Estimation of causal effect measures with the R -package stdReg

Abstract

Measures of causal effects play a central role in epidemiology. A wide range of measures exist, which are designed to give relevant answers to substantive epidemiological research questions. However, due to mathematical convenience and software limitations most studies only report odds ratios for binary outcomes and hazard ratios for time-to-event outcomes. In this paper we show how logistic regression models and Cox proportional hazards regression models can be used to estimate a wide range of causal effect measures, with the R-package stdReg. For illustration we focus on the attributable fraction, the number needed to treat and the relative excess risk due to interaction. We use two publicly available data sets, so that the reader can easily replicate and elaborate on the analyses. The first dataset includes information on 487 births among 188 women, and the second dataset includes information on 2982 women diagnosed with primary breast cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/2tTbY71
via IFTTT

Cisplatin suppresses proliferation, migration and invasion of nasopharyngeal carcinoma cells in vitro by repressing the Wnt/β-catenin/Endothelin-1 axis via activating B cell translocation gene 1

Abstract

Purpose

Nasopharyngeal carcinoma (NPC) is one of the most commonly diagnosed cancers worldwide with significantly high prevalence in Southern China. Chemoprevention of cancer with alkylating agent compounds could potentially reverse, suppress, or prevent cancer progression. Cisplatin (CIS) is an antineoplastic or cytotoxic platinum-based drug used for chemotherapy of different types of human cancers such as NPC. Nevertheless, the effects of CIS on the migration and invasion of human NPC cells and the underlying molecular mechanisms have not yet been fully scrutinized.

Methods

In this work, we tested the effect of CIS on the proliferation, migration and invasion of NPC cells. The results exhibited that this drug exerts remarkable inhibitory effects on the proliferation, migration and invasion of NPC cells in a dose-dependent manner. Western blotting and real time RT-PCR were used for expression analyses.

Results

We found that CIS treatment led to a dose-dependent inhibition of Endothelin-1 (ET1) expression, at protein as well as mRNA levels in NPC cells. CIS was also found to activate the expression of BTG1 in NPC cells. Moreover, mechanistic analyses revealed that CIS increased the expression of B cell translocation gene 1 (BTG1) to suppress the expression of ET1. Furthermore, we show that ET1 could not be induced in CIS-resistant cells with suppressed BTG1 expression, and subsequently demote the proliferation, migration and invasion of NPC cells.

Conclusions

These findings provided compelling evidence of the role of CIS in suppressing NPC metastasis and its underlying molecular mechanisms.

http://ift.tt/2pcTRTB

Cisplatin suppresses proliferation, migration and invasion of nasopharyngeal carcinoma cells in vitro by repressing the Wnt/β-catenin/Endothelin-1 axis via activating B cell translocation gene 1

Abstract

Purpose

Nasopharyngeal carcinoma (NPC) is one of the most commonly diagnosed cancers worldwide with significantly high prevalence in Southern China. Chemoprevention of cancer with alkylating agent compounds could potentially reverse, suppress, or prevent cancer progression. Cisplatin (CIS) is an antineoplastic or cytotoxic platinum-based drug used for chemotherapy of different types of human cancers such as NPC. Nevertheless, the effects of CIS on the migration and invasion of human NPC cells and the underlying molecular mechanisms have not yet been fully scrutinized.

Methods

In this work, we tested the effect of CIS on the proliferation, migration and invasion of NPC cells. The results exhibited that this drug exerts remarkable inhibitory effects on the proliferation, migration and invasion of NPC cells in a dose-dependent manner. Western blotting and real time RT-PCR were used for expression analyses.

Results

We found that CIS treatment led to a dose-dependent inhibition of Endothelin-1 (ET1) expression, at protein as well as mRNA levels in NPC cells. CIS was also found to activate the expression of BTG1 in NPC cells. Moreover, mechanistic analyses revealed that CIS increased the expression of B cell translocation gene 1 (BTG1) to suppress the expression of ET1. Furthermore, we show that ET1 could not be induced in CIS-resistant cells with suppressed BTG1 expression, and subsequently demote the proliferation, migration and invasion of NPC cells.

Conclusions

These findings provided compelling evidence of the role of CIS in suppressing NPC metastasis and its underlying molecular mechanisms.

from Cancer via ola Kala on Inoreader http://ift.tt/2pcTRTB
via IFTTT

HDR Salvage Brachytherapy: Multiple Hypothesis Testing vs Machine Learning Analysis

Publication date: Available online 13 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Gilmer Valdes, Albert J. Chang, Yannet Interian, Kenton Owen, Shane T. Jensen, Lyle H. Ungar, Adam Cunnan, Timothy D. Solberg, I-Chow Hsu

Teaser

Approximately only 50% of patients benefit from Salvage High Dose Rate Brachytherapy (sHDRB) with the majority of second recurrences occurring distantly. Therefore, a better patient selection before sHDRB is critical. Using Machine learning we found that patients with a Fraction of Positive Cores > 0.35 and a Disease Free Interval < 4.12 years after their initial radiation treatment experienced a higher failure rate after salvage HDRB of 0.75 vs 0.38 for the rest of the population.


from Cancer via ola Kala on Inoreader http://ift.tt/2tPYmJk
via IFTTT

Close margin <2mm is not associated with higher risks of 10-year local recurrence and breast cancer mortality compared to negative margins in women treated with breast-conserving therapy

Publication date: Available online 13 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Susan Tyler, Pauline T. Truong, Mary Lesperance, Alan Nichol, Chris Baliski, Rebecca Warburton, Scott Tyldesley
PurposeThe 2014 SS0/ASTRO consensus suggests "no ink on tumor" is a sufficient surgical margin for invasive breast cancer treated with breast conserving surgery (BCS). Whether close margin <2 mm is associated with inferior outcomes remains controversial. This study evaluates 10-year outcomes by margin status in a population-based cohort treated with BCS and adjuvant radiotherapy (RT).MethodsSubjects were 10,863 women with pT1-T3, any N, M0 invasive cancer referred from 2001-2011, an era in which the institutional policy was to re-excise close or positive margins, except in select cases. All women underwent BCS and whole breast ± boost RT. Local recurrence (LR) and breast cancer-specific survival (BCSS) were examined using competing risk analysis in cohorts with negative (≥2 mm; n=9241, 85%), close (<2 mm; n=1310, 12%), or positive (tumor touching ink; n=312, 3%) margins. Multivariable analysis (MVA) and matched-pair analysis were performed.ResultsMedian follow-up was 8 years. Systemic therapy was used in 87% of patients. Boost RT was used in 34.1%, 76.9% and 79.5% of patients with negative, close, and positive margins, respectively. In the negative, close, and positive margin cohorts, 10-year cumulative incidence of LR were 1.8%, 2.0%, and 1.1%, (p=0.759). Corresponding BCSS estimates were 93.9%, 91.8%, and 87.9%, (p<0.001). On MVA, close margins were not associated with increased LR (HR 1.25, 95% CI 0.79-1.97, p=0.350) or reduced BCSS (HR 1.25, 95% CI 0.98-1.58, p=0.071) relative to negative margins. On matched-pair analysis, close margin cases had similar LR (p=0.114) and BCSS (p=0.100) compared to negative margin controls.ConclusionSelect cases with close or positive margins in this population-based analysis had similar LR and BCSS compared to negative margins. While these findings do not endorse omitting re-excision for all cases, the data support a policy of accepting carefully selected cases with close margins for adjuvant radiation therapy without re-excision.



from Cancer via ola Kala on Inoreader http://ift.tt/2FzcLiK
via IFTTT

HDR Salvage Brachytherapy: Multiple Hypothesis Testing vs Machine Learning Analysis

Publication date: Available online 13 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Gilmer Valdes, Albert J. Chang, Yannet Interian, Kenton Owen, Shane T. Jensen, Lyle H. Ungar, Adam Cunnan, Timothy D. Solberg, I-Chow Hsu

Teaser

Approximately only 50% of patients benefit from Salvage High Dose Rate Brachytherapy (sHDRB) with the majority of second recurrences occurring distantly. Therefore, a better patient selection before sHDRB is critical. Using Machine learning we found that patients with a Fraction of Positive Cores > 0.35 and a Disease Free Interval < 4.12 years after their initial radiation treatment experienced a higher failure rate after salvage HDRB of 0.75 vs 0.38 for the rest of the population.


http://ift.tt/2tPYmJk

Close margin <2mm is not associated with higher risks of 10-year local recurrence and breast cancer mortality compared to negative margins in women treated with breast-conserving therapy

Publication date: Available online 13 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Susan Tyler, Pauline T. Truong, Mary Lesperance, Alan Nichol, Chris Baliski, Rebecca Warburton, Scott Tyldesley
PurposeThe 2014 SS0/ASTRO consensus suggests "no ink on tumor" is a sufficient surgical margin for invasive breast cancer treated with breast conserving surgery (BCS). Whether close margin <2 mm is associated with inferior outcomes remains controversial. This study evaluates 10-year outcomes by margin status in a population-based cohort treated with BCS and adjuvant radiotherapy (RT).MethodsSubjects were 10,863 women with pT1-T3, any N, M0 invasive cancer referred from 2001-2011, an era in which the institutional policy was to re-excise close or positive margins, except in select cases. All women underwent BCS and whole breast ± boost RT. Local recurrence (LR) and breast cancer-specific survival (BCSS) were examined using competing risk analysis in cohorts with negative (≥2 mm; n=9241, 85%), close (<2 mm; n=1310, 12%), or positive (tumor touching ink; n=312, 3%) margins. Multivariable analysis (MVA) and matched-pair analysis were performed.ResultsMedian follow-up was 8 years. Systemic therapy was used in 87% of patients. Boost RT was used in 34.1%, 76.9% and 79.5% of patients with negative, close, and positive margins, respectively. In the negative, close, and positive margin cohorts, 10-year cumulative incidence of LR were 1.8%, 2.0%, and 1.1%, (p=0.759). Corresponding BCSS estimates were 93.9%, 91.8%, and 87.9%, (p<0.001). On MVA, close margins were not associated with increased LR (HR 1.25, 95% CI 0.79-1.97, p=0.350) or reduced BCSS (HR 1.25, 95% CI 0.98-1.58, p=0.071) relative to negative margins. On matched-pair analysis, close margin cases had similar LR (p=0.114) and BCSS (p=0.100) compared to negative margin controls.ConclusionSelect cases with close or positive margins in this population-based analysis had similar LR and BCSS compared to negative margins. While these findings do not endorse omitting re-excision for all cases, the data support a policy of accepting carefully selected cases with close margins for adjuvant radiation therapy without re-excision.



http://ift.tt/2FzcLiK

Cisplatin suppresses proliferation, migration and invasion of nasopharyngeal carcinoma cells in vitro by repressing the Wnt/β-catenin/Endothelin-1 axis via activating B cell translocation gene 1

Abstract

Purpose

Nasopharyngeal carcinoma (NPC) is one of the most commonly diagnosed cancers worldwide with significantly high prevalence in Southern China. Chemoprevention of cancer with alkylating agent compounds could potentially reverse, suppress, or prevent cancer progression. Cisplatin (CIS) is an antineoplastic or cytotoxic platinum-based drug used for chemotherapy of different types of human cancers such as NPC. Nevertheless, the effects of CIS on the migration and invasion of human NPC cells and the underlying molecular mechanisms have not yet been fully scrutinized.

Methods

In this work, we tested the effect of CIS on the proliferation, migration and invasion of NPC cells. The results exhibited that this drug exerts remarkable inhibitory effects on the proliferation, migration and invasion of NPC cells in a dose-dependent manner. Western blotting and real time RT-PCR were used for expression analyses.

Results

We found that CIS treatment led to a dose-dependent inhibition of Endothelin-1 (ET1) expression, at protein as well as mRNA levels in NPC cells. CIS was also found to activate the expression of BTG1 in NPC cells. Moreover, mechanistic analyses revealed that CIS increased the expression of B cell translocation gene 1 (BTG1) to suppress the expression of ET1. Furthermore, we show that ET1 could not be induced in CIS-resistant cells with suppressed BTG1 expression, and subsequently demote the proliferation, migration and invasion of NPC cells.

Conclusions

These findings provided compelling evidence of the role of CIS in suppressing NPC metastasis and its underlying molecular mechanisms.

from Cancer via ola Kala on Inoreader http://ift.tt/2pcTRTB
via IFTTT

Estimation of causal effect measures with the R -package stdReg

Abstract

Measures of causal effects play a central role in epidemiology. A wide range of measures exist, which are designed to give relevant answers to substantive epidemiological research questions. However, due to mathematical convenience and software limitations most studies only report odds ratios for binary outcomes and hazard ratios for time-to-event outcomes. In this paper we show how logistic regression models and Cox proportional hazards regression models can be used to estimate a wide range of causal effect measures, with the R-package stdReg. For illustration we focus on the attributable fraction, the number needed to treat and the relative excess risk due to interaction. We use two publicly available data sets, so that the reader can easily replicate and elaborate on the analyses. The first dataset includes information on 487 births among 188 women, and the second dataset includes information on 2982 women diagnosed with primary breast cancer.

http://ift.tt/2tTbY71

Estimation of causal effect measures with the R -package stdReg

Abstract

Measures of causal effects play a central role in epidemiology. A wide range of measures exist, which are designed to give relevant answers to substantive epidemiological research questions. However, due to mathematical convenience and software limitations most studies only report odds ratios for binary outcomes and hazard ratios for time-to-event outcomes. In this paper we show how logistic regression models and Cox proportional hazards regression models can be used to estimate a wide range of causal effect measures, with the R-package stdReg. For illustration we focus on the attributable fraction, the number needed to treat and the relative excess risk due to interaction. We use two publicly available data sets, so that the reader can easily replicate and elaborate on the analyses. The first dataset includes information on 487 births among 188 women, and the second dataset includes information on 2982 women diagnosed with primary breast cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/2tTbY71
via IFTTT

Organoids May Point to Best Therapy [News in Brief]

Patient-specific 3D tumor models accurately predict treatment response in patients with gastrointestinal cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/2pg4TI6
via IFTTT

Exosome-based Detection of EGFR T790M in Plasma from Non-Small Cell Lung Cancer Patients

Purpose: About 60% of non-small cell lung cancer (NSCLC) patients develop resistance to targeted epidermal growth factor receptor (EGFR) inhibitor therapy through the EGFR T790M mutation. Patients with this mutation respond well to third generation tyrosine kinase inhibitors, but obtaining a tissue biopsy to confirm the mutation poses risks and is often not feasible. Liquid biopsies using circulating free tumor DNA (cfDNA) have emerged as a non-invasive option to detect the mutation, however sensitivity is low as many patients have too few detectable copies in circulation. Here we have developed and validated a novel test that overcomes the limited abundance of the mutation by simultaneously capturing and interrogating exosomal RNA/DNA and cfDNA (exoNA) in a single step followed by a sensitive allele specific qPCR. Experimental design: ExoNA was extracted from the plasma of NSCLC patients with biopsy-confirmed T790M-positive (N = 102) and T790M-negative (N = 108) samples. The T790M mutation status was determined using an analytically validated allele-specific qPCR assay in a CLIA laboratory. Results: Detection of the T790M mutation on exoNA achieved 92% sensitivity and 89% specificity using tumor biopsy results as gold standard. We also obtained high sensitivity (88%) in patients with intrathoracic disease (M0/M1a), for whom detection by liquid biopsy has been particularly challenging. Conclusions: The combination of exoRNA/DNA and cfDNA for T790M detection has higher sensitivity and specificity compared to historical cohorts using cfDNA alone. This could further help avoid unnecessary tumor biopsies for T790M mutation testing.

http://ift.tt/2tHNmhc

p95HER2 methionine 611 carboxy-terminal fragment is predictive of trastuzumab adjuvant treatment benefit in the FinHer trial

Purpose: Expression of p95HER2 (p95), a truncated form of the HER2 receptor, which lacks the trastuzumab binding site but retains kinase activity, has been reported as a prognostic biomarker for poor outcomes in trastuzumab-treated HER2-positive metastatic breast cancer. The impact of p95 expression on trastuzumab treatment efficacy in early HER2-positive breast cancer is less clear. In the current study, p95 was tested as a predictive marker of trastuzumab treatment benefit in the HER2-positive subset of the FinHer adjuvant phase III trial. Experimental Design: In the FinHer trial, 232 HER2-positive early breast cancer patients were randomized to receive chemotherapy plus 9-weeks of trastuzumab or no trastuzumab treatment. Quantitative p95 protein expression was measured in formalin-fixed paraffin-embedded samples using the p95 VeraTag® assay (Monogram Biosciences), specific for the M611 form of p95. Quantitative HER2 protein expression was measured using the HERmark® assay (Monogram Biosciences). Distant disease-free survival (DDFS) was used as the primary outcome measure. Results: In the arm receiving chemotherapy only, increasing log10(p95) correlated with shorter DDFS (HR=2.0; P=.02). In the arm receiving chemotherapy plus trastuzumab (N=95), increasing log10(p95) was not correlated with a shorter DDFS. In a combined analysis of both treatment arms, high breast tumor p95 content was significantly correlated with trastuzumab treatment benefit in multivariate models (interaction P=.01). Conclusions: p95 expression levels were prognostic in the chemotherapy-alone arm and predictive of trastuzumab treatment benefit in FinHer. These results warrant further investigation of p95 as a predictive marker of trastuzumab treatment benefit in the adjuvant setting.

http://ift.tt/2Go0niF

Endogenous replication stress marks melanomas sensitive to CHK1 inhibitors in vivo

Purpose: CHEK1 inhibitors (CHEK1i) have single agent activity in vitro and in vivo. Here we have investigated the molecular basis of this activity. Experimental Design: We have assessed a panel of melanoma cell lines for their sensitivity to the CHEK1i GNE-323 and GDC-0575 in vitro and in vivo. The effects of these compounds on responses to DNA replication stress were analyzed in the hypersensitive cell lines. Results: A subset of melanoma cell lines are hypersensitive to CHEK1i-induced cell death in vitro, and the drug effectively inhibits tumour growth in vivo. In the hypersensitive cell lines, GNE-323 triggers cell death without cells entering mitosis. CHEK1i treatment triggers strong RPA2 hyper-phosphorylation and increased DNA damage in only hypersensitive cells. The increased replication stress was associated with a defective S phase cell cycle checkpoint. The number and intensity of pRPA2 Ser4/8 foci in untreated tumours appeared to be a marker of elevated replication stress correlated with sensitivity to CHEK1i. Conclusions: CHEK1i have single-agent activity in a subset of melanomas with elevated endogenous replication stress. CHEK1i treatment strongly increased this replication stress and DNA damage, and this correlated to increased cell death. The level of endogenous replication is marked by the pRPA2Ser4/8 foci in the untreated tumours, and may be useful marker of replication stress in vivo. 

http://ift.tt/2tNVSvj

TFAP2E Methylation and Expression Status Does Not Predict Response to 5FU-based Chemotherapy in Colorectal Cancer

Purpose:A recent study reported that 5-fluorouracil (5FU)-based chemotherapy is less effective in treating advanced colorectal cancer (CRC) patients demonstrating hypermethylation of TFAP2E gene. The aim of our study was to confirm and validate these findings in large, uniformly treated, well-characterized patient cohorts. Experimental Design: Two cohorts of 783 CRC patients: 532 from a population-based, multicenter cohort (EPICOLON I) and 251 patients from a clinic-based trial were used to study the effectiveness of TFAP2E methylation and expression as a predictor of response of CRC patients to 5FU-based chemotherapy. DNA methylation status of the TFAP2E gene in CRC patients was assessed by quantitative bisulfite pyrosequencing analysis. IHC analysis of the TFAP2E protein expression was also performed. Results: Correlation between TFAP2E methylation status and IHC staining was performed in 607 CRC. Among 357 hypermethylated tumors, only 141 (39.6%) exhibited loss of protein expression. Survival was not affected by TFAP2E hypermethylation in stage IV patients (HR 1.21; 95% CI 0.79-1.87; log rank p 0.6). In stage II-III cases disease-free survival was not influenced by TFAP2E hypermethylation status in 5-FU treated (HR 0.91; 95% CI 0.52-1.59; log rank p 0.9) as well as in non-treated patients (HR 0.88; 95% CI 0.5-1.54; log rank p 0.7). Conclusions: TFAP2E hypermethylation does not correlate with loss of its protein expression. Our large, systematic and comprehensive study indicates that TFAP2E methylation and expression may not play a major role in predicting response to 5FU-based chemotherapy in CRC patients.

http://ift.tt/2FBbJTi

RIP1-HAT1-SirT complex identification and targeting in treatment and prevention of cancer

Purpose: Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis and necroptosis has been attributed to RIP1/3 complexes. Experimental design: We have investigated the role of RIP1 and the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis and in vivo studies with different mice models. Results: Here, we show that RIP1 is highly expressed in cancer and we define a novel RIP1/3-SIRT1/2-HAT1/4 complex. Mass Spectrometry identified 5 acetylations in the kinase and death domain of RIP1. The novel characterised pan-SirT inhibitor, MC2494, increases RIP1 acetylation at 2 additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death suggesting a role for acetylation of the RIP1 complex in cell death modulation. Accordingly, MC2494 displays tumour-selective potential in vitro, in leukemic blasts ex vivo, and in vivo in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumour-restricted acetylated RIP1/caspase-8-mediated apoptosis. Excitingly, MC2494 displays tumour-preventive activity by blocking DMBA-induced mammary gland hyper-proliferation in vivo. Conclusions: These preventive features might prove useful in patients who may benefit from a recurrence-preventive approach with low toxicity during follow-up phases and in cases of established cancer predisposition. Thus, targeting the newly identified RIP1 complex may represent an attractive novel paradigm in cancer treatment and prevention.

http://ift.tt/2tKCzmv

Report of the 14th International Conference on Malignant Lymphoma (ICML) closed workshop on future design of clinical trials in lymphomas.

The 14th ICML held in Lugano in June 2017 was preceded by a closed workshop (organized in collaboration with the American Association for Cancer Research and the European School of Oncology) where experts in preclinical and clinical research in lymphomas met to discuss the current drug development landscape focusing on critical open questions that need to be addressed in the future in order to permit a more efficient drug development paradigm in lymphoma. Topics discussed included both preclinical models that can be used to test new drugs and drug combinations, as well as the optimal design of clinical trials and the endpoints that should be used to facilitate accelerated progress. This report represents a summary of the workshop.

http://ift.tt/2GqgV9X

A Phase I Clinical Trial of AZD1775 in Combination With Neoadjuvant Weekly Docetaxel and Cisplatin Before Definitive Therapy in Head and Neck Squamous Cell Carcinoma

Purpose: The WEE1 tyrosine kinase regulates G2/M transition and maintains genomic stability, particularly in p53-deficient tumors which require DNA repair after genotoxic therapy. There is a need to exploit the role of WEE1 inhibition in head and neck squamous cell carcinoma (HNSCC) mostly driven by tumor-suppressor loss. This completed phase I clinical trial represents the first published clinical experience using the WEE1 inhibitor, AZD1775, with cisplatin and docetaxel. Experimental Design: We implemented an open-label phase I clinical trial using a 3+3 dose-escalation design for patients with Stage III/IVB HNSCC with borderline-resectable or unresectable disease, who were candidates for definitive chemoradiation. AZD1775 was administered orally twice a day over 2.5 days on the first week, then in combination with cisplatin (25mg/m 2) and docetaxel (35mg/m 2) for three weeks. The primary outcome measure was adverse events to establish maximum-tolerated-dose (MTD). Secondary measures included response, pharmacokinetics, pharmacodynamics, and genomic data. Results: The MTD for AZD1775 was established at 150mg orally twice per day for 2.5 days. RECISTv1.1 responses were seen in 5 of 10 patients; histological adjustment revealed 3 additional responders. The only drug-limiting toxicity was Grade-3 diarrhea. The PK C8hr target of 240nM was achieved on Day 4 at all three doses tested. Pharmacodynamic analysis revealed a reduction in pY15-Cdk and increases in gH2AX, CC3 and RPA32/RPA2 were noted in responders vs. non-responders. Conclusions:The triplet combination of AZD1775, cisplatin and docetaxel is safe and tolerable. Preliminary results show promising anti-tumor efficacy in advanced HNSCC, meriting further investigation at the recommended phase 2 dose.

http://ift.tt/2tNVDQV

Exosome-based Detection of EGFR T790M in Plasma from Non-Small Cell Lung Cancer Patients

Purpose: About 60% of non-small cell lung cancer (NSCLC) patients develop resistance to targeted epidermal growth factor receptor (EGFR) inhibitor therapy through the EGFR T790M mutation. Patients with this mutation respond well to third generation tyrosine kinase inhibitors, but obtaining a tissue biopsy to confirm the mutation poses risks and is often not feasible. Liquid biopsies using circulating free tumor DNA (cfDNA) have emerged as a non-invasive option to detect the mutation, however sensitivity is low as many patients have too few detectable copies in circulation. Here we have developed and validated a novel test that overcomes the limited abundance of the mutation by simultaneously capturing and interrogating exosomal RNA/DNA and cfDNA (exoNA) in a single step followed by a sensitive allele specific qPCR. Experimental design: ExoNA was extracted from the plasma of NSCLC patients with biopsy-confirmed T790M-positive (N = 102) and T790M-negative (N = 108) samples. The T790M mutation status was determined using an analytically validated allele-specific qPCR assay in a CLIA laboratory. Results: Detection of the T790M mutation on exoNA achieved 92% sensitivity and 89% specificity using tumor biopsy results as gold standard. We also obtained high sensitivity (88%) in patients with intrathoracic disease (M0/M1a), for whom detection by liquid biopsy has been particularly challenging. Conclusions: The combination of exoRNA/DNA and cfDNA for T790M detection has higher sensitivity and specificity compared to historical cohorts using cfDNA alone. This could further help avoid unnecessary tumor biopsies for T790M mutation testing.

from Cancer via ola Kala on Inoreader http://ift.tt/2tHNmhc
via IFTTT

Endogenous replication stress marks melanomas sensitive to CHK1 inhibitors in vivo

Purpose: CHEK1 inhibitors (CHEK1i) have single agent activity in vitro and in vivo. Here we have investigated the molecular basis of this activity. Experimental Design: We have assessed a panel of melanoma cell lines for their sensitivity to the CHEK1i GNE-323 and GDC-0575 in vitro and in vivo. The effects of these compounds on responses to DNA replication stress were analyzed in the hypersensitive cell lines. Results: A subset of melanoma cell lines are hypersensitive to CHEK1i-induced cell death in vitro, and the drug effectively inhibits tumour growth in vivo. In the hypersensitive cell lines, GNE-323 triggers cell death without cells entering mitosis. CHEK1i treatment triggers strong RPA2 hyper-phosphorylation and increased DNA damage in only hypersensitive cells. The increased replication stress was associated with a defective S phase cell cycle checkpoint. The number and intensity of pRPA2 Ser4/8 foci in untreated tumours appeared to be a marker of elevated replication stress correlated with sensitivity to CHEK1i. Conclusions: CHEK1i have single-agent activity in a subset of melanomas with elevated endogenous replication stress. CHEK1i treatment strongly increased this replication stress and DNA damage, and this correlated to increased cell death. The level of endogenous replication is marked by the pRPA2Ser4/8 foci in the untreated tumours, and may be useful marker of replication stress in vivo. 

from Cancer via ola Kala on Inoreader http://ift.tt/2tNVSvj
via IFTTT

p95HER2 methionine 611 carboxy-terminal fragment is predictive of trastuzumab adjuvant treatment benefit in the FinHer trial

Purpose: Expression of p95HER2 (p95), a truncated form of the HER2 receptor, which lacks the trastuzumab binding site but retains kinase activity, has been reported as a prognostic biomarker for poor outcomes in trastuzumab-treated HER2-positive metastatic breast cancer. The impact of p95 expression on trastuzumab treatment efficacy in early HER2-positive breast cancer is less clear. In the current study, p95 was tested as a predictive marker of trastuzumab treatment benefit in the HER2-positive subset of the FinHer adjuvant phase III trial. Experimental Design: In the FinHer trial, 232 HER2-positive early breast cancer patients were randomized to receive chemotherapy plus 9-weeks of trastuzumab or no trastuzumab treatment. Quantitative p95 protein expression was measured in formalin-fixed paraffin-embedded samples using the p95 VeraTag® assay (Monogram Biosciences), specific for the M611 form of p95. Quantitative HER2 protein expression was measured using the HERmark® assay (Monogram Biosciences). Distant disease-free survival (DDFS) was used as the primary outcome measure. Results: In the arm receiving chemotherapy only, increasing log10(p95) correlated with shorter DDFS (HR=2.0; P=.02). In the arm receiving chemotherapy plus trastuzumab (N=95), increasing log10(p95) was not correlated with a shorter DDFS. In a combined analysis of both treatment arms, high breast tumor p95 content was significantly correlated with trastuzumab treatment benefit in multivariate models (interaction P=.01). Conclusions: p95 expression levels were prognostic in the chemotherapy-alone arm and predictive of trastuzumab treatment benefit in FinHer. These results warrant further investigation of p95 as a predictive marker of trastuzumab treatment benefit in the adjuvant setting.

from Cancer via ola Kala on Inoreader http://ift.tt/2Go0niF
via IFTTT

TFAP2E Methylation and Expression Status Does Not Predict Response to 5FU-based Chemotherapy in Colorectal Cancer

Purpose:A recent study reported that 5-fluorouracil (5FU)-based chemotherapy is less effective in treating advanced colorectal cancer (CRC) patients demonstrating hypermethylation of TFAP2E gene. The aim of our study was to confirm and validate these findings in large, uniformly treated, well-characterized patient cohorts. Experimental Design: Two cohorts of 783 CRC patients: 532 from a population-based, multicenter cohort (EPICOLON I) and 251 patients from a clinic-based trial were used to study the effectiveness of TFAP2E methylation and expression as a predictor of response of CRC patients to 5FU-based chemotherapy. DNA methylation status of the TFAP2E gene in CRC patients was assessed by quantitative bisulfite pyrosequencing analysis. IHC analysis of the TFAP2E protein expression was also performed. Results: Correlation between TFAP2E methylation status and IHC staining was performed in 607 CRC. Among 357 hypermethylated tumors, only 141 (39.6%) exhibited loss of protein expression. Survival was not affected by TFAP2E hypermethylation in stage IV patients (HR 1.21; 95% CI 0.79-1.87; log rank p 0.6). In stage II-III cases disease-free survival was not influenced by TFAP2E hypermethylation status in 5-FU treated (HR 0.91; 95% CI 0.52-1.59; log rank p 0.9) as well as in non-treated patients (HR 0.88; 95% CI 0.5-1.54; log rank p 0.7). Conclusions: TFAP2E hypermethylation does not correlate with loss of its protein expression. Our large, systematic and comprehensive study indicates that TFAP2E methylation and expression may not play a major role in predicting response to 5FU-based chemotherapy in CRC patients.

from Cancer via ola Kala on Inoreader http://ift.tt/2FBbJTi
via IFTTT

RIP1-HAT1-SirT complex identification and targeting in treatment and prevention of cancer

Purpose: Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis and necroptosis has been attributed to RIP1/3 complexes. Experimental design: We have investigated the role of RIP1 and the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis and in vivo studies with different mice models. Results: Here, we show that RIP1 is highly expressed in cancer and we define a novel RIP1/3-SIRT1/2-HAT1/4 complex. Mass Spectrometry identified 5 acetylations in the kinase and death domain of RIP1. The novel characterised pan-SirT inhibitor, MC2494, increases RIP1 acetylation at 2 additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death suggesting a role for acetylation of the RIP1 complex in cell death modulation. Accordingly, MC2494 displays tumour-selective potential in vitro, in leukemic blasts ex vivo, and in vivo in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumour-restricted acetylated RIP1/caspase-8-mediated apoptosis. Excitingly, MC2494 displays tumour-preventive activity by blocking DMBA-induced mammary gland hyper-proliferation in vivo. Conclusions: These preventive features might prove useful in patients who may benefit from a recurrence-preventive approach with low toxicity during follow-up phases and in cases of established cancer predisposition. Thus, targeting the newly identified RIP1 complex may represent an attractive novel paradigm in cancer treatment and prevention.

from Cancer via ola Kala on Inoreader http://ift.tt/2tKCzmv
via IFTTT

Report of the 14th International Conference on Malignant Lymphoma (ICML) closed workshop on future design of clinical trials in lymphomas.

The 14th ICML held in Lugano in June 2017 was preceded by a closed workshop (organized in collaboration with the American Association for Cancer Research and the European School of Oncology) where experts in preclinical and clinical research in lymphomas met to discuss the current drug development landscape focusing on critical open questions that need to be addressed in the future in order to permit a more efficient drug development paradigm in lymphoma. Topics discussed included both preclinical models that can be used to test new drugs and drug combinations, as well as the optimal design of clinical trials and the endpoints that should be used to facilitate accelerated progress. This report represents a summary of the workshop.

from Cancer via ola Kala on Inoreader http://ift.tt/2GqgV9X
via IFTTT

A Phase I Clinical Trial of AZD1775 in Combination With Neoadjuvant Weekly Docetaxel and Cisplatin Before Definitive Therapy in Head and Neck Squamous Cell Carcinoma

Purpose: The WEE1 tyrosine kinase regulates G2/M transition and maintains genomic stability, particularly in p53-deficient tumors which require DNA repair after genotoxic therapy. There is a need to exploit the role of WEE1 inhibition in head and neck squamous cell carcinoma (HNSCC) mostly driven by tumor-suppressor loss. This completed phase I clinical trial represents the first published clinical experience using the WEE1 inhibitor, AZD1775, with cisplatin and docetaxel. Experimental Design: We implemented an open-label phase I clinical trial using a 3+3 dose-escalation design for patients with Stage III/IVB HNSCC with borderline-resectable or unresectable disease, who were candidates for definitive chemoradiation. AZD1775 was administered orally twice a day over 2.5 days on the first week, then in combination with cisplatin (25mg/m 2) and docetaxel (35mg/m 2) for three weeks. The primary outcome measure was adverse events to establish maximum-tolerated-dose (MTD). Secondary measures included response, pharmacokinetics, pharmacodynamics, and genomic data. Results: The MTD for AZD1775 was established at 150mg orally twice per day for 2.5 days. RECISTv1.1 responses were seen in 5 of 10 patients; histological adjustment revealed 3 additional responders. The only drug-limiting toxicity was Grade-3 diarrhea. The PK C8hr target of 240nM was achieved on Day 4 at all three doses tested. Pharmacodynamic analysis revealed a reduction in pY15-Cdk and increases in gH2AX, CC3 and RPA32/RPA2 were noted in responders vs. non-responders. Conclusions:The triplet combination of AZD1775, cisplatin and docetaxel is safe and tolerable. Preliminary results show promising anti-tumor efficacy in advanced HNSCC, meriting further investigation at the recommended phase 2 dose.

from Cancer via ola Kala on Inoreader http://ift.tt/2tNVDQV
via IFTTT

Organelle-derived acetyl-CoA promotes prostate cancer cell survival, migration, and metastasis via activation of calmodulin kinase II

Although emerging evidence suggests a potential role of calcium/calmodulin-dependent kinase II (CaMKII) in prostate cancer (PCa), its role in PCa tumorigenesis is largely unknown. Here we examine whether the acetyl CoA-CaMKII pathway, first described in frog oocytes, promotes PCa tumorigenesis. In human PCa specimens, metastatic PCa expressed higher levels of active CaMKII compared to localized PCa. Correspondingly, basal CaMKII activity was significantly higher in the more tumorigenic PC3 and PC3-mm2 cells relative to the less tumorigenic LNCaP and C4-2B4 cells. Deletion of CaMKII by CRISPR/Cas9 in PC3-mm2 cells abrogated cell survival under low-serum conditions, anchorage-independent growth and cell migration; overexpression of constitutively active CaMKII in C4-2B4 cells promoted these phenotypes. In an animal model of PCa metastasis, genetic ablation of CaMKII reduced PC3-mm2 cell metastasis from the prostate to the lymph nodes. Knockdown of the acetyl-CoA transporter carnitine acetyltransferase (CRAT) abolished CaMKII activation, providing evidence that acetyl-CoA generated from organelles is a major activator of CaMKII. Genetic deletion of the β-oxidation rate-limiting enzyme ACOX family proteins decreased CaMKII activation, while overexpression of ACOXI increased CaMKII activation. Overall, our studies identify active CaMKII as a novel connection between organelle β-oxidation and acetyl-CoA transport with cell survival, migration, and PCa metastasis.

from Cancer via ola Kala on Inoreader http://ift.tt/2tJIGrb
via IFTTT

Inhibin is a novel paracrine factor for tumor angiogenesis and metastasis

Inhibin is a heterodimeric TGF-β family ligand that is expressed in many cancers and is a selective biomarker for ovarian cancers, however its tumor-specific functions remain unknown. Here we demonstrate that the α subunit of Inhibin (INHA), which is critical for the functionality of dimeric Inhibin A/B, correlates with microvessel density (MVD) in human ovarian tissues and xenografts and is predictive of poor clinical outcomes in multiple cancers. We demonstrate that Inhibin regulated angiogenesis is necessary for metastasis. While Inhibin had no direct impact on tumor cell signaling, both tumor cell-derived and recombinant Inhibin elicit a strong paracrine response from endothelial cells by triggering SMAD1/5 activation and angiogenesis in vitro and in vivo. Inhibin-induced angiogenesis was abrogated via anti-Inhibinα antibodies. The endothelial-specific TGF-β receptor complex comprising ALK1 and endoglin were crucial mediators of Inhibin signaling, offering a molecular mechanism for Inhibin-mediated angiogenesis. These results are the first to define a role for Inhibin in tumor metastasis and vascularization and offer an antibody-based approach for targeting Inhibin therapeutically

from Cancer via ola Kala on Inoreader http://ift.tt/2GnYXER
via IFTTT

Visualization of breast cancer metabolism using multimodal non-linear optical microscopy of cellular lipids and redox state

Label-free non-linear optical microscopy (NLOM) based on two-photon excited fluorescence (TPEF) from cofactors Nicotinamide Adenine Dinucleotide (NADH) and Flavin Adenine Dinucleotide (FAD+) is widely used for high-resolution cellular redox imaging. In this work, we combined three, label-free NLOM imaging methods to quantitatively characterize breast cancer cells and their relative invasive potential: 1) TPEF optical redox ratio (ORR = FAD+/NADH + FAD+), 2) coherent Raman scattering (CRS) of cellular lipids, and 3) second harmonic generation (SHG) of extracellular matrix (ECM) collagen. 3D spheroid models of primary mammary epithelial cells (PME) and breast cancer cell lines (T47D and MDA-MB-231) were characterized based on their unique ORR and lipid volume fraction signatures. Treatment with 17β-estradiol (E2) increased glycolysis in both PME and T47D ER+ breast cancer cells. However, PME cells displayed increased lipid content with no ECM effect, while T47D cells had decreased lipid storage (p<0.001) and significant reorganization of collagen. By measuring deuterated lipids synthesized from exogenously administered deuterium-labeled glucose, treatment of T47D cells with E2 increased both lipid synthesis and consumption rates. These results confirm that glucose is a significant source for the cellular synthesis of lipid in glycolytic breast cancer cells and that the combination of cellular redox and lipid fraction imaging endpoints is a powerful approach with new and complementary information content.

from Cancer via ola Kala on Inoreader http://ift.tt/2tMt85V
via IFTTT

Visualization of breast cancer metabolism using multimodal non-linear optical microscopy of cellular lipids and redox state

Label-free non-linear optical microscopy (NLOM) based on two-photon excited fluorescence (TPEF) from cofactors Nicotinamide Adenine Dinucleotide (NADH) and Flavin Adenine Dinucleotide (FAD+) is widely used for high-resolution cellular redox imaging. In this work, we combined three, label-free NLOM imaging methods to quantitatively characterize breast cancer cells and their relative invasive potential: 1) TPEF optical redox ratio (ORR = FAD+/NADH + FAD+), 2) coherent Raman scattering (CRS) of cellular lipids, and 3) second harmonic generation (SHG) of extracellular matrix (ECM) collagen. 3D spheroid models of primary mammary epithelial cells (PME) and breast cancer cell lines (T47D and MDA-MB-231) were characterized based on their unique ORR and lipid volume fraction signatures. Treatment with 17β-estradiol (E2) increased glycolysis in both PME and T47D ER+ breast cancer cells. However, PME cells displayed increased lipid content with no ECM effect, while T47D cells had decreased lipid storage (p<0.001) and significant reorganization of collagen. By measuring deuterated lipids synthesized from exogenously administered deuterium-labeled glucose, treatment of T47D cells with E2 increased both lipid synthesis and consumption rates. These results confirm that glucose is a significant source for the cellular synthesis of lipid in glycolytic breast cancer cells and that the combination of cellular redox and lipid fraction imaging endpoints is a powerful approach with new and complementary information content.

http://ift.tt/2tMt85V

Organelle-derived acetyl-CoA promotes prostate cancer cell survival, migration, and metastasis via activation of calmodulin kinase II

Although emerging evidence suggests a potential role of calcium/calmodulin-dependent kinase II (CaMKII) in prostate cancer (PCa), its role in PCa tumorigenesis is largely unknown. Here we examine whether the acetyl CoA-CaMKII pathway, first described in frog oocytes, promotes PCa tumorigenesis. In human PCa specimens, metastatic PCa expressed higher levels of active CaMKII compared to localized PCa. Correspondingly, basal CaMKII activity was significantly higher in the more tumorigenic PC3 and PC3-mm2 cells relative to the less tumorigenic LNCaP and C4-2B4 cells. Deletion of CaMKII by CRISPR/Cas9 in PC3-mm2 cells abrogated cell survival under low-serum conditions, anchorage-independent growth and cell migration; overexpression of constitutively active CaMKII in C4-2B4 cells promoted these phenotypes. In an animal model of PCa metastasis, genetic ablation of CaMKII reduced PC3-mm2 cell metastasis from the prostate to the lymph nodes. Knockdown of the acetyl-CoA transporter carnitine acetyltransferase (CRAT) abolished CaMKII activation, providing evidence that acetyl-CoA generated from organelles is a major activator of CaMKII. Genetic deletion of the β-oxidation rate-limiting enzyme ACOX family proteins decreased CaMKII activation, while overexpression of ACOXI increased CaMKII activation. Overall, our studies identify active CaMKII as a novel connection between organelle β-oxidation and acetyl-CoA transport with cell survival, migration, and PCa metastasis.

http://ift.tt/2tJIGrb

Inhibin is a novel paracrine factor for tumor angiogenesis and metastasis

Inhibin is a heterodimeric TGF-β family ligand that is expressed in many cancers and is a selective biomarker for ovarian cancers, however its tumor-specific functions remain unknown. Here we demonstrate that the α subunit of Inhibin (INHA), which is critical for the functionality of dimeric Inhibin A/B, correlates with microvessel density (MVD) in human ovarian tissues and xenografts and is predictive of poor clinical outcomes in multiple cancers. We demonstrate that Inhibin regulated angiogenesis is necessary for metastasis. While Inhibin had no direct impact on tumor cell signaling, both tumor cell-derived and recombinant Inhibin elicit a strong paracrine response from endothelial cells by triggering SMAD1/5 activation and angiogenesis in vitro and in vivo. Inhibin-induced angiogenesis was abrogated via anti-Inhibinα antibodies. The endothelial-specific TGF-β receptor complex comprising ALK1 and endoglin were crucial mediators of Inhibin signaling, offering a molecular mechanism for Inhibin-mediated angiogenesis. These results are the first to define a role for Inhibin in tumor metastasis and vascularization and offer an antibody-based approach for targeting Inhibin therapeutically

http://ift.tt/2GnYXER

Clinical predictors of bevacizumab-associated intestinal perforation in non-small cell lung cancer

Summary

Background Bevacizumab (Bev) is generally well-tolerated, and Bev-associated intestinal perforation (BAP) is a rare albeit serious side effect in cases of non-small cell lung cancer (NSCLC). Therefore, the present study aimed to identify clinical predictors of BAP to help predict and manage the development of life-threatening intestinal complications among patients receiving Bev. Methods This retrospective study evaluated demographic, clinical, and treatment factors for patients with NSCLC who were treated with Bev between February 2010 and August 2015 at our center. Results We identified 314 regimens (208 patients; median age: 65 years; 115 women) for analysis, which included 119 first-line regimens, 74 s-line regimens, and 121 third-line or later regimens. BAP occurred in 7 cases (2.23% among all regimens and 3.37% among all patients), which generally occurred during first- or second-line treatment and was caused by ulcerative colitis (1 case), colon diverticulitis (1 case), and idiopathic perforations (5 cases). Univariate analyses revealed that BAP was significantly associated with deteriorating PS during the first cycle of chemotherapy (odd ratio [OR]: 11.07, 95% confidence interval [CI]: 2.37–51.63, p = 0.0022), grade ≥ 3 diarrhea (OR: 11.37, 95% CI: 2.37–54.50, p = 0.0024), febrile neutropenia (OR: 9.16, 95% CI: 1.98–42.49, p = 0.0047), and stomatitis (OR: 4.60, 95% CI: 1.01–21.04, p = 0.0492). Conclusions Among patients with NSCLC, BAP was associated with deteriorating PS during the first cycle of chemotherapy, grade ≥ 3 diarrhea, febrile neutropenia, and stomatitis. Therefore, careful observation is needed for patients with NSCLC who receive Bev in any line of treatment, especially if they develop serious side effects that affect their PS or mucous membrane.

http://ift.tt/2Gqn6uB

Clinical predictors of bevacizumab-associated intestinal perforation in non-small cell lung cancer

Summary

Background Bevacizumab (Bev) is generally well-tolerated, and Bev-associated intestinal perforation (BAP) is a rare albeit serious side effect in cases of non-small cell lung cancer (NSCLC). Therefore, the present study aimed to identify clinical predictors of BAP to help predict and manage the development of life-threatening intestinal complications among patients receiving Bev. Methods This retrospective study evaluated demographic, clinical, and treatment factors for patients with NSCLC who were treated with Bev between February 2010 and August 2015 at our center. Results We identified 314 regimens (208 patients; median age: 65 years; 115 women) for analysis, which included 119 first-line regimens, 74 s-line regimens, and 121 third-line or later regimens. BAP occurred in 7 cases (2.23% among all regimens and 3.37% among all patients), which generally occurred during first- or second-line treatment and was caused by ulcerative colitis (1 case), colon diverticulitis (1 case), and idiopathic perforations (5 cases). Univariate analyses revealed that BAP was significantly associated with deteriorating PS during the first cycle of chemotherapy (odd ratio [OR]: 11.07, 95% confidence interval [CI]: 2.37–51.63, p = 0.0022), grade ≥ 3 diarrhea (OR: 11.37, 95% CI: 2.37–54.50, p = 0.0024), febrile neutropenia (OR: 9.16, 95% CI: 1.98–42.49, p = 0.0047), and stomatitis (OR: 4.60, 95% CI: 1.01–21.04, p = 0.0492). Conclusions Among patients with NSCLC, BAP was associated with deteriorating PS during the first cycle of chemotherapy, grade ≥ 3 diarrhea, febrile neutropenia, and stomatitis. Therefore, careful observation is needed for patients with NSCLC who receive Bev in any line of treatment, especially if they develop serious side effects that affect their PS or mucous membrane.

from Cancer via ola Kala on Inoreader http://ift.tt/2Gqn6uB
via IFTTT

Doing the right thing: Quality in radiotherapy, a European perspective

"You must never be fearful about what you are doing when it is right!"Marie Curie

http://ift.tt/2tKGzn4

Cancer Trials Ireland (ICORG) 06-34: A multi-centre clinical trial using three-dimensional conformal radiation therapy to reduce the toxicity of palliative radiation for lung cancer

Cancer Trials Ireland (ICORG) 06-34: A multi-centre clinical trial using three-dimensional conformal radiation therapy to reduce the toxicity of palliative radiation for lung cancer. NCT01176487.

http://ift.tt/2GpgxIt

Influence of inhomogeneous radiosensitivity distributions and intrafractional organ movement on the tumour control probability of focused IMRT in prostate cancer

To evaluate the influence of radioresistance and intrafractional movement on the tumour control probability (TCP) in IMRT prostate treatments using simultaneous integrated boosts to PSMA-PET/CT-delineated GTVs.

http://ift.tt/2tJSTno

The EPTN consensus-based atlas for CT- and MR-based contouring in neuro-oncology

To create a digital, online atlas for organs at risk (OAR) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging.

http://ift.tt/2Gpgw7n

A prospective cohort study of hepatic toxicity after stereotactic body radiation therapy for hepatocellular carcinoma

To build and validate multivariate normal tissue complication probability (NTCP) models for radiation-induced hepatic toxicity (RIHT) after stereotactic body radiation therapy (SBRT).

http://ift.tt/2tKGvDQ

Impact of database quality in knowledge-based treatment planning for prostate cancer

Publication date: Available online 13 March 2018
Source:Practical Radiation Oncology
Author(s): Phillip D.H. Wall, Robert L. Carver, Jonas D. Fontenot
PurposeInvestigate dose-volume prediction improvements in a common knowledge-based planning (KBP) method using a Pareto plan database compared to using a conventional, clinical plan database.MethodsTwo plan databases were created using retrospective, anonymized data of 124 VMAT prostate cancer patients. The clinical plan database (CPD) contained planning data from each patient's clinically-treated VMAT plan, which were manually optimized by various planners. The multi-criteria optimization database (MCOD) contained Pareto-optimal plan data from VMAT plans created using a standardized multi-criteria optimization protocol. Overlap volume histograms, incorporating fractional OAR volumes only within the treatment fields, were computed for each patient and used to match new patient anatomy to similar database patients. For each database patient, CPD and MCOD KBP predictions were generated for D10, D30, D50, D65, and D80 of the bladder and rectum in a leave-one-out manner. Prediction achievability was evaluated through a re-planning study on a subset of 31 randomly selected database patients using the best KBP predictions, regardless of plan database origin, as planning goals.ResultsMCOD predictions were significantly lower than CPD predictions for all five bladder dose-volumes and rectum D50 (p=0.004) and D65 (p<0.001), while CPD predictions for rectum D10 (p=0.005) and D30 (p<0.001) were significantly less than MCOD predictions. KBP predictions were statistically achievable in the re-plans for all predicted dose-volumes, excluding D10 of bladder (p=0.03) and rectum (p=0.04). Compared to clinical plans, re-plans showed significant average reductions in Dmean for bladder (7.8Gy; p<0.001) and rectum (9.4Gy; p<0.001), while maintaining statistically similar PTV, femoral head, and penile bulb dose.ConclusionKBP dose-volume predictions derived from Pareto plans were more optimal overall than those resulting from manually optimized clinical plans, which significantly improved KBP-assisted plan quality.



from Cancer via ola Kala on Inoreader http://ift.tt/2FOdYlA
via IFTTT

Impact of database quality in knowledge-based treatment planning for prostate cancer

Publication date: Available online 13 March 2018
Source:Practical Radiation Oncology
Author(s): Phillip D.H. Wall, Robert L. Carver, Jonas D. Fontenot
PurposeInvestigate dose-volume prediction improvements in a common knowledge-based planning (KBP) method using a Pareto plan database compared to using a conventional, clinical plan database.MethodsTwo plan databases were created using retrospective, anonymized data of 124 VMAT prostate cancer patients. The clinical plan database (CPD) contained planning data from each patient's clinically-treated VMAT plan, which were manually optimized by various planners. The multi-criteria optimization database (MCOD) contained Pareto-optimal plan data from VMAT plans created using a standardized multi-criteria optimization protocol. Overlap volume histograms, incorporating fractional OAR volumes only within the treatment fields, were computed for each patient and used to match new patient anatomy to similar database patients. For each database patient, CPD and MCOD KBP predictions were generated for D10, D30, D50, D65, and D80 of the bladder and rectum in a leave-one-out manner. Prediction achievability was evaluated through a re-planning study on a subset of 31 randomly selected database patients using the best KBP predictions, regardless of plan database origin, as planning goals.ResultsMCOD predictions were significantly lower than CPD predictions for all five bladder dose-volumes and rectum D50 (p=0.004) and D65 (p<0.001), while CPD predictions for rectum D10 (p=0.005) and D30 (p<0.001) were significantly less than MCOD predictions. KBP predictions were statistically achievable in the re-plans for all predicted dose-volumes, excluding D10 of bladder (p=0.03) and rectum (p=0.04). Compared to clinical plans, re-plans showed significant average reductions in Dmean for bladder (7.8Gy; p<0.001) and rectum (9.4Gy; p<0.001), while maintaining statistically similar PTV, femoral head, and penile bulb dose.ConclusionKBP dose-volume predictions derived from Pareto plans were more optimal overall than those resulting from manually optimized clinical plans, which significantly improved KBP-assisted plan quality.



http://ift.tt/2FOdYlA

Blood Epstein–Barr virus DNA does not predict outcome in advanced HIV-associated Hodgkin lymphoma

Abstract

In HIV-seronegative patients with advanced Hodgkin lymphoma (HL), Epstein–Barr virus (EBV) viraemia at diagnosis predicts a worse progression-free survival (PFS), independent of the International Prognostic Score. However, its role in HIV-associated HL is uncharacterised. We collected clinico-pathologic and treatment data from a prospective series of 44 HIV-associated HLs from 2000 to 2016. We evaluated circulating EBV DNA as a prognostic factor on uni- and multivariable analyses in relationship to the International Prognostic Index criteria. In 44 patients with HIV-associated HL, EBV was detected by in situ hybridisation in all diagnostic biopsies. Blood EBV DNA was detectable in 26 patients (59%) with a median of 600 copies/mL (range 0–161,000). EBV DNA was independent of CD4 cell count (p = 0.9) or HIV viral load (p = 0.6) and did not predict PFS (HR 1.6, 95% CI 0.39–6.7, p = 0.49). EBV DNA is not a prognostic trait in HIV-associated HL. Prognostication in HIV-associated HL should be solely based on the International Prognostic Index criteria.

http://ift.tt/2FAWPg4

Blood Epstein–Barr virus DNA does not predict outcome in advanced HIV-associated Hodgkin lymphoma

Abstract

In HIV-seronegative patients with advanced Hodgkin lymphoma (HL), Epstein–Barr virus (EBV) viraemia at diagnosis predicts a worse progression-free survival (PFS), independent of the International Prognostic Score. However, its role in HIV-associated HL is uncharacterised. We collected clinico-pathologic and treatment data from a prospective series of 44 HIV-associated HLs from 2000 to 2016. We evaluated circulating EBV DNA as a prognostic factor on uni- and multivariable analyses in relationship to the International Prognostic Index criteria. In 44 patients with HIV-associated HL, EBV was detected by in situ hybridisation in all diagnostic biopsies. Blood EBV DNA was detectable in 26 patients (59%) with a median of 600 copies/mL (range 0–161,000). EBV DNA was independent of CD4 cell count (p = 0.9) or HIV viral load (p = 0.6) and did not predict PFS (HR 1.6, 95% CI 0.39–6.7, p = 0.49). EBV DNA is not a prognostic trait in HIV-associated HL. Prognostication in HIV-associated HL should be solely based on the International Prognostic Index criteria.

from Cancer via ola Kala on Inoreader http://ift.tt/2FAWPg4
via IFTTT

Clinicopathological and prognostic features of Epstein-Barr virus infection, microsatellite instability, and PD-L1 expression in gastric cancer

Background and Objectives

Gastric cancer (GC) has recently been categorized in molecular subtypes, which include Epstein-Barr (EBV)-positive and microsatellite instability (MSI) tumors. This distinction may provide prognostic information and identifies therapeutic targets. The aim of this study was to evaluate EBV, MSI, and PD-L1 immunoexpression in GC and its relationship with clinicopathological characteristics and patient's prognosis.

Methods

We evaluated 287 GC patients who underwent D2-gastrectomy through immunohistochemistry for DNA mismatch repair proteins and PD-L1, and in situ hybridization for EBV detection utilizing tissue microarray.

Results

EBV-positive and MSI were identified in 10.5% and 27% of the GCs, respectively. EBV positivity was associated to male gender (P = 0.032), proximal location (P < 0.001), undetermined Lauren type (P < 0.001), poorly differentiated histology (P = 0.043) and severe inflammatory infiltrate (P < 0.001). MSI-tumors were associated to older age (P = 0.002), subtotal gastrectomy (P = 0.004), pN0 (P = 0.024) and earlier TNM stage (P = 0.020). PD-L1-positive was seen in 8.8% of cases, with predominant expression in EBV-positive GC (P < 0.001). MSI was associated to better survival outcomes.

Conclusion

EBV-positive GCs had increased PD-L1 expression, while MSI GC had better survival outcome. EBV and MSI subgroups are distinct GC entities, their recognition is feasible by conventional techniques, and it may help individualize follow-up and guide adjuvant therapy.

from Cancer via ola Kala on Inoreader http://ift.tt/2InfYQb
via IFTTT

Editorial Board

Publication date: April 2018
Source:Critical Reviews in Oncology/Hematology, Volume 124





from Cancer via ola Kala on Inoreader http://ift.tt/2pbTusr
via IFTTT

Clinicopathological and prognostic features of Epstein-Barr virus infection, microsatellite instability, and PD-L1 expression in gastric cancer

Background and Objectives

Gastric cancer (GC) has recently been categorized in molecular subtypes, which include Epstein-Barr (EBV)-positive and microsatellite instability (MSI) tumors. This distinction may provide prognostic information and identifies therapeutic targets. The aim of this study was to evaluate EBV, MSI, and PD-L1 immunoexpression in GC and its relationship with clinicopathological characteristics and patient's prognosis.

Methods

We evaluated 287 GC patients who underwent D2-gastrectomy through immunohistochemistry for DNA mismatch repair proteins and PD-L1, and in situ hybridization for EBV detection utilizing tissue microarray.

Results

EBV-positive and MSI were identified in 10.5% and 27% of the GCs, respectively. EBV positivity was associated to male gender (P = 0.032), proximal location (P < 0.001), undetermined Lauren type (P < 0.001), poorly differentiated histology (P = 0.043) and severe inflammatory infiltrate (P < 0.001). MSI-tumors were associated to older age (P = 0.002), subtotal gastrectomy (P = 0.004), pN0 (P = 0.024) and earlier TNM stage (P = 0.020). PD-L1-positive was seen in 8.8% of cases, with predominant expression in EBV-positive GC (P < 0.001). MSI was associated to better survival outcomes.

Conclusion

EBV-positive GCs had increased PD-L1 expression, while MSI GC had better survival outcome. EBV and MSI subgroups are distinct GC entities, their recognition is feasible by conventional techniques, and it may help individualize follow-up and guide adjuvant therapy.

http://ift.tt/2InfYQb

Editorial Board

Publication date: April 2018
Source:Critical Reviews in Oncology/Hematology, Volume 124





http://ift.tt/2pbTusr

Clinicopathological and prognostic features of Epstein-Barr virus infection, microsatellite instability, and PD-L1 expression in gastric cancer

Background and Objectives

Gastric cancer (GC) has recently been categorized in molecular subtypes, which include Epstein-Barr (EBV)-positive and microsatellite instability (MSI) tumors. This distinction may provide prognostic information and identifies therapeutic targets. The aim of this study was to evaluate EBV, MSI, and PD-L1 immunoexpression in GC and its relationship with clinicopathological characteristics and patient's prognosis.

Methods

We evaluated 287 GC patients who underwent D2-gastrectomy through immunohistochemistry for DNA mismatch repair proteins and PD-L1, and in situ hybridization for EBV detection utilizing tissue microarray.

Results

EBV-positive and MSI were identified in 10.5% and 27% of the GCs, respectively. EBV positivity was associated to male gender (P = 0.032), proximal location (P < 0.001), undetermined Lauren type (P < 0.001), poorly differentiated histology (P = 0.043) and severe inflammatory infiltrate (P < 0.001). MSI-tumors were associated to older age (P = 0.002), subtotal gastrectomy (P = 0.004), pN0 (P = 0.024) and earlier TNM stage (P = 0.020). PD-L1-positive was seen in 8.8% of cases, with predominant expression in EBV-positive GC (P < 0.001). MSI was associated to better survival outcomes.

Conclusion

EBV-positive GCs had increased PD-L1 expression, while MSI GC had better survival outcome. EBV and MSI subgroups are distinct GC entities, their recognition is feasible by conventional techniques, and it may help individualize follow-up and guide adjuvant therapy.

http://ift.tt/2InfYQb

Head and neck squamous cell cancers in the United States are rare and the risk now is higher among white individuals compared with black individuals

BACKGROUND

The increasing incidence of oropharyngeal squamous cell cancer (OPSCC) is well established. However, up-to-date incidence estimates and trends for head and neck squamous cell cancers (HNSCCs) overall, including major anatomic sites, and nonoropharyngeal (non-OP) HNSCCs by sex, race, and age in the United States are not well described.

METHODS

A retrospective analysis of incident HNSCCs during 1992 through 2014 using the Surveillance, Epidemiology, and End Results database was performed to evaluate the incidence of HNSCCs overall, OPSCC, and non-OP HNSCC (those of the larynx, oral cavity, hypopharynx, nasopharynx, and nasal cavity). Incidence rates were calculated overall and by subgroups of interest, and incidence rate ratios were used to compare rates between groups. The incidence rates presented were per 100,000 population and were age adjusted to the 2000 US standard population (19 age groups; Census P25-1130). The annual percent change (APC) was modeled with and without joinpoints.

RESULTS

The incidence of HNSCC overall declined (average APC [aAPC], -0.8; P<.001) despite significant increases in the incidence of OPSCCs, most notably between 2000 and 2014 (APC, 2.1; P<.001). Significant declines in incidence were observed for all non-OP HNSCC sites for both women and men (P<.001 each). Among women, the risk of OPSCC also significantly decreased (aAPC, -0.8; P = .002), whereas the risk among men was stable during 1992 through 2001 (APC, 0.4; P = .42) and then significantly increased from 2001 to 2014 (APC, 2.7; P<.001). Decreases in the risk of non-OP HNSCC were especially large for black women (aAPC, -2.6; P<.001) and men (aAPC, -3.0; P<.001). Although the incidence of HNSCC previously was highest among black individuals, since 2009 its incidence has been higher among white compared with black individuals.

CONCLUSIONS

The incidence of HNSCC is declining, especially for non-OP HNSCC and among black individuals. Cancer 2018. © 2018 American Cancer Society.

http://ift.tt/2FTFVsp

Efficacy and safety results of depatuxizumab mafodotin (ABT-414) in patients with advanced solid tumors likely to overexpress epidermal growth factor receptor

BACKGROUND

Epidermal growth factor receptor (EGFR) alterations are associated with multiple cancers. Current EGFR-directed therapies have led to increased efficacy but are associated with specific side effects. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) targets EGFR with a monoclonal antibody linked to a cytotoxin, and is highly tumor-specific.

METHODS

This phase 1/2 study evaluated the safety, pharmacokinetics, and efficacy of depatux-m in patients who had advanced solid tumors with known wild-type EGFR overexpression, amplification, or mutated EGFR variant III. A 3 + 3 dose escalation was used, and 2 dosing schedules were evaluated. Depatux-m also was manufactured under an alternate process to reduce the drug load and improve the safety profile, and it was tested at the maximum tolerated dose (MTD). In another cohort, prolonged infusion time of depatux-m was evaluated; and a cohort with confirmed EGFR amplification also was evaluated at the MTD.

RESULTS

Fifty-six patients were treated. The MTD and the recommended phase 2 dose for depatux-m was 3.0 mg/kg. Common adverse events (AEs) were blurred vision (48%) and fatigue (41%). A majority of patients (66%) experienced 1 or more ocular AEs. Grade 3 or 4 AEs were observed in 43% of patients. One patient with EGFR-amplified, triple-negative breast cancer had a partial response. Stable disease was observed in 23% of patients. Pharmacokinetics revealed that depatux-m exposures were approximately dose-proportional.

CONCLUSIONS

Depatux-m resulted in infrequent nonocular AEs but increased ocular AEs. Patient follow-up confirmed that ocular AEs were reversible. Lowering the drug-antibody ratio did not decrease the number of ocular AEs. A partial response in 1 patient with EGFR-amplified disease provides the opportunity to study depatux-m in diseases with a high incidence of EGFR amplification. Cancer 2018. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

http://ift.tt/2HuOiaJ

Malignant triton tumor of the duodenum: report of a case

Abstract

We report a case of malignant triton tumor of the duodenum, which is extremely rare. A submucosal malignant tumor was detected in the duodenum of a 49-year-old woman. The tumor was completely resected by performing pancreaticoduodenectomy. Pathological examination revealed that the lesion was a malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation, i.e., a malignant triton tumor. Long-term survival has been achieved with no recurrence at 8.5 years after surgery.

http://ift.tt/2p8uK5h

Head and neck squamous cell cancers in the United States are rare and the risk now is higher among white individuals compared with black individuals

BACKGROUND

The increasing incidence of oropharyngeal squamous cell cancer (OPSCC) is well established. However, up-to-date incidence estimates and trends for head and neck squamous cell cancers (HNSCCs) overall, including major anatomic sites, and nonoropharyngeal (non-OP) HNSCCs by sex, race, and age in the United States are not well described.

METHODS

A retrospective analysis of incident HNSCCs during 1992 through 2014 using the Surveillance, Epidemiology, and End Results database was performed to evaluate the incidence of HNSCCs overall, OPSCC, and non-OP HNSCC (those of the larynx, oral cavity, hypopharynx, nasopharynx, and nasal cavity). Incidence rates were calculated overall and by subgroups of interest, and incidence rate ratios were used to compare rates between groups. The incidence rates presented were per 100,000 population and were age adjusted to the 2000 US standard population (19 age groups; Census P25-1130). The annual percent change (APC) was modeled with and without joinpoints.

RESULTS

The incidence of HNSCC overall declined (average APC [aAPC], -0.8; P<.001) despite significant increases in the incidence of OPSCCs, most notably between 2000 and 2014 (APC, 2.1; P<.001). Significant declines in incidence were observed for all non-OP HNSCC sites for both women and men (P<.001 each). Among women, the risk of OPSCC also significantly decreased (aAPC, -0.8; P = .002), whereas the risk among men was stable during 1992 through 2001 (APC, 0.4; P = .42) and then significantly increased from 2001 to 2014 (APC, 2.7; P<.001). Decreases in the risk of non-OP HNSCC were especially large for black women (aAPC, -2.6; P<.001) and men (aAPC, -3.0; P<.001). Although the incidence of HNSCC previously was highest among black individuals, since 2009 its incidence has been higher among white compared with black individuals.

CONCLUSIONS

The incidence of HNSCC is declining, especially for non-OP HNSCC and among black individuals. Cancer 2018. © 2018 American Cancer Society.

from Cancer via ola Kala on Inoreader http://ift.tt/2FTFVsp
via IFTTT

Efficacy and safety results of depatuxizumab mafodotin (ABT-414) in patients with advanced solid tumors likely to overexpress epidermal growth factor receptor

BACKGROUND

Epidermal growth factor receptor (EGFR) alterations are associated with multiple cancers. Current EGFR-directed therapies have led to increased efficacy but are associated with specific side effects. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) targets EGFR with a monoclonal antibody linked to a cytotoxin, and is highly tumor-specific.

METHODS

This phase 1/2 study evaluated the safety, pharmacokinetics, and efficacy of depatux-m in patients who had advanced solid tumors with known wild-type EGFR overexpression, amplification, or mutated EGFR variant III. A 3 + 3 dose escalation was used, and 2 dosing schedules were evaluated. Depatux-m also was manufactured under an alternate process to reduce the drug load and improve the safety profile, and it was tested at the maximum tolerated dose (MTD). In another cohort, prolonged infusion time of depatux-m was evaluated; and a cohort with confirmed EGFR amplification also was evaluated at the MTD.

RESULTS

Fifty-six patients were treated. The MTD and the recommended phase 2 dose for depatux-m was 3.0 mg/kg. Common adverse events (AEs) were blurred vision (48%) and fatigue (41%). A majority of patients (66%) experienced 1 or more ocular AEs. Grade 3 or 4 AEs were observed in 43% of patients. One patient with EGFR-amplified, triple-negative breast cancer had a partial response. Stable disease was observed in 23% of patients. Pharmacokinetics revealed that depatux-m exposures were approximately dose-proportional.

CONCLUSIONS

Depatux-m resulted in infrequent nonocular AEs but increased ocular AEs. Patient follow-up confirmed that ocular AEs were reversible. Lowering the drug-antibody ratio did not decrease the number of ocular AEs. A partial response in 1 patient with EGFR-amplified disease provides the opportunity to study depatux-m in diseases with a high incidence of EGFR amplification. Cancer 2018. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

from Cancer via ola Kala on Inoreader http://ift.tt/2HuOiaJ
via IFTTT

Malignant triton tumor of the duodenum: report of a case

Abstract

We report a case of malignant triton tumor of the duodenum, which is extremely rare. A submucosal malignant tumor was detected in the duodenum of a 49-year-old woman. The tumor was completely resected by performing pancreaticoduodenectomy. Pathological examination revealed that the lesion was a malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation, i.e., a malignant triton tumor. Long-term survival has been achieved with no recurrence at 8.5 years after surgery.

from Cancer via ola Kala on Inoreader http://ift.tt/2p8uK5h
via IFTTT

The Frequency of Metabolic Syndrome and Serum Osteopontin Levels in Survivors of Childhood Acute Lymphoblastic Leukemia

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


from Cancer via ola Kala on Inoreader http://ift.tt/2Injf27
via IFTTT

The Frequency of Metabolic Syndrome and Serum Osteopontin Levels in Survivors of Childhood Acute Lymphoblastic Leukemia

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


http://ift.tt/2Injf27

OCT4 but not SOX2 expression correlates with worse prognosis in surgical patients with triple-negative breast cancer

Abstract

Background

Octamer-binding transcription factor 4 (OCT4) and SRY (sex determining region Y)-box 2 (SOX2) are common biomarkers of cancer stem cells, which contribute to the pathological processes of several carcinomas, while little is known about the effects of OCT4 and SOX2 on the prognosis of triple-negative breast cancer (TNBC). The purpose was to evaluate the correlation of tumor tissue OCT4 and SOX2 expressions with clinicopathological features and overall survival (OS) in surgical TNBC patients.

Methods

127 surgical patients with TNBC were enrolled in this cohort study. Tumor tissue samples were obtained during the operation. OCT4 and SOX2 expressions were assessed by immunofluorescent staining.

Results

32 (25%) TNBC patients with OCT4 positive expression (OCT4⁺), 21 (17%) patients with SOX2 positive expression (SOX2⁺), and 11 (9%) patients with both OCT4⁺ and SOX2⁺ were observed. OCT4 expression was positively associated with histologic grade (P < 0.001), pathological tumor size (P = 0.014), N stage (P < 0.001) and TNM stage (P < 0.001), while SOX2 expression was positively correlated with histologic grade (P < 0.001), pathological tumor size (P = 0.033) and Ki-67 expression (P = 0.016). Kaplan–Meier (K–M) curves suggested OCT4⁺ was correlated with shorter OS compared with OCT4⁻ (P < 0.001), while no correlation between SOX2⁺ with OS in all patients (P = 0.128) was observed. Multivariate Cox model indicated that OCT4⁺ (P < 0.001) were independent factors for worse OS.

Conclusions

Tumor tissue OCT4 but not SOX2 expression was positively correlated with histologic grade, pathological tumor size, N stage and TNM stage, and it could be served as an independent biomarker to predict worse prognosis in surgical patients with TNBC.

http://ift.tt/2Dog4mX

Cancers, Vol. 10, Pages 70: Any Place for Immunohistochemistry within the Predictive Biomarkers of Treatment in Lung Cancer Patients?

Cancers, Vol. 10, Pages 70: Any Place for Immunohistochemistry within the Predictive Biomarkers of Treatment in Lung Cancer Patients?

Cancers doi: 10.3390/cancers10030070

Authors: Véronique Hofman Sandra Lassalle Coraline Bence Elodie Long-Mira Sacha Nahon-Estève Simon Heeke Virginie Lespinet-Fabre Catherine Butori Marius Ilié Paul Hofman

The identification of certain genomic alterations (EGFR, ALK, ROS1, BRAF) or immunological markers (PD-L1) in tissues or cells has led to targeted treatment for patients presenting with late stage or metastatic lung cancer. These biomarkers can be detected by immunohistochemistry (IHC) and/or by molecular biology (MB) techniques. These approaches are often complementary but depending on, the quantity and quality of the biological material, the urgency to get the results, the access to technological platforms, the financial resources and the expertise of the team, the choice of the approach can be questioned. The possibility of detecting simultaneously several molecular targets, and of analyzing the degree of tumor mutation burden and of the micro-satellite instability, as well as the recent requirement to quantify the expression of PD-L1 in tumor cells, has led to case by case development of algorithms and international recommendations, which depend on the quality and quantity of biological samples. This review will highlight the different predictive biomarkers detected by IHC for treatment of lung cancer as well as the present advantages and limitations of this approach. A number of perspectives will be considered.

http://ift.tt/2p81tYy

Cancers, Vol. 10, Pages 70: Any Place for Immunohistochemistry within the Predictive Biomarkers of Treatment in Lung Cancer Patients?

Cancers, Vol. 10, Pages 70: Any Place for Immunohistochemistry within the Predictive Biomarkers of Treatment in Lung Cancer Patients?

Cancers doi: 10.3390/cancers10030070

Authors: Véronique Hofman Sandra Lassalle Coraline Bence Elodie Long-Mira Sacha Nahon-Estève Simon Heeke Virginie Lespinet-Fabre Catherine Butori Marius Ilié Paul Hofman

The identification of certain genomic alterations (EGFR, ALK, ROS1, BRAF) or immunological markers (PD-L1) in tissues or cells has led to targeted treatment for patients presenting with late stage or metastatic lung cancer. These biomarkers can be detected by immunohistochemistry (IHC) and/or by molecular biology (MB) techniques. These approaches are often complementary but depending on, the quantity and quality of the biological material, the urgency to get the results, the access to technological platforms, the financial resources and the expertise of the team, the choice of the approach can be questioned. The possibility of detecting simultaneously several molecular targets, and of analyzing the degree of tumor mutation burden and of the micro-satellite instability, as well as the recent requirement to quantify the expression of PD-L1 in tumor cells, has led to case by case development of algorithms and international recommendations, which depend on the quality and quantity of biological samples. This review will highlight the different predictive biomarkers detected by IHC for treatment of lung cancer as well as the present advantages and limitations of this approach. A number of perspectives will be considered.

from Cancer via ola Kala on Inoreader http://ift.tt/2p81tYy
via IFTTT

Associations between aspirin use and the risk of cancers: a meta-analysis of observational studies

Abstract

Background

Epidemiological studies have clarified the potential associations between regular aspirin use and cancers. However, it remains controversial on whether aspirin use decreases the risk of cancers risks. Therefore, we conducted an updated meta-analysis to assess the associations between aspirin use and cancers.

Methods

The PubMed, Embase, and Web of Science databases were systematically searched up to March 2017 to identify relevant studies. Relative risks (RRs) with 95% confidence intervals (CIs) were used to assess the strength of associations.

Results

A total of 218 studies with 309 reports were eligible for this meta-analysis. Aspirin use was associated with a significant decrease in the risk of overall cancer (RR = 0.89, 95% CI: 0.87–0.91), and gastric (RR = 0.75, 95% CI: 0.65–0.86), esophageal (RR = 0.75, 95% CI: 0.62–0.89), colorectal (RR = 0.79, 95% CI: 0.74–0.85), pancreatic (RR = 0.80, 95% CI: 0.68–0.93), ovarian (RR = 0.89, 95% CI: 0.83–0.95), endometrial (RR = 0.92, 95% CI: 0.85–0.99), breast (RR = 0.92, 95% CI: 0.88–0.96), and prostate (RR = 0.94, 95% CI: 0.90–0.99) cancers, as well as small intestine neuroendocrine tumors (RR = 0.17, 95% CI: 0.05–0.58).

Conclusions

These findings suggest that aspirin use is associated with a reduced risk of gastric, esophageal, colorectal, pancreatic, ovarian, endometrial, breast, and prostate cancers, and small intestine neuroendocrine tumors.

http://ift.tt/2tJ5vv5

Associations between aspirin use and the risk of cancers: a meta-analysis of observational studies

Abstract

Background

Epidemiological studies have clarified the potential associations between regular aspirin use and cancers. However, it remains controversial on whether aspirin use decreases the risk of cancers risks. Therefore, we conducted an updated meta-analysis to assess the associations between aspirin use and cancers.

Methods

The PubMed, Embase, and Web of Science databases were systematically searched up to March 2017 to identify relevant studies. Relative risks (RRs) with 95% confidence intervals (CIs) were used to assess the strength of associations.

Results

A total of 218 studies with 309 reports were eligible for this meta-analysis. Aspirin use was associated with a significant decrease in the risk of overall cancer (RR = 0.89, 95% CI: 0.87–0.91), and gastric (RR = 0.75, 95% CI: 0.65–0.86), esophageal (RR = 0.75, 95% CI: 0.62–0.89), colorectal (RR = 0.79, 95% CI: 0.74–0.85), pancreatic (RR = 0.80, 95% CI: 0.68–0.93), ovarian (RR = 0.89, 95% CI: 0.83–0.95), endometrial (RR = 0.92, 95% CI: 0.85–0.99), breast (RR = 0.92, 95% CI: 0.88–0.96), and prostate (RR = 0.94, 95% CI: 0.90–0.99) cancers, as well as small intestine neuroendocrine tumors (RR = 0.17, 95% CI: 0.05–0.58).

Conclusions

These findings suggest that aspirin use is associated with a reduced risk of gastric, esophageal, colorectal, pancreatic, ovarian, endometrial, breast, and prostate cancers, and small intestine neuroendocrine tumors.

from Cancer via ola Kala on Inoreader http://ift.tt/2tJ5vv5
via IFTTT

Surgical outcomes after gastrectomy in very elderly patients with gastric cancer

Abstract

Purpose

Whether or not gastrectomy is feasible for very elderly gastric cancer patients is unclear. This study aimed to clarify the feasibility and safety of surgical treatment for patients in this age group.

Method

The study included 55 very elderly patients with resectable gastric cancer who underwent gastrectomy (≥ 85 years of age; very-E group). The surgical outcomes were compared with those of 611 elderly patients (75–84 years old; E group).

Results

Female sex, a poor physical and performance status, and a low serum albumin level patients were more frequent in the very-E group than in the E group. Lymphadenectomy was less aggressive in the very-E group than in the E group (P < 0.001). The overall postoperative complication rate was not significantly different between the groups (46 vs 33%; P = 0.073). A multivariate analysis to predict the overall survival identified male sex (hazard ratio 1.75, 95% confidence interval 1.30–2.36), low body mass index (2.19, 1.52–3.16), poor performance status (2.14, 1.60–2.86), low serum albumin level (1.84, 1.37–2.48), and advanced tumor stage (1.71, 1.29–2.27) but not age (1.31, 0.84–2.03) as independent prognostic factors.

Conclusion

Chronological age alone is not a contraindicative factor for gastrectomy in very elderly patients.

http://ift.tt/2FF5IRE

Surgical outcomes after gastrectomy in very elderly patients with gastric cancer

Abstract

Purpose

Whether or not gastrectomy is feasible for very elderly gastric cancer patients is unclear. This study aimed to clarify the feasibility and safety of surgical treatment for patients in this age group.

Method

The study included 55 very elderly patients with resectable gastric cancer who underwent gastrectomy (≥ 85 years of age; very-E group). The surgical outcomes were compared with those of 611 elderly patients (75–84 years old; E group).

Results

Female sex, a poor physical and performance status, and a low serum albumin level patients were more frequent in the very-E group than in the E group. Lymphadenectomy was less aggressive in the very-E group than in the E group (P < 0.001). The overall postoperative complication rate was not significantly different between the groups (46 vs 33%; P = 0.073). A multivariate analysis to predict the overall survival identified male sex (hazard ratio 1.75, 95% confidence interval 1.30–2.36), low body mass index (2.19, 1.52–3.16), poor performance status (2.14, 1.60–2.86), low serum albumin level (1.84, 1.37–2.48), and advanced tumor stage (1.71, 1.29–2.27) but not age (1.31, 0.84–2.03) as independent prognostic factors.

Conclusion

Chronological age alone is not a contraindicative factor for gastrectomy in very elderly patients.

from Cancer via ola Kala on Inoreader http://ift.tt/2FF5IRE
via IFTTT

Validity of self-reported weight, height, and body mass index among African American breast cancer survivors

Abstract

Purpose

Self-reported weight, height, and body mass index (BMI) are commonly used in cancer epidemiology studies, but information on the validity of self-reports among cancer survivors is lacking. This study aimed to evaluate the validity of these self-reported measures among African American (AA) breast cancer survivors, known to have high obesity prevalence.

Methods

We compared the self-reported and measured values among 243 participants from the Women's Circle of Health Follow-Up Study (WCHFS), a population-based longitudinal study of AA breast cancer survivors. Multivariable-adjusted linear regressions were used to identify factors associated with reporting errors. We also examined the associations of self-reported and measured BMI with obesity-related health outcomes using multivariable logistic regressions, with hypertension as an example, to evaluate the impact of misreporting.

Results

We found that self-reported and measured values were highly correlated among all and when stratified by participants' characteristics (intraclass correlation coefficients ≥ 0.99, 0.84, and 0.96 for weight, height, and BMI, respectively). The agreement between BMI categories (normal, overweight and obese) based on self-reported and measured data was excellent (kappa = 0.81). Women who were older, never smoked, had higher grade tumors, or had greater BMI tended to have overestimated BMI calculated from self-reported weight and height. The BMI-hypertension association was similar using self-reported (OR per 5 kg/m² increase 1.63; 95% CI 1.27–2.10) and measured BMI (1.58; 95% CI 1.23–2.03).

Conclusions

Self-reported weight, height, and BMI were reasonably accurate in the WCHFS.

Implications for Cancer Survivors

Our study supports the use of these self-reported values among cancer survivors when direct measurements are not possible.

from Cancer via ola Kala on Inoreader http://ift.tt/2GnnbPC
via IFTTT

Pro-survival autophagy and cancer cell resistance to therapy

Abstract

Resistance to therapy is one of the prime causes for treatment failure in cancer and recurrent disease. In recent years, autophagy has emerged as an important cell survival mechanism in response to different stress conditions that are associated with cancer treatment and aging. Autophagy is an evolutionary conserved catabolic process through which damaged cellular contents are degraded after uptake into autophagosomes that subsequently fuse with lysosomes for cargo degradation, thereby alleviating stress. In addition, autophagy serves to maintain cellular homeostasis by enriching nutrient pools. Although autophagy can act as a double-edged sword at the interface of cell survival and cell death, increasing evidence suggest that in the context of cancer therapy-induced stress responses, it predominantly functions as a cell survival mechanism. Here, we provide an up-to-date overview on our current knowledge of the role of pro-survival autophagy in cancer therapy at the preclinical and clinical stages and delineate the molecular mechanisms of autophagy regulation in response to therapy-related stress conditions. A better understanding of the interplay of cancer therapy and autophagy may allow to unveil new targets and avenues for an improved treatment of therapy-resistant tumors in the foreseeable future.

from Cancer via ola Kala on Inoreader http://ift.tt/2FFiG1R
via IFTTT

Integrated genomic analysis identifies clinically relevant subtypes of renal clear cell carcinoma

Abstract

Background

Renal cell carcinoma (RCC) account for over 80% of renal malignancies. The most common type of RCC can be classified into three subtypes including clear cell, papillary and chromophobe. ccRCC (the Clear Cell Renal Cell Carcinoma) is the most frequent form and shows variations in genetics and behavior. To improve accuracy and personalized care and increase the cure rate of cancer, molecular typing for individuals is necessary.

Methods

We adopted the genome, transcriptome and methylation HMK450 data of ccRCC in The Cancer Genome Atlas Network in this research. Consensus Clustering algorithm was used to cluster the expression data and three subtypes were found. To further validate our results, we analyzed an independent data set and arrived at a consistent conclusion. Next, we characterized the subtype by unifying genomic and clinical dimensions of ccRCC molecular stratification. We also implemented GSEA between the malignant subtype and the other subtypes to explore latent pathway varieties and WGCNA to discover intratumoral gene interaction network. Moreover, the epigenetic state changes between subgroups on methylation data are discovered and Kaplan-Meier survival analysis was performed to delve the relation between specific genes and prognosis.

Results

We found a subtype of poor prognosis in clear cell renal cell carcinoma, which is abnormally upregulated in focal adhesions and cytoskeleton related pathways, and the expression of core genes in the pathways are negatively correlated with patient outcomes.

Conclusions

Our work of classification schema could provide an applicable framework of molecular typing to ccRCC patients which has implications to influence treatment decisions, judge biological mechanisms involved in ccRCC tumor progression, and potential future drug discovery.

from Cancer via ola Kala on Inoreader http://ift.tt/2FxHXyS
via IFTTT

Prognostic nutritional index as a predictor of survival in resectable gastric cancer patients with normal preoperative serum carcinoembryonic antigen levels: a propensity score matching analysis

Abstract

Background

An ideal tumor marker should be capable of being detected at any stage of the disease. However, gastric cancer patients do not always have elevated serum carcinoembryonic antigen (CEA) levels, even in advanced cases. Recently, several studies have investigated the associations between preoperative PNI and postoperative long-term outcomes. In this study, we focused on the significance of the prognostic nutritional index (PNI) as a potential predictor of survival in resectable gastric cancer patients with normal preoperative serum CEA levels.

Methods

We retrospectively conducted cohort study to evaluate the PNI as a predictor of survival in 368 resectable gastric cancer patients who underwent potentially curative gastrectomy at our institute between January 2010 and December 2016. We selected 218 patients by propensity score matching to reduce biases due to the different distributions of co-variables among the comparable groups.

Results

In the multivariate analysis, pStage (hazard ratio [HR]: 14.003, 95% confidence interval [CI]: 5.033–44.487; p <  0.001), PNI (HR: 2.794, 95% CI: 1.352–6.039; p <  0.001) were identified as independent prognostic factors of CSS in 218 propensity matched gastric cancer patients. The Kaplan-Meier analysis demonstrated that low PNI patients had a significantly poorer cancer specific survival (CSS) than high PNI patients (p = 0.008).

Among 166 propensity matched gastric cancer patients with normal preoperative serum CEA levels, multivariate analysis demonstrated that pStage (HR: 7.803, 95% CI: 3.015–24.041; p <  0.001) and PNI (HR: 3.078, 95% CI: 1.232–8.707; p = 0.016) were identified as independent prognostic factors of CSS. And Kaplan-Meier analysis demonstrated that low PNI had a significantly poorer CSS than high PNI value (p = 0.011).

Conclusions

This study demonstrates that a low preoperative PNI value is a potential independent risk factor for poorer CSS in patients with gastric cancer, even in those with normal serum CEA levels.

from Cancer via ola Kala on Inoreader http://ift.tt/2DocuJw
via IFTTT

A novel splicing site IRP1 somatic mutation in a patient with pheochromocytoma and JAK2 V617F positive polycythemia vera: a case report

Abstract

Background

The role of the hypoxia signaling pathway in the pathogenesis of pheochromocytoma/paraganglioma (PPGL)-polycythemia syndrome has been elucidated. Novel somatic mutations in hypoxia-inducible factor type 2A (HIF2A) and germline mutations in prolyl hydroxylase type 1 and type 2 (PHD1 and PHD2) have been identified to cause upregulation of the hypoxia signaling pathway and its target genes including erythropoietin (EPO) and its receptor (EPOR). However, in a minority of patients presenting with this syndrome, the genetics and molecular pathogenesis remain unexplained. The aim of the present study was to uncover novel genetic causes of PPGL-polycythemia syndrome.

Case presentation

A female presented with a history of JAK2^V617F positive PV, diagnosed in 2007, and right adrenal pheochromocytoma diagnosed and resected in 2011. Her polycythemia symptoms and hematocrit levels continued to worsen from 2007 to 2011, with an increased frequency of phlebotomies. Postoperatively, until early 2013, her hematocrit levels remained normalized. Following this, the hematocrit levels ranged between 46.4 and 48.9% [35–45%]. Tumor tissue from the patient was further tested for mutations in genes related to upregulation of the hypoxia signaling pathway including iron regulatory protein 1 (IRP1), which is a known regulator of HIF-2α mRNA translation. Functional studies were performed to investigate the consequences of these mutations, especially their effect on the HIF signaling pathway and EPO. Indel mutations (c.267-1_267delGGinsTA) were discovered at the exon 3 splicing site of IRP1. Minigene construct and splicing site analysis showed that the mutation led to a new splicing site and a frameshift mutation of IRP1, which caused a truncated protein. Fluorescence in situ hybridization analysis demonstrated heterozygous IRP1 deletions in tumor cells. Immunohistochemistry results confirmed the truncated IRP1 and overexpressed HIF-2α, EPO and EPOR in tumor cells.

Conclusions

This is the first report which provides direct molecular genetic evidence of association between a somatic IRP1 loss-of-function mutation and PHEO and secondary polycythemia. In patients diagnosed with PHEO/PGL and polycythemia with negative genetic testing for mutations in HIF2A, PHD1/2, and VHL, IRP1 should be considered as a candidate gene.

from Cancer via ola Kala on Inoreader http://ift.tt/2GnmB4o
via IFTTT