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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τετάρτη 26 Απριλίου 2017
New-onset diabetes mellitus after living-donor liver transplantation: association with graft synthetic function
Abstract
Background and purpose
It is now known that post-transplant graft function after deceased-donor liver transplantation and living-donor liver transplantation (LDLT) differ; however, there is no report assessing the relationship between graft function and the development of new-onset diabetes mellitus after transplantation (NODAT). We conducted this study to identify the predictive risk factors for NODAT, including graft function after LDLT.
Methods
The subjects of this study were 175 adult recipients who underwent LDLT at Kyoto University Hospital between 2006 and 2010, and survived for more than 3 months (median observation period, 1046 days).
Results
The 1-, 2-, and 3-year incidences of NODAT after LDLT were 26.1, 32.0, and 33.4%, respectively. Pre-transplant diabetes was associated with poor survival (p = 0.0048), whereas NODAT was not associated with patient survival. In the multivariate analysis, recipient age ≥40, a tacrolimus trough level ≥8 ng/mL 3 months after LDLT, and cholinesterase (ChE) <185 IU/L 3 months after LDLT were the independent risk factors for NODAT.
Conclusions
Poor graft synthetic function 3 months after LDLT as well as older age of the recipient and a higher tacrolimus concentration were strongly associated with NODAT development after LDLT.
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Immune function monitoring in lung transplantation using adenosine triphosphate production: time trends and relationship to postoperative infection
Abstract
Purpose
The ImmuKnow (IK) assay is a comprehensive immune function test that involves measuring adenosine triphosphate produced by the cluster of differentiation 4+ T lymphocytes in peripheral blood. The aim of this study was to analyze the time trends of IK values and assess the relationship between IK values and infections in lung transplants.
Methods
We prospectively collected 178 blood samples from 22 deceased-donor lung transplant (DDLT) recipients and 17 living-donor lobar lung transplant (LDLLT) recipients. A surveillance IK assay was performed postoperatively, then after 1 week and 1, 3, 6, and 12 months.
Results
Time trends of IK values in stable recipients peaked 1 week after DDLT (477 ± 247 ATP ng/ml), and 1 month after LDLLT (433 ± 134 ng/ml), followed by a gradual decline over 1 year. The mean IK values in infections were significantly lower than those in the stable state (119 vs 312 ATP ng/ml, p = 0.0002).
Conclusions
IK values increased sharply after lung transplantation and then decreased gradually over time in the first year, suggesting a natural history of immune function. IK values were also significantly reduced during infections. These results may provide new insights into the utility of immune monitoring after lung transplantation.
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The impact of age on the postoperative response of the diastolic function and left ventricular mass regression after surgical or transcatheter aortic valve replacement for severe aortic stenosis
Abstract
Purpose
We examined the impact of advanced age on left ventricular mass regression and the change in the diastolic function after aortic valve replacement in patients with aortic stenosis.
Methods
The present study included 129 patients who underwent either surgical or transcatheter aortic valve replacement and 1-year postoperative echocardiography. The patient characteristics and echocardiographic findings were compared between patients who were <80 years of age (group Y: n = 69) and those who were ≥80 years of age (group O: n = 60).
Results
Preoperative echocardiography revealed that although the left ventricular mass was similar between the groups, the patients in group O had more severe diastolic dysfunction in comparison to those in group Y. Postoperatively, left ventricular mass regression was significantly greater (p = 0.02) and diastolic dysfunction was less prevalent in group Y (p = 0.02) in comparison to group O. The change in E/e′ was significantly correlated with the left ventricular mass regression in group Y (p = 0.02), but not in Group O (p = 0.21).
Conclusions
The patients in group O were less susceptible to improvements in myocardial remodeling and the diastolic function in comparison to those in group Y. The altered physiological response to aortic valve replacement might help to determine the appropriate timing of surgery in elderly patients.
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Outcomes of prosthetic valve replacement in women of child-bearing age
Abstract
Purpose
The outcomes of pregnancy are more favorable for women with bioprostheses than for those with mechanical prostheses. However, bioprostheses are associated with a high reoperation rate in young women and it remains unclear whether these young women can give birth without any complications. We analyzed the outcomes of prosthetic valve replacement and investigated the effectiveness and problems associated with bioprostheses in women of child-bearing age in Japan.
Methods
The subjects of this study were six consecutive young adult women aged under 40 years, who underwent prosthetic valve replacement between January 2007 and April 2016.
Results
Bioprostheses were selected for four of these six women in consideration of their child-bearing age. Mechanical valves were selected for the other two women who underwent the Konno procedure and double valve replacement (AVR, MVR) in view of their high risk for reoperation. The cardiac operations, although without mortality or morbidity, were complex and some involved multi-time procedures. Three of the women with bioprostheses had uneventful term pregnancies.
Conclusions
These young women with bioprostheses were able to give birth safely; however, as multiple operations are often required, and bioprostheses may not be ideal for young women. Prosthetic valve selection for young women of child-bearing age requires adequate pregnancy counseling and long-term planning.
http://ift.tt/2oOt9Q7
New-onset diabetes mellitus after living-donor liver transplantation: association with graft synthetic function
Abstract
Background and purpose
It is now known that post-transplant graft function after deceased-donor liver transplantation and living-donor liver transplantation (LDLT) differ; however, there is no report assessing the relationship between graft function and the development of new-onset diabetes mellitus after transplantation (NODAT). We conducted this study to identify the predictive risk factors for NODAT, including graft function after LDLT.
Methods
The subjects of this study were 175 adult recipients who underwent LDLT at Kyoto University Hospital between 2006 and 2010, and survived for more than 3 months (median observation period, 1046 days).
Results
The 1-, 2-, and 3-year incidences of NODAT after LDLT were 26.1, 32.0, and 33.4%, respectively. Pre-transplant diabetes was associated with poor survival (p = 0.0048), whereas NODAT was not associated with patient survival. In the multivariate analysis, recipient age ≥40, a tacrolimus trough level ≥8 ng/mL 3 months after LDLT, and cholinesterase (ChE) <185 IU/L 3 months after LDLT were the independent risk factors for NODAT.
Conclusions
Poor graft synthetic function 3 months after LDLT as well as older age of the recipient and a higher tacrolimus concentration were strongly associated with NODAT development after LDLT.
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Immune function monitoring in lung transplantation using adenosine triphosphate production: time trends and relationship to postoperative infection
Abstract
Purpose
The ImmuKnow (IK) assay is a comprehensive immune function test that involves measuring adenosine triphosphate produced by the cluster of differentiation 4+ T lymphocytes in peripheral blood. The aim of this study was to analyze the time trends of IK values and assess the relationship between IK values and infections in lung transplants.
Methods
We prospectively collected 178 blood samples from 22 deceased-donor lung transplant (DDLT) recipients and 17 living-donor lobar lung transplant (LDLLT) recipients. A surveillance IK assay was performed postoperatively, then after 1 week and 1, 3, 6, and 12 months.
Results
Time trends of IK values in stable recipients peaked 1 week after DDLT (477 ± 247 ATP ng/ml), and 1 month after LDLLT (433 ± 134 ng/ml), followed by a gradual decline over 1 year. The mean IK values in infections were significantly lower than those in the stable state (119 vs 312 ATP ng/ml, p = 0.0002).
Conclusions
IK values increased sharply after lung transplantation and then decreased gradually over time in the first year, suggesting a natural history of immune function. IK values were also significantly reduced during infections. These results may provide new insights into the utility of immune monitoring after lung transplantation.
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The impact of age on the postoperative response of the diastolic function and left ventricular mass regression after surgical or transcatheter aortic valve replacement for severe aortic stenosis
Abstract
Purpose
We examined the impact of advanced age on left ventricular mass regression and the change in the diastolic function after aortic valve replacement in patients with aortic stenosis.
Methods
The present study included 129 patients who underwent either surgical or transcatheter aortic valve replacement and 1-year postoperative echocardiography. The patient characteristics and echocardiographic findings were compared between patients who were <80 years of age (group Y: n = 69) and those who were ≥80 years of age (group O: n = 60).
Results
Preoperative echocardiography revealed that although the left ventricular mass was similar between the groups, the patients in group O had more severe diastolic dysfunction in comparison to those in group Y. Postoperatively, left ventricular mass regression was significantly greater (p = 0.02) and diastolic dysfunction was less prevalent in group Y (p = 0.02) in comparison to group O. The change in E/e′ was significantly correlated with the left ventricular mass regression in group Y (p = 0.02), but not in Group O (p = 0.21).
Conclusions
The patients in group O were less susceptible to improvements in myocardial remodeling and the diastolic function in comparison to those in group Y. The altered physiological response to aortic valve replacement might help to determine the appropriate timing of surgery in elderly patients.
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Outcomes of prosthetic valve replacement in women of child-bearing age
Abstract
Purpose
The outcomes of pregnancy are more favorable for women with bioprostheses than for those with mechanical prostheses. However, bioprostheses are associated with a high reoperation rate in young women and it remains unclear whether these young women can give birth without any complications. We analyzed the outcomes of prosthetic valve replacement and investigated the effectiveness and problems associated with bioprostheses in women of child-bearing age in Japan.
Methods
The subjects of this study were six consecutive young adult women aged under 40 years, who underwent prosthetic valve replacement between January 2007 and April 2016.
Results
Bioprostheses were selected for four of these six women in consideration of their child-bearing age. Mechanical valves were selected for the other two women who underwent the Konno procedure and double valve replacement (AVR, MVR) in view of their high risk for reoperation. The cardiac operations, although without mortality or morbidity, were complex and some involved multi-time procedures. Three of the women with bioprostheses had uneventful term pregnancies.
Conclusions
These young women with bioprostheses were able to give birth safely; however, as multiple operations are often required, and bioprostheses may not be ideal for young women. Prosthetic valve selection for young women of child-bearing age requires adequate pregnancy counseling and long-term planning.
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Perceptions of Cancer Risk: Differences by Weight Status
Abstract
Despite the strong link between obesity and cancer development, individuals are less likely to identify obesity as a risk factor for cancer than family history. Family history of cancer has been documented to influence perceived risk of developing cancer, yet it is unclear if excess weight impacts cancer risk perceptions. The purpose of this study was to examine absolute and relative risk perceptions for cancer by weight status. Cross-sectional data were obtained from the National Cancer Institute's 2011 Health Information National Trends Survey (n = 2585). Demographics, anthropometric data, family history of cancer, health behaviors, and absolute and relative cancer risk perceptions were evaluated. The effect of weight and family history on absolute and relative cancer risk perceptions was analyzed through weighted descriptive and logistic regression analyses. 22.8 and 28.6 % of subjects reported that they were very unlikely/unlikely to develop cancer in their lifetime (absolute risk) and when compared to others their age (relative risk), respectively. Findings indicated differences in risk perceptions between those with and without a family history of cancer (p < 0.0001). No significant differences were found between BMI categories for absolute cancer risk perceptions despite stratification by family history. Obese subjects were more likely to have an increased relative risk perception of cancer compared to healthy weight subjects (p = 0.0066); this association remained significant when stratified by family history (p = 0.0161). Educating individuals, especially those who are overweight/obese, about the impact of excess weight on cancer risk may improve risk accuracy and promote cancer risk reduction through weight management.
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Teaching of Independent Exercises for Prehabilitation in Breast Cancer
Abstract
We attempted to determine the feasibility of studying prehabilitation exercises to improve shoulder pain and abduction range of motion (ROM) after breast cancer surgery. We evaluated methods of exercise teaching and assessed effect on postsurgical seroma formation. This was a feasibility study with two non-blinded groups of subjects randomized by timing of appointment. This single-site study was performed at an academic tertiary medical center. Sixty cancer patients were randomly assigned to either group 1, in-person teaching arm, n = 36, or group 2, video-only teaching arm, n = 24. Forty-five patients completed the study. Shoulder exercises were assigned to both groups 1 month prior to surgery during evaluation. Group 1 received in-person instruction on exercises, plus an information sheet with exercises and a link to an online video. Group 2 received only the information sheet with exercises and a link to the online video. The primary outcomes considered are as follows: exercise compliance, shoulder pain (via visual analog scale), shoulder abduction ROM (via goniometer), and presence or absence of seroma. Seventy-six percent of study patients chose to exercise. There was no difference in exercise compliance between in-person teaching versus video teaching (75 %, 24/32 vs. 77 %, 10/13, OR = 1.03). Sixty-six of patients (20/30) lost greater than 10° shoulder abduction ROM at 1 month post surgery. Twenty-nine of patients (9/31) had worse shoulder pain than baseline at 1 month post surgery (24 %, 6/25 exercisers, and 50 %, 3/6 non-exercisers). Fifteen percent of patients (4/27) had worse shoulder pain than baseline at 3 months post surgery (8 %, 2/23 exercisers, and 100 %, 2/2 non-exercisers). Prehabilitation exercise program inferred no additional risk of seroma formation (Exercisers 21 %, 7/33 vs. non-exercisers 22 %, 2/9, OR = 0.94). Our subjects were able to perform three exercises independently in the preoperative period. A high-quality randomized controlled trial is necessary to assess the appropriate timing and efficacy of this intervention.
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A Fulbright Specialist in Poland
Abstract
One of the greatest rewards in cancer education is working with colleagues from around the world. This manuscript reports on the development and conduct of a cancer research training program in Wroclaw, Poland, supported by the Fulbright Commission. The precipitating need for this program was the desire and lack of opportunity for medical trainees to develop skills necessary to conduct cancer education research. A 2-week program was developed consisting of didactic, Socratic, and individual/group consultations. Support from the Fulbright Commission was essential to the success of this program. Information will be presented in this paper on the completion of the funding application as well as lessons learned in the development and implementation of this program.
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Issue Information
Cover of this issue. Mosaic expression of SMARCB1/INI1 in schwannomatosis. See also Kohashi et al. (pages 547–552 of this issue).
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Issue Information
Tracking the Evolution of Non–Small-Cell Lung Cancer
Lung cancer is the leading cause of cancer-related death worldwide, with non–small-cell lung cancer (NSCLC) being the most common type. Large-scale sequencing studies have revealed the complex genomic landscape of NSCLC and genomic differences between lung adenocarcinomas and lung squamous-cell…
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Feasibility of ultra-high-throughput functional screening of melanoma biopsies for discovery of novel cancer drug combinations
Purpose: Successful development of targeted therapy combinations for cancer patients depends on first discovering such combinations in predictive preclinical models. Stable cell lines and mouse xenograft models can have genetic and phenotypic drift and may take too long to generate to be useful as a personalized medicine tool. <p>Experimental Design: To overcome these limitations, we have used a platform of ultra-high-throughput functional screening of primary biopsies preserving both cancer and stroma cell populations from melanoma patients to nominate such novel combinations from a library of thousands of drug combinations in a patient-specific manner within days of biopsy. In parallel, patient-derived xenograft (PDX) mouse models were created and novel combinations tested for their ability to shrink matched patient-derived tumors.</p> <p>Results: The screening method identifies specific drug combinations in tumor cells with patterns that are distinct from those obtained from stable cell lines. Screening results were highly specific to individual patients. For patients with matched PDX models, we confirmed that individualized novel targeted therapy combinations could inhibit tumor growth. In particular, a combination of multi-kinase and PI3K/Akt inhibitors was effective in some BRAF-wild-type melanomas, and the addition of cediranib to the BRAF inhibitor PLX4720 was effective in a PDX model with BRAF mutation.</p> Conclusions: This proof-of-concept study demonstrates the feasibility of using primary biopsies directly for combinatorial drug discovery, complementing stable cell lines and xenografts, but with much greater speed and efficiency. This process could potentially be used in a clinical setting to rapidly identify therapeutic strategies for individual patients.
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Analytic, Pre-analytic and Clinical Validation of p53 Immunohistochemistry for Detection of TP53 Missense Mutation in Prostate Cancer
PURPOSE: TP53 missense mutations may help to identify prostate cancer (PCa) with lethal potential. Here, we pre-analytically, analytically and clinically validated a robust immunohistochemistry (IHC) assay to detect subclonal and focal TP53 missense mutations in PCa. <p>EXPERIMENTAL DESIGN: The p53 IHC assay was performed in a CLIA-accredited laboratory on the Ventana Benchmark immunostaining system. p53 protein nuclear accumulation was defined as any p53 nuclear labeling in >10% of tumor cells. 54 formalin fixed paraffin embedded (FFPE) cell lines from the NCI-60 panel and 103 FFPE PCa tissues (88 primary adenocarcinomas, 15 metastases) with known TP53 mutation status were studied. DU145 and VCaP xenografts were subjected to varying fixation conditions to investigate the effects of pre-analytic variables. Clinical validation was performed in two partially overlapping radical prostatectomy (RP) cohorts.</p> <p>RESULTS: p53 nuclear accumulation by IHC was 100% sensitive for detection of TP53 missense mutations in the NCI-60 panel (25/25 missense mutations correctly identified). Lack of p53 nuclear accumulation was 86% (25/29) specific for absence of TP53 missense mutation. In FFPE prostate tumors, the positive predictive value (PPV) of p53 nuclear accumulation for underlying missense mutation was 84% (38/45), while the negative predictive value (NPV) was 97% (56/58). In a cohort of men who experienced biochemical recurrence after RP, the multivariable hazard ratio for metastasis among cases with p53 nuclear accumulation compared to those without was 2.55 (95% CI: 1.1-5.91).</p> <p>CONCLUSIONS: IHC is widely available method to assess for the presence of deleterious and heterogeneous TP53 missense mutations in clinical PCa specimens.
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Clinical features and outcomes of patients with colorectal cancers harboring NRAS mutations
Purpose: NRAS mutations are now routinely included in RAS testing prior to EGFR (epidermal growth factor receptor) inhibitor therapy for metastatic colorectal cancer (mCRC). The clinical implications of NRAS mutation beyond lack of response to anti-EGFR therapy, however, are not known. We undertook this study to determine the clinical features and treatment outcomes of patients with NRAS mutant mCRC.<br />Experimental Design: We reviewed clinical characteristics, concurrent mutations, and outcomes for all mCRC cases with NRAS mutations undergoing standard genotyping at our institution from 2008-2015. Comparison groups consisted of RAS wild-type and KRAS mutant mCRC consecutive cases genotyped from 2008-2012.<br />Results: Three percent (87/2764) of mCRC patients had NRAS mutant tumors (45% exon 2, 55% exon 3), including three cases with concurrent NRAS and KRAS mutations. Left-sided primary site and African-American self-reported race were associated with NRAS mutation (p<0.01). Resection rate at 12 months was lower for NRAS mutant mCRC than for RAS wild-type or KRAS mutant mCRC. Median survival from time of first known metastasis was 33 months for NRAS mutant, 47 months for KRAS mutant, and 78 months for RAS wild-type cases (p<0.001). Multivariate analysis assigned a hazard ratio for overall survival of 2.0 for NRAS mutation and 1.5 for KRAS mutation (p<0.01).<br />Conclusions: NRAS defines a molecular subset with distinct clinical characteristics from KRAS mutant and wild-type mCRC. NRAS mutations are enriched in left-sided primary tumors and among African Americans. Mutations in NRAS are associated with poor survival and worse outcomes than either KRAS mutant or wild-type mCRC.
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The microbiota: a new variable impacting cancer treatment outcomes
Preclinical evidence has established that the host commensal microbiota can contribute to therapeutic response in cancer models, a finding supported by early clinical data. This connection between the microbiome and clinical outcome in oncology is cause for new consideration in the administration of antibiotics and microbiota-modulating interventions to improve outcomes.
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Enrichment of PIK3-AKT-MTOR pathway activation in hepatic metastases from breast cancer
Purpose: Little is known about the molecular signatures associated with specific metastatic sites in breast cancer. Using comprehensive multi-omic molecular profiling, we assessed whether alterations or activation of the PI3K-AKT-mTOR pathway is associated with specific sites of breast cancer metastasis. <p>Experimental Design: NGS-based whole exome sequencing was coupled with Reverse Phase Protein Microarray (RPPA) functional signaling network analysis to explore the PI3K-AKT-mTOR axis in 32 pretreated breast cancer metastases. RPPA-based signaling data were further validated in an independent cohort of 154 metastatic lesions from breast cancer and 101 un-matched primary breast tumors. The proportion of cases with PI3K-AKT-mTOR genomic alterations or signaling network activation were compared between hepatic and non-hepatic lesions.</p> <p>Results: PIK3CA mutation and activation of AKT (S473) and p70S6K (T389) were detected more frequently among liver metastases than non-hepatic lesions (p<0.01, p=0.056, and p=0.053 respectively). However, PIK3CA mutations alone were insufficient in predicting protein activation (p=0.32 and p=0.19 for activated AKT and p70S6K respectively). RPPA analysis of an independent cohort of 154 tumors confirmed the relationship between pathway activation and hepatic metastasis (AKT (S473), mTOR (S2448), and 4EBP1 (S65); p<0.01, p=0.02, and p=0.01 respectively). Similar results were also seen between liver metastases and primary breast tumors (AKT (S473) p<0.01, mTOR (S2448) p<0.01, 4EBP1 (S65) p=0.01). This signature was lost when primary tumors were compared to all metastatic sites combined.</p> <p>Conclusions: Breast cancer patients with liver metastasis may represent a molecularly homogenized cohort with increased incidence of PIK3CA mutations and activation of the PI3K-AKT-mTOR signaling network.
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Sensitivity and Specificity of Cetuximab-IRDye800CW to Identify Regional Metastatic Disease in Head and Neck Cancer
Purpose: Comprehensive cervical lymphadenectomy can be associated with significant morbidity and poor quality of life. This study evaluated the sensitivity and specificity of cetuximab-IRDye800CW to identify metastatic disease in patients with head and neck cancer. <p>Experimental Design: Consenting patients scheduled for curative resection were enrolled in a clinical trial to evaluate the safety and specificity of cetuximab-IRDye800CW. Patients (n=12) received escalating doses of the study drug. Where indicated, cervical lymphadenectomy accompanied primary tumor resection, which occurred 3-7days following intravenous infusion of cetuximab-IRDye800CW. All 471 dissected lymph nodes were imaged with a closed-field, near-infrared imaging device during gross processing of the fresh specimens. Intraoperative imaging of exposed neck levels was performed with an open-field fluorescence-imaging device. Blinded assessments of the fluorescence data were compared to histopathology to calculate sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV).</p> <p>Results: Of the 35 nodes diagnosed pathologically positive, 34 were correctly identified with fluorescence imaging, yielding a sensitivity of 97.2%. Of the 435 pathologically negative nodes, 401 were correctly assessed using fluorescence imaging, yielding a specificity of 92.7%. The NPV was determined to be 99.7%, and the PPV was 50.7%. When 37 fluorescently false-positive nodes were sectioned deeper (1mm) into their respective blocks, metastatic cancer was found in 8.1% of the re-cut nodal specimens, which altered staging in two of those cases.</p> Conclusions: Fluorescence imaging of lymph nodes after systemic cetuximab-IRDye800CW administration demonstrated high sensitivity and was capable of identifying additional positive nodes on deep sectioning.
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risk of pneumonitis associated with programmed cell death 1 inhibitors in cancer patients: a meta-analysis
Pneumonitis, a rare but potentially life-threatening adverse event in cancer patients receiving programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) inhibitors, has been reported in case reports, clinical trials and retrospective studies. We performed a systematic review and meta-analysis to calculate the relative risk of pneumonitis associated with the use of PD-1/L1 inhibitors in randomized clinical trials (RCTs).We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant randomized trials RCTs comparing PD-1/L1 inhibitors to control with available data on pneumonitis. The pooled incidence, relative risk and 95% CI were calculated using fixed effects or random effects model according to the heterogeneity of included trials. 12 RCTs were eligible for the meta-analysis, yielding a total of 5,775 patients, included in trials evaluating a PD-1 inhibitor; no eligible trials evaluated a PD-L1 inhibitor. The pooled incidence of all grade pneumonitis for patients treated with PD-1 inhibitors was 3.2% (95% CI, 2.3%-4.5%), and that of high grade pneumonitis was 1.1% (95% CI, 0.7%-1.7%). The relative risk of all grade and high grade pneumonitis was 4.36 (95% CI, 2.58-7.38) and 2.86 (95% CI, 1.30-6.31), respectively. In a sensitivity analysis, PD-1 inhibitors were also associated with significantly increased risk of pneumonitis per person-month (for all grade, RR=3.37, 95% CI, 1.97-5.76; for high grade, RR=2.25, 95% CI, 1.03-4.94). PD-1 inhibitors were associated with significant increase of all grade and high grade pneumonitis both per treatment episode and per person-month.
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Feasibility of ultra-high-throughput functional screening of melanoma biopsies for discovery of novel cancer drug combinations
Purpose: Successful development of targeted therapy combinations for cancer patients depends on first discovering such combinations in predictive preclinical models. Stable cell lines and mouse xenograft models can have genetic and phenotypic drift and may take too long to generate to be useful as a personalized medicine tool. <p>Experimental Design: To overcome these limitations, we have used a platform of ultra-high-throughput functional screening of primary biopsies preserving both cancer and stroma cell populations from melanoma patients to nominate such novel combinations from a library of thousands of drug combinations in a patient-specific manner within days of biopsy. In parallel, patient-derived xenograft (PDX) mouse models were created and novel combinations tested for their ability to shrink matched patient-derived tumors.</p> <p>Results: The screening method identifies specific drug combinations in tumor cells with patterns that are distinct from those obtained from stable cell lines. Screening results were highly specific to individual patients. For patients with matched PDX models, we confirmed that individualized novel targeted therapy combinations could inhibit tumor growth. In particular, a combination of multi-kinase and PI3K/Akt inhibitors was effective in some BRAF-wild-type melanomas, and the addition of cediranib to the BRAF inhibitor PLX4720 was effective in a PDX model with BRAF mutation.</p> Conclusions: This proof-of-concept study demonstrates the feasibility of using primary biopsies directly for combinatorial drug discovery, complementing stable cell lines and xenografts, but with much greater speed and efficiency. This process could potentially be used in a clinical setting to rapidly identify therapeutic strategies for individual patients.
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Analytic, Pre-analytic and Clinical Validation of p53 Immunohistochemistry for Detection of TP53 Missense Mutation in Prostate Cancer
PURPOSE: TP53 missense mutations may help to identify prostate cancer (PCa) with lethal potential. Here, we pre-analytically, analytically and clinically validated a robust immunohistochemistry (IHC) assay to detect subclonal and focal TP53 missense mutations in PCa. <p>EXPERIMENTAL DESIGN: The p53 IHC assay was performed in a CLIA-accredited laboratory on the Ventana Benchmark immunostaining system. p53 protein nuclear accumulation was defined as any p53 nuclear labeling in >10% of tumor cells. 54 formalin fixed paraffin embedded (FFPE) cell lines from the NCI-60 panel and 103 FFPE PCa tissues (88 primary adenocarcinomas, 15 metastases) with known TP53 mutation status were studied. DU145 and VCaP xenografts were subjected to varying fixation conditions to investigate the effects of pre-analytic variables. Clinical validation was performed in two partially overlapping radical prostatectomy (RP) cohorts.</p> <p>RESULTS: p53 nuclear accumulation by IHC was 100% sensitive for detection of TP53 missense mutations in the NCI-60 panel (25/25 missense mutations correctly identified). Lack of p53 nuclear accumulation was 86% (25/29) specific for absence of TP53 missense mutation. In FFPE prostate tumors, the positive predictive value (PPV) of p53 nuclear accumulation for underlying missense mutation was 84% (38/45), while the negative predictive value (NPV) was 97% (56/58). In a cohort of men who experienced biochemical recurrence after RP, the multivariable hazard ratio for metastasis among cases with p53 nuclear accumulation compared to those without was 2.55 (95% CI: 1.1-5.91).</p> <p>CONCLUSIONS: IHC is widely available method to assess for the presence of deleterious and heterogeneous TP53 missense mutations in clinical PCa specimens.
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Clinical features and outcomes of patients with colorectal cancers harboring NRAS mutations
Purpose: NRAS mutations are now routinely included in RAS testing prior to EGFR (epidermal growth factor receptor) inhibitor therapy for metastatic colorectal cancer (mCRC). The clinical implications of NRAS mutation beyond lack of response to anti-EGFR therapy, however, are not known. We undertook this study to determine the clinical features and treatment outcomes of patients with NRAS mutant mCRC.<br />Experimental Design: We reviewed clinical characteristics, concurrent mutations, and outcomes for all mCRC cases with NRAS mutations undergoing standard genotyping at our institution from 2008-2015. Comparison groups consisted of RAS wild-type and KRAS mutant mCRC consecutive cases genotyped from 2008-2012.<br />Results: Three percent (87/2764) of mCRC patients had NRAS mutant tumors (45% exon 2, 55% exon 3), including three cases with concurrent NRAS and KRAS mutations. Left-sided primary site and African-American self-reported race were associated with NRAS mutation (p<0.01). Resection rate at 12 months was lower for NRAS mutant mCRC than for RAS wild-type or KRAS mutant mCRC. Median survival from time of first known metastasis was 33 months for NRAS mutant, 47 months for KRAS mutant, and 78 months for RAS wild-type cases (p<0.001). Multivariate analysis assigned a hazard ratio for overall survival of 2.0 for NRAS mutation and 1.5 for KRAS mutation (p<0.01).<br />Conclusions: NRAS defines a molecular subset with distinct clinical characteristics from KRAS mutant and wild-type mCRC. NRAS mutations are enriched in left-sided primary tumors and among African Americans. Mutations in NRAS are associated with poor survival and worse outcomes than either KRAS mutant or wild-type mCRC.
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The microbiota: a new variable impacting cancer treatment outcomes
Preclinical evidence has established that the host commensal microbiota can contribute to therapeutic response in cancer models, a finding supported by early clinical data. This connection between the microbiome and clinical outcome in oncology is cause for new consideration in the administration of antibiotics and microbiota-modulating interventions to improve outcomes.
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Enrichment of PIK3-AKT-MTOR pathway activation in hepatic metastases from breast cancer
Purpose: Little is known about the molecular signatures associated with specific metastatic sites in breast cancer. Using comprehensive multi-omic molecular profiling, we assessed whether alterations or activation of the PI3K-AKT-mTOR pathway is associated with specific sites of breast cancer metastasis. <p>Experimental Design: NGS-based whole exome sequencing was coupled with Reverse Phase Protein Microarray (RPPA) functional signaling network analysis to explore the PI3K-AKT-mTOR axis in 32 pretreated breast cancer metastases. RPPA-based signaling data were further validated in an independent cohort of 154 metastatic lesions from breast cancer and 101 un-matched primary breast tumors. The proportion of cases with PI3K-AKT-mTOR genomic alterations or signaling network activation were compared between hepatic and non-hepatic lesions.</p> <p>Results: PIK3CA mutation and activation of AKT (S473) and p70S6K (T389) were detected more frequently among liver metastases than non-hepatic lesions (p<0.01, p=0.056, and p=0.053 respectively). However, PIK3CA mutations alone were insufficient in predicting protein activation (p=0.32 and p=0.19 for activated AKT and p70S6K respectively). RPPA analysis of an independent cohort of 154 tumors confirmed the relationship between pathway activation and hepatic metastasis (AKT (S473), mTOR (S2448), and 4EBP1 (S65); p<0.01, p=0.02, and p=0.01 respectively). Similar results were also seen between liver metastases and primary breast tumors (AKT (S473) p<0.01, mTOR (S2448) p<0.01, 4EBP1 (S65) p=0.01). This signature was lost when primary tumors were compared to all metastatic sites combined.</p> <p>Conclusions: Breast cancer patients with liver metastasis may represent a molecularly homogenized cohort with increased incidence of PIK3CA mutations and activation of the PI3K-AKT-mTOR signaling network.
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Sensitivity and Specificity of Cetuximab-IRDye800CW to Identify Regional Metastatic Disease in Head and Neck Cancer
Purpose: Comprehensive cervical lymphadenectomy can be associated with significant morbidity and poor quality of life. This study evaluated the sensitivity and specificity of cetuximab-IRDye800CW to identify metastatic disease in patients with head and neck cancer. <p>Experimental Design: Consenting patients scheduled for curative resection were enrolled in a clinical trial to evaluate the safety and specificity of cetuximab-IRDye800CW. Patients (n=12) received escalating doses of the study drug. Where indicated, cervical lymphadenectomy accompanied primary tumor resection, which occurred 3-7days following intravenous infusion of cetuximab-IRDye800CW. All 471 dissected lymph nodes were imaged with a closed-field, near-infrared imaging device during gross processing of the fresh specimens. Intraoperative imaging of exposed neck levels was performed with an open-field fluorescence-imaging device. Blinded assessments of the fluorescence data were compared to histopathology to calculate sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV).</p> <p>Results: Of the 35 nodes diagnosed pathologically positive, 34 were correctly identified with fluorescence imaging, yielding a sensitivity of 97.2%. Of the 435 pathologically negative nodes, 401 were correctly assessed using fluorescence imaging, yielding a specificity of 92.7%. The NPV was determined to be 99.7%, and the PPV was 50.7%. When 37 fluorescently false-positive nodes were sectioned deeper (1mm) into their respective blocks, metastatic cancer was found in 8.1% of the re-cut nodal specimens, which altered staging in two of those cases.</p> Conclusions: Fluorescence imaging of lymph nodes after systemic cetuximab-IRDye800CW administration demonstrated high sensitivity and was capable of identifying additional positive nodes on deep sectioning.
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Co-targeting mTORC and EGFR signaling as a therapeutic strategy in HNSCC.
Head and neck squamous cell carcinomas (HNSCCs) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials and identification of predictive biomarkers remains challenging. To investigate mTORC specific inhibition we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors +/- cetuximab in a panel of HNSCC cell lines and patient derived xenografts (PDX). Cell lines were assayed for response to all agents and siRNA knockdown of targets by multiple approaches. All cell lines showed similar response to both drug and siRNA inhibition of both PI3K and mTORC pathways, with anti-EGFR combination producing modest additive effect. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. In vivo single agent mTORC inhibition inhibited growth of a PIK3CA mutant cancer, but had little effect on any PIK3CAWT or a second PIK3CA mutant model. In all models the combination therapy showed greater growth delay than monotherapy. The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway's role in driving proliferation. While single agent therapy was largely ineffective in vivo, improved response of combination treatment in an array of PDXs suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence suggesting approaches that attempt to match biomarkersin HNSCC remains complex and challenging.
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Concordance of genomic alterations by next-generation sequencing (NGS) in tumor tissue versus circulating tumor DNA in breast cancer
While identifying genomic alterations in tumor tissue is the current gold-standard technique for molecular profiling, circulating tumor DNA (ctDNA) represents a non-invasive method of assessing genomic alterations using peripheral blood. The concordance of genomic alterations between two commercially-available ctDNA and tissue biopsies was compared in 45 patients with breast cancer using paired next-generation sequencing tissue and ctDNA biopsies. Across all genes, concordance between the two platforms was 91.0-94.2%. When only considering genomic alterations in either assay (e.g., excluding wild type/wild type genes), concordance was 10.8-15.1% with full plus partial concordance of 13.8-19.3%. Concordant mutations were associated with significantly higher variant allele frequency. Over half of mutations detected in either technique were not detected using the other biopsy technique. Including variants of unknown significance, the average number of alterations per patient was significantly higher for tissue (4.56) compared to ctDNA (2.16). When eliminating alterations not detectable in the ctDNA assay, mean number of alterations for tissue and ctDNA was similar (2.67 for tissue, 2.16 for ctDNA). Across five representative genes (TP53, PIK3CA, ERBB2, BRCA1, BRCA2), sensitivity and specificity were 35.7% and 95.0%, respectively. Concordance when genomic alterations were detected in either tissue or ctDNA was low with each technique detecting a significant amount of non-overlapping mutations. Potential explanations for the lack of concordance include tumor heterogeneity, different sequencing techniques, spatial and temporal factors, and potential germline DNA contamination. The study indicates that both tissue and blood-based NGS may be necessary to describe the complex biology of breast cancer.
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Ref-1/APE1 as Transcriptional Regulator and Novel Therapeutic Target in Pediatric T-cell Leukemia
The increasing characterization of childhood acute lymphoblastic leukemia (ALL) has led to the identification of multiple molecular targets, but have yet to translate into more effective targeted therapies, particularly for high-risk, relapsed T-cell ALL. Searching for master regulators controlling multiple signaling pathways in T-ALL, we investigated the multi-functional protein redox factor-1 (Ref-1/APE1), which acts as a signaling "node" by exerting redox regulatory control of transcription factors important in leukemia. Leukemia patients' transcriptome databases showed increased expression in T-ALL of Ref-1 and other genes of the Ref-1/SET interactome. Validation studies demonstrated that Ref-1 is expressed in high-risk leukemia T-cells, including in patient biopsies. Ref-1 redox function is active in leukemia T-cells, regulating the Ref-1 target NF-kB, and inhibited by the redox-selective Ref-1 inhibitor E3330. Ref-1 expression is not regulated by Notch signaling, but is upregulated by glucocorticoid treatment. E3330 disrupted Ref-1 redox activity in functional studies and resulted in marked inhibition of leukemia cell viability, including T-ALL lines representing different genotypes and risk groups. Potent leukemia cell inhibition was seen in primary cells from ALL patients, relapsed and glucocorticoid-resistant T-ALL cells, and cells from a murine model of Notch-induced leukemia. Ref-1 redox inhibition triggered leukemia cell apoptosis and down-regulation of survival genes regulated by Ref-1 targets. For the first time, this work identifies Ref-1 as a novel molecular effector in T-ALL and demonstrates that Ref-1 redox inhibition results in potent inhibition of leukemia T-cells, including relapsed T-ALL. These data also support E3330 as a specific Ref-1 small molecule inhibitor for leukemia.<br />
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Ref-1/APE1 as Transcriptional Regulator and Novel Therapeutic Target in Pediatric T-cell Leukemia
The increasing characterization of childhood acute lymphoblastic leukemia (ALL) has led to the identification of multiple molecular targets, but have yet to translate into more effective targeted therapies, particularly for high-risk, relapsed T-cell ALL. Searching for master regulators controlling multiple signaling pathways in T-ALL, we investigated the multi-functional protein redox factor-1 (Ref-1/APE1), which acts as a signaling "node" by exerting redox regulatory control of transcription factors important in leukemia. Leukemia patients' transcriptome databases showed increased expression in T-ALL of Ref-1 and other genes of the Ref-1/SET interactome. Validation studies demonstrated that Ref-1 is expressed in high-risk leukemia T-cells, including in patient biopsies. Ref-1 redox function is active in leukemia T-cells, regulating the Ref-1 target NF-kB, and inhibited by the redox-selective Ref-1 inhibitor E3330. Ref-1 expression is not regulated by Notch signaling, but is upregulated by glucocorticoid treatment. E3330 disrupted Ref-1 redox activity in functional studies and resulted in marked inhibition of leukemia cell viability, including T-ALL lines representing different genotypes and risk groups. Potent leukemia cell inhibition was seen in primary cells from ALL patients, relapsed and glucocorticoid-resistant T-ALL cells, and cells from a murine model of Notch-induced leukemia. Ref-1 redox inhibition triggered leukemia cell apoptosis and down-regulation of survival genes regulated by Ref-1 targets. For the first time, this work identifies Ref-1 as a novel molecular effector in T-ALL and demonstrates that Ref-1 redox inhibition results in potent inhibition of leukemia T-cells, including relapsed T-ALL. These data also support E3330 as a specific Ref-1 small molecule inhibitor for leukemia.<br />
http://ift.tt/2pBnmBc
risk of pneumonitis associated with programmed cell death 1 inhibitors in cancer patients: a meta-analysis
Pneumonitis, a rare but potentially life-threatening adverse event in cancer patients receiving programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) inhibitors, has been reported in case reports, clinical trials and retrospective studies. We performed a systematic review and meta-analysis to calculate the relative risk of pneumonitis associated with the use of PD-1/L1 inhibitors in randomized clinical trials (RCTs).We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant randomized trials RCTs comparing PD-1/L1 inhibitors to control with available data on pneumonitis. The pooled incidence, relative risk and 95% CI were calculated using fixed effects or random effects model according to the heterogeneity of included trials. 12 RCTs were eligible for the meta-analysis, yielding a total of 5,775 patients, included in trials evaluating a PD-1 inhibitor; no eligible trials evaluated a PD-L1 inhibitor. The pooled incidence of all grade pneumonitis for patients treated with PD-1 inhibitors was 3.2% (95% CI, 2.3%-4.5%), and that of high grade pneumonitis was 1.1% (95% CI, 0.7%-1.7%). The relative risk of all grade and high grade pneumonitis was 4.36 (95% CI, 2.58-7.38) and 2.86 (95% CI, 1.30-6.31), respectively. In a sensitivity analysis, PD-1 inhibitors were also associated with significantly increased risk of pneumonitis per person-month (for all grade, RR=3.37, 95% CI, 1.97-5.76; for high grade, RR=2.25, 95% CI, 1.03-4.94). PD-1 inhibitors were associated with significant increase of all grade and high grade pneumonitis both per treatment episode and per person-month.
http://ift.tt/2pka7lH
Co-targeting mTORC and EGFR signaling as a therapeutic strategy in HNSCC.
Head and neck squamous cell carcinomas (HNSCCs) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials and identification of predictive biomarkers remains challenging. To investigate mTORC specific inhibition we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors +/- cetuximab in a panel of HNSCC cell lines and patient derived xenografts (PDX). Cell lines were assayed for response to all agents and siRNA knockdown of targets by multiple approaches. All cell lines showed similar response to both drug and siRNA inhibition of both PI3K and mTORC pathways, with anti-EGFR combination producing modest additive effect. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. In vivo single agent mTORC inhibition inhibited growth of a PIK3CA mutant cancer, but had little effect on any PIK3CAWT or a second PIK3CA mutant model. In all models the combination therapy showed greater growth delay than monotherapy. The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway's role in driving proliferation. While single agent therapy was largely ineffective in vivo, improved response of combination treatment in an array of PDXs suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence suggesting approaches that attempt to match biomarkersin HNSCC remains complex and challenging.
http://ift.tt/2pBqcXd
Concordance of genomic alterations by next-generation sequencing (NGS) in tumor tissue versus circulating tumor DNA in breast cancer
While identifying genomic alterations in tumor tissue is the current gold-standard technique for molecular profiling, circulating tumor DNA (ctDNA) represents a non-invasive method of assessing genomic alterations using peripheral blood. The concordance of genomic alterations between two commercially-available ctDNA and tissue biopsies was compared in 45 patients with breast cancer using paired next-generation sequencing tissue and ctDNA biopsies. Across all genes, concordance between the two platforms was 91.0-94.2%. When only considering genomic alterations in either assay (e.g., excluding wild type/wild type genes), concordance was 10.8-15.1% with full plus partial concordance of 13.8-19.3%. Concordant mutations were associated with significantly higher variant allele frequency. Over half of mutations detected in either technique were not detected using the other biopsy technique. Including variants of unknown significance, the average number of alterations per patient was significantly higher for tissue (4.56) compared to ctDNA (2.16). When eliminating alterations not detectable in the ctDNA assay, mean number of alterations for tissue and ctDNA was similar (2.67 for tissue, 2.16 for ctDNA). Across five representative genes (TP53, PIK3CA, ERBB2, BRCA1, BRCA2), sensitivity and specificity were 35.7% and 95.0%, respectively. Concordance when genomic alterations were detected in either tissue or ctDNA was low with each technique detecting a significant amount of non-overlapping mutations. Potential explanations for the lack of concordance include tumor heterogeneity, different sequencing techniques, spatial and temporal factors, and potential germline DNA contamination. The study indicates that both tissue and blood-based NGS may be necessary to describe the complex biology of breast cancer.
http://ift.tt/2pk8B2G
The National Cancer Institute ALMANAC: A Comprehensive Screening Resource for the Detection of Anticancer Drug Pairs with Enhanced Therapeutic Activity
To date, over 100 small molecule oncology drugs have been approved by the US Food and Drug Administration. Due to the inherent heterogeneity of tumors, these small molecules are often administered in combination to prevent emergence of resistant cell subpopulations. Therefore, new combination strategies to overcome drug resistance in patients with advanced cancer are needed. In this study, we performed a systematic evaluation of the therapeutic activity of over 5,000 pairs of FDA-approved cancer drugs against a panel of 60 well-characterized human tumor cell lines (NCI-60) to uncover combinations with greater than additive growth-inhibitory activity. Screening results were compiled into a database, termed the NCI‑ALMANAC (A Large Matrix of Anti-Neoplastic Agent Combinations), publicly available at http://ift.tt/2q9TSKL. Subsequent in vivo experiments in mouse xenograft models of human cancer confirmed combinations with greater than single-agent efficacy. Concomitant detection of mechanistic biomarkers for these combinations in vivo supported the initiation of two phase I clinical trials at the NCI to evaluate clofarabine with bortezomib and nilotinib with paclitaxel in patients with advanced cancer. Consequently, the hypothesis-generating NCI-ALMANAC web-based resource has demonstrated value in identifying promising combinations of approved drugs with potent anticancer activity for further mechanistic study and translation to clinical trials.
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Landscape of combination immunotherapy and targeted therapy to improve cancer management
Cancer treatments composed of immune checkpoint inhibitors and oncogene-targeted drugs might improve cancer management, but there has been little investigation of their combined potential as yet. To estimate the fraction of cancer cases that might benefit from such combination therapy, we conducted an exploratory study of cancer genomic data sets to determine the proportion with somatic mutation profiles amenable to either immunotherapy or targeted therapy. We surveyed 13,349 genomic profiles from public databases for cases with specific mutations targeted by current agents or a burden of exome-wide non-synonymous mutations (NsM) that exceeds a proposed threshold for response to checkpoint inhibitors. Overall, 8.9% of cases displayed profiles that could benefit from combination therapy, which corresponded to approximately 11.2% of US annual incident cancer cases. Frequently targetable mutations were in PIK3CA, BRAF, NF1, NRAS and PTEN. We also noted a high burden of NsM in cases with targetable mutations in SMO, DDR2, FGFR1, PTCH1, FGFR2 and MET. Our results indicate that a significant proportion of solid tumor patients are eligible for immuno-targeted combination therapy, and they suggest prioritizing specific cancers for trials of certain targeted and checkpoint inhibitor drugs.
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Deletion of lactate dehydrogenase-A in myeloid cells triggers antitumor immunity.
Immunometabolism is emerging as a critical determinant of cancer pathophysiology. In this study, we explored the contributions of macrophage-expressed lactate dehydrogenase-A (LDH-A) to tumor formation in a K-Ras murine model of lung carcinoma. Myeloid-specific deletion of LDH-A promoted accumulation of macrophages with a CD86high and MCP-1high M1-like phenotype that suppressed tumor growth. This phenotypic effect was accompanied by reduced VEGF expression and angiogenesis; diminished numbers of PD-L1+ cancer cells; increased numbers of CD3+ T cells and activation status of CD8+ T cells. Further, it was associated with more pronounced antitumor T cell immunity via induction of IL-17 and IFNγ-producing CD8+ T (Tc17 and Tc1) cells, likely via suppression of lactate-driven PD-L1 expression. Our results suggest that expression of LDH-A and lactate by macrophage in the tumor microenvironment are major drivers of T cell immunosuppression, strongly supporting the concept of targeting stromal LDH-A as an effective strategy to blunt tumoral immune escape.
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tRF/miR-1280 suppresses stem cell-like cells and metastasis in colorectal cancer
Several studies have shown that tRNAs can be enzymatically cleaved to generate distinct classes of tRNA-derived fragments (tRF). Here we report that tRF/miR-1280, a 17bp fragment derived from tRNALeu and pre-miRNA, influences Notch signaling pathways that support the function of cancer stem-like cells (CSC) in colorectal cancer progression. tRF/miR-1280 expression was decreased in human specimens of colorectal cancer (CRC). Ectopic expression of tRF/miR-1280 reduced cell proliferation and colony formation, whereas its suppression reversed these effects. Mechanistic investigations implicated the Notch ligand JAG2 as a direct target of tRF/miR-1280 binding through which it reduced tumor formation and metastasis. Notably, tRF/miR-1280-mediated inactivation of Notch signaling suppressed CSC phenotypes, including by direct transcriptional repression of the Gata1/3 and miR-200b genes. These results were consistent with findings of decreased levels of miR-200b and elevated levels of JAG2, Gata1, Gata3, Zeb1 and Suz12 in CRC tissue specimens. Taken together, our results established that tRF/miR-1280 suppresses CRC growth and metastasis by repressing Notch signaling pathways that support CSC phenotypes. Further, they provide evidence that functionally active miRNA can be derived from tRNA, offering potential biomarker and therapeutic uses.
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Landscape of combination immunotherapy and targeted therapy to improve cancer management
Cancer treatments composed of immune checkpoint inhibitors and oncogene-targeted drugs might improve cancer management, but there has been little investigation of their combined potential as yet. To estimate the fraction of cancer cases that might benefit from such combination therapy, we conducted an exploratory study of cancer genomic data sets to determine the proportion with somatic mutation profiles amenable to either immunotherapy or targeted therapy. We surveyed 13,349 genomic profiles from public databases for cases with specific mutations targeted by current agents or a burden of exome-wide non-synonymous mutations (NsM) that exceeds a proposed threshold for response to checkpoint inhibitors. Overall, 8.9% of cases displayed profiles that could benefit from combination therapy, which corresponded to approximately 11.2% of US annual incident cancer cases. Frequently targetable mutations were in PIK3CA, BRAF, NF1, NRAS and PTEN. We also noted a high burden of NsM in cases with targetable mutations in SMO, DDR2, FGFR1, PTCH1, FGFR2 and MET. Our results indicate that a significant proportion of solid tumor patients are eligible for immuno-targeted combination therapy, and they suggest prioritizing specific cancers for trials of certain targeted and checkpoint inhibitor drugs.
http://ift.tt/2q9P0Fu
Deletion of lactate dehydrogenase-A in myeloid cells triggers antitumor immunity.
Immunometabolism is emerging as a critical determinant of cancer pathophysiology. In this study, we explored the contributions of macrophage-expressed lactate dehydrogenase-A (LDH-A) to tumor formation in a K-Ras murine model of lung carcinoma. Myeloid-specific deletion of LDH-A promoted accumulation of macrophages with a CD86high and MCP-1high M1-like phenotype that suppressed tumor growth. This phenotypic effect was accompanied by reduced VEGF expression and angiogenesis; diminished numbers of PD-L1+ cancer cells; increased numbers of CD3+ T cells and activation status of CD8+ T cells. Further, it was associated with more pronounced antitumor T cell immunity via induction of IL-17 and IFNγ-producing CD8+ T (Tc17 and Tc1) cells, likely via suppression of lactate-driven PD-L1 expression. Our results suggest that expression of LDH-A and lactate by macrophage in the tumor microenvironment are major drivers of T cell immunosuppression, strongly supporting the concept of targeting stromal LDH-A as an effective strategy to blunt tumoral immune escape.
http://ift.tt/2oNWyJV
tRF/miR-1280 suppresses stem cell-like cells and metastasis in colorectal cancer
Several studies have shown that tRNAs can be enzymatically cleaved to generate distinct classes of tRNA-derived fragments (tRF). Here we report that tRF/miR-1280, a 17bp fragment derived from tRNALeu and pre-miRNA, influences Notch signaling pathways that support the function of cancer stem-like cells (CSC) in colorectal cancer progression. tRF/miR-1280 expression was decreased in human specimens of colorectal cancer (CRC). Ectopic expression of tRF/miR-1280 reduced cell proliferation and colony formation, whereas its suppression reversed these effects. Mechanistic investigations implicated the Notch ligand JAG2 as a direct target of tRF/miR-1280 binding through which it reduced tumor formation and metastasis. Notably, tRF/miR-1280-mediated inactivation of Notch signaling suppressed CSC phenotypes, including by direct transcriptional repression of the Gata1/3 and miR-200b genes. These results were consistent with findings of decreased levels of miR-200b and elevated levels of JAG2, Gata1, Gata3, Zeb1 and Suz12 in CRC tissue specimens. Taken together, our results established that tRF/miR-1280 suppresses CRC growth and metastasis by repressing Notch signaling pathways that support CSC phenotypes. Further, they provide evidence that functionally active miRNA can be derived from tRNA, offering potential biomarker and therapeutic uses.
http://ift.tt/2q9uPHO
The National Cancer Institute ALMANAC: A Comprehensive Screening Resource for the Detection of Anticancer Drug Pairs with Enhanced Therapeutic Activity
To date, over 100 small molecule oncology drugs have been approved by the US Food and Drug Administration. Due to the inherent heterogeneity of tumors, these small molecules are often administered in combination to prevent emergence of resistant cell subpopulations. Therefore, new combination strategies to overcome drug resistance in patients with advanced cancer are needed. In this study, we performed a systematic evaluation of the therapeutic activity of over 5,000 pairs of FDA-approved cancer drugs against a panel of 60 well-characterized human tumor cell lines (NCI-60) to uncover combinations with greater than additive growth-inhibitory activity. Screening results were compiled into a database, termed the NCI‑ALMANAC (A Large Matrix of Anti-Neoplastic Agent Combinations), publicly available at http://ift.tt/2q9TSKL. Subsequent in vivo experiments in mouse xenograft models of human cancer confirmed combinations with greater than single-agent efficacy. Concomitant detection of mechanistic biomarkers for these combinations in vivo supported the initiation of two phase I clinical trials at the NCI to evaluate clofarabine with bortezomib and nilotinib with paclitaxel in patients with advanced cancer. Consequently, the hypothesis-generating NCI-ALMANAC web-based resource has demonstrated value in identifying promising combinations of approved drugs with potent anticancer activity for further mechanistic study and translation to clinical trials.
http://ift.tt/2oO2Id5
Occupation and risk of prostate cancer in Canadian men: A case-control study across eight Canadian provinces
Source:Cancer Epidemiology, Volume 48
Author(s): Jeavana Sritharan, Paul A. Demers, Shelley A. Harris, Donald C. Cole, Cheryl E. Peters
BackgroundThe etiology of prostate cancer continues to be poorly understood, including the role of occupation. Past Canadian studies have not been able to thoroughly examine prostate cancer by occupation with detailed information on individual level factors.MethodsOccupation, industry and prostate cancer were examined using data from the National Enhanced Cancer Surveillance System, a large population-based case-control study conducted across eight Canadian provinces from 1994 to 1997. This analysis included 1737 incident cases and 1803 controls aged 50 to 79 years. Lifetime occupational histories were used to group individuals by occupation and industry employment. Odds ratios and 95% confidence intervals were calculated and adjustments were made for known and possible risk factors.ResultsBy occupation, elevated risks were observed in farming and farm management (OR=1.37, 95% CI 1.02–1.84), armed forces (OR=1.33, 95% CI 1.06-1.65) and legal work (OR=2.58, 95% CI 1.05–6.35). Elevated risks were also observed in office work (OR=1.20, 95% CI 1.00–1.43) and plumbing (OR=1.77, 95% CI 1.07–2.93) and with ≥10 years duration of employment. Decreased risks were observed in senior management (OR=0.65, 95% CI 0.46–0.91), construction management (OR=0.69, 95% CI 0.50–0.94) and travel work (OR=0.37, 95% CI 0.16–0.88). Industry results were similar to occupation results, except for an elevated risk in forestry/logging (OR=1.54, 95% CI 1.06–2.25) and a decreased risk in primary metal products (OR=0.70, 95% CI 0.51–0.96).ConclusionThis study presents associations between occupation, industry and prostate cancer, while accounting for individual level factors. Further research is needed on potential job-specific exposures and screening behaviours.
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Pathogenic role and therapeutic potential of pleiotrophin in mouse models of ocular vascular disease
Abstract
Angiogenic factors play an important role in the pathogenesis of diabetic retinopathy (DR), neovascular age-related macular degeneration (nAMD) and retinopathy of prematurity (ROP). Pleiotrophin, a well-known angiogenic factor, was recently reported to be upregulated in the vitreous fluid of patients with proliferative DR (PDR). However, its pathogenic role and therapeutic potential in ocular vascular diseases have not been defined in vivo. Here using corneal pocket assays, we demonstrated that pleiotrophin induced angiogenesis in vivo. To investigate the pathological role of pleiotrophin we used neutralizing antibody to block its function in multiple in vivo models of ocular vascular diseases. In a mouse model of DR, intravitreal injection of pleiotrophin-neutralizing antibody alleviated diabetic retinal vascular leakage. In a mouse model of oxygen-induced retinopathy (OIR), which is a surrogate model of ROP and PDR, we demonstrated that intravitreal injection of anti-pleiotrophin antibody prevented OIR-induced pathological retinal neovascularization and aberrant vessel tufts. Finally, pleiotrophin-neutralizing antibody ameliorated laser-induced choroidal neovascularization, a mouse model of nAMD, suggesting that pleiotrophin is involved in choroidal vascular disease. These findings suggest that pleiotrophin plays an important role in the pathogenesis of DR with retinal vascular leakage, ROP with retinal neovascularization and nAMD with choroidal neovascularization. The results also support pleiotrophin as a promising target for anti-angiogenic therapy.
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Editor’s perspective on the 4th edition of the WHO head and neck tumor classification
Publication date: Available online 25 April 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Adel K. El-Naggar
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Occupation and risk of prostate cancer in Canadian men: A case-control study across eight Canadian provinces
Source:Cancer Epidemiology, Volume 48
Author(s): Jeavana Sritharan, Paul A. Demers, Shelley A. Harris, Donald C. Cole, Cheryl E. Peters
BackgroundThe etiology of prostate cancer continues to be poorly understood, including the role of occupation. Past Canadian studies have not been able to thoroughly examine prostate cancer by occupation with detailed information on individual level factors.MethodsOccupation, industry and prostate cancer were examined using data from the National Enhanced Cancer Surveillance System, a large population-based case-control study conducted across eight Canadian provinces from 1994 to 1997. This analysis included 1737 incident cases and 1803 controls aged 50 to 79 years. Lifetime occupational histories were used to group individuals by occupation and industry employment. Odds ratios and 95% confidence intervals were calculated and adjustments were made for known and possible risk factors.ResultsBy occupation, elevated risks were observed in farming and farm management (OR=1.37, 95% CI 1.02–1.84), armed forces (OR=1.33, 95% CI 1.06-1.65) and legal work (OR=2.58, 95% CI 1.05–6.35). Elevated risks were also observed in office work (OR=1.20, 95% CI 1.00–1.43) and plumbing (OR=1.77, 95% CI 1.07–2.93) and with ≥10 years duration of employment. Decreased risks were observed in senior management (OR=0.65, 95% CI 0.46–0.91), construction management (OR=0.69, 95% CI 0.50–0.94) and travel work (OR=0.37, 95% CI 0.16–0.88). Industry results were similar to occupation results, except for an elevated risk in forestry/logging (OR=1.54, 95% CI 1.06–2.25) and a decreased risk in primary metal products (OR=0.70, 95% CI 0.51–0.96).ConclusionThis study presents associations between occupation, industry and prostate cancer, while accounting for individual level factors. Further research is needed on potential job-specific exposures and screening behaviours.
http://ift.tt/2q9DnhV
Pathogenic role and therapeutic potential of pleiotrophin in mouse models of ocular vascular disease
Abstract
Angiogenic factors play an important role in the pathogenesis of diabetic retinopathy (DR), neovascular age-related macular degeneration (nAMD) and retinopathy of prematurity (ROP). Pleiotrophin, a well-known angiogenic factor, was recently reported to be upregulated in the vitreous fluid of patients with proliferative DR (PDR). However, its pathogenic role and therapeutic potential in ocular vascular diseases have not been defined in vivo. Here using corneal pocket assays, we demonstrated that pleiotrophin induced angiogenesis in vivo. To investigate the pathological role of pleiotrophin we used neutralizing antibody to block its function in multiple in vivo models of ocular vascular diseases. In a mouse model of DR, intravitreal injection of pleiotrophin-neutralizing antibody alleviated diabetic retinal vascular leakage. In a mouse model of oxygen-induced retinopathy (OIR), which is a surrogate model of ROP and PDR, we demonstrated that intravitreal injection of anti-pleiotrophin antibody prevented OIR-induced pathological retinal neovascularization and aberrant vessel tufts. Finally, pleiotrophin-neutralizing antibody ameliorated laser-induced choroidal neovascularization, a mouse model of nAMD, suggesting that pleiotrophin is involved in choroidal vascular disease. These findings suggest that pleiotrophin plays an important role in the pathogenesis of DR with retinal vascular leakage, ROP with retinal neovascularization and nAMD with choroidal neovascularization. The results also support pleiotrophin as a promising target for anti-angiogenic therapy.
http://ift.tt/2q9NYt6
Editor’s perspective on the 4th edition of the WHO head and neck tumor classification
Publication date: Available online 25 April 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Adel K. El-Naggar
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Head and neck cancer Series: The Lancet Oncology: April 26, 2017
Sandro Porceddu discusses the new Lancet Oncology Series on head and neck cancer.
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Inhibition of the insulin-like growth factor-1 receptor potentiates acute effects of castration in a rat model for prostate cancer growth in bone
Abstract
Prostate cancer (PCa) patients with bone metastases are primarily treated with androgen deprivation therapy (ADT). Less pronounced ADT effects are seen in metastases than in primary tumors. To test if acute effects of ADT was enhanced by concurrent inhibition of pro-survival insulin-like growth factor 1 (IGF-1), rats were inoculated with Dunning R3327-G tumor cells into the tibial bone marrow cavity and established tumors were treated with castration in combination with IGF-1 receptor (IGF-1R) inhibitor NVP-AEW541, or by each treatment alone. Dunning R3327-G cells were stimulated by androgens and IGF-1 in vitro. In rat tibia, Dunning R3327-G cells induced bone remodeling, identified through increased immunoreactivity of osteoblast and osteoclast markers. Tumor cells occasionally grew outside the tibia, and proliferation and apoptotic rates a few days after treatment were evaluated by scoring BrdU- and caspase-3-positive tumor cells inside and outside the bone marrow cavity, separately. Apoptosis was significantly induced outside, but unaffected inside, the tibial bone by either castration or NVP-AEW541, and the maximum increase (2.7-fold) was obtained by the combined treatment. Proliferation was significantly reduced by NVP-AEW541, independently of growth site, although the maximum decrease (24%) was observed when NVP-AEW541 was combined with castration. Tumor cell IGF-1R immunoreactivity was evaluated in clinical PCa bone metastases (n = 61), and positive staining was observed in most cases (74%). In conclusion, IGF-1R inhibition may be evaluated in combination with ADT in patients with metastatic PCa, or in combination with therapies for the subsequent development of castration-resistant disease, although diverse responses could be anticipated depending on metastasis site.
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Inhibition of the insulin-like growth factor-1 receptor potentiates acute effects of castration in a rat model for prostate cancer growth in bone
Abstract
Prostate cancer (PCa) patients with bone metastases are primarily treated with androgen deprivation therapy (ADT). Less pronounced ADT effects are seen in metastases than in primary tumors. To test if acute effects of ADT was enhanced by concurrent inhibition of pro-survival insulin-like growth factor 1 (IGF-1), rats were inoculated with Dunning R3327-G tumor cells into the tibial bone marrow cavity and established tumors were treated with castration in combination with IGF-1 receptor (IGF-1R) inhibitor NVP-AEW541, or by each treatment alone. Dunning R3327-G cells were stimulated by androgens and IGF-1 in vitro. In rat tibia, Dunning R3327-G cells induced bone remodeling, identified through increased immunoreactivity of osteoblast and osteoclast markers. Tumor cells occasionally grew outside the tibia, and proliferation and apoptotic rates a few days after treatment were evaluated by scoring BrdU- and caspase-3-positive tumor cells inside and outside the bone marrow cavity, separately. Apoptosis was significantly induced outside, but unaffected inside, the tibial bone by either castration or NVP-AEW541, and the maximum increase (2.7-fold) was obtained by the combined treatment. Proliferation was significantly reduced by NVP-AEW541, independently of growth site, although the maximum decrease (24%) was observed when NVP-AEW541 was combined with castration. Tumor cell IGF-1R immunoreactivity was evaluated in clinical PCa bone metastases (n = 61), and positive staining was observed in most cases (74%). In conclusion, IGF-1R inhibition may be evaluated in combination with ADT in patients with metastatic PCa, or in combination with therapies for the subsequent development of castration-resistant disease, although diverse responses could be anticipated depending on metastasis site.
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Long term radiographic findings of breast brachytherapy: Implications of surgical volume
Purpose
Little is known about long-term radiographic findings after treatment with accelerated partial breast irradiation (APBI).
Methods
Univariate and multivariate analysis of factors leading to formation and resolution of seroma were performed in patients treated with lumpectomy and APBI.
Results
Post-treatment images of 129 patients were reviewed by one radiologist. Median surgical excision volume was 108.9 cc (range 20.5-681.9). Primary mode of imaging was mammogram. Median time from end of RT to first and last surveillance image was 6 and 54 months, respectively. Median number of images was 7 (range 3-12). Seroma was identified in 98 (76%) patients, with median maximum diameter of 3.9 cm. Forty (41%) patients experienced resolution of seroma, at a median time of 29 months (range 6-74). On univariate analysis, surgical excision volume was associated with seroma formation, and tumor stage and margin re-excision were significant on univariate and multivariate analysis. No factors were associated with seroma resolution.
Conclusion
Seroma formation after APBI resolves around 2.5 years for many patients, but persists for others possibly due to primary tumor and surgical excision volumes. With revised criteria on the definition of positive margins, smaller volumes may lead to decreased risk of seroma formation for future patients.
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Screening endoscopy finds high prevalence of Helicobacter pylori and intestinal metaplasia in Korean American with limited access to health care
Background
Gastric cancer (GC) is the leading cause of cancer death among Korean Americans. Prevention and early detection is improved by screening.
Methods
Between September 2013 and March 2015, ethnic Koreans age 40 or older without history or symptoms of GC and without upper endoscopy (UE) during previous 3 years were enrolled. Participants were offered screening with GC risk assessment followed by UE with biopsies.
Results
Risk assessment was provided to 146 participants (age 55.6 ± 8.3 years; 52.1% female; 92.5% uninsured), of whom 99 (67.8%) returned for UE. Undergoing UE was independently associated with family history of GC (OR 12.33, 95% CI:1.52-100.17), being a former smoker (6.68,1.42-31.32), and Hp-negative status (0.25,0.11-0.57). Among UE recipients, half (49.5%) had intestinal metaplasia (IM) only (n = 24), Hp only (n = 12), or both (n = 13). No case of GC was found. Adjusted for age, IM was independently associated with male sex (2.89,1.12-7.42), current Hp (2.90,0.99-8.51), unmarried status (single or divorced) (4.23,1.23-14.56).
Conclusions
High prevalence of risk factors associated with gastric carcinogenesis including Hp infection and IM exists in Korean Americans who underwent upper endoscopic screening. Acceptance of GC screening is informed by personal risk factors. These findings support the need to improve access to screening UE among KAs.
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NR5A2 discovering compounds that block tumor growth in PDAC
Pancreatic cancers depend on driver molecules, oncogene proteins such as RAS. NR5A2 protein is a transcription factor and either activates or inhibits transcription through actions at hundreds of enhancers. It has unusual properties with effects appearing in multiple signaling networks. NR5A2 is a pluripotency reprogramming factor in the class nuclear receptor. Its controlling hormone is PIP3. Experiments suggest NR5A2 activation drives PDAC and inhibitors blunt cancer cell proliferation.
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Program Spotlight: Training Navigation
Dr. Hana Odeh talks about CRCHD's new training navigation initiative and her role as training navigator.
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Program Spotlight: Training Navigation
Dr. Hana Odeh talks about CRCHD's new training navigation initiative and her role as training navigator.
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Long term radiographic findings of breast brachytherapy: Implications of surgical volume
Purpose
Little is known about long-term radiographic findings after treatment with accelerated partial breast irradiation (APBI).
Methods
Univariate and multivariate analysis of factors leading to formation and resolution of seroma were performed in patients treated with lumpectomy and APBI.
Results
Post-treatment images of 129 patients were reviewed by one radiologist. Median surgical excision volume was 108.9 cc (range 20.5-681.9). Primary mode of imaging was mammogram. Median time from end of RT to first and last surveillance image was 6 and 54 months, respectively. Median number of images was 7 (range 3-12). Seroma was identified in 98 (76%) patients, with median maximum diameter of 3.9 cm. Forty (41%) patients experienced resolution of seroma, at a median time of 29 months (range 6-74). On univariate analysis, surgical excision volume was associated with seroma formation, and tumor stage and margin re-excision were significant on univariate and multivariate analysis. No factors were associated with seroma resolution.
Conclusion
Seroma formation after APBI resolves around 2.5 years for many patients, but persists for others possibly due to primary tumor and surgical excision volumes. With revised criteria on the definition of positive margins, smaller volumes may lead to decreased risk of seroma formation for future patients.
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Screening endoscopy finds high prevalence of Helicobacter pylori and intestinal metaplasia in Korean American with limited access to health care
Background
Gastric cancer (GC) is the leading cause of cancer death among Korean Americans. Prevention and early detection is improved by screening.
Methods
Between September 2013 and March 2015, ethnic Koreans age 40 or older without history or symptoms of GC and without upper endoscopy (UE) during previous 3 years were enrolled. Participants were offered screening with GC risk assessment followed by UE with biopsies.
Results
Risk assessment was provided to 146 participants (age 55.6 ± 8.3 years; 52.1% female; 92.5% uninsured), of whom 99 (67.8%) returned for UE. Undergoing UE was independently associated with family history of GC (OR 12.33, 95% CI:1.52-100.17), being a former smoker (6.68,1.42-31.32), and Hp-negative status (0.25,0.11-0.57). Among UE recipients, half (49.5%) had intestinal metaplasia (IM) only (n = 24), Hp only (n = 12), or both (n = 13). No case of GC was found. Adjusted for age, IM was independently associated with male sex (2.89,1.12-7.42), current Hp (2.90,0.99-8.51), unmarried status (single or divorced) (4.23,1.23-14.56).
Conclusions
High prevalence of risk factors associated with gastric carcinogenesis including Hp infection and IM exists in Korean Americans who underwent upper endoscopic screening. Acceptance of GC screening is informed by personal risk factors. These findings support the need to improve access to screening UE among KAs.
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NR5A2 discovering compounds that block tumor growth in PDAC
Pancreatic cancers depend on driver molecules, oncogene proteins such as RAS. NR5A2 protein is a transcription factor and either activates or inhibits transcription through actions at hundreds of enhancers. It has unusual properties with effects appearing in multiple signaling networks. NR5A2 is a pluripotency reprogramming factor in the class nuclear receptor. Its controlling hormone is PIP3. Experiments suggest NR5A2 activation drives PDAC and inhibitors blunt cancer cell proliferation.
from Cancer via ola Kala on Inoreader http://ift.tt/2q7eWyG
via IFTTT
Long term radiographic findings of breast brachytherapy: Implications of surgical volume
Purpose
Little is known about long-term radiographic findings after treatment with accelerated partial breast irradiation (APBI).
Methods
Univariate and multivariate analysis of factors leading to formation and resolution of seroma were performed in patients treated with lumpectomy and APBI.
Results
Post-treatment images of 129 patients were reviewed by one radiologist. Median surgical excision volume was 108.9 cc (range 20.5-681.9). Primary mode of imaging was mammogram. Median time from end of RT to first and last surveillance image was 6 and 54 months, respectively. Median number of images was 7 (range 3-12). Seroma was identified in 98 (76%) patients, with median maximum diameter of 3.9 cm. Forty (41%) patients experienced resolution of seroma, at a median time of 29 months (range 6-74). On univariate analysis, surgical excision volume was associated with seroma formation, and tumor stage and margin re-excision were significant on univariate and multivariate analysis. No factors were associated with seroma resolution.
Conclusion
Seroma formation after APBI resolves around 2.5 years for many patients, but persists for others possibly due to primary tumor and surgical excision volumes. With revised criteria on the definition of positive margins, smaller volumes may lead to decreased risk of seroma formation for future patients.
http://ift.tt/2q75yel
Screening endoscopy finds high prevalence of Helicobacter pylori and intestinal metaplasia in Korean American with limited access to health care
Background
Gastric cancer (GC) is the leading cause of cancer death among Korean Americans. Prevention and early detection is improved by screening.
Methods
Between September 2013 and March 2015, ethnic Koreans age 40 or older without history or symptoms of GC and without upper endoscopy (UE) during previous 3 years were enrolled. Participants were offered screening with GC risk assessment followed by UE with biopsies.
Results
Risk assessment was provided to 146 participants (age 55.6 ± 8.3 years; 52.1% female; 92.5% uninsured), of whom 99 (67.8%) returned for UE. Undergoing UE was independently associated with family history of GC (OR 12.33, 95% CI:1.52-100.17), being a former smoker (6.68,1.42-31.32), and Hp-negative status (0.25,0.11-0.57). Among UE recipients, half (49.5%) had intestinal metaplasia (IM) only (n = 24), Hp only (n = 12), or both (n = 13). No case of GC was found. Adjusted for age, IM was independently associated with male sex (2.89,1.12-7.42), current Hp (2.90,0.99-8.51), unmarried status (single or divorced) (4.23,1.23-14.56).
Conclusions
High prevalence of risk factors associated with gastric carcinogenesis including Hp infection and IM exists in Korean Americans who underwent upper endoscopic screening. Acceptance of GC screening is informed by personal risk factors. These findings support the need to improve access to screening UE among KAs.
http://ift.tt/2pAoSDO
NR5A2 discovering compounds that block tumor growth in PDAC
Pancreatic cancers depend on driver molecules, oncogene proteins such as RAS. NR5A2 protein is a transcription factor and either activates or inhibits transcription through actions at hundreds of enhancers. It has unusual properties with effects appearing in multiple signaling networks. NR5A2 is a pluripotency reprogramming factor in the class nuclear receptor. Its controlling hormone is PIP3. Experiments suggest NR5A2 activation drives PDAC and inhibitors blunt cancer cell proliferation.
http://ift.tt/2q7eWyG
Tumor specific regulatory T cells in the bone marrow of breast cancer patients selectively upregulate the emigration receptor S1P1
Abstract
Regulatory T cells (Treg) hamper anti-tumor T-cell responses resulting in reduced survival and failure of cancer immunotherapy. Among lymphoid organs, the bone marrow (BM) is a major site of Treg residence and recirculation. However, the process governing the emigration of Treg from BM into the circulation remains elusive. We here show that breast cancer patients harbour reduced Treg frequencies in the BM as compared to healthy individuals or the blood. This was particularly the case for tumor antigen-specific Treg which were quantified by MHCII tumor peptide loaded tetramers. We further demonstrate that decreased Treg distribution in the BM correlated with increased Treg redistribution to tumor tissue, suggesting that TCR triggering induces a translocation of Treg from the BM into tumor tissue. Sphingosine-1-phosphate receptor 1 (S1P1)—which is known to mediate exit of immune cells from lymphoid organs was selectively expressed by tumor antigen-specific BM Treg. S1P1 expression could be induced in Treg by BM-resident antigen-presenting cells (BMAPCs) in conjunction with TCR stimulation, but not by TCR stimulation or BMAPCs alone and triggered the migration of Treg but not conventional T cells (Tcon) to its ligand Sphingosine-1-phosphate (S1P). Interestingly, we detected marked S1P gradients between PB and BM in breast cancer patients but not in healthy individuals. Taken together, our data suggest a role for S1P1 in mediating the selective mobilization of tumor specific Treg from the BM of breast cancer patients and their translocation into tumor tissue.
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Elevated basal antibody-dependent cell-mediated cytotoxicity (ADCC) and high epidermal growth factor receptor (EGFR) expression predict favourable outcome in patients with locally advanced head and neck cancer treated with cetuximab and radiotherapy
Abstract
Background
Antibody-dependent cell-mediated cytotoxicity (ADCC) may contribute to the antitumor activity of cetuximab. However, the extent of this contribution is unclear. In this study, we investigated the impact of baseline ADCC on the outcome of patients with locally advanced squamous cell carcinoma treated with cetuximab and radiotherapy.
Methods
We determined baseline ADCC in 28 patients treated with cetuximab and radiotherapy and in 15 patients treated with chemoradiation. We linked the values observed with complete response and with overall survival. We also considered the role of epidermal growth factor receptor (EGFR) expression and studied the combined effect of EGFR and ADCC.
Results
We observed a wide range of baseline values of ADCC. Complete response did not correlate with either ADCC or EGFR expression. However, when ADCC and EGFR were considered together using a mixed score, they significantly correlated with achieving a complete response (p = 0.04). High baseline ADCC significantly correlated with outcome compared to low (p = 0.03), but not in patients treated without cetuximab. Patients showing high baseline levels of both ADCC and EGFR3+ achieved the best outcome compared to the others (p = 0.02).
Conclusions
In this study, patients treated with cetuximab and radiotherapy, showing high baseline of both ADCC and EGFR3+, have significant higher probability of achieving a complete response and a long overall survival compared to the others.
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FOXO3, estrogen receptor alpha, and androgen receptor impact tumor growth rate and infiltration of dendritic cell subsets differentially between male and female mice
Abstract
Tumors evade immune recognition and destruction in many ways including the creation of an immune-suppressive tumor microenvironment (TME). Dendritic cells (DC) that infiltrate the TME are tolerogenic, and suppress effector T cells and anti-tumor activity. Previous reports demonstrated that a key regulator of tolerance in DC is the transcription factor FOXO3. Gender disparity has been studied in cancer in relation to incidence, aggressiveness, and prognosis. Few studies have touched on the importance in relation to impact on the immune system. In the current study, we show that there are significant differences in tumor growth between males and females. Additionally, frequencies and the function of FOXO3 expressed by DC subsets that infiltrate tumors vary between genders. Our results show for the first time that DC FOXO3 expression and function is altered in females. In vitro results indicate that these differences may be the result of exposure to estrogen. These differences may be critical considerations for the enhancement of immunotherapy for cancer.
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Expression of VISTA correlated with immunosuppression and synergized with CD8 to predict survival in human oral squamous cell carcinoma
Abstract
V-domain Ig suppressor of T cell activation (VISTA), a novel immune checkpoint regulatory molecule, suppresses T cell mediated immune responses. The aim of the present study was to profile the immunological expression, clinical significance and correlation of VISTA in human oral squamous cell carcinoma (OSCC). Human tissue microarrays, containing 165 primary OSCCs, 48 oral epithelial dysplasias and 43 normal oral mucosae, were applied to investigate the expression levels of VISTA, CD8, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death ligand 1 (PD-L1), PI3Kα p110, IL13Rα2, phospho-STAT3 at tyrosine 705 (p-STAT3) and myeloid-derived suppressor cell (MDSC) markers (CD11b and CD33) by immunohistochemistry and digital pathology analysis. The results demonstrated that the protein level of VISTA was significantly higher in human OSCC specimens, and that VISTA expression in primary OSCCs was correlated with lymph node status. VISTA expression did not serve as an independent predictor for poor prognosis, while patient subgroup with VISTA high and CD8 low expression (22/165) had significantly poorer overall survival compared with other subgroups based on the multivariate and Cox hazard analyses among the primary OSCC patients in the present cohort. Additionally, the expression of VISTA was significantly correlated with PD-L1, CTLA-4, IL13Rα2, PI3K, p-STAT3, CD11b and CD33 according to Pearson's correlation coefficient test. Taken together, the results indicated that the VISTA high and CD8 low group, as an immunosuppressive subgroup, might be associated with a poor prognosis in primary OSCC. These findings indicated that VISTA might be a potential immunotherapeutic target in OSCC treatment.
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PD-1 and PD-L1 antibodies in cancer: current status and future directions
Abstract
Immunotherapy has moved to the center stage of cancer treatment with the recent success of trials in solid tumors with PD-1/PD-L1 axis blockade. Programmed death-1 or PD-1 is a checkpoint molecule on T cells that plays a vital role in limiting adaptive immune responses and preventing autoimmune and auto-inflammatory reactivity in the normal host. In cancer patients, PD-1 expression is very high on T cells in the tumor microenvironment, and PD-L1, its primary ligand, is variably expressed on tumor cells and antigen-presenting cells within tumors, providing a potent inhibitory influence within the tumor microenvironment. While PD-L1 expression on tumors is often regarded as a negative prognostic factor, it is clearly associated with a positive outcome for treatment with PD-1/PD-L1 blocking antibodies, and has been used to select patients for this therapy. Responses of long duration, a minority of patients with atypical responses in which progression may precede tumor shrinkage, and a pattern of autoimmune side effects often seen with this class of drugs characterize therapy with PD-1/PD-L1 blocking drugs. While excellent efficacy has been seen with a limited number of tumor types, most epithelial cancers do not show responses of long duration with these agents. In the current review, we will briefly summarize the scientific background data supporting the development of PD-1/PD-L1 blockade, and then describe the track record of these antibodies in multiple different histologies ranging from melanoma and lung cancer to less common tumor types as well as discuss biomarkers that may assist in patient selection.
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Interleukin 21 inhibits cancer-mediated FOXP3 induction in naïve human CD4 T cells
Abstract
IL-21 is known to promote anti-tumour immunity due to its ability to promote T cell responses and counteract Treg-mediated suppression. It has also been shown to limit Treg frequencies during tumour-antigen stimulations. However, whether this represents inhibition of FOXP3 induction in naïve CD4 T cells or curtailed expansion of natural Treg remains unclear. Moreover, whether this effect is maintained in an environment of tumour-derived immunosuppressive factors is not known. Here, we show that in the context of a number of cancers, naïve CD45RA+ CD4 T cells are induced to express high levels of FOXP3, and that FOXP3 expression correlates with inhibition of T cell proliferation. FOXP3 expression was most potently induced by tumours secreting higher levels of total and active TGFβ1 and this induction could be potently counteracted with IL-21, restoring T cell proliferation. We conclude that Treg induction in naïve T cells is a common phenomenon amongst a number of different cancers and that the ability of IL-21 to counteract this effect is further evidence of its promise in cancer therapy.
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