT and lactate dehydrogenase release assays; angiogenesis was determined by the tube formation assay. In addition, cell signaling pathways related to angiogenesis were investigated by Western blotting.
Results: Myricetin induced apoptosis and procaspase-3 cleavage though the induction of reactive oxygen species (ROS). It significantly inhibited cell migration, tube formation, and PI3K/Akt/mTOR signaling in HUVECs.
Conclusions: Myricetin exerts antiangiogenic effects by inducing ROS-mediated apoptosis and inhibiting PI3K/Akt/mTOR signaling in HUVECs.

PMID: 29302579 [PubMed]

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Epigenomic Hard Drive Imprinting: A Hidden Code Beyond the Biological Death of Cancer Patients.

Epigenomic Hard Drive Imprinting: A Hidden Code Beyond the Biological Death of Cancer Patients.

J Cancer Prev. 2017 Dec;22(4):211-218

Authors: Nilendu P, Sharma NK

Abstract
Several genetic and epigenetic theories have been suggested to explain the intricacies of life and death. However, several questions remain unsettled regarding cellular death events, particularly of living tissue in the case of cancer patients, such as the fate and adaptation of cancer cells after biological death. It is possible that cancer cells can display the intent to communicate with the external environment after biological death by means of molecular, genetic, and epigenetic pathways. Whether these cancer cells contain special information in the form of coding that may help them survive beyond the biological death of cancer patients is unknown. To understand these queries in the cancer field, we hypothesize the epigenomic hard drive (EHD) as a cellular component to record and store global epigenetic events in cancerous and non-cancerous tissues of cancer patients. This mini-review presents the novel concept of EHD that is reinforced with the existing knowledge of genetic and epigenetic events in cancer. Further, we summarize the EHD understanding that may impart much potential and interest for basic and clinical scientists to unravel mechanisms of carcinogenesis, therapeutic markers, and differential drug responses.

PMID: 29302578 [PubMed]

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RNA Binding Protein as an Emerging Therapeutic Target for Cancer Prevention and Treatment.

RNA Binding Protein as an Emerging Therapeutic Target for Cancer Prevention and Treatment.

J Cancer Prev. 2017 Dec;22(4):203-210

Authors: Hong S

Abstract
After transcription, RNAs are always associated with RNA binding proteins (RBPs) to perform biological activities. RBPs can interact with target RNAs in sequence- and structure-dependent manner through their unique RNA binding domains. In development and progression of carcinogenesis, RBPs are aberrantly dysregulated in many human cancers with various mechanisms, such as genetic alteration, epigenetic change, noncoding RNA-mediated regulation, and post-translational modifications. Upon deregulation in cancers, RBPs influence every step in the development and progression of cancer, including sustained cell proliferation, evasion of apoptosis, avoiding immune surveillance, inducing angiogenesis, and activating metastasis. To develop therapeutic strategies targeting RBPs, RNA interference-based oligonucleotides or small molecule inhibitors have been screened based on reduced RBP-RNA interaction and changed level of target RNAs. Identification of binding RNAs with high-throughput techniques and integral analysis of multiple datasets will help us develop new therapeutic drugs or prognostic biomarkers for human cancers.

PMID: 29302577 [PubMed]

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Aplastic anemia secondary to nivolumab and ipilimumab in a patient with metastatic melanoma: a case report

Abstract

Background

Immune checkpoint blockade (ICB) is becoming an increasingly prevalent strategy in the clinical realm of cancer therapeutics. With more patients being administered ICB for a host of tumor types, the scope of adverse events associated with these drugs will likely grow. Here we report a case of aplastic anemia (AA) in a patient with metastatic melanoma secondary to dual ICB therapy. To our knowledge, this is only the second case of AA secondary to dual ICB in the literature, and the first to have a positive patient outcome.

Case presentation

A 51-year old male with metastatic melanoma was started on dual immune checkpoint blockade, in the form ipilimumab (3 mg/kg) and nivolumab (1 mg/kg). Two weeks following the second cycle, he presented to the emergency department with profound polypipsia, polyuria and fatigue. The patient was diagnosed with diabetic ketoacidosis secondary to immune therapy induced type-1 diabetes and was admitted to the ICU. While in hospital the patient developed a symptomatic anemia and neutropenia. A bone marrow biopsy revealed a markedly hypocellular marrow with trinlineage hypoplasia with no evidence of myelodysplasia, neoplasm or excess blasts. Flow cytometry revealed an inverted CD4⁺:CD8⁺ ratio and an absence of hematogones. Taken together the presumed etiology was AA secondary to immunotherapy. The patient was subsequently started in IV methylprednisone 70 mg/day for 8 days, followed by a prednisone taper. This intervention rectified the bicytopenia and to date the patient has shown stable blood counts.

Conclusion

With the use of ICBs becoming increasingly prevalent in the clinical arena, the number of patients presenting with immune-related adverse events will likely increase. The current case illustrates the need to be vigilant when managing cancer patients receiving ICB. The resolution of this patient's AA with corticosteroids highlights the value of early detection and appropriate treatment of these rare immune-mediated adverse events.

http://ift.tt/2prA42W

CircRNAs as biomarkers of cancer: a meta-analysis

Abstract

Background

The expression of circular RNA (circRNA) may affect tumor progression. However, there have been no systemic meta-analysis for cancer diagnosis by using circRNAs in clinical till now. Herein, we aimed to collect and examined all the evidence on the potential role of circRNA as novel biomarker in human cancers.

Methods

A comprehensive search strategy was used to search relevant literatures in the databases of PubMed, Embase, and the Web of Science from 2015 to August 2017. The correlation between circRNA expression and the diagnostic accuracy of tumor markers was analyzed. The methodological quality of each study was assessed by quality assessment for the diagnostic accuracies of the eligible studies (QUADAS-2). Statistical analysis was performed by applying the STATA (version 12.0) software.

Results

The present meta-analysis included 1752 patients with circRNA expression data of tumor and paired adjacent non-tumorous tissues from 17 publications (19 studies). The pooled sensitivity, specificity, positive likelihood ratios (PLR), negative likelihood ratios (NLR), and diagnostic OR (DOR) with their 95% confidential intervals (95%CIs), and AUC values were 0.72 (0.67–0.76), 0.74 (0.69–0.78), 2.80 (2.40–3.10), 0.38 (0.33–0.44), 7.00 (6.00–9.00), and 0.79, respectively. Subgroup analyses showed that the expression of circRNA in tissues of hepatocellular carcinoma (HCC) group was more prone to be detected than other tumor types, with a high values of the specificity, DOR, and AUC.

Conclusions

circRNAs might be suitable as diagnostic biomarkers for tumors, especially in HCC diagnosis. Further prospective studies on the diagnostic value of circRNAs from the different tumors are needed in the future.

http://ift.tt/2Iz0vN7

Aplastic anemia secondary to nivolumab and ipilimumab in a patient with metastatic melanoma: a case report

Abstract

Background

Case presentation

Conclusion

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Re-challenging immune checkpoint inhibitor in a patient with advanced non-small cell lung cancer: a case report

Abstract

Background

Currently, immune checkpoint (ICP) inhibitors are essential drugs for the treatment of non-small cell lung cancer (NSCLC). However, in patients previously treated with ICP inhibitors, the efficacy and safety of re-challenging the same or another ICP inhibitor remain unclear.

Case presentation

We present the case of a patient treated with nivolumab for advanced NSCLC who was previously treated with an ICP inhibitor as the first-line chemotherapy along with heavy cytotoxic chemotherapy. After the failure of five lines of chemotherapy, 3 cycles of nivolumab, as the ICP inhibitor re-challenge, the patient achieved a partial response.

Conclusions

This case might suggest that re-challenging an ICP inhibitor could be clinically active in selected patients with advanced NSCLC who progress after achieving an initial clinical benefit with an ICP inhibitor.

http://ift.tt/2prdqYD

CircRNAs as biomarkers of cancer: a meta-analysis

Abstract

Background

Methods

Results

Conclusions

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Re-challenging immune checkpoint inhibitor in a patient with advanced non-small cell lung cancer: a case report

Abstract

Background

Case presentation

Conclusions

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The novel deubiquitinase inhibitor b-AP15 induces direct and NK cell-mediated antitumor effects in human mantle cell lymphoma

Abstract

The first therapeutic proteasome inhibitor bortezomib has clinical efficacy in mantle cell lymphoma (MCL) which resulted in its incorporation in treatment algorithms for this disease. Impairment of proteasomal function by bortezomib is mediated via inhibition of the 20S core particle. However, proteasome function can also be modified by targeting upstream components of the ubiquitin–proteasome system. Recently, b-AP15 has been identified as a small molecule achieving proteasome inhibition by targeting the deubiquitinase (DUB) activity of the 19S regulatory subunit and was found to inhibit cancer cell growth in preclinical analyses. In the present study, both direct antitumor effects and the possibility to induce natural killer group 2 member D ligands (NKG2DL) to reinforce NK cell immunity with b-AP15 were investigated to provide a rational basis for clinical evaluation of this novel DUB inhibitor in MCL. Treatment with b-AP15 resulted in reduced viability as well as induction of apoptosis in a time- and dose-dependent manner, which could be attributed to caspase activation in MCL cells. In addition, treatment with b-AP15 differentially induced NKG2DL expression and subsequent NK cell lysis of MCL cells. These results indicate that the DUB inhibitor b-AP15 displays substantial antitumor activity in human MCL and suggest that b-AP15 might be a novel therapeutic option in the treatment of MCL that warrants clinical investigation.

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Prospective evaluation of plasma Epstein–Barr virus DNA clearance and fluorodeoxyglucose positron emission scan in assessing early response to chemotherapy in patients with advanced or recurrent nasopharyngeal carcinoma

Prospective evaluation of plasma Epstein–Barr virus DNA clearance and fluorodeoxyglucose positron emission scan in assessing early response to chemotherapy in patients with advanced or recurrent nasopharyngeal carcinoma

Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study

Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study

Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study, Published online: 20 March 2018; doi:10.1038/s41416-018-0011-3

Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study

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Prospective evaluation of plasma Epstein–Barr virus DNA clearance and fluorodeoxyglucose positron emission scan in assessing early response to chemotherapy in patients with advanced or recurrent nasopharyngeal carcinoma

Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study

Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study

Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study, Published online: 20 March 2018; doi:10.1038/s41416-018-0011-3

Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study

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Transcription factor FoxM1 is the downstream target of c-Myc and contributes to the development of prostate cancer

Abstract

Background

Prostate cancer is a common malignancy and the second leading cause of cancer death in men. Elevated expression of the transcription factor FoxM1 and c-Myc has been identified in prostate cancer. However, the potential mechanism of elevated FoxM1 and c-Myc to the development of prostate cancer has not been identified.

Methods

In this report, the mRNA level of FoxM1 and c-Myc was detected in 30 prostate cancer and para-cancer tissues. Then, we detected the expression level of FoxM1 by real-time PCR and Western blot after disturbance of the expression level of c-Myc in PC-3 cells. Whether c-Myc could bind to FoxM1 promoter was identified by ChIP assay. Finally, the migratory, invasive, and proliferative abilities in FoxM1 overexpressing and silencing PC-3 cells were detected by wound healing, transwell assay, CCK-8 assays, and Ki-67 protein level.

Results

We found that the expression level of FoxM1 and c-Myc were both increased in prostate cancer samples compared with para-cancer samples. The expression level of FoxM1 was changed consistent with the protein level of c-Myc. ChIP assay detected the direct binding of c-Myc in FoxM1 gene promoter. Lastly, overexpression of FoxM1 increased the migratory, invasive, and proliferative abilities of PC-3 cells, and its downregulation significantly decreased the migratory, invasive, and proliferative abilities.

Conclusions

In conclusion, FoxM1 was significantly increased in prostate cancer samples, and it could regulate the proliferative and invasive ability of prostate cancer cells which might be a new target for prostate cancer. Besides, c-Myc could regulate the expression level of FoxM1 by directly binding to its gene promoter.

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Transcription factor FoxM1 is the downstream target of c-Myc and contributes to the development of prostate cancer

Abstract

Background

Methods

Results

Conclusions

http://ift.tt/2pq4McJ

Impact of donor type in patients with AML given allogeneic hematopoietic cell transplantation after low-dose TBI based regimen

Purpose: We assessed the impact of donor type in acute myeloid leukemia (AML) patients transplanted with 2 Gy total body irradiation (TBI)-based nonmyeloablative conditioning regimen. Experimental Design: Data from 1715 adult patients, with AML in CR1 or CR2 were included in this retrospective survey. Results: Donors consisted either of HLA-matched sibling donors (MSD, n=701), 10/10 HLA-matched unrelated donors (MUD, n=611), HLA-haplo-identical donors (haplo, n=112) or single or double umbilical cord bloods (CBT, n=291). Chronic graft-versus-host disease (GVHD) was less frequent in CBT (28%) and in haplo (30%) patients than in MSD (50%) and MUD (51%) recipients (P<0.001). Two-year incidence of relapse was 32%, 30%, 34% and 34% in MSD, MUD, CBT and haplo patients, respectively (P=0.7). Two-year overall (OS) and GVHD-free relapse free survival (GRFS) were 59% and 29% in MSD patients, 56% and 39% in CBT recipients, 53% and 23% in MUD recipients, and 43% and 37% in haplo patients, respectively. In multivariate analyses, MUD patients had lower GRFS than MSD patients beyond day 100 (HR 1.3, P=0.001) while CBT was associated with a better GRFS than MSD beyond day 100 (HR 0.6, P=0.002). Conclusions: In this large cohort of AML patients transplanted following low-dose TBI-based conditioning the relapse incidence was not affected by donor type suggesting that the intensity of GVL effects might be comparable with these four transplant approaches. Further, CBT was associated with better GRFS beyond day 100 than MSD while the opposite was observed for MUD.

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Targeting bromodomain and extra-terminal (BET) family proteins in castration resistant prostate cancer (CRPC)

Purpose: Persistent androgen receptor (AR) signaling drives castration resistant prostate cancer (CRPC) and confers resistance to AR targeting therapies. Novel therapeutic strategies to overcome this are urgently required. We evaluated how bromodomain and extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR signaling in CRPC. Experimental Design: We determined associations between BET expression, AR driven transcription and patient outcome; and the effect and mechanism by which chemical BETi (JQ1 and GSK1210151A; I-BET151) and BET family protein knockdown regulates AR-V7 expression and AR signaling in prostate cancer (PC) models. Results: Nuclear BRD4 protein expression increases significantly (p=<0.01) with castration resistance in same patient treatment naïve (median H-score; interquartile range: 100; 100-170) and CRPC (150; 110-200) biopsies, with higher expression at diagnosis associating with worse outcome (HR 3.25, 95% CI 1.50-7.01; p=<0.001). BRD2, BRD3 and BRD4 RNA expression in CRPC biopsies correlates with AR driven transcription (all p=<0.001). Chemical BETi, and combined BET family protein knockdown, reduce AR-V7 expression and AR signaling. This was not recapitulated by C-MYC knockdown. In addition, we show that BETi regulates RNA processing thereby reducing alternative splicing and AR-V7 expression. Furthermore, BETi reduce growth of PC cells and patient derived organoids with known AR mutations, AR amplification and AR-V7 expression. Finally, BETi, unlike enzalutamide, decreases persistent AR signaling and growth (p=<0.001) of a patient derived xenograft model of CRPC with AR amplification and AR-V7 expression. Conclusion: BETi merit clinical evaluation as inhibitors of AR splicing and function, with trials demonstrating their blockade in proof of mechanism pharmacodynamic studies.

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Salivary gland cancer patient-derived xenografts enable characterization of cancer stem cells and new gene fusions associated with tumor progression

Purpose: Salivary gland cancers (SGC) frequently present with distant metastases many years after diagnosis, suggesting a cancer stem cell (CSC) subpopulation that initiates late recurrences; however current models are limited both in their availability and suitability to characterize these rare cells. Experimental Design: Patient-derived xenografts (PDX) were generated by engrafting patient tissue onto nude mice from one acinic cell carcinoma (AciCC), four adenoid cystic carcinoma (ACC), and three mucoepidermoid carcinoma (MEC) cases, which were derived from successive relapses from the same MEC patient. Patient and PDX samples were analyzed by RNA-seq and Exome-seq. Sphere formation potential and in vivo tumorigenicity was assessed by sorting for Aldefluor (ALDH) activity and CD44 expressing subpopulations. Results: For successive MEC relapses we found a time-dependent increase in CSCs (ALDH+CD44high), increasing from 0.2% to 4.5% (P=0.033), but more importantly we observed an increase in individual CSC sphere formation and tumorigenic potential. A 50% increase in mutational burden was documented in subsequent MEC tumors, and this was associated with increased expression of tumor promoting genes (MT1E, LGR5, LEF1), decreased expression of tumor suppressor genes (CDKN2B, SIK1, TP53), and higher expression of CSC-related proteins such as SOX2, MYC, and ALDH1A1. Finally, genomic analyses identified a novel NFIB-MTFR2 fusion in an ACC tumor and confirmed previously reported fusions (NTRK3-ETV6 and MYB-NFIB). Conclusions: Sequential MEC PDX models preserved key patient features and enabled the identification of genetic events putatively contributing to increases in both CSC proportion and intrinsic tumorigenicity, which mirrored the patient's clinical course.

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Elevated circulatory levels of leptin and resistin impair therapeutic efficacy of dacarbazine in melanoma under obese state

Abstract

Background

Obesity is associated with increased risk, poor prognosis and outcome of therapy, in various cancers. Obesity-associated factors or adipokines, especially leptin and resistin, are purported to promote growth, survival, proliferation, and invasiveness of cancer cells. However, the mechanistic link between these adipokines and therapeutic response in malignancies is not clearly understood.

Methods

ob/ob and db/db mouse models were used in this study to evaluate the role of leptin and resistin towards the outcome of dacarbazine (DTIC) therapy in melanoma. Unique in vitro approaches were employed to complement in vivo findings by culturing melanoma cells in the serum collected from the experimental mice.

Results

Here, we have shown the role of important adipokines leptin and resistin in growth and the outcome of DTIC therapy in melanoma. Both leptin and resistin not only enhance proliferation of melanoma cells but also are involved in impairing the therapeutic efficacy of DTIC. Leptin and resistin treatment caused an increase in the protein levels of fatty acid synthase (FASN) and caveolin 1 (Cav-1) respectively, through their stabilization in A375 cells. Further, it was observed that leptin and resistin impaired the response of melanoma cells to DTIC via upregulation of heat shock protein 90 (Hsp90) and P-glycoprotein (P-gp) respectively.

Conclusion

These findings unraveled the involvement of adipokines (leptin and resistin) in melanoma progression, and more importantly, in the outcome of DTIC therapy.

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Impact of donor type in patients with AML given allogeneic hematopoietic cell transplantation after low-dose TBI based regimen

http://ift.tt/2G5SMrf

Targeting bromodomain and extra-terminal (BET) family proteins in castration resistant prostate cancer (CRPC)

http://ift.tt/2HPnkuJ

Salivary gland cancer patient-derived xenografts enable characterization of cancer stem cells and new gene fusions associated with tumor progression

http://ift.tt/2G4d5W6

Elevated circulatory levels of leptin and resistin impair therapeutic efficacy of dacarbazine in melanoma under obese state

Abstract

Background

Methods

Results

Conclusion

These findings unraveled the involvement of adipokines (leptin and resistin) in melanoma progression, and more importantly, in the outcome of DTIC therapy.

http://ift.tt/2DJk2a4

Reactivation of mutant-EGFR degradation through clathrin inhibition overcomes resistance to EGFR tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) targeting mutant-EGFR in NSCLC have been successful to control cancer growth, but acquired resistance inevitably occurs, including mutations directly on EGFR e.g. T790M and C797S. Strategies to prevent such acquired mutations by reducing mutant-EGFR expression have met limited success. Here we propose a new model of mutant-EGFR trafficking and demonstrate that clathrin inhibition induces rapid degradation across a large panel of endogenous mutant-EGFR (Ex19del, L858R, Ex20Ins). This panel included mutant-EGFR (T790M) resistant to the first- and second-generation EGFR inhibitors and to the third-generation TKI osimertinib, and occurs through both mutational (C797S) and non-mutational EGFR mechanisms. Clathrin-mediated endocytosis inhibition of mutant-EGFR induced a macropinocytosis-dependent lysosomal pathway associated with a loss of mutant-EGFR dependent signalling (pAKT, pERK). Moreover, induction of this macropinocytic pathway led to robust apoptosis-dependent death across all mutant-EGFR cell lines tested, including those resistant to TKIs. We therefore propose a novel strategy to target mutant-EGFR refractory to approved existing TKI treatments in NSCLC and where new treatment strategies remain a key area of unmet need.

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Pain: A Neglected Problem in the Low-Resource Setting

Approximately 80% of the world's population lives in countries with little or no access to pain management. These countries also have 74% of the world's deaths from cancer and human immunodeficiency virus. Appropriate use of oral opioids can control 80%–90% of cancer pain. However, only 6.7% of the world's medical opioids are available in these low-resource countries. With the Lancet Commission on Global Surgery calling for a significant expansion of surgical services, postoperative pain management will need to be an increasing focus of our attention. There are multiple barriers to providing effective pain management. These include the type and funding of the health care system, the size and educational level of the workforce, the ease of access to effective medications, and the expectations and knowledge base of the community. Some barriers can be addressed by education at the undergraduate level, postgraduate level, and community level. Others will require continued advocacy at government level. Only when we tackle these problems will the considerable neglect of access to effective pain treatment in low- and middle-income countries be lessened.

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Strengthening the Anesthesia Workforce in Low- and Middle-Income Countries

The majority of the world's population lacks access to safe, timely, and affordable surgical care. Although there is a health workforce crisis across the board in the poorest countries in the world, anesthesia is disproportionally affected. This article explores some of the key issues that must be tackled to strengthen the anesthesia workforce in low- and lower-middle-income countries. First, we need to increase the overall number of safe anesthesia providers to match a huge burden of disease, particularly in the poorest countries in the world and in remote and rural areas. Through using a task-sharing model, an increase is required in both nonphysician anesthesia providers and anesthesia specialists. Second, there is a need to improve and support the competency of anesthesia providers overall. It is important to include a broad base of knowledge, skills, and attitudes required to manage complex and high-risk patients and to lead improvements in the quality of care. Third, there needs to be a concerted effort to encourage interprofessional skills and the aspects of working and learning together with colleagues in a complex surgical ecosystem. Finally, there has to be a focus on developing a workforce that is resilient to burnout and the challenges of an overwhelming clinical burden and very restricted resources. This is essential for anesthesia providers to stay healthy and effective and necessary to reduce the inevitable loss of human resources through migration and cessation of professional practice. It is vital to realize that all of these issues need to be tackled simultaneously, and none neglected, if a sustainable and scalable solution is to be achieved.

http://ift.tt/2FNOuFA