Ultrasound-guided fine needle aspiration of retropharyngeal lymph nodes after radiotherapy for nasopharyngeal carcinoma: a novel technique for accurate diagnosis

Abstract

Background

Enlarged retropharyngeal lymph nodes (RLNs) are very common in patients with nasopharyngeal carcinoma (NPC) undergoing radiotherapy. The most suitable treatment option for enlarged RLNs depends on the pathological results. However, RLN sampling is difficult and imminent in the clinic setting. We recently developed a novel minimally invasive technique termed endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for sampling RLN tissues sufficient for pathological or cytological diagnosis.

Methods

We enrolled 30 post-radiotherapy patients with NPC with suspected RLN metastasis detected via magnetic resonance imaging (MRI). The EUS probe was introduced into the nasopharynx via the nostrils, and EUS was then used to scan the retropharyngeal space and locate the RLN in the anterior carotid sheath. EUS-FNA was subsequently performed. The safety and efficacy of using EUS-FNA to sample the RLN tissues were assessed.

Results

Strips of tissue were successfully sampled from all patients using EUS-FNA. Of the 30 patients, 23 were confirmed to have cancer cells in the biopsied tissues via pathology or cytology examinations with 1 EUS-FNA biopsy session. The seven cases without confirmed cancer cells were subsequently reanalyzed by using another EUS-FNA biopsy session, and two more cases were confirmed possessing cancer cells. The other five patients without confirmed cancer cells were closely followed with MRI every month for 3 months. After follow-up for 3 months, three patients were still considered cancer-free due to the presence of RLNs with stable or shrinking diameters. The rest two patients who showed progressive disease underwent a third EUS-FNA biopsy procedure and were further confirmed to be cancer cell-positive. In the whole cohort reported here, the EUS-FNA procedure was not associated with any severe complications.

Conclusion

EUS-FNA is a safe and effective diagnostic approach for sampling tissues from the RLNs in patients with suspected recurrent NPC.

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Ultrasound-guided fine needle aspiration of retropharyngeal lymph nodes after radiotherapy for nasopharyngeal carcinoma: a novel technique for accurate diagnosis

Abstract

Background

Enlarged retropharyngeal lymph nodes (RLNs) are very common in patients with nasopharyngeal carcinoma (NPC) undergoing radiotherapy. The most suitable treatment option for enlarged RLNs depends on the pathological results. However, RLN sampling is difficult and imminent in the clinic setting. We recently developed a novel minimally invasive technique termed endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for sampling RLN tissues sufficient for pathological or cytological diagnosis.

Methods

We enrolled 30 post-radiotherapy patients with NPC with suspected RLN metastasis detected via magnetic resonance imaging (MRI). The EUS probe was introduced into the nasopharynx via the nostrils, and EUS was then used to scan the retropharyngeal space and locate the RLN in the anterior carotid sheath. EUS-FNA was subsequently performed. The safety and efficacy of using EUS-FNA to sample the RLN tissues were assessed.

Results

Strips of tissue were successfully sampled from all patients using EUS-FNA. Of the 30 patients, 23 were confirmed to have cancer cells in the biopsied tissues via pathology or cytology examinations with 1 EUS-FNA biopsy session. The seven cases without confirmed cancer cells were subsequently reanalyzed by using another EUS-FNA biopsy session, and two more cases were confirmed possessing cancer cells. The other five patients without confirmed cancer cells were closely followed with MRI every month for 3 months. After follow-up for 3 months, three patients were still considered cancer-free due to the presence of RLNs with stable or shrinking diameters. The rest two patients who showed progressive disease underwent a third EUS-FNA biopsy procedure and were further confirmed to be cancer cell-positive. In the whole cohort reported here, the EUS-FNA procedure was not associated with any severe complications.

Conclusion

EUS-FNA is a safe and effective diagnostic approach for sampling tissues from the RLNs in patients with suspected recurrent NPC.

https://ift.tt/2IsnWdy

You are smarter than you think: (super) machine learning in context

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Incidence of Esophageal Cancer in Iran, a Population-Based Study: 2001–2015

Abstract

Purpose

Even though Kurdistan, the western province of Iran, has a cancer surveillance system, a detailed analysis of incidence rate has not been yet performed. We describe Age Standardized Incidence Rates (ASRs) for esophageal cancer (EC) in Kurdistan Province of Iran in 2001–2015.

Methods

Incidence cases of EC were obtained from a population-based cancer registry. We obtained ASRs and 95% confidence intervals (CI) per 100,000 populations for each calendar year group.

Results

Between 2001 and 2015, 1362 incidence cases with EC were reported to the cancer registry. Annual ASRs in 2006–2010 were more than the other years in both men and women, respectively. Most ASRs were reported among women in Divandarreh (18.95, 95% CI 14.76, 23.92), Saqez (12.75, 95% CI 10.73, 15.01), Sanandaj (8.84, 95% CI 7.64, 10.17), and Qorveh (8.19, 95% CI 6.54, 10.12), and among men in Divandarreh (19.38, 95% CI 15.38, 24.06), Saqez (13.64, 95% CI 11.49, 16.05), Sanandaj (8.70, 95% CI 7.56, 9.96), and Marivan (7.93, 95% CI 6.26, 9.88).

Conclusions

It was concluded that EC in Divandarreh, Saqez, and Sanandaj has the highest ASRs, and these areas are considered as high-risk areas for this disease in the Iranian province of Kurdistan. Therefore, to understand the reasons of these problems, a considerable work is needed.

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You are smarter than you think: (super) machine learning in context

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Incidence of Esophageal Cancer in Iran, a Population-Based Study: 2001–2015

Abstract

Purpose

Even though Kurdistan, the western province of Iran, has a cancer surveillance system, a detailed analysis of incidence rate has not been yet performed. We describe Age Standardized Incidence Rates (ASRs) for esophageal cancer (EC) in Kurdistan Province of Iran in 2001–2015.

Methods

Incidence cases of EC were obtained from a population-based cancer registry. We obtained ASRs and 95% confidence intervals (CI) per 100,000 populations for each calendar year group.

Results

Between 2001 and 2015, 1362 incidence cases with EC were reported to the cancer registry. Annual ASRs in 2006–2010 were more than the other years in both men and women, respectively. Most ASRs were reported among women in Divandarreh (18.95, 95% CI 14.76, 23.92), Saqez (12.75, 95% CI 10.73, 15.01), Sanandaj (8.84, 95% CI 7.64, 10.17), and Qorveh (8.19, 95% CI 6.54, 10.12), and among men in Divandarreh (19.38, 95% CI 15.38, 24.06), Saqez (13.64, 95% CI 11.49, 16.05), Sanandaj (8.70, 95% CI 7.56, 9.96), and Marivan (7.93, 95% CI 6.26, 9.88).

Conclusions

It was concluded that EC in Divandarreh, Saqez, and Sanandaj has the highest ASRs, and these areas are considered as high-risk areas for this disease in the Iranian province of Kurdistan. Therefore, to understand the reasons of these problems, a considerable work is needed.

https://ift.tt/2rsablI

A novel tricarbonylmethane agent (CMC2.24) reduces human pancreatic tumor growth in mice by targeting Ras

Molecular Carcinogenesis, EarlyView.


https://ift.tt/2jJHcFH

A supercritical CO2 extract of neem leaf (A. indica) and its bioactive liminoid, nimbolide, suppresses colon cancer in preclinical models by modulating pro‐inflammatory pathways

Molecular Carcinogenesis, EarlyView.


https://ift.tt/2FWWLT7

A novel tricarbonylmethane agent (CMC2.24) reduces human pancreatic tumor growth in mice by targeting Ras

Molecular Carcinogenesis, EarlyView.


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A supercritical CO2 extract of neem leaf (A. indica) and its bioactive liminoid, nimbolide, suppresses colon cancer in preclinical models by modulating pro‐inflammatory pathways

Molecular Carcinogenesis, EarlyView.


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You are smarter than you think: (super) machine learning in context

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Carotid artery intima-media thickness measurement in children with normal and increased body mass index: a comparison of three techniques

Abstract

Background

Common carotid artery intima-media thickness is a marker of subclinical atherosclerosis. In children, increased intima-media thickness is associated with obesity and the risk of cardiovascular events in adulthood.

Objective

To compare intima-media thickness measurements using B-mode ultrasound, radiofrequency (RF) echo tracking, and RF speckle probability distribution in children with normal and increased body mass index (BMI).

Materials and methods

We prospectively measured intima-media thickness in 120 children randomly selected from two groups of a longitudinal cohort: normal BMI and increased BMI, defined by BMI ≥85th percentile for age and gender. We followed Mannheim recommendations. We used M'Ath-Std for automated B-mode imaging, M-line processing of RF signal amplitude for RF echo tracking, and RF signal segmentation and averaging using probability distributions defining image speckle. Statistical analysis included Wilcoxon and Mann-Whitney tests, and Pearson correlation coefficient and intra-class correlation coefficient (ICC).

Results

Children were 10–13 years old (mean: 11.7 years); 61% were boys. The mean age was 11.4 years (range: 10.0–13.1 years) for the normal BMI group and 12.0 years (range: 10.1–13.5 years) for the increased BMI group. The normal BMI group included 58% boys and the increased BMI group 63% boys. RF echo tracking method was successful in 79 children as opposed to 114 for the B-mode method and all 120 for the probability distribution method. Techniques were weakly correlated: ICC=0.34 (95% confidence interval [CI]: 0.27–0.39). Intima-media thickness was significantly higher in the increased BMI than normal BMI group using the RF techniques and borderline for the B-mode technique. Mean differences between weight groups were: B-mode, 0.02 mm (95% CI: 0.00 to 0.04), P=0.05; RF echo tracking, 0.03 mm (95% CI: 0.01 to 0.05), P=0.01; and RF speckle probability distribution, 0.03 mm (95% CI: 0.01 to 0.05), P=0.002.

Conclusion

Though techniques are not interchangeable, all showed increased intima-media thickness in children with increased BMI. RF echo tracking method had the lowest success rate at calculating intima-media thickness. For patient follow-up and cohort comparisons, the same technique should be used throughout.

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Carotid artery intima-media thickness measurement in children with normal and increased body mass index: a comparison of three techniques

Abstract

Background

Common carotid artery intima-media thickness is a marker of subclinical atherosclerosis. In children, increased intima-media thickness is associated with obesity and the risk of cardiovascular events in adulthood.

Objective

To compare intima-media thickness measurements using B-mode ultrasound, radiofrequency (RF) echo tracking, and RF speckle probability distribution in children with normal and increased body mass index (BMI).

Materials and methods

We prospectively measured intima-media thickness in 120 children randomly selected from two groups of a longitudinal cohort: normal BMI and increased BMI, defined by BMI ≥85th percentile for age and gender. We followed Mannheim recommendations. We used M'Ath-Std for automated B-mode imaging, M-line processing of RF signal amplitude for RF echo tracking, and RF signal segmentation and averaging using probability distributions defining image speckle. Statistical analysis included Wilcoxon and Mann-Whitney tests, and Pearson correlation coefficient and intra-class correlation coefficient (ICC).

Results

Children were 10–13 years old (mean: 11.7 years); 61% were boys. The mean age was 11.4 years (range: 10.0–13.1 years) for the normal BMI group and 12.0 years (range: 10.1–13.5 years) for the increased BMI group. The normal BMI group included 58% boys and the increased BMI group 63% boys. RF echo tracking method was successful in 79 children as opposed to 114 for the B-mode method and all 120 for the probability distribution method. Techniques were weakly correlated: ICC=0.34 (95% confidence interval [CI]: 0.27–0.39). Intima-media thickness was significantly higher in the increased BMI than normal BMI group using the RF techniques and borderline for the B-mode technique. Mean differences between weight groups were: B-mode, 0.02 mm (95% CI: 0.00 to 0.04), P=0.05; RF echo tracking, 0.03 mm (95% CI: 0.01 to 0.05), P=0.01; and RF speckle probability distribution, 0.03 mm (95% CI: 0.01 to 0.05), P=0.002.

Conclusion

Though techniques are not interchangeable, all showed increased intima-media thickness in children with increased BMI. RF echo tracking method had the lowest success rate at calculating intima-media thickness. For patient follow-up and cohort comparisons, the same technique should be used throughout.

https://ift.tt/2rw78I6

Two successful pregnancies following fertility preservation in a patient with anaplastic astrocytoma: a case report

Abstract

Background

Astrocytomas are the most common malignant glial tumors. With improved prognosis, it is possible for patients to pursue pregnancy post-treatment. However, with potential gonadotoxicity of oncology treatments, fertility preservation prior to chemotherapy and/or radiation therapy should be considered. This requires close collaboration between the oncologist and reproductive endocrinologist. To our knowledge this is the first report of successful pregnancies following fertility preservation for AA.

Case presentation

33-year-old nulligravid woman with newly diagnosed anaplastic astrocytoma (AA; WHO grade III, IDH1-negative) sought fertility preservation. Prior to chemotherapy and radiation for AA, the patient underwent in vitro fertilization (IVF) for fertility preservation, resulting in 8 vitrified embryos. Following chemo-radiation, the patient underwent two rounds of frozen embryo transfers (FET), each resulting in a successful singleton pregnancy.

Conclusion

This case illustrates the realistic possibility, in carefully selected patients with brain tumors, of oocyte or embryo cryo-preservation prior to chemo-radiation and subsequent pregnancies.

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Two successful pregnancies following fertility preservation in a patient with anaplastic astrocytoma: a case report

Abstract

Background

Astrocytomas are the most common malignant glial tumors. With improved prognosis, it is possible for patients to pursue pregnancy post-treatment. However, with potential gonadotoxicity of oncology treatments, fertility preservation prior to chemotherapy and/or radiation therapy should be considered. This requires close collaboration between the oncologist and reproductive endocrinologist. To our knowledge this is the first report of successful pregnancies following fertility preservation for AA.

Case presentation

33-year-old nulligravid woman with newly diagnosed anaplastic astrocytoma (AA; WHO grade III, IDH1-negative) sought fertility preservation. Prior to chemotherapy and radiation for AA, the patient underwent in vitro fertilization (IVF) for fertility preservation, resulting in 8 vitrified embryos. Following chemo-radiation, the patient underwent two rounds of frozen embryo transfers (FET), each resulting in a successful singleton pregnancy.

Conclusion

This case illustrates the realistic possibility, in carefully selected patients with brain tumors, of oocyte or embryo cryo-preservation prior to chemo-radiation and subsequent pregnancies.

https://ift.tt/2IpTHUx

Xenograft tumors derived from malignant pleural effusion of the patients with non-small-cell lung cancer as models to explore drug resistance

Abstract

Background

Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions show dramatic responses to specific tyrosine kinase inhibitors (TKIs); however, after 10–12 months, secondary mutations arise that confer resistance. We generated a murine xenograft model using patient-derived NSCLC cells isolated from the pleural fluid of two patients with NSCLC to investigate the mechanisms of resistance against the ALK- and EGFR-targeted TKIs crizotinib and osimertinib, respectively.

Methods

Genotypes of patient biopsies and xenograft tumors were determined by whole exome sequencing (WES), and patients and xenograft-bearing mice received targeted treatment (crizotinib or osimertinib) accordingly. Xenograft mice were also treated for prolonged periods to identify whether the development of drug resistance and/or treatment responses were associated with tumor size. Finally, the pathology of patients biopsies and xenograft tumors were compared histologically.

Results

The histological characteristics and chemotherapy responses of xenograft tumors were similar to the actual patients. WES showed that the genotypes of the xenograft and patient tumors were similar (an echinoderm microtubule-associated protein-like 4-ALK (EML4–ALK) gene fusion (patient/xenograft: CTC15035_EML4–ALK) and EGFR L858R and T790M mutations (patient/xenograft: CTC15063_{EGFR L858R, T790M})). After continuous crizotinib or osimertinib treatment, WES data suggested that acquired ALK E1210K mutation conferred crizotinib resistance in the CTC15035_EML4–ALK xenograft, while decreased frequencies of EGFR L858R and T790M mutations plus the appearance of v-RAF murine sarcoma viral oncogene homolog B (BRAF) G7V mutations and phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha (PIK3C2A) A86fs frame shift mutations led to osimertinib resistance in the CTC15063_{EGFR L858R, T790M} xenografts.

Conclusions

We successfully developed a new method of generating drug resistance xenograft models from liquid biopsies using microfluidic technology, which might be a useful tool to investigate the mechanisms of drug resistance in NSCLC.

https://ift.tt/2I4c9yK

Xenograft tumors derived from malignant pleural effusion of the patients with non-small-cell lung cancer as models to explore drug resistance

Abstract

Background

Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions show dramatic responses to specific tyrosine kinase inhibitors (TKIs); however, after 10–12 months, secondary mutations arise that confer resistance. We generated a murine xenograft model using patient-derived NSCLC cells isolated from the pleural fluid of two patients with NSCLC to investigate the mechanisms of resistance against the ALK- and EGFR-targeted TKIs crizotinib and osimertinib, respectively.

Methods

Genotypes of patient biopsies and xenograft tumors were determined by whole exome sequencing (WES), and patients and xenograft-bearing mice received targeted treatment (crizotinib or osimertinib) accordingly. Xenograft mice were also treated for prolonged periods to identify whether the development of drug resistance and/or treatment responses were associated with tumor size. Finally, the pathology of patients biopsies and xenograft tumors were compared histologically.

Results

The histological characteristics and chemotherapy responses of xenograft tumors were similar to the actual patients. WES showed that the genotypes of the xenograft and patient tumors were similar (an echinoderm microtubule-associated protein-like 4-ALK (EML4–ALK) gene fusion (patient/xenograft: CTC15035_EML4–ALK) and EGFR L858R and T790M mutations (patient/xenograft: CTC15063_{EGFR L858R, T790M})). After continuous crizotinib or osimertinib treatment, WES data suggested that acquired ALK E1210K mutation conferred crizotinib resistance in the CTC15035_EML4–ALK xenograft, while decreased frequencies of EGFR L858R and T790M mutations plus the appearance of v-RAF murine sarcoma viral oncogene homolog B (BRAF) G7V mutations and phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha (PIK3C2A) A86fs frame shift mutations led to osimertinib resistance in the CTC15063_{EGFR L858R, T790M} xenografts.

Conclusions

We successfully developed a new method of generating drug resistance xenograft models from liquid biopsies using microfluidic technology, which might be a useful tool to investigate the mechanisms of drug resistance in NSCLC.

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Optimal collimator rotation based on the outline of multiple brain targets in VMAT

Abstract

Background

The aim of this study was to investigate the dosimetric quality in volumetric modulated arc therapy (VMAT) plans with optimal collimator angles that can represent the outline of multiple brain targets.

Methods

Twenty patients with multiple target volumes in the brain cases were selected retrospectively. To better represent the outline of the multiple brain targets, four conformal arc plans were generated for each patient using one full arc with four collimator settings. The optimal collimator angles calculated from the integrated multi-leaf collimator (MLC) aperture that had the smallest aperture size for certain collimator settings of the conformal arc plan were selected. VMAT plans with the optimal collimator angles with angular sections of 40° and 60° (Colli-VMAT (40°), Colli-VMAT (60°)) were generated, followed by evaluation of field sizes, dose-volumetric parameters and total monitor units (MUs).

Results

Patient-averaged values of field sizes for Colli-VMAT (40°) (111.5 cm²) were lowest and 1.3 times smaller than those for Std-VMAT (143.6 cm²). Colli-VMAT plans improved sparing of most normal organs but for brain stem and left parotid gland. For the total MUs, the averaged values obtained with the Colli-VMAT (40°) (390 ± 148 MU) were smaller than those obtained with the Std-VMAT (472 ± 235 MU).

Conclusions

The Colli-VMAT plans with smaller angular sections could be suitable in the clinic for multiple brain targets as well as for irregularly shaped targets. Determination of the optimal collimator rotation generally showed good normal tissue sparing and MU reduction for multiple brain targets.

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Optimal collimator rotation based on the outline of multiple brain targets in VMAT

Abstract

Background

The aim of this study was to investigate the dosimetric quality in volumetric modulated arc therapy (VMAT) plans with optimal collimator angles that can represent the outline of multiple brain targets.

Methods

Twenty patients with multiple target volumes in the brain cases were selected retrospectively. To better represent the outline of the multiple brain targets, four conformal arc plans were generated for each patient using one full arc with four collimator settings. The optimal collimator angles calculated from the integrated multi-leaf collimator (MLC) aperture that had the smallest aperture size for certain collimator settings of the conformal arc plan were selected. VMAT plans with the optimal collimator angles with angular sections of 40° and 60° (Colli-VMAT (40°), Colli-VMAT (60°)) were generated, followed by evaluation of field sizes, dose-volumetric parameters and total monitor units (MUs).

Results

Patient-averaged values of field sizes for Colli-VMAT (40°) (111.5 cm²) were lowest and 1.3 times smaller than those for Std-VMAT (143.6 cm²). Colli-VMAT plans improved sparing of most normal organs but for brain stem and left parotid gland. For the total MUs, the averaged values obtained with the Colli-VMAT (40°) (390 ± 148 MU) were smaller than those obtained with the Std-VMAT (472 ± 235 MU).

Conclusions

The Colli-VMAT plans with smaller angular sections could be suitable in the clinic for multiple brain targets as well as for irregularly shaped targets. Determination of the optimal collimator rotation generally showed good normal tissue sparing and MU reduction for multiple brain targets.

https://ift.tt/2wooTiq

Curation of the pancreatic ductal adenocarcinoma subset of The Cancer Genome Atlas is essential for accurate conclusions about survival related molecular mechanisms

Purpose: Publically available databases, e.g. The Cancer Genome Atlas (TCGA), containing clinical and molecular data from large number of patients are useful in validating the contribution of particular genes to disease mechanisms and in forming novel hypotheses relating to clinical outcomes. Experimental Design: The impact of key drivers of cancer progression can be assessed by segregating a patient cohort by certain molecular features and constructing survival plots using the associated clinical data. However, conclusions drawn from this straightforward analysis are highly dependent on the quality and source of tissue samples, as demonstrated through the pancreatic ductal adenocarcinoma (PDAC) subset of TCGA. Results: Analyses of the PDAC-TCGA database, which contains mainly resectable cancer samples from patients in stage IIB, reveal a difference from widely known historical median and 5-year survival rates of PDAC. A similar discrepancy was observed in lung, stomach and liver cancer subsets of TCGA. The whole transcriptome expression patterns of PDAC-TCGA revealed a cluster of samples derived from neuroendocrine tumors, which have a distinctive biology and better disease prognosis than PDAC. Furthermore, PDAC-TCGA contains numerous pseudo-normal samples, as well as those that arose from tumors not classified as PDAC. Conclusions: Inclusion of misclassified samples in the bioinformatic analyses distorts the association of molecular biomarkers with clinical outcomes, altering multiple published conclusions used to support and motivate experimental research. Hence, the stringent scrutiny of type and origin of samples included in the bioinformatic analyses by researchers, databases and web-tool developers is of crucial importance for generating accurate conclusions.

https://ift.tt/2I9Bjfh

{Delta}Np63{gamma}/SRC/Slug signalling axis promotes epithelial-to-mesenchymal transition in squamous cancers

Purpose: To investigate the regulation of epithelial-to-mesenchymal transition (EMT) in  Head and Neck Squamous Cell Carcinoma (HNSCC) and its importance in tumour invasion. Experimental design: We use a 3D invasive organotypic raft culture model of human foreskin keratinocytes expressing the E6/E7 genes of the Human Papilloma Virus-16, coupled with bioinformatics and immunohistochemical analysis of patient samples to investigate  the role played by EMT in invasion and identify effectors and upstream regulatory pathways. Results: We identify SNAI2 (Slug) as a critical effector of EMT activated downstream of TP63 overexpression in Head and Neck Squamous Cell Carcinoma (HNSCC). Splice-form specific depletion and rescue experiments further identify the Np63 isoform as both necessary and sufficient to activate the SRC signalling axis and SNAI2-mediated EMT and invasion. Moreover, elevated SRC levels are associated with poor outcome in HNSCC patients in the cancer genome atlas dataset. Importantly, the effects on EMT and invasions and SNAI2 expression can be reversed by genetic or pharmacological inhibition of SRC. Conclusion:Overexpression of Np63 modulates cell invasion by inducing targetable SRC-Slug-evoked EMT in HNSCC, which can be reversed by inhibitors of the SRC signalling.

https://ift.tt/2rv5abT

MAPK reliance via acquired CDK4/6 inhibitor resistance in cancer

Purpose: Loss of cell cycle control is a hallmark of cancer, which can be targeted with agents, including Cyclin Dependent Kinase-4/6 (CDK4/6) kinase inhibitors that impinge upon the G1-S cell cycle checkpoint via maintaining activity of the retinoblastoma tumor suppressor (RB). This class of drugs is under clinical investigation for various solid tumor types, and has recently been FDA-approved for treatment of breast cancer. However, development of therapeutic resistance is not uncommon.  Experimental Design: In this study, palbociclib (a CDK4/6 inhibitor) resistance was established in models of early stage, RB-positive cancer.  Results: This study demonstrates that acquired palbociclib resistance renders cancer cells broadly resistant to CDK4/6 inhibitors. Acquired resistance was associated with aggressive in vitro and in vivo phenotypes, including proliferation, migration, and invasion. Integration of RNA sequencing analysis and phospho-proteomics profiling revealed rewiring of the kinome, with a strong enrichment for enhanced MAPK signaling across all resistance models, which resulted in aggressive in vitro and in vivo phenotypes and pro-metastatic signaling. However, CDK4/6 inhibitor resistant models were sensitized to MEK inhibitors, revealing reliance on active MAPK signaling to promote tumor cell growth and invasion. Conclusions: In sum, these studies identify MAPK reliance in acquired CDK4/6 inhibitor resistance that promotes aggressive disease, while nominating MEK inhibition as putative novel therapeutic strategy to treat or prevent CDK4/6 inhibitor resistance in cancer.

https://ift.tt/2I7SL46

PHASE IB/II STUDY OF SECOND LINE THERAPY WITH PANITUMUMAB, IRINOTECAN AND EVEROLIMUS (PIE) IN KRAS WILD TYPE METASTATIC COLORECTAL CANCER

Purpose: Inhibition of mTOR in addition to EGFR may overcome resistance to EGFR inhibitors in metastatic colorectal cancer (mCRC). This phase Ib/II study evaluated the safety and efficacy of the combination of irinotecan, panitumumab and everolimus. Experimental Design: Patients with KRAS exon 2 WT mCRC following failure of fluoropyrimidine based therapy received IV irinotecan and panitumumab every 2 weeks, and everolimus orally throughout a 14 day cycle. The primary endpoint of the phase II study was response rate (RR). Secondary survival outcomes were calculated using Kaplan-Meier method and analysed as intention to treat. A pre-planned exploratory biomarker analysis was performed. Results: 49 patients were enrolled. Dose level 1 (irinotecan 200mg/m2, panitumumab 6mg/kg, everolimus 5mg alternate day) was declared the MTD with no dose limiting toxicities (DLT) in 6 patients. 40 patients were treated at dose level 1: median age 60 years (37-76), 65% male, 45 and 52.5% respectively ECOG 0/1. Median dose intensity was 85%. Grade 3 toxicities were diarrhoea 23%, mucositis 18%, rash 13%, fatigue 8%, dehydration 5%, neutropenia 20%, febrile neutropenia 8%, hypomagnesemia 20% and hypokalaemia 8%. Grade 4 toxicities were hypomagnesemia 5% and neutropenia 3%. RR was 48%, stable disease 43%. Median PFS was 5.6 months and median OS 10.8 months.   25 patients were RAS/RAF WT and had a RR of 60%, median PFS of 6.4 months and OS 11.8 months. Conclusions: The toxicity of the PIE regimen is as expected and manageable. The RR of 60% in all RAS/RAF WT supports further study of this combination.

https://ift.tt/2jLUDVj

A method to summarize toxicity in cancer randomized clinical trials

Background/Aims: Despite development of clinical "value frameworks" by national and international groups, there remains no generally accepted method to summarize toxicity in cancer clinical trials. We explored ways to simplify toxicity data of an arm of a cancer clinical trial to a single value, termed a weighted toxicity score (WTS). Methods: We compiled 58 randomized clinical trials of FDA-approved kinase-directed inhibitors. We generated 5 models, each of which assigned different weights for each observed grade 1 to 4 toxicity. For each model, we calculated WTS values as different weighted averages of the sum of the toxicities. We correlated each WTS with the dose reduction rate in each trial, using the dose reduction rate as a clinically relevant surrogate of treatment that is too toxic. The WTS method yielding the strongest correlation with frequency of dose reduction was declared the best model. Results: Nineteen of 58 trials were placebo-controlled and had complete data. Of the 5 models examined, differences in dose reduction rates correlated best with differences in WTS using a model employing a clinician-weighted scale for toxicities (model M5). The WTS difference thus serves as a surrogate for a desired dose reduction rate difference, and could be used to adjust dose/schedule as patients are accrued to a clinical trial. Conclusion: The WTS distills a tabular listing of toxicities of a treatment into a single value, and provides a simple method that can be incorporated into value frameworks, or used to guide discussion of the risks and benefits of systemic therapy.

https://ift.tt/2I7Sr5o

Curation of the pancreatic ductal adenocarcinoma subset of The Cancer Genome Atlas is essential for accurate conclusions about survival related molecular mechanisms

Purpose: Publically available databases, e.g. The Cancer Genome Atlas (TCGA), containing clinical and molecular data from large number of patients are useful in validating the contribution of particular genes to disease mechanisms and in forming novel hypotheses relating to clinical outcomes. Experimental Design: The impact of key drivers of cancer progression can be assessed by segregating a patient cohort by certain molecular features and constructing survival plots using the associated clinical data. However, conclusions drawn from this straightforward analysis are highly dependent on the quality and source of tissue samples, as demonstrated through the pancreatic ductal adenocarcinoma (PDAC) subset of TCGA. Results: Analyses of the PDAC-TCGA database, which contains mainly resectable cancer samples from patients in stage IIB, reveal a difference from widely known historical median and 5-year survival rates of PDAC. A similar discrepancy was observed in lung, stomach and liver cancer subsets of TCGA. The whole transcriptome expression patterns of PDAC-TCGA revealed a cluster of samples derived from neuroendocrine tumors, which have a distinctive biology and better disease prognosis than PDAC. Furthermore, PDAC-TCGA contains numerous pseudo-normal samples, as well as those that arose from tumors not classified as PDAC. Conclusions: Inclusion of misclassified samples in the bioinformatic analyses distorts the association of molecular biomarkers with clinical outcomes, altering multiple published conclusions used to support and motivate experimental research. Hence, the stringent scrutiny of type and origin of samples included in the bioinformatic analyses by researchers, databases and web-tool developers is of crucial importance for generating accurate conclusions.

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{Delta}Np63{gamma}/SRC/Slug signalling axis promotes epithelial-to-mesenchymal transition in squamous cancers

Purpose: To investigate the regulation of epithelial-to-mesenchymal transition (EMT) in  Head and Neck Squamous Cell Carcinoma (HNSCC) and its importance in tumour invasion. Experimental design: We use a 3D invasive organotypic raft culture model of human foreskin keratinocytes expressing the E6/E7 genes of the Human Papilloma Virus-16, coupled with bioinformatics and immunohistochemical analysis of patient samples to investigate  the role played by EMT in invasion and identify effectors and upstream regulatory pathways. Results: We identify SNAI2 (Slug) as a critical effector of EMT activated downstream of TP63 overexpression in Head and Neck Squamous Cell Carcinoma (HNSCC). Splice-form specific depletion and rescue experiments further identify the Np63 isoform as both necessary and sufficient to activate the SRC signalling axis and SNAI2-mediated EMT and invasion. Moreover, elevated SRC levels are associated with poor outcome in HNSCC patients in the cancer genome atlas dataset. Importantly, the effects on EMT and invasions and SNAI2 expression can be reversed by genetic or pharmacological inhibition of SRC. Conclusion:Overexpression of Np63 modulates cell invasion by inducing targetable SRC-Slug-evoked EMT in HNSCC, which can be reversed by inhibitors of the SRC signalling.

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MAPK reliance via acquired CDK4/6 inhibitor resistance in cancer

Purpose: Loss of cell cycle control is a hallmark of cancer, which can be targeted with agents, including Cyclin Dependent Kinase-4/6 (CDK4/6) kinase inhibitors that impinge upon the G1-S cell cycle checkpoint via maintaining activity of the retinoblastoma tumor suppressor (RB). This class of drugs is under clinical investigation for various solid tumor types, and has recently been FDA-approved for treatment of breast cancer. However, development of therapeutic resistance is not uncommon.  Experimental Design: In this study, palbociclib (a CDK4/6 inhibitor) resistance was established in models of early stage, RB-positive cancer.  Results: This study demonstrates that acquired palbociclib resistance renders cancer cells broadly resistant to CDK4/6 inhibitors. Acquired resistance was associated with aggressive in vitro and in vivo phenotypes, including proliferation, migration, and invasion. Integration of RNA sequencing analysis and phospho-proteomics profiling revealed rewiring of the kinome, with a strong enrichment for enhanced MAPK signaling across all resistance models, which resulted in aggressive in vitro and in vivo phenotypes and pro-metastatic signaling. However, CDK4/6 inhibitor resistant models were sensitized to MEK inhibitors, revealing reliance on active MAPK signaling to promote tumor cell growth and invasion. Conclusions: In sum, these studies identify MAPK reliance in acquired CDK4/6 inhibitor resistance that promotes aggressive disease, while nominating MEK inhibition as putative novel therapeutic strategy to treat or prevent CDK4/6 inhibitor resistance in cancer.

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PHASE IB/II STUDY OF SECOND LINE THERAPY WITH PANITUMUMAB, IRINOTECAN AND EVEROLIMUS (PIE) IN KRAS WILD TYPE METASTATIC COLORECTAL CANCER

Purpose: Inhibition of mTOR in addition to EGFR may overcome resistance to EGFR inhibitors in metastatic colorectal cancer (mCRC). This phase Ib/II study evaluated the safety and efficacy of the combination of irinotecan, panitumumab and everolimus. Experimental Design: Patients with KRAS exon 2 WT mCRC following failure of fluoropyrimidine based therapy received IV irinotecan and panitumumab every 2 weeks, and everolimus orally throughout a 14 day cycle. The primary endpoint of the phase II study was response rate (RR). Secondary survival outcomes were calculated using Kaplan-Meier method and analysed as intention to treat. A pre-planned exploratory biomarker analysis was performed. Results: 49 patients were enrolled. Dose level 1 (irinotecan 200mg/m2, panitumumab 6mg/kg, everolimus 5mg alternate day) was declared the MTD with no dose limiting toxicities (DLT) in 6 patients. 40 patients were treated at dose level 1: median age 60 years (37-76), 65% male, 45 and 52.5% respectively ECOG 0/1. Median dose intensity was 85%. Grade 3 toxicities were diarrhoea 23%, mucositis 18%, rash 13%, fatigue 8%, dehydration 5%, neutropenia 20%, febrile neutropenia 8%, hypomagnesemia 20% and hypokalaemia 8%. Grade 4 toxicities were hypomagnesemia 5% and neutropenia 3%. RR was 48%, stable disease 43%. Median PFS was 5.6 months and median OS 10.8 months.   25 patients were RAS/RAF WT and had a RR of 60%, median PFS of 6.4 months and OS 11.8 months. Conclusions: The toxicity of the PIE regimen is as expected and manageable. The RR of 60% in all RAS/RAF WT supports further study of this combination.

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A method to summarize toxicity in cancer randomized clinical trials

Background/Aims: Despite development of clinical "value frameworks" by national and international groups, there remains no generally accepted method to summarize toxicity in cancer clinical trials. We explored ways to simplify toxicity data of an arm of a cancer clinical trial to a single value, termed a weighted toxicity score (WTS). Methods: We compiled 58 randomized clinical trials of FDA-approved kinase-directed inhibitors. We generated 5 models, each of which assigned different weights for each observed grade 1 to 4 toxicity. For each model, we calculated WTS values as different weighted averages of the sum of the toxicities. We correlated each WTS with the dose reduction rate in each trial, using the dose reduction rate as a clinically relevant surrogate of treatment that is too toxic. The WTS method yielding the strongest correlation with frequency of dose reduction was declared the best model. Results: Nineteen of 58 trials were placebo-controlled and had complete data. Of the 5 models examined, differences in dose reduction rates correlated best with differences in WTS using a model employing a clinician-weighted scale for toxicities (model M5). The WTS difference thus serves as a surrogate for a desired dose reduction rate difference, and could be used to adjust dose/schedule as patients are accrued to a clinical trial. Conclusion: The WTS distills a tabular listing of toxicities of a treatment into a single value, and provides a simple method that can be incorporated into value frameworks, or used to guide discussion of the risks and benefits of systemic therapy.

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Isolated Peritoneal Recurrence After Liver Resection for Hepatocellular Carcinoma

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Isolated Peritoneal Recurrence After Liver Resection for Hepatocellular Carcinoma

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Efficacy and safety of cytotoxic drug chemotherapy after first-line EGFR–TKI treatment in elderly patients with non-small-cell lung cancer harboring sensitive EGFR mutations

Abstract

Purpose

Epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR–TKI) is effective as first-line chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitive EGFR mutations. However, whether the efficacy of second-line cytotoxic drug chemotherapy after first-line EGFR–TKI treatment is similar to that of first-line cytotoxic drug chemotherapy in elderly patients aged ≥ 75 years harboring sensitive EGFR mutations is unclear. Therefore, we aimed to investigate the efficacy and safety of cytotoxic drug chemotherapy after first-line EGFR–TKI treatment in elderly patients with NSCLC harboring sensitive EGFR mutations.

Methods

We retrospectively evaluated the clinical effects and safety profiles of second-line cytotoxic drug chemotherapy after first-line EGFR–TKI treatment in elderly patients with NSCLC harboring sensitive EGFR mutations (exon 19 deletion/exon 21 L858R mutation). Between April 2008 and December 2015, 78 elderly patients with advanced NSCLC harboring sensitive EGFR mutations received first-line EGFR–TKI at four Japanese institutions. Baseline characteristics, regimens, responses to first- and second-line treatments, whether or not patients received subsequent treatment, and if not, the reasons for non-administration were recorded.

Results

Overall, 20 patients with a median age of 79.5 years (range 75–85 years) were included in our analysis. The overall response, disease control, median progression-free survival, and overall survival rates were 15.0, 60.0%, 2.4, and 13.2 months, respectively. Common adverse events included leukopenia, neutropenia, anemia, thrombocytopenia, malaise, and anorexia. Major grade 3 or 4 toxicities included leukopenia (25.0%) and neutropenia (45.0%). No treatment-related deaths were noted.

Conclusion

Second-line cytotoxic drug chemotherapy after first-line EGFR–TKI treatment among elderly patients with NSCLC harboring sensitive EGFR mutations was effective and safe and showed equivalent outcomes to first-line cytotoxic drug chemotherapy.

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Evidence of inter-tissue differences in the DNA damage response and the pro-oncogenic role of NF{kappa}B in mice with disengaged BRCA1-PALB2 interaction

The BRCA1-PALB2-BRCA2 axis plays an essential role in DNA homologous recombination repair (HRR), defect in which drives genome instability and cancer development. How cells with defects in this pathway respond to DNA damage in vivo and how tumors develop from these cells remain poorly defined. Here we analyzed several aspects of the DNA damage response in multiple tissues of Palb2 mutant mice in which the interaction between PALB2 and BRCA1 is disengaged. Without any challenge, the mutant mice showed increased endogenous DNA damage. Following ionizing radiation (IR), the mutant mice displayed higher levels of DNA breaks and stronger induction of p53 and p21, but continued DNA synthesis, reduced apoptosis, and accelerated tumor development. The differences in p21 induction, DNA synthesis and apoptosis between wild-type and mutant mice were substantially more pronounced in the mammary gland than in the intestine, suggesting a potential contributing factor to the increased risk and the tissue specificity of BRCA/PALB2-associated tumor development. Moreover, the mutant mice showed higher levels of reactive oxygen species (ROS) and constitutive activation of NFκB, an anti-apoptotic transcription factor inducible by both DNA damage and oxidative stress. Treatment of the mutant mice with an inhibitor of NFκB reactivated apoptosis and delayed tumor development following radiation. Thus, our results also suggest a pro-survival and pro-oncogenic role of NFκB in PALB2 mutant cells.

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Alternatively activated macrophages upregulate mesothelial expression of P-selectin to enhance adhesion of ovarian cancer cells

Peritoneal metastasis of high-grade serous ovarian cancer (HGSOC) occurs when tumor cells suspended in ascites adhere to mesothelial cells. Despite the strong relationship between metastatic burden and prognosis in HGSOC, there are currently no therapies specifically targeting the metastatic process. We utilized a co-culture model and multivariate analysis to examine how interactions between tumor cells, mesothelial cells, and alternatively-activated macrophages (AAMs) influence the adhesion of tumor cells to mesothelial cells. We found that AAM-secreted MIP-1β activates CCR5/PI3K signaling in mesothelial cells, resulting in expression of P-selectin on the mesothelial cell surface. Tumor cells attached to this de novo P-selectin through CD24, resulting in increased tumor cell adhesion in static conditions and rolling under flow. C57/BL6 mice treated with MIP-1β exhibited increased P-selectin expression on mesothelial cells lining peritoneal tissues, which enhanced CaOV3 adhesion ex vivo and ID8 adhesion in vivo. Analysis of samples from HGSOC patients confirmed increased MIP-1β and P-selectin, suggesting that this novel multi-cellular mechanism could be targeted to slow or stop metastasis in HGSOC by repurposing anti- CCR5 and P-selectin therapies developed for other indications.

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Evidence of inter-tissue differences in the DNA damage response and the pro-oncogenic role of NF{kappa}B in mice with disengaged BRCA1-PALB2 interaction

The BRCA1-PALB2-BRCA2 axis plays an essential role in DNA homologous recombination repair (HRR), defect in which drives genome instability and cancer development. How cells with defects in this pathway respond to DNA damage in vivo and how tumors develop from these cells remain poorly defined. Here we analyzed several aspects of the DNA damage response in multiple tissues of Palb2 mutant mice in which the interaction between PALB2 and BRCA1 is disengaged. Without any challenge, the mutant mice showed increased endogenous DNA damage. Following ionizing radiation (IR), the mutant mice displayed higher levels of DNA breaks and stronger induction of p53 and p21, but continued DNA synthesis, reduced apoptosis, and accelerated tumor development. The differences in p21 induction, DNA synthesis and apoptosis between wild-type and mutant mice were substantially more pronounced in the mammary gland than in the intestine, suggesting a potential contributing factor to the increased risk and the tissue specificity of BRCA/PALB2-associated tumor development. Moreover, the mutant mice showed higher levels of reactive oxygen species (ROS) and constitutive activation of NFκB, an anti-apoptotic transcription factor inducible by both DNA damage and oxidative stress. Treatment of the mutant mice with an inhibitor of NFκB reactivated apoptosis and delayed tumor development following radiation. Thus, our results also suggest a pro-survival and pro-oncogenic role of NFκB in PALB2 mutant cells.

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Alternatively activated macrophages upregulate mesothelial expression of P-selectin to enhance adhesion of ovarian cancer cells

Peritoneal metastasis of high-grade serous ovarian cancer (HGSOC) occurs when tumor cells suspended in ascites adhere to mesothelial cells. Despite the strong relationship between metastatic burden and prognosis in HGSOC, there are currently no therapies specifically targeting the metastatic process. We utilized a co-culture model and multivariate analysis to examine how interactions between tumor cells, mesothelial cells, and alternatively-activated macrophages (AAMs) influence the adhesion of tumor cells to mesothelial cells. We found that AAM-secreted MIP-1β activates CCR5/PI3K signaling in mesothelial cells, resulting in expression of P-selectin on the mesothelial cell surface. Tumor cells attached to this de novo P-selectin through CD24, resulting in increased tumor cell adhesion in static conditions and rolling under flow. C57/BL6 mice treated with MIP-1β exhibited increased P-selectin expression on mesothelial cells lining peritoneal tissues, which enhanced CaOV3 adhesion ex vivo and ID8 adhesion in vivo. Analysis of samples from HGSOC patients confirmed increased MIP-1β and P-selectin, suggesting that this novel multi-cellular mechanism could be targeted to slow or stop metastasis in HGSOC by repurposing anti- CCR5 and P-selectin therapies developed for other indications.

https://ift.tt/2jJtMcs

Melanotic Schwannoma: Two Cases of Rare Lesions

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Melanotic Schwannoma: Two Cases of Rare Lesions

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Assessment of the Risk of Antiangiogenic Agents Before and After Surgery

Publication date: Available online 8 May 2018
Source:Cancer Treatment Reviews
Author(s): Christina E. Bailey, Alexander A. Parikh
Angiogenesis plays a critical role in the growth, progression, and metastasis of numerous solid tumor types, and thus, antiangiogenic agents have been studied for many years as potential therapeutic agents. Many different antiangiogenic agents, including monoclonal antibodies and multi-targeted tyrosine kinase inhibitors (TKIs), have been approved for various oncology indications, and promising clinical activity has been demonstrated. However, some of these agents have also been associated with serious safety concerns. Because angiogenesis is an important step in the wound healing process, agents targeting the angiogenesis pathway may interfere with wound healing, thus increasing the risk of surgical wound complications, such as dehiscence, surgical site bleeding, and wound infection. Nevertheless, antiangiogenic agents can be safely used in the perioperative setting if oncologists and surgeons are educated on the biology and pharmacokinetics of these agents. This review discusses the available published literature regarding surgical complications associated with the use of antiangiogenic agents and provides updated clinical recommendations on the optimal timing between surgery and antiangiogenic therapy. Due to the paucity of data surrounding this topic, current and future clinical trials need to evaluate prospectively the potential risks for surgical complications associated with antiangiogenic therapies to establish specific guidelines for their safe and effective use within the surgical oncology community.

Graphical abstract

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Toward innovative combinational immunotherapy: a systems biology perspective

Publication date: Available online 8 May 2018
Source:Cancer Treatment Reviews
Author(s): Xue-Tao Li, Jin-Ji Yang, Yi-Long Wu, Jun Hou
The treatment of non-small-cell lung cancer (NSCLC) has advanced significantly in the last decades. Especially immune checkpoint inhibitors have shown inconceivable effect on enhancing host anti-tumor activity in NSCLC. However, the limitation of checkpoint blockade monotherapy seems unavoidable in most of the NSCLC patients and only ∼20% of them achieved response to monotherapy with immune checkpoint inhibitors. Thus combining immune checkpoint inhibitors with other agents with different action mechanisms holds a promise to revitalize NSCLC treatment, such as the combination of checkpoint inhibitors with angiogenesis inhibitors, or with chemotherapy, as well as the combination of two checkpoint inhibitors. Recently, various combinational strategies have been explored to setup promising combination regimens and to understand the action mechanisms. In this review, we summarize the suspected synergistic mechanisms of several combinational approaches by reviewing the available preclinical and clinical data. Then we discuss in light of the current knowledge of cancer biology and systems biology the important facets to be examined when setting up a framework for developing immunotherapy-based combination strategies.



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Identification of inhibitors synergizing gemcitabine sensitivity in the squamous subtype of pancreatic ductal adenocarcinoma (PDAC)

Abstract

Pancreatic adenocarcinoma (PDAC) is a highly aggressive cancer with a high chance of recurrence, limited treatment options, and poor prognosis. A recent study has classified pancreatic cancers into four molecular subtypes: (1) squamous, (2) immunogenic, (3) pancreatic progenitor and (4) aberrantly differentiated endocrine exocrine. Among all the subtypes, the squamous subtype has the worst prognosis. This study aims to utilize large scale genomic datasets and computational systems biology to identify potential drugs targeting the squamous subtype of PDAC through combination therapy. Using the transcriptomic data available from the International Cancer Genome Consortium, Cancer Cell Line Encyclopedia and Connectivity Map, we identified 26 small molecules that could target the squamous subtype of PDAC. Among them include inhibitors targeting the SRC proto-oncogene (SRC) and the mitogen-activated protein kinase kinase 1/2 (MEK1/2). Further analyses demonstrated that the SRC inhibitors (dasatinib and PP2) and MEK1/2 inhibitor (pimasertib) synergized gemcitabine sensitivity specifically in the squamous subtype of PDAC cells (SW1990 and BxPC3), but not in the PDAC progenitor cells (AsPC1). Further analysis revealed that the synergistic effects are dependent on SRC or MEK1/2 activities, as overexpression of SRC or MEK1/2 completely abrogated the synergistic effects SRC inhibitors (dasatinib and PP2) and MEK1/2 inhibitor (pimasertib). In contrast, no significant toxicity was observed in the MRC5 human lung fibroblast and ARPE-19 human retinal pigment epithelial cells. Together, our findings suggest that combinations of SRC or MEK inhibitors with gemcitabine possess synergistic effects on the squamous subtype of PDAC cells and warrant further investigation.

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Early ultrasonographic tumor regression after linear accelerator stereotactic fractionated photon radiotherapy of choroidal melanoma as a predictor for metastatic spread

During extended follow-up (of up to 15 years), approximately fifty percent of patients with choroidal melanoma will develop metastatic disease and eventually die. Thus, continuing research on prognostic factors, early detection and treatment is necessary. Height regression rates both after plaque brachytherapy and proton beam irradiation have been shown to have prognostic value. The purpose of this study was to analyze the influence of early tumor regression rate after treatment of choroidal melanoma with LINAC stereotactic fractionated radiotherapy (SFRT) as an independent risk factor for metastasis.

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Outcomes of Rectal Cancer Patients With Low Sphincter-Preserving Operations Compared to Patients With Abdominoperineal Resection

Abstract

Purpose of Review

The surgical management for low rectal cancer patients has evolved as a result of the introduction of preoperative chemoradiotherapy and innovative technical developments. As a result, abdominoperineal resection (APR) for low rectal cancer has decreased over time. Further, the introduction of intersphincteric resection and preoperative chemoradiotherapy has made it possible to proceed with sphincter preservation. However, the oncologic and functional outcomes of intersphincteric resection have been questioned because of the narrow radical margin and sphincter excision. We review the literature to evaluate the oncologic outcomes of sphincter-preserving surgery in low rectal cancer compared to abdominoperineal resection. The oncologic outcome of extended abdominoperineal resection, which was developed to improve result of surgical outcome for low rectal cancer, is also discussed.

Recent Findings

The present manuscript addresses the evidence that shows oncologic safety and acceptable functional outcomes of intersphincteric resection. Our review shows that intersphincteric resection should be considered as an established acceptable operation for the management of low rectal cancer. On the other hand, APR results in frequent positive circumferential margins, higher local recurrence rate compared to sphincter-preserving resection. Nonetheless, abdominoperineal resection was inevitable for some subset of patients; therefore, efforts to improve oncologic outcomes after abdominoperineal resection have to be made. Extended APR which considers tumor extensiveness and standardizes perineal surgical extent has been proposed and oncologic benefits as well as overall outcomes are being evaluated.

Summary

The current trend appears to indicate that the rate of intershincteric resection is increasing while APR decreasing. However, a multidisciplinary approach to low rectal cancers should emphasize oncologic and overall outcomes independent of sphincter preservation.

https://ift.tt/2rpgaaP

Characteristics of adult patients treated for acute myeloid leukemia with inv 16 in Casablanca (Morocco).

Related Articles

Characteristics of adult patients treated for acute myeloid leukemia with inv 16 in Casablanca (Morocco).

Bull Cancer. 2018 May 04;:

Authors: Houssou B, Lamchahab M, Massi R, Oukkache B, Quessar A

PMID: 29735159 [PubMed - as supplied by publisher]

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[Psychological impact of ostomy on the quality of life of colorectal cancer patients: Role of body image, self-esteem and anxiety].

Related Articles

[Psychological impact of ostomy on the quality of life of colorectal cancer patients: Role of body image, self-esteem and anxiety].

Bull Cancer. 2018 May 04;:

Authors: Beaubrun En Famille Diant L, Sordes F, Chaubard T

Abstract
Surgery accounts for an important part of the therapeutic arsenal of colorectal cancer treatment. In digestive cancers, ostomy devices induce the loss of anal function and control. This medical appliance generates changes affecting all aspects of patients' lives. This study explores, on the one hand, the psychological impact of colostomy on colorectal cancer patients' quality of life and on the other hand, it analyzes the correlational links between body image, self-esteem and anxiety during the stoma. Thirty-five patients with colorectal cancer participated in the study, divided into 2 subgroups: 23 were carriers of a definitive stoma and the 12 others with a temporary stoma. All completed the Functional Assessment Cancer Therapy (FACT-C), the Body Image Scale (BIS), the State Trait Anxiety Inventory (STAI-Y) and the Self Esteem Scale (ETES). Analysis revealed the quality of life of temporary ostomates is more affected than that of the definitive ones. All three of them, body image, self-esteem and anxiety negatively affect the quality of life regardless of the type of stoma. This study highlights the prevalence of physical self-esteem for temporary ostomy; the role of a good body image and substantial emotional self-esteem for the permanent ostomy. Future studies are required to explore the underlying causes of the acceptance of this equipment and the mediating role of care devices.

PMID: 29735158 [PubMed - as supplied by publisher]

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[CDK4/6 inhibitors: biomarkers, mechanisms of resistance and interest of the study of the circulating tumor DNA].

Related Articles

[CDK4/6 inhibitors: biomarkers, mechanisms of resistance and interest of the study of the circulating tumor DNA].

Bull Cancer. 2018 May 02;:

Authors: Gonçalves A

PMID: 29729807 [PubMed - as supplied by publisher]

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[Adherence to the Clinical Practice Guidelines in the management of Soft Tissue Sarcomas in Lebanon: Lessons from French Sarcoma Group's experience].

Related Articles

[Adherence to the Clinical Practice Guidelines in the management of Soft Tissue Sarcomas in Lebanon: Lessons from French Sarcoma Group's experience].

Bull Cancer. 2018 May 02;:

Authors: Assi T, El Rassy E, Kattan J

PMID: 29729806 [PubMed - as supplied by publisher]

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Initial brain metastasis velocity: does the rate at which cancers first seed the brain affect outcomes?

Abstract

Purpose/objective(s)

Brain metastasis velocity (BMV) is a metric that describes the rate of development of new brain metastases (BM) after initial stereotactic radiosurgery (SRS). A limitation in the application of BMV is it cannot be applied until time of first BM failure after SRS. We developed initial BM velocity (iBMV), a new metric that accounts for the number of BM at first SRS and the time since initial cancer diagnosis.

Materials/methods

We reviewed patients with BM treated at our institution with upfront SRS without WBRT. iBMV was calculated as the number of BM at initial SRS divided by time (years) from initial cancer diagnosis to first SRS. We performed a linear regression to correlate BMV as a continuous variable and with low, intermediate, and high BMV risk groups. Kaplan–Meier estimation of OS was calculated from time of first SRS to death. iBMV was not calculated for patients who presented with BM at initial cancer diagnosis.

Results

994 patients were treated with upfront SRS without WBRT between 2000 and 2017. Median OS was 8.5 mos. 595 (60%) patients developed BM after cancer diagnosis and median time to first SRS from time of initial diagnosis was 2.2 years. Median iBMV was 0.79 BM/year. iBMV correlated with BMV (β = 1.57 p = 0.021) and independently predicted for mortality [Cox proportional hazard ratio (HR) 1.11, p = 0.036] after accounting for histology, number of initial brain metastases (HR 1.03, p = 0.32), time from cancer diagnosis to SRS (HR 0.98, p = 0.157) in a multivariate model.

Conclusion

iBMV correlates with BMV and OS. With further validation, iBMV could serve as a metric to risk stratify patients for WBRT or SRS at time of first BM presentation.

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Re-irradiation in lung disease by SBRT: a retrospective, single institutional study

Abstract

Background

The loco regional relapse is frequent in the lung disease. The aim of this study was to evaluate the outcomes of re-irradiation by SBRT in terms of Local Control (LC) and toxicities.

Methods

From April 2011 to December 2016, twenty-two patients received a re-irradiation by SBRT. Twenty- seven lesions were treated. The medium BED(10) of re-irradiation was 100.6 Gy (range: 48–151.2 Gy) and the medium EQD2(10) was 93.8 Gy (range: 40–126 Gy). In the previous treatment the medium BED(10) was 97.2 Gy (range: 40–120 Gy), the medium EQD2(10) was 81 Gy (range: 32.5–100 Gy). The median time between the first and the second treatment was 18 months.

Results

Local Control was reached in 18 out of 27 (66%) re-irradiated lesions, with rates of 67 and 54% at 1- year and 2- years respectively. The treatment was well tolerated; the maximum recorded toxicity was Grade 3.

Conclusions

Re- irradiation by SBRT may represent an option for the treatment of lung disease with good results in terms of LC and toxicity.

https://ift.tt/2wqCPZ6

American Journal of Cancer Research; +17 new citations

17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

American Journal of Cancer Research

These pubmed results were generated on 2018/05/08

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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Verlängerung des rezidivfreien und Gesamtüberlebens beim Ovarialkarzinom im Stadium III durch hypertherme intraperitoneale Chemotherapie (HIPEC)

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Abschätzung von Langzeitrisiken der modernen Strahlentherapie bei Patientinnen mit Mammakarzinom: Evidenz zu Strahlendosen an Lunge und Herz

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External validation of four dementia prediction models for use in the general community-dwelling population: a comparative analysis from the Rotterdam Study

Abstract

To systematically review the literature for dementia prediction models for use in the general population and externally validate their performance in a head-to-head comparison. We selected four prediction models for validation: CAIDE, BDSI, ANU-ADRI and DRS. From the Rotterdam Study, 6667 non-demented individuals aged 55 years and older were assessed between 1997 and 2001. Subsequently, participants were followed for dementia until 1 January, 2015. For each individual, we computed the risk of dementia using the reported scores from each prediction model. We used the C-statistic and calibration plots to assess the performance of each model to predict 10-year risk of all-cause dementia. For comparisons, we also evaluated discriminative accuracy using only the age component of these risk scores for each model separately. During 75,581 person-years of follow-up, 867 participants developed dementia. C-statistics for 10-year dementia risk prediction were 0.55 (95% CI 0.53–0.58) for CAIDE, 0.78 (0.76–0.81) for BDSI, 0.75 (0.74–0.77) for ANU-ADRI, and 0.81 (0.78–0.83) for DRS. Calibration plots showed that predicted risks were too extreme with underestimation at low risk and overestimation at high risk. Importantly, in all models age alone already showed nearly identical discriminative accuracy as the full model (C-statistics: 0.55 (0.53–0.58) for CAIDE, 0.81 (0.78–0.83) for BDSI, 0.77 (0.75–0.79) for ANU-ADRI, and 0.81 (0.78–0.83) for DRS). In this study, we found high variability in discriminative ability for predicting dementia in an elderly, community-dwelling population. All models showed similar discriminative ability when compared to prediction based on age alone. These findings highlight the urgent need for updated or new models to predict dementia risk in the general population.

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Low mood, visual hallucinations, and falls – heralding the onset of rapidly progressive probable sporadic Creutzfeldt–Jakob disease in a 73-year old: a case report

Creutzfeldt–Jakob disease is a rare and rapidly fatal neurodegenerative disease. Since clinicians may see only very few cases during their professional career, it is important to be familiar with the clinical ...

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Infective endocarditis due to Burkholderia cepacia in a neonate: a case report

Burkholderia is a pathogen that is rarely seen in clinical cases. However, this organism is being found more commonly in hospitals.

https://ift.tt/2KLcEzn

External validation of four dementia prediction models for use in the general community-dwelling population: a comparative analysis from the Rotterdam Study

Abstract

To systematically review the literature for dementia prediction models for use in the general population and externally validate their performance in a head-to-head comparison. We selected four prediction models for validation: CAIDE, BDSI, ANU-ADRI and DRS. From the Rotterdam Study, 6667 non-demented individuals aged 55 years and older were assessed between 1997 and 2001. Subsequently, participants were followed for dementia until 1 January, 2015. For each individual, we computed the risk of dementia using the reported scores from each prediction model. We used the C-statistic and calibration plots to assess the performance of each model to predict 10-year risk of all-cause dementia. For comparisons, we also evaluated discriminative accuracy using only the age component of these risk scores for each model separately. During 75,581 person-years of follow-up, 867 participants developed dementia. C-statistics for 10-year dementia risk prediction were 0.55 (95% CI 0.53–0.58) for CAIDE, 0.78 (0.76–0.81) for BDSI, 0.75 (0.74–0.77) for ANU-ADRI, and 0.81 (0.78–0.83) for DRS. Calibration plots showed that predicted risks were too extreme with underestimation at low risk and overestimation at high risk. Importantly, in all models age alone already showed nearly identical discriminative accuracy as the full model (C-statistics: 0.55 (0.53–0.58) for CAIDE, 0.81 (0.78–0.83) for BDSI, 0.77 (0.75–0.79) for ANU-ADRI, and 0.81 (0.78–0.83) for DRS). In this study, we found high variability in discriminative ability for predicting dementia in an elderly, community-dwelling population. All models showed similar discriminative ability when compared to prediction based on age alone. These findings highlight the urgent need for updated or new models to predict dementia risk in the general population.

https://ift.tt/2I3PjaA

External validation of four dementia prediction models for use in the general community-dwelling population: a comparative analysis from the Rotterdam Study

Abstract

To systematically review the literature for dementia prediction models for use in the general population and externally validate their performance in a head-to-head comparison. We selected four prediction models for validation: CAIDE, BDSI, ANU-ADRI and DRS. From the Rotterdam Study, 6667 non-demented individuals aged 55 years and older were assessed between 1997 and 2001. Subsequently, participants were followed for dementia until 1 January, 2015. For each individual, we computed the risk of dementia using the reported scores from each prediction model. We used the C-statistic and calibration plots to assess the performance of each model to predict 10-year risk of all-cause dementia. For comparisons, we also evaluated discriminative accuracy using only the age component of these risk scores for each model separately. During 75,581 person-years of follow-up, 867 participants developed dementia. C-statistics for 10-year dementia risk prediction were 0.55 (95% CI 0.53–0.58) for CAIDE, 0.78 (0.76–0.81) for BDSI, 0.75 (0.74–0.77) for ANU-ADRI, and 0.81 (0.78–0.83) for DRS. Calibration plots showed that predicted risks were too extreme with underestimation at low risk and overestimation at high risk. Importantly, in all models age alone already showed nearly identical discriminative accuracy as the full model (C-statistics: 0.55 (0.53–0.58) for CAIDE, 0.81 (0.78–0.83) for BDSI, 0.77 (0.75–0.79) for ANU-ADRI, and 0.81 (0.78–0.83) for DRS). In this study, we found high variability in discriminative ability for predicting dementia in an elderly, community-dwelling population. All models showed similar discriminative ability when compared to prediction based on age alone. These findings highlight the urgent need for updated or new models to predict dementia risk in the general population.

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A New Prostate Cancer Screening Recommendation

The US Preventive Services Task Force (USPSTF) recommendation statement for screening for prostate cancer, supported by the evidence report, has been updated to a grade C recommendation, from the grade D recommendation of the 2012 statement, regarding prostate-specific antigen (PSA)-based screening. In 2012, the USPSTF recommended against PSA-based screening for prostate cancer, but now the Task Force concludes that "for men aged 55 to 69 years, the decision to undergo periodic PSA-based screening for prostate cancer should be an individual one." (For men 70 years or older, the Task Force maintains its D recommendation for PSA-based prostate cancer screening.) After the 2012 USPSTF recommendation and prior to this updated statement, other groups had responded to the complexity of the prostate cancer screening decision with additional recommendations. For example, in 2013, the American Urologic Association recommended a shared decision-making approach to prostate cancer screening for men aged 55 to 69 years, and the American College of Physicians also recommended a screening approach incorporating patient preferences for men aged 50 to 69 years, with both organizations recommending against screening in men 70 years or older or with life expectancy less than 10 to 15 years. However, even with these recommendations, shared decision making for prostate cancer screening overall has not significantly increased.

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Evaluation of particle radiotherapy for the re-irradiation of recurrent intracranial meningioma

With the advance of modern irradiation techniques, the role of radiotherapy (RT) for intracranial meningioma has increased significantly throughout the past years. Despite that tumor's generally favorable outc...

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Patterns of failure after resection of extrahepatic bile duct cancer: implications for adjuvant radiotherapy indication and treatment volumes

The role of adjuvant radiotherapy (RT) and setting proper RT target volumes have not been clearly demonstrated for extrahepatic bile duct (EHBD) cancer, due to the rarity of the disease and the lack of randomi...

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Survival after cancer diagnosis in a cohort of HIV-positive individuals in Latin America

Abstract

Background

This study aimed to evaluate trends and predictors of survival after cancer diagnosis in persons living with HIV in the Caribbean, Central, and South America network for HIV epidemiology cohort.

Methods

Demographic, cancer, and HIV-related data from HIV-positive adults diagnosed with cancer ≤ 1 year before or any time after HIV diagnosis from January 1, 2000-June 30, 2015 were retrospectively collected. Cancer cases were classified as AIDS-defining cancers (ADC) and non-AIDS-defining cancers (NADC). The association of mortality with cancer- and HIV-related factors was assessed using Kaplan-Meier curves and Cox proportional hazards models stratified by clinic site and cancer type.

Results

Among 15,869 patients, 783 had an eligible cancer diagnosis; 82% were male and median age at cancer diagnosis was 39 years (interquartile range [IQR]: 32–47). Patients were from Brazil (36.5%), Argentina (19.9%), Chile (19.7%), Mexico (19.3%), and Honduras (4.6%). A total of 564 ADC and 219 NADC were diagnosed. Patients with NADC had similar survival probabilities as those with ADC at one year (81% vs. 79%) but lower survival at five years (60% vs. 69%). In the adjusted analysis, risk of mortality increased with detectable viral load (adjusted hazard ratio [aHR] = 1.63, p = 0.02), age (aHR = 1.02 per year, p = 0.002) and time between HIV and cancer diagnoses (aHR = 1.03 per year, p = 0.01).

Conclusion

ADC remain the most frequent cancers in the region. Overall mortality was related to detectable viral load and age. Longer-term survival was lower after diagnosis of NADC than for ADC, which may be due to factors unrelated to HIV.

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Computer-aided diagnosis for ( 123 I)FP-CIT imaging: impact on clinical reporting

Abstract

Background

For (¹²³I)FP-CIT imaging, a number of algorithms have shown high performance in distinguishing normal patient images from those with disease, but none have yet been tested as part of reporting workflows. This study aims to evaluate the impact on reporters' performance of a computer-aided diagnosis (CADx) tool developed from established machine learning technology.

Three experienced (¹²³I)FP-CIT reporters (two radiologists and one clinical scientist) were asked to visually score 155 reconstructed clinical and research images on a 5-point diagnostic confidence scale (read 1). Once completed, the process was then repeated (read 2). Immediately after submitting each image score for a second time, the CADx system output was displayed to reporters alongside the image data. With this information available, the reporters submitted a score for the third time (read 3). Comparisons between reads 1 and 2 provided evidence of intra-operator reliability, and differences between reads 2 and 3 showed the impact of the CADx.

Results

The performance of all reporters demonstrated a degree of variability when analysing images through visual analysis alone. However, inclusion of CADx improved consistency between reporters, for both clinical and research data. The introduction of CADx increased the accuracy of the radiologists when reporting (unfamiliar) research images but had less impact on the clinical scientist and caused no significant change in accuracy for the clinical data.

Conclusions

The outcomes for this study indicate the value of CADx as a diagnostic aid in the clinic and encourage future development for more refined incorporation into clinical practice.

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Conservative management of nivolumab-induced pericardial effusion: a case report and review of literature

Abstract

Background

Nivolumab is an immune checkpoint inhibitor targeting programmed death-1 protein and has been approved for the treatment of multiple advanced malignancies. Adverse effects of immune checkpoint inhibitors are distinct from conventional cytotoxic chemotherapy and can be life-threatening if left unrecognized. Here, we present a case of nivolumab-induced pericardial effusion successfully managed with high-dose corticosteroids.

Case presentation

A 70-year-old Caucasian female with a history of 50-pack-year cigarette smoking was diagnosed of recurrent adenocarcinoma of lung after initial surgery. She progressed through multiple lines of chemotherapy and was eventually started on nivolumab. She developed a large pericardial effusion, grade 3 by Common Terminology Criteria for Adverse Events v4.0, about 4 days after receiving first nivolumab treatment. She was treated with oral prednisone at 1 mg/kg daily with gradual resolution of pericardial effusion over 5 weeks while she still received nivolumab every 2 weeks. Prednisone treatment was eventually tapered off about 10 weeks from initial nivolumab treatment. However 1 week after stopping prednisone, she again presented with shortness of breath and bilateral ankle edema, imaging confirmed recurrent pericardial effusion measuring 2.8 cm. Nivolumab was stopped and patient was again started back on prednisone 1 mg/kg daily which resulted in complete resolution of pericardial effusion in 3 weeks. Nivolumab was resumed 1 week afterwards while patient was on tapering dose of prednisone. There was no recurrent pericardial effusion when she continued low-dose prednisone during the remaining course of nivolumab treatment.

Conclusions

With increasing use of immune checkpoint inhibitors, clinicians need to be aware of the unusual immune-related adverse events in order to provide timely management and effective patient care. To our knowledge, this is the first reported case of immune-related pericardial effusion from nivolumab successfully managed with high-dose corticosteroids. Furthermore, recurrent pericardial effusion was prevented by using low-dose corticosteroids as maintenance in order for patient to continue nivolumab treatment.

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eNOS expression and NO release during hypoxia is inhibited by miR-200b in human endothelial cells

Abstract

The nitric oxide (NO) secreted by vascular endothelium is required for the maintenance of cardiovascular homeostasis. Diminished release of NO generated by endothelial NO synthase contributes to endothelial dysfunction. Hypoxia and ischemia reduce endothelial eNOS expression via posttranscriptional mechanisms that result in NOS3 transcript destabilization. Here, we examine whether microRNAs contribute to this mechanism. We followed the kinetics of hypoxia-induced changes in NOS3 mRNA and eNOS protein levels in primary human umbilical vein endothelial cells (HUVECs). Utilizing in silico predictive protocols to identify potential miRNAs that regulate eNOS expression, we identified miR-200b as a candidate. We established the functional miR-200b target sequence within the NOS3 3′UTR, and demonstrated that manipulation of the miRNA levels during hypoxia using miR-200b mimics and antagomirs regulates eNOS levels, and established that miR-200b physiologically limits eNOS expression during hypoxia. Furthermore, we demonstrated that the specific ablation of the hypoxic induction of miR-200b in HUVECs restored eNOS-driven hypoxic NO release to the normoxic levels. To determine whether miR-200b might be the only miRNA that had this effect, we utilized Next Generation Sequencing (NGS) to follow hypoxia-induced changes in the miRNA levels in HUVECS and found 83 novel hypoxamiRs, with two candidate miRNAs besides miR-200b that could potentially influence eNOS levels. Taken together, the data establish miR-200b-eNOS regulation as a first hypoxamiR-based mechanism that limits NO bioavailability during hypoxia in endothelial cells, and show that hypoxamiRs could become useful therapeutic targets for cardiovascular diseases and other hypoxic-related diseases including various types of cancer.

https://ift.tt/2FUewT7

Korean Society of Coloproctology (KSCP) trial of cONsolidation Chemotherapy for Locally advanced mid or low rectal cancer after neoadjUvant concurrent chemoraDiothErapy: a multicenter, randomized controlled trial (KONCLUDE)

Abstract

Background

Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) has been a standard treatment option for locally advanced rectal cancer with improved local control. However, systemic recurrence despite neoadjuvant CRT remained unchanged. The only significant prognostic factor proven to be important was pathologic complete response (pCR) after neoadjuvant CRT. Several efforts have been tried to improve survival of patients who treated with neoadjuvant CRT and to achieve more pCR including adding cytotoxic chemotherapeutic agents, chronologic modification of chemotherapy schedule or adding chemotherapy during the perioperative period. Consolidation chemotherapy is adding several cycles of chemotherapy between neoadjuvant CRT and TME. It could increase pCR rate, subsequently could show better oncologic outcomes.

Methods

Patients with advanced mid or low rectal cancer who received neoadjuvant CRT will be included after screening. They will be randomized and assigned to undergo TME followed by 8 cycles of adjuvant chemotherapy (control arm) or receive 3 cycles of consolidation chemotherapy before TME, and receive 5 cycles of adjuvant chemotherapy (experimental arm). The primary endpoints are pCR and 3-year disease-free survival (DFS), and the secondary endpoints are radiotherapy-related complications, R0 resection rate, tumor response rate, surgery-related morbidity, and peripheral neuropathy at 3 year after the surgery. The authors hypothesize that the experimental arm would show a 15% improvement in pCR (15 to 30%) and in 3-year DFS (65 to 80%), compared with the control arm. The accrual period is 2 years and the follow-up period is 3 years. Based on the superiority design, one-sided log-rank test with α-error of 0.025 and a power of 80% was conducted. Allowing for a drop-out rate of 10%, 358 patients (179 per arm) will need to be recruited. Patients will be followed up at every 3 months for 2 years and then every 6 months for 3 years after the last patient has been randomized.

Discussion

KONCLUDE trial aims to investigate whether consolidation chemotherapy shows better pCR and 3-year DFS than adjuvant chemotherapy alone for the patients who received neoadjuvant CRT for locally advanced rectal cancer. This trial is expected to provide evidence to support clear treatment guidelines for patients with locally advanced rectal cancer.

Trial registration

Clinicaltrials.gov NCT02843191 (First posted on July 25, 2016).

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M1 macrophage recruitment correlates with worse outcome in SHH Medulloblastomas

Abstract

Background

Recent progress in molecular analysis has advanced the understanding of medulloblastoma (MB) and is anticipated to facilitate management of the disease. MB is composed of 4 molecular subgroups: WNT, SHH, Group 3, and Group 4. Macrophages play a crucial role in the tumor microenvironment; however, the functional role of their activated phenotype (M1/M2) remains controversial. Herein, we investigate the correlation between tumor-associated macrophage (TAM) recruitment within the MB subgroups and prognosis.

Methods

Molecular subgrouping was performed by a nanoString-based RNA assay on retrieved snap-frozen tissue samples. Immunohistochemistry (IHC) and immunofluorescence (IF) assays were performed on subgroup identified samples, and the number of polarized macrophages was quantified from IHC. Survival analyses were conducted on collected clinical data and quantified macrophage data.

Results

TAM (M1/M2) recruitment in SHH MB was significantly higher compared to that in other subgroups. A Kaplan-Meier survival curve and multivariate Cox regression demonstrated that high M1 expressers showed worse overall survival (OS) and progression-free survival (PFS) than low M1 expressers in SHH MB, with relative risk (RR) values of 11.918 and 6.022, respectively.

Conclusion

M1 rather than M2 correlates more strongly with worse outcome in SHH medulloblastoma.

https://ift.tt/2rsEjNB

Incidence of breast and colorectal cancer among immigrants in Ontario, Canada: a retrospective cohort study from 2004-2014

Abstract

Background

Studies have shown that morbidity and mortality rates due to cancer among recent immigrants are lower than those among the native-born population. The objectives of this study were to describe the incidence of colorectal and breast cancer among immigrants from major regions of the world compared to Canadian-born residents of the province of Ontario and to examine the role of length of stay and neighborhood income.

Methods

Retrospective cohort study including all individuals 18 years and over residing in Ontario from 2004 to 2014. Age-standardized incidence rates (ASIR) were calculated for immigrants from each world region versus Canadian-born residents and stratified by neighborhood income quintile and length of stay. Binomial regression analysis was used to determine the association of neighbourhood income, length of stay, and location of birth with colorectal and breast cancer incidence.

Results

Canadian immigrants born in South Asia had the lowest colorectal and breast cancer incidence (colorectal: women: ASIR = 0.14; men: ASIR = 0.18; breast: ASIR = 1.00) compared to long-term residents during the study period (colorectal: women: ASIR = .57; men: ASIR = .72; breast cancer ASIR = 1.61). In multivariate analyses, neighboorhood income did not consistently play a significant role in colorectal cancer incidence; however higher neighbourhood income was a risk factor for breast cancer among immigrant women (adjusted relative risk for highest neighboorhood income quintile versus lowest income quintile =1.21, 95% CI = 1.18–1.24). Increased length of stay was associated with higher risk of cancer. After adjusting for age, neighborhood income, and length of stay, those born in Europe and Central Asia had the highest risk of colorectal cancer compared to those born in East Asia and Pacific and those born in the Middle East had the greatest additional risk of breast cancer.

Conclusions

After correcting for age, breast and colorectal cancer incidence rates among immigrants differ according to their region of birth and recent immigrants to Ontario have lower colorectal and breast cancer incidence rates than their native-born peers. However, those advantages diminish over time. These findings call for Ontario to generate tools and interventions to maintain the health of the immigrant population, particularly for those groups with a higher incidence of cancer.

https://ift.tt/2jJs9vA

Histone methyltransferase SETDB1 promotes cells proliferation and migration by interacting withTiam1 in hepatocellular carcinoma

Abstract

Background

SETDB1 is a histone H3K9 methyltransferase, which plays a significant role in the occurrence and progression of tumors. Previous studies have confirmed that T-lymphom invasion and metastasis gene (Tiam1) is a protein associated with the metastasis of hepatocellular carcinoma (HCC); however, we have not yet been successful in elucidating the specific mechanism of HCC.

Methods

Yeast two-hybrid test was conducted to screen proteins that interacted with Tiam1 gene. Glutathione-S-transferase (GST) pull-down and crosslinking-immunoprecipitation (CLIP) assays were performed to determine whether SETDB1 can interact with Tiam1 gene. A series of related experiments were performed to explore role of SETDB1 on cell proliferation, migration, and invasion in HCC. Recovery experiment was performed to investigate the effect of Tiam1 knockdown on cell proliferation and migration, which was caused by SETDB1 overexpression in HCC cells. The expression of SETDB1 was frequently upregulated in HCC tissues and positively correlated with Tiam1.

Results

GST pull-down and CLIP assays were performed to elucidate the interaction between SETDB1 and Tiam1. Cell proliferation, migration, and epithelial mesenchymal transformation (EMT) in HCC cells was promoted with the overexpression of SETDB1. Following the knockdown of Tiam1 gene, the effect of SETDB1 on cell proliferation and migration was reversed in HCC cells. The expression of SETDB1 was frequently up-regulated in HCC tissues, and it was positively correlated with Tiam1 gene.

Conclusions

Ours is the first study to prove that SETDB1 promotes the proliferation and migration of cells by forming SETDB1-Tiam1 compounds. We found that SETDB1-Tiam1 compounds were involved in a novel pathway, which regulated epigenetic modification of gene expression in HCC samples.

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Angiopoietin-like 4 promotes osteosarcoma cell proliferation and migration and stimulates osteoclastogenesis

Abstract

Background

Osteosarcoma is the most common primary bone cancer in children and young adults. It is highly aggressive and patients that present with metastasis have a poor prognosis. Angiopoietin-like 4 (ANGPTL4) drives the progression and metastasis of many solid tumours, but has not been described in osteosarcoma tissue. ANGPTL4 also enhances osteoclast activity, which is required for osteosarcoma growth in bone. We therefore investigated the expression and function of ANGPTL4 in human osteosarcoma tissue and cell lines.

Methods

Expression of ANGPTL4 in osteosarcoma tissue microarrays was determined by immunohistochemistry. Hypoxic secretion of ANGPTL4 was tested by ELISA and Western blot. Regulation of ANGPTL4 by hypoxia-inducible factor (HIF) was investigated using isoform specific HIF siRNA (HIF-1α, HIF-2α). Effects of ANGPTL4 on cell proliferation, migration (scratch wound assay), colony formation and osteoblastogenesis were assessed using exogenous ANGPTL4 or cells stably transfected with ANGPTL4. Osteoclastogenic differentiation of CD14+ monocytes was assessed by staining for tartrate-resistant acid phosphatase (TRAP), bone resorption was assessed by lacunar resorption of dentine.

Results

ANGPTL4 was immunohistochemically detectable in 76/109 cases. ANGPTL4 was induced by hypoxia in 6 osteosarcoma cell lines, under the control of the HIF-1α transcription factor. MG-63 cells transfected with an ANGPTL4 over-expression plasmid exhibited increased proliferation and migration capacity and promoted osteoclastogenesis and osteoclast-mediated bone resorption. Individually the full-length form of ANGPTL4 could increase MG-63 cell proliferation, whereas N-terminal ANGPTL4 mediated the other pro-tumourigenic phenotypes.

Conclusions

This study describes a role(s) for ANGPTL4 in osteosarcoma and identifies ANGPTL4 as a treatment target that could potentially reduce tumour progression, inhibit angiogenesis, reduce bone destruction and prevent metastatic events.

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Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells

Abstract

Background

Currently, there are no available targeted therapy options for non-V600 BRAF mutated tumors. The aim of this study was to investigate the effects of RAF and MEK concurrent inhibition on tumor growth, migration, signaling and apoptosis induction in preclinical models of non-V600 BRAF mutant tumor cell lines.

Methods

Six BRAF mutated human tumor cell lines CRL5885 (G466 V), WM3629 (D594G), WM3670 (G469E), MDAMB231 (G464 V), CRL5922 (L597 V) and A375 (V600E as control) were investigated. Pan-RAF inhibitor (sorafenib or AZ628) and MEK inhibitor (selumetinib) or their combination were used in in vitro viability, video microscopy, immunoblot, cell cycle and TUNEL assays. The in vivo effects of the drugs were assessed in an orthotopic NSG mouse breast cancer model.

Results

All cell lines showed a significant growth inhibition with synergism in the sorafenib/AZ628 and selumetinib combination. Combination treatment resulted in higher Erk1/2 inhibition and in increased induction of apoptosis when compared to single agent treatments. However, single selumetinib treatment could cause adverse therapeutic effects, like increased cell migration in certain cells, selumetinib and sorafenib combination treatment lowered migratory capacity in all the cell lines. Importantly, combination resulted in significantly increased tumor growth inhibition in orthotropic xenografts of MDAMB231 cells when compared to sorafenib - but not to selumetinib – treatment.

Conclusions

Our data suggests that combined blocking of RAF and MEK may achieve increased therapeutic response in non-V600 BRAF mutant tumors.

https://ift.tt/2rudqJ6

Cancer incidence in Yemen from 1997 to 2011: a report from the Aden cancer registry

Abstract

Background

This study aims to report on the trend and incidence of cancers in Yemen (Aden) using data from Aden Cancer Registry (ACR), as a population-based cancer registry in Yemen over a period of 15 years (1997–2011). Such comprehensive, valid and detailed information on cancer trend is badly needed for planning a cancer control program in the country.

Methods

All cancer cases were abstracted from patients' medical records – based on clinical, histopathology, and radiological diagnosis. Data were coded using the International Classification of Diseases for Oncology (ICD-O) and the International Classification of Childhood Cancer (ICCC-3) to code childhood tumors. The CanReg4 program was used to analyze the data for 15 years study period.

Results

A total of 6974 cases were included in this study, 47% were males and 53% females. The overall annual incidence rate was 21.6/100,000 populations; however, the incidence in males was little lower than in females (20.0 and 22.9 per 100,000 populations, respectively). The top five cancers among males were leukaemia (10.5%), nonhodgkin lymphoma [(NHL), 10.1%], colon (7.5%), Hodgkin diseases [(HD), 6.1%] and stomach cancer (5.1%). For females, breast cancer was the top (30.0%), followed by leukaemia (7.6%), NHL (6.6%), colonic (4.9%) and ovarian cancer (4.5%).

Conclusion

Our findings reveal that, there is urgent need to commence the early screening of breast cancer due to its high frequency among Yemeni women. The government should give more support for cancer registries in the country to sustain its vital contribution to cancer care.

https://ift.tt/2wttL62

Real-time Management of Incident Learning Reports in a Radiation Oncology Department

Publication date: Available online 8 May 2018
Source:Practical Radiation Oncology
Author(s): Jean L Wright, Arti Parekh, Byung-Han Rhieu, Valentina Opris, Annette Souranis, Amanda Choflet, Akila N Viswanathan, Theodore DeWeese, Todd McNutt, Stephanie A Terezakis
PurposeThe optimal approach to managing incident learning system (ILS) reports remains unclear. Here we describe our experience with prospective coding of events reported to the ILS, with comparisons of risk scores based on event type and process map location.Methods and MaterialsReported events were coded by type, origin, and method of discovery. Events were given Risk Priority Number (RPN) and a Near-Miss Risk Index (NMRI) score. We compared workflow versus near-miss events with respect to origin and detection in the process map and by risk scores. Chi square test was used to compare differences between workflow and near-miss events and comparison of RPN scores was done by independent t-test.ResultsDuring 2016, 1351 events were reported. 1300 (96.2%) were workflow and 51 (3.8%) near-miss. Workflow events were more likely to both originate in pre-treatment (1041/1300 , 81.2%), compared to near-miss (31/51, 62.7%, p=0.005), and to be detected pre-treatment (997/1300, 76.7%) compared to near-miss (24/51, 47%, p<0.001). Average occurrence (scale 1-10) was 6.14 for workflow vs 3.33 for near-miss events respectively (p<0.001); average severity was 2.94 vs 7.35 (p<0.001); average detectability was 1.33 vs 4.67 (p<0.001). Mean overall RPN was 22.4 for workflow vs 108.4 for near-miss events (p=0.07) and mean NMRI was 1.16 vs 3.19. Events originating and detected in treatment delivery had the greatest mean overall RPN (38.2 and 32.1) and NMRI scores (1.62 and 1.6).ConclusionsOur experience demonstrates that workflow event reports are far more common than near-misses, and that near-misses are more likely to both originate and be discovered in later treatment phases. The frequency of workflow reports highlights the imperative for safety and operational teams to work collaboratively to maximize the benefit of ILS. We suggest a potential utility of the RPN system to guide mitigation strategies for future near-miss events.



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Liver Re-irradiation for Patients With Hepatocellular Carcinoma and Liver Metastasis

Publication date: Available online 26 April 2018
Source:Practical Radiation Oncology
Author(s): Susan G.R. McDuff, Kyla A. Remillard, Hui Zheng, Ann C. Raldow, Jennifer Y. Wo, Christine E. Eyler, Lorraine C. Drapek, Lipika Goyal, Lawrence S. Blaszkowsky, Jeffrey W. Clark, Jill N. Allen, Aparna R. Parikh, David P. Ryan, Cristina R. Ferrone, Kenneth K. Tanabe, John A. Wolfgang, Andrew X. Zhu, Theodore S. Hong
PurposeTo assess the safety and efficacy of administering liver re-irradiation to patients with primary liver tumors or liver metastasis.Methods and Materials49 patients (with 64 individual tumors) who received liver re-irradiation at our institution between 6/2008 and 12/2016 were identified for retrospective review. Patients were treated to the same, different, or combination of previously treated liver tumors for recurrent primary (53%) or metastatic (47%) disease using photons or protons. Clinical and treatment-related factors were compiled, and patients were monitored for toxicity and evidence of "classic" or "non-classic" RILD. Survival was estimated via the Kaplan-Meier method, and cumulative incidence of local failure (LF) used to estimate LF (using RECIST 1.1).ResultsMedian age at re-irradiation was 72 years and median interval between radiation courses was 9 months. At a median follow-up of 10.5 months, 36 (73%) patients had died, 9 (18%) were alive, and 4 (8%) were lost to follow-up. Median survival for the cohort was 14 months. Overall one-year estimate of LF was 46.4%. One-year estimates of LF for liver metastases and HCC were 61.0% and 32.5%, respectively. Average prescription dose was similar between re-irradiation and initial courses (EQD2: 65.0 versus 64.3 Gyα/β=10, respectively), but average dose to the untreated liver was lower at re-irradiation (EQD2: 10.5 versus 13.9 Gyα/β=3, respectively, p = 0.01). Among hepatocellular carcinoma patients, the average normal liver dose was significantly larger for patients who exhibited a worsening of Child-Pugh score following re-irradiation compared to those who did not (1210 cGy versus 759 cGy, p = 0.04). 85.7% experienced grade 1-2 toxicity, 4.1% developed grade 3 toxicity, and only two patients met criteria for RILD (4.1%) following re-irradiation.ConclusionsLiver re-irradiation may be an effective and safe option for select patients, however further prospective study is necessary to establish treatment guidelines and recommended dosing.



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