JNA Journal Club

No abstract available

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Correction to: Ionizing radiation from computed tomography versus anesthesia for magnetic resonance imaging in infants and children: patient safety considerations

Abstract

The published version of this article incorrectly lists Dr. Joseph P. Cravero in the Department of Radiology at Boston Children's Hospital. Dr. Cravero's correct affiliation is given below.

http://ift.tt/2DLWoNW

Correction to: Ionizing radiation from computed tomography versus anesthesia for magnetic resonance imaging in infants and children: patient safety considerations

Abstract

The published version of this article incorrectly lists Dr. Joseph P. Cravero in the Department of Radiology at Boston Children's Hospital. Dr. Cravero's correct affiliation is given below.

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Prevalence of human papillomavirus infection among Iranian women using COBAS HPV DNA testing

Abstract

Background

Persistent infection with High Risk Human Papillomavirus (HR HPV) typesplaysamajor role in the development of cervical cancer. Therefore, the detection of HR HPV types is an essential part of cervical cancer screening. The aim of this study was to estimate the prevalence of HR HPV infection among healthy women undergoing routine cervical cancer screening in Iran.

Methods

In this cross-sectional study,the results of HPV DNA typing in 2453 normal Iranian womenwhowere referred for routine cervical cancer screening from September 2015 to March 2017 were analyzed. Participants were screened using COBAS assay for HPV DNA typing and liquid based cytology.

Results

A total of 2453 healthy sexually active women were included in this study. The mean age was 35.1 ± 8.08 years. The overall prevalence of HR HPV infection was 10.3%. HPV16 was found in 73 (3%) women. The prevalence of HPV18 and other HR HPV typeswere 16(0.7%) and166 (8.2%),respectively. Approximately, 5% of the study population had an abnormal cervical cytology (ASCUS or worse), of whom 34% were infected by HR HPV.

Conclusion

The prevalence of HR HPV infection among Iranian women has increased in the recent years which indicates the need for public education and health planning toprevent this cancer through vaccination and early diagnosis using screening tests.HPV DNA typing, diagnosisand the distribution of prevalent genotypes should be considered in the development of comprehensive cervical cancer prevention programs in Iran.

http://ift.tt/2n8tRc0

Prevalence of human papillomavirus infection among Iranian women using COBAS HPV DNA testing

Abstract

Background

Persistent infection with High Risk Human Papillomavirus (HR HPV) typesplaysamajor role in the development of cervical cancer. Therefore, the detection of HR HPV types is an essential part of cervical cancer screening. The aim of this study was to estimate the prevalence of HR HPV infection among healthy women undergoing routine cervical cancer screening in Iran.

Methods

In this cross-sectional study,the results of HPV DNA typing in 2453 normal Iranian womenwhowere referred for routine cervical cancer screening from September 2015 to March 2017 were analyzed. Participants were screened using COBAS assay for HPV DNA typing and liquid based cytology.

Results

A total of 2453 healthy sexually active women were included in this study. The mean age was 35.1 ± 8.08 years. The overall prevalence of HR HPV infection was 10.3%. HPV16 was found in 73 (3%) women. The prevalence of HPV18 and other HR HPV typeswere 16(0.7%) and166 (8.2%),respectively. Approximately, 5% of the study population had an abnormal cervical cytology (ASCUS or worse), of whom 34% were infected by HR HPV.

Conclusion

The prevalence of HR HPV infection among Iranian women has increased in the recent years which indicates the need for public education and health planning toprevent this cancer through vaccination and early diagnosis using screening tests.HPV DNA typing, diagnosisand the distribution of prevalent genotypes should be considered in the development of comprehensive cervical cancer prevention programs in Iran.

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Association of Low Bone Mineral Density with Anti-Citrullinated Protein Antibody Positivity and Disease Activity in Established Rheumatoid Arthritis: Findings from a US Observational Cohort

Abstract

Introduction

To assess the relationship between low bone mineral density (BMD), anti-cyclic citrullinated peptide-2 (anti-CCP2) antibodies, and disease activity in patients with established rheumatoid arthritis (RA).

Methods

Patients enrolled in a single-center, observational cohort registry of patients with RA. Eligible patients had known BMD, as measured by digital X-ray radiogrammetry (DXR–BMD), and anti-CCP2 antibody measurements at the same time point or within 6 months. Anti-CCP2–immunoglobulin (Ig)G-positive (+) patients (≥ 20 U/mL) were distributed into three equal groups (Gp1–3), representing increasing anti-CCP2 antibody concentrations. Associations between BMD and anti-CCP2 antibody status and titer were explored in multivariate regression analyses controlling for covariates (including age, duration of RA, use of steroids, use of osteoporosis medication). Association between disease activity (DAS28 [CRP] < 2.6) and bone loss was also explored.

Results

A total of 149 patients (all women) were included (47 anti-CCP2 antibody negative [−], 102 anti-CCP2+ [34\titer group]). Mean disease duration was greater in the three anti-CCP2+ groups vs. the anti-CCP2− group. DXR–BMD was lower in the anti-CCP2+ vs. the anti-CCP2− groups (Gp1–3 vs. anti-CCP2−: P < 0.0001 for left and right hands). DXR–BMD decreased with increasing anti-CCP2 titer (P < 0.001 for left and right hands). Patients with low DXR–BMD were less likely to have a DAS28 (CRP) < 2.6 (P = 0.0181).

Conclusion

Among patients with established RA, data suggest that anti-CCP2+ patients, particularly those with high anti-CCP2 antibody titers, have lower hand BMD, and patients with lower hand BMD are less likely to have low disease activity.

Funding

Bristol-Myers Squibb.

Trial Registration

Clinicaltrials.gov identifier, NCT01793103.

http://ift.tt/2BqDiIc

Association of Low Bone Mineral Density with Anti-Citrullinated Protein Antibody Positivity and Disease Activity in Established Rheumatoid Arthritis: Findings from a US Observational Cohort

Abstract

Introduction

To assess the relationship between low bone mineral density (BMD), anti-cyclic citrullinated peptide-2 (anti-CCP2) antibodies, and disease activity in patients with established rheumatoid arthritis (RA).

Methods

Patients enrolled in a single-center, observational cohort registry of patients with RA. Eligible patients had known BMD, as measured by digital X-ray radiogrammetry (DXR–BMD), and anti-CCP2 antibody measurements at the same time point or within 6 months. Anti-CCP2–immunoglobulin (Ig)G-positive (+) patients (≥ 20 U/mL) were distributed into three equal groups (Gp1–3), representing increasing anti-CCP2 antibody concentrations. Associations between BMD and anti-CCP2 antibody status and titer were explored in multivariate regression analyses controlling for covariates (including age, duration of RA, use of steroids, use of osteoporosis medication). Association between disease activity (DAS28 [CRP] < 2.6) and bone loss was also explored.

Results

A total of 149 patients (all women) were included (47 anti-CCP2 antibody negative [−], 102 anti-CCP2+ [34\titer group]). Mean disease duration was greater in the three anti-CCP2+ groups vs. the anti-CCP2− group. DXR–BMD was lower in the anti-CCP2+ vs. the anti-CCP2− groups (Gp1–3 vs. anti-CCP2−: P < 0.0001 for left and right hands). DXR–BMD decreased with increasing anti-CCP2 titer (P < 0.001 for left and right hands). Patients with low DXR–BMD were less likely to have a DAS28 (CRP) < 2.6 (P = 0.0181).

Conclusion

Among patients with established RA, data suggest that anti-CCP2+ patients, particularly those with high anti-CCP2 antibody titers, have lower hand BMD, and patients with lower hand BMD are less likely to have low disease activity.

Funding

Bristol-Myers Squibb.

Trial Registration

Clinicaltrials.gov identifier, NCT01793103.

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The Novel Oncolytic Adenoviral Mutant Ad5-3{Delta}-A20T Retargeted to {alpha}v{beta}6 Integrins Efficiently Eliminates Pancreatic Cancer Cells

Metastatic pancreatic ductal adenocarcinomas (PDAC) are incurable due to the rapid development of resistance to all current therapeutics. Oncolytic adenoviral mutants have emerged as a promising new strategy that negates such resistance. In contrast to normal tissue, the majority of PDACs express the αvβ6 integrin receptor. To exploit this feature, we modified our previously reported oncolytic adenovirus, Ad, to selectively target αvβ6 integrins to facilitate systemic delivery. Structural modifications to Ad include the expression of the small but potent αvβ6-binding peptide, A20FMDV2, and ablation of binding to the native coxsackie and adenovirus receptor (CAR) within the fiber knob region. The resultant mutant, Ad5-3-A20T, infected and killed αvβ6 integrin–expressing cells more effectively than the parental wild-type (Ad5wt) virus and Ad. Viral uptake through αvβ6 integrins rather than native viral receptors (CAR, αvβ3 and αvβ5 integrins) promoted viral propagation and spread. Superior efficacy of Ad5-3-A20T compared with Ad5wt was demonstrated in 3D organotypic cocultures, and similar potency between the two viruses was observed in Suit-2 in vivo models. Importantly, Ad5-3-A20T infected pancreatic stellate cells at low levels, which may further facilitate viral spread and cancer cell elimination either as a single agent or in combination with the chemotherapy drug, gemcitabine. We demonstrate that Ad5-3-A20T is highly selective for αvβ6 integrin–expressing pancreatic cancer cells, and with further development, this new and exciting strategy can potentially be extended to improve the systemic delivery of adenoviruses to pancreatic cancer patients. Mol Cancer Ther; 17(2); 1–13. ©2018 AACR.

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The Novel Oncolytic Adenoviral Mutant Ad5-3{Delta}-A20T Retargeted to {alpha}v{beta}6 Integrins Efficiently Eliminates Pancreatic Cancer Cells

Metastatic pancreatic ductal adenocarcinomas (PDAC) are incurable due to the rapid development of resistance to all current therapeutics. Oncolytic adenoviral mutants have emerged as a promising new strategy that negates such resistance. In contrast to normal tissue, the majority of PDACs express the αvβ6 integrin receptor. To exploit this feature, we modified our previously reported oncolytic adenovirus, Ad, to selectively target αvβ6 integrins to facilitate systemic delivery. Structural modifications to Ad include the expression of the small but potent αvβ6-binding peptide, A20FMDV2, and ablation of binding to the native coxsackie and adenovirus receptor (CAR) within the fiber knob region. The resultant mutant, Ad5-3-A20T, infected and killed αvβ6 integrin–expressing cells more effectively than the parental wild-type (Ad5wt) virus and Ad. Viral uptake through αvβ6 integrins rather than native viral receptors (CAR, αvβ3 and αvβ5 integrins) promoted viral propagation and spread. Superior efficacy of Ad5-3-A20T compared with Ad5wt was demonstrated in 3D organotypic cocultures, and similar potency between the two viruses was observed in Suit-2 in vivo models. Importantly, Ad5-3-A20T infected pancreatic stellate cells at low levels, which may further facilitate viral spread and cancer cell elimination either as a single agent or in combination with the chemotherapy drug, gemcitabine. We demonstrate that Ad5-3-A20T is highly selective for αvβ6 integrin–expressing pancreatic cancer cells, and with further development, this new and exciting strategy can potentially be extended to improve the systemic delivery of adenoviruses to pancreatic cancer patients. Mol Cancer Ther; 17(2); 1–13. ©2018 AACR.

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Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations

Purpose: Immune checkpoint inhibition has been shown to generate profound and durable responses in MMR-D solid tumors and has elicited interest in detection tools and strategies to guide therapeutic decision-making. Herein we address questions on the appropriate screening, detection methods, patient selection, and initiation of therapy for MMR-D PDAC and assess the utility of NGS in providing additional prognostic and predictive information for MMR-D PDAC. Experimental Design: Archival and prospectively acquired samples and matched normal DNA from N= 833 PDAC cases were analyzed using a hybridization capture based, NGS assay designed to perform targeted deep sequencing of all exons and selected introns of 341- 468 cancer-associated genes. A computational program using NGS data derived the MSI status from the tumor-normal paired genome sequencing data. Review of available germline testing, IHC, and MSI PCR results were performed to assess and confirm MMR-D and MSI status. Results: MMR-D in PDAC is a rare event among PDAC patients (7/833) occurring at a frequency of 0.8%. Loss of MMR protein expression by IHC, high mutational load and elevated MSIsensor scores were correlated with MMR-D PDAC. All 7 MMR-D PDAC patients in the study were found to have Lynch Syndrome. Four (57%) of the MMR-D patients treated with immune checkpoint blockade had treatment benefit (1 complete response; 2 partial responses; 1 stable disease). Conclusions: An integrated approach of germline testing and somatic analyses of tumor tissues in advanced PDAC using NGS may help guide future development of immune and molecularly directed therapies in PDAC patients.

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Molecular markers increase precision of the European Association of Urology non-muscle invasive bladder cancer progression risk groups

Purpose: The European Association of Urology (EAU) guidelines for non-muscle invasive bladder cancer (NMIBC) recommend risk stratification based on clinicopathological parameters. Our aim was to investigate the added value of biomarkers to improve risk stratification of NMIBC. Experimental Design: We prospectively included 1239 patients in follow-up for NMIBC in six European countries. Fresh frozen tumor samples were analyzed for GATA2, TBX2, TBX3 and ZIC4 methylation and FGFR3, TERT, PIK3CA and RAS mutation status. Cox-regression analyses identified markers that were significantly associated with progression to muscle-invasive disease. The progression incidence rate (PIR=rate of progression per 100 patient-years) was calculated for subgroups. Results: In our cohort, 276 patients had a low, 273 an intermediate and 555 a high risk of tumor progression based on the EAU NMIBC guideline. Fifty-seven patients (4.6%) progressed to muscle-invasive disease. The limited number of progressors in this large cohort compared to older studies is likely due to improved treatment in the last two decades. Overall, wild type FGFR3 and methylation of GATA2 and TBX3 were significantly associated with progression (HR 0.34, 2.53 and 2.64, respectively). The PIR for EAU high risk patients was 4.25. Based on FGFR3 mutation status and methylation of GATA2 this cohort could be reclassified into a good class (PIR=0.86, 26.2% of patients), a moderate class (PIR=4.32, 49.7%) and a poor class (PIR=7.66, 24.0%). Conclusions: We conclude that addition of selected biomarkers to the EAU risk stratification, increases its accuracy and identifies a subset of NMIBC patients with a very high risk of progression.

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Krüppel-like Factor 4 Suppresses Serine/Threonine Kinase 33 Activation and Metastasis of Gastric Cancer through Reversing Epithelial-Mesenchymal Transition

Purpose: Cancers with aberrant expression of Serine/threonine kinase 33 (STK33) is particularly aggressive. However, its expression, clinical significance and biological functions in gastric cancer remain largely unknown. In the present study, we determined the expression and function of STK33 in gastric cancer and delineated the clinical significance of Krüppel-like factor 4 (KLF4) /STK33 signaling pathway. Experimental Design: STK33 expression and its association with multiple clinicopathologic characteristics were analyzed immunohistochemically in human gastric cancer specimens. STK33 knockdown and overexpression were used to dissect the underlying mechanism of its functions in gastric cancer cells. Regulation and underlying mechanisms of STK33 expression by KLF4 in gastric cancer cells were studied using cell and molecular biological methods. Results: Drastically higher expression of STK33 was observed in gastric cancer and gastric intraepithelial neoplasia tissues compared to adjacent normal gastric tissues. Increased STK33 expression correlated directly with tumor size, lymph node and distant metastasis; and patients with low STK33 expression gastric cancer were predicted to have a favorable prognosis. Enforced expression of STK33 promoted gastric cancer cell proliferation, migration, and invasion in vitro and in vivo, whereas reduced STK33 did the opposite. Moreover, STK33 promoted epithelial-mesenchymal transition (EMT) in vitro. Mechanistically, KLF4 transcriptionally inhibited STK33 expression in gastric cancer cells. KLF4-mediated inhibition of gastric cancer cell invasion was reversed by upregulation of STK33 expression. Conclusions: STK33 has pro-tumor function and is a critical downstream mediator of KLF4 in gastric cancer. STK33 may serve as a potential prognostic marker and therapeutic target for gastric cancer.

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Flt-3L expansion of recipient CD8{alpha}+ dendritic cells deletes alloreactive donor T cells and represents an alternative to post-transplant cyclophosphamide for the prevention of GVHD

Purpose: Allogeneic bone marrow transplantation (BMT) provides curative therapy for leukemia via immunological graft-versus-leukemia (GVL) effects. In practice, this must be balanced against life threatening pathology induced by graft-versus-host disease (GVHD). Recipient dendritic cells (DC) are thought to be important in the induction of GVL and GVHD. Experimental Design: We have utilized preclinical models of allogeneic BMT to dissect the role and modulation of recipient DC in controlling donor T cell mediated GVHD and GVL. Results: We demonstrate that recipient CD8a+ DC promote activation-induced clonal deletion of allospecific donor T cells after BMT. We compared pre-transplant fms-like tyrosine kinase-3 ligand (Flt-3L) treatment to the current clinical strategy of post-transplant cyclophosphamide (PT-Cy) therapy. Our results demonstrate superior protection from GVHD with the immunomodulatory Flt-3L approach, and similar attenuation of GVL responses with both strategies. Strikingly, Flt-3L treatment permitted maintenance of the donor polyclonal T cell pool, where PT-Cy did not. Conclusions: These data highlight pre-transplant Flt-3L therapy as a potent new therapeutic strategy to delete alloreactive T cells and prevent GVHD, which appears particularly well suited to haploidentical BMT where the control of infection and the prevention of GVHD are paramount.

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Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer [Research Articles]

Primary resistance to androgen receptor (AR) directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 treatment-naive mCRPC patients to abiraterone or enzalutamide, and performed whole exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR directed therapy in mCRPC and identify potential minimally-invasive biomarkers.

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Chromatin-Remodeling Genes Promote Immunotherapy Resistance [News in Brief]

Components of SWI/SNF complex help tumors evade T-cell attack.

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Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations

Purpose: Immune checkpoint inhibition has been shown to generate profound and durable responses in MMR-D solid tumors and has elicited interest in detection tools and strategies to guide therapeutic decision-making. Herein we address questions on the appropriate screening, detection methods, patient selection, and initiation of therapy for MMR-D PDAC and assess the utility of NGS in providing additional prognostic and predictive information for MMR-D PDAC. Experimental Design: Archival and prospectively acquired samples and matched normal DNA from N= 833 PDAC cases were analyzed using a hybridization capture based, NGS assay designed to perform targeted deep sequencing of all exons and selected introns of 341- 468 cancer-associated genes. A computational program using NGS data derived the MSI status from the tumor-normal paired genome sequencing data. Review of available germline testing, IHC, and MSI PCR results were performed to assess and confirm MMR-D and MSI status. Results: MMR-D in PDAC is a rare event among PDAC patients (7/833) occurring at a frequency of 0.8%. Loss of MMR protein expression by IHC, high mutational load and elevated MSIsensor scores were correlated with MMR-D PDAC. All 7 MMR-D PDAC patients in the study were found to have Lynch Syndrome. Four (57%) of the MMR-D patients treated with immune checkpoint blockade had treatment benefit (1 complete response; 2 partial responses; 1 stable disease). Conclusions: An integrated approach of germline testing and somatic analyses of tumor tissues in advanced PDAC using NGS may help guide future development of immune and molecularly directed therapies in PDAC patients.

http://ift.tt/2Dxmp0g

Molecular markers increase precision of the European Association of Urology non-muscle invasive bladder cancer progression risk groups

Purpose: The European Association of Urology (EAU) guidelines for non-muscle invasive bladder cancer (NMIBC) recommend risk stratification based on clinicopathological parameters. Our aim was to investigate the added value of biomarkers to improve risk stratification of NMIBC. Experimental Design: We prospectively included 1239 patients in follow-up for NMIBC in six European countries. Fresh frozen tumor samples were analyzed for GATA2, TBX2, TBX3 and ZIC4 methylation and FGFR3, TERT, PIK3CA and RAS mutation status. Cox-regression analyses identified markers that were significantly associated with progression to muscle-invasive disease. The progression incidence rate (PIR=rate of progression per 100 patient-years) was calculated for subgroups. Results: In our cohort, 276 patients had a low, 273 an intermediate and 555 a high risk of tumor progression based on the EAU NMIBC guideline. Fifty-seven patients (4.6%) progressed to muscle-invasive disease. The limited number of progressors in this large cohort compared to older studies is likely due to improved treatment in the last two decades. Overall, wild type FGFR3 and methylation of GATA2 and TBX3 were significantly associated with progression (HR 0.34, 2.53 and 2.64, respectively). The PIR for EAU high risk patients was 4.25. Based on FGFR3 mutation status and methylation of GATA2 this cohort could be reclassified into a good class (PIR=0.86, 26.2% of patients), a moderate class (PIR=4.32, 49.7%) and a poor class (PIR=7.66, 24.0%). Conclusions: We conclude that addition of selected biomarkers to the EAU risk stratification, increases its accuracy and identifies a subset of NMIBC patients with a very high risk of progression.

http://ift.tt/2E7rxte

Krüppel-like Factor 4 Suppresses Serine/Threonine Kinase 33 Activation and Metastasis of Gastric Cancer through Reversing Epithelial-Mesenchymal Transition

Purpose: Cancers with aberrant expression of Serine/threonine kinase 33 (STK33) is particularly aggressive. However, its expression, clinical significance and biological functions in gastric cancer remain largely unknown. In the present study, we determined the expression and function of STK33 in gastric cancer and delineated the clinical significance of Krüppel-like factor 4 (KLF4) /STK33 signaling pathway. Experimental Design: STK33 expression and its association with multiple clinicopathologic characteristics were analyzed immunohistochemically in human gastric cancer specimens. STK33 knockdown and overexpression were used to dissect the underlying mechanism of its functions in gastric cancer cells. Regulation and underlying mechanisms of STK33 expression by KLF4 in gastric cancer cells were studied using cell and molecular biological methods. Results: Drastically higher expression of STK33 was observed in gastric cancer and gastric intraepithelial neoplasia tissues compared to adjacent normal gastric tissues. Increased STK33 expression correlated directly with tumor size, lymph node and distant metastasis; and patients with low STK33 expression gastric cancer were predicted to have a favorable prognosis. Enforced expression of STK33 promoted gastric cancer cell proliferation, migration, and invasion in vitro and in vivo, whereas reduced STK33 did the opposite. Moreover, STK33 promoted epithelial-mesenchymal transition (EMT) in vitro. Mechanistically, KLF4 transcriptionally inhibited STK33 expression in gastric cancer cells. KLF4-mediated inhibition of gastric cancer cell invasion was reversed by upregulation of STK33 expression. Conclusions: STK33 has pro-tumor function and is a critical downstream mediator of KLF4 in gastric cancer. STK33 may serve as a potential prognostic marker and therapeutic target for gastric cancer.

http://ift.tt/2Dxmdhy

Flt-3L expansion of recipient CD8{alpha}+ dendritic cells deletes alloreactive donor T cells and represents an alternative to post-transplant cyclophosphamide for the prevention of GVHD

Purpose: Allogeneic bone marrow transplantation (BMT) provides curative therapy for leukemia via immunological graft-versus-leukemia (GVL) effects. In practice, this must be balanced against life threatening pathology induced by graft-versus-host disease (GVHD). Recipient dendritic cells (DC) are thought to be important in the induction of GVL and GVHD. Experimental Design: We have utilized preclinical models of allogeneic BMT to dissect the role and modulation of recipient DC in controlling donor T cell mediated GVHD and GVL. Results: We demonstrate that recipient CD8a+ DC promote activation-induced clonal deletion of allospecific donor T cells after BMT. We compared pre-transplant fms-like tyrosine kinase-3 ligand (Flt-3L) treatment to the current clinical strategy of post-transplant cyclophosphamide (PT-Cy) therapy. Our results demonstrate superior protection from GVHD with the immunomodulatory Flt-3L approach, and similar attenuation of GVL responses with both strategies. Strikingly, Flt-3L treatment permitted maintenance of the donor polyclonal T cell pool, where PT-Cy did not. Conclusions: These data highlight pre-transplant Flt-3L therapy as a potent new therapeutic strategy to delete alloreactive T cells and prevent GVHD, which appears particularly well suited to haploidentical BMT where the control of infection and the prevention of GVHD are paramount.

http://ift.tt/2E7rkWY

Biomarkers of immunotherapy in urothelial and renal cell carcinoma: PD-L1, tumor mutational burden, and beyond

Abstract

Immune checkpoint inhibitors targeting the PD-1 pathway have greatly changed clinical management of metastatic urothelial carcinoma and metastatic renal cell carcinoma. However, response rates are low, and biomarkers are needed to predict for treatment response. Immunohistochemical quantification of PD-L1 was developed as a promising biomarker in early clinical trials, but many shortcomings of the four different assays (different antibodies, disparate cellular populations, and different thresholds of positivity) have limited its clinical utility. Further limitations include the use of archival specimens to measure this dynamic biomarker. Indeed, until PD-L1 testing is standardized and can consistently predict treatment outcome, the currently available PD-L1 assays are not clinically useful in urothelial and renal cell carcinoma. Other more promising biomarkers include tumor mutational burden, profiles of tumor infiltrating lymphocytes, molecular subtypes, and PD-L2. Potentially, a composite biomarker may be best but will need prospective testing to validate such a biomarker.

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Biomarkers of immunotherapy in urothelial and renal cell carcinoma: PD-L1, tumor mutational burden, and beyond

Abstract

Immune checkpoint inhibitors targeting the PD-1 pathway have greatly changed clinical management of metastatic urothelial carcinoma and metastatic renal cell carcinoma. However, response rates are low, and biomarkers are needed to predict for treatment response. Immunohistochemical quantification of PD-L1 was developed as a promising biomarker in early clinical trials, but many shortcomings of the four different assays (different antibodies, disparate cellular populations, and different thresholds of positivity) have limited its clinical utility. Further limitations include the use of archival specimens to measure this dynamic biomarker. Indeed, until PD-L1 testing is standardized and can consistently predict treatment outcome, the currently available PD-L1 assays are not clinically useful in urothelial and renal cell carcinoma. Other more promising biomarkers include tumor mutational burden, profiles of tumor infiltrating lymphocytes, molecular subtypes, and PD-L2. Potentially, a composite biomarker may be best but will need prospective testing to validate such a biomarker.

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Technical aspects of abdominal ultrasound and color Doppler assessment of bowel viability in necrotizing enterocolitis

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Technical aspects of abdominal ultrasound and color Doppler assessment of bowel viability in necrotizing enterocolitis

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Young Adult Female Cancer Survivors' Concerns About Future Children's Health and Genetic Risk

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Young Adult Female Cancer Survivors' Concerns About Future Children's Health and Genetic Risk

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


http://ift.tt/2BqBT44

Concomitant high expression of ERα36, GRP78 and GRP94 is associated with aggressive papillary thyroid cancer behavior

Abstract

Purpose

Papillary thyroid cancer (PTC) is more common in women than in men. It has been suggested that estrogen may be involved in its development, as has previously been shown for breast, endometrial and ovarian cancer. The purpose of this study was to assess correlations between the expression of the estrogen receptor alpha36 (ERα36) and the glucose regulated proteins GRP78 and GRP94 (chaperones involved in glycoprotein folding) and various PTC clinicopathological features, as well as to evaluate the potential usefulness of these three potential oncogenic proteins in the prediction of aggressive PTC behavior.

Methods

ERα36, GRP78 and GRP94 protein expression in 218 primary PTC tissues and PTC-derived BCPAP cells was examined using immunohistochemistry, Western blotting and immunocytochemistry. The proliferative, invasive and migrative capacities of BCPAP cells in which the respective genes were either exogenously over-expressed or silenced were assessed using BrdU incorporation and Transwell assays, respectively.

Results

We found that ERα36, GRP78 and GRP94 protein expression was upregulated in the primary PTC tissues tested. We also found that ERα36, GRP78 and GRP94 expression modulation affected the proliferation, invasion and migration of PTC-derived BCPAP cells. A positive correlation and a positive feedback loop were noted between ERα36, GRP78 and GRP94 protein expression in the primary PTC tissues and in BCPAP cells, respectively. High ERα36 expression in combination with a high GRP78/ GRP94 expression was found to have a stronger correlation with extrathyroid extension (ETE), lymph node metastasis (LNM), distant metastasis (DM) and high TNM stage than high ERα36 expression in combination with either high GRP78 or high GRP94 expression (p = 0.028 for ETE, p = 0.002 for DM and p ≤ 0.001 for LNM and high TNM stage) or high ERα36 expression alone (p < 0.001 for ETE, LNM, DM and high TNM stage).

Conclusions

From our data we conclude that a concomitant high expression of ERα36, GRP78 and GRP94 is strongly associated with aggressive PTC behavior and may be used as a predictor for ETE, LNM, DM and high TNM stage.

http://ift.tt/2rFE708

Foot posture in female patients 5 years after breast-conserving surgery: a case–control study

Abstract

Purpose

Along with the improvement in the outcomes of breast cancer treatment being observed in the recent years, long-term studies to assess distant adverse effects of the treatment have become increasingly important. The objective of this study was to assess the foot posture in patients subjected to breast-conserving therapy. The assessment was made 5 years after the surgical procedure.

Methods

116 female patients (mean age of 58.75 years) were qualified into a case–control study. Foot posture on the operated breast side (F1) as well as on the contralateral side (F2) was evaluated using a computer-based foot analysis tool as an extension of projection moiré-based podoscopic examination. Comparisons were made for the following parameters: limb load, L—foot length, W—foot width, L/W—Wejsflog index, ALPHA—hallux valgus angle, BETA—little toe varus angle, GAMMA—heel angle, KY—Sztriter–Godunov index, CL—Clarke's angle, HW—heel width.

Results

Five years after BCT, patients placed higher load on the foot on the side of the healthy breast (p = 0.0011). No statistically significant differences were observed between F1 and F2 with respect to other foot posture parameters (p > 0.05). No statistically significant differences were observed in foot posture parameters in patients having undergone BCT + ALND (axillary lymph node dissection) procedure as compared to patients subjected to BCT + SLNB (sentinel lymph node biopsy) procedure (p > 0.05).

Conclusions

No changes in foot posture were observed in patients 5 years after the BCT procedure. The type of the surgical procedure related to the lymph nodes within the axillary fossa has no effect on changes in foot posture.

http://ift.tt/2n6XNFu

Importance of whole-body imaging with complete coverage of hands and feet in alveolar rhabdomyosarcoma staging

Abstract

Background

Alveolar rhabdomyosarcoma commonly arises in the extremities and is characterized by aggressive biology and high frequency of metastases. Whole-body imaging is increasingly employed in pediatric oncology but not recommended as standard in the staging of soft-tissue sarcomas.

Objective

After observing patients with a large symptomatic alveolar rhabdomyosarcoma lesion and a smaller silent lesion in the more distal part of an extremity we sought to estimate the frequency of this constellation.

Materials and Methods

We retrospectively evaluated the data of prospectively registered paediatric patients (age <21 years) with alveolar rhabdomyosarcoma in the SoTiSaR (Soft Tissue Sarcoma Registry) of the Cooperative Weichteilsarkom Studiengruppe (CWS) 09/2011–04/2015 with regard to whole-body imaging.

Results

Seventy-five patients were eligible. Images of 57 patients had been submitted for reference consultation, including 80 whole-body examinations in 36 patients. Among them were 5 patients (14%, 95% confidence interval 3–25%) who had been diagnosed because of a symptomatic lesion while an additional silent lesion in the distal part of an extremity had remained unnoticed and had only been detected by later whole-body imaging. It is noteworthy that in 42 (53%) of all 80 whole-body examinations, the hands and feet had been only partially covered or completely excluded.

Conclusion

In alveolar rhabdomyosarcoma silent lesions can be overlooked when the distal parts of the limbs are not thoroughly examined and not completely covered by imaging. Missing them influences treatment decisions and prognosis. Our results should be considered when evaluating the potential role of whole-body imaging in rhabdomyosarcoma.

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Importance of whole-body imaging with complete coverage of hands and feet in alveolar rhabdomyosarcoma staging

Abstract

Background

Alveolar rhabdomyosarcoma commonly arises in the extremities and is characterized by aggressive biology and high frequency of metastases. Whole-body imaging is increasingly employed in pediatric oncology but not recommended as standard in the staging of soft-tissue sarcomas.

Objective

After observing patients with a large symptomatic alveolar rhabdomyosarcoma lesion and a smaller silent lesion in the more distal part of an extremity we sought to estimate the frequency of this constellation.

Materials and Methods

We retrospectively evaluated the data of prospectively registered paediatric patients (age <21 years) with alveolar rhabdomyosarcoma in the SoTiSaR (Soft Tissue Sarcoma Registry) of the Cooperative Weichteilsarkom Studiengruppe (CWS) 09/2011–04/2015 with regard to whole-body imaging.

Results

Seventy-five patients were eligible. Images of 57 patients had been submitted for reference consultation, including 80 whole-body examinations in 36 patients. Among them were 5 patients (14%, 95% confidence interval 3–25%) who had been diagnosed because of a symptomatic lesion while an additional silent lesion in the distal part of an extremity had remained unnoticed and had only been detected by later whole-body imaging. It is noteworthy that in 42 (53%) of all 80 whole-body examinations, the hands and feet had been only partially covered or completely excluded.

Conclusion

In alveolar rhabdomyosarcoma silent lesions can be overlooked when the distal parts of the limbs are not thoroughly examined and not completely covered by imaging. Missing them influences treatment decisions and prognosis. Our results should be considered when evaluating the potential role of whole-body imaging in rhabdomyosarcoma.

http://ift.tt/2n4I7m7

The Challenging Landscape of Cancer and Aging: Charting a Way Forward

NCI Director Dr. Norman Sharpless discusses research on aging and cancer, including understanding the biology of aging and its relationship to cancer, the treatment of older patients, and ensuring older patients participate in cancer clinical trials.

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The Challenging Landscape of Cancer and Aging: Charting a Way Forward

NCI Director Dr. Norman Sharpless discusses research on aging and cancer, including understanding the biology of aging and its relationship to cancer, the treatment of older patients, and ensuring older patients participate in cancer clinical trials.

http://ift.tt/2n4Mu0v

The impact of parity on life course blood pressure trajectories: the HUNT study in Norway

Abstract

The drop in blood pressure during pregnancy may persist postpartum, but the impact of pregnancy on blood pressure across the life course is not known. In this study we examined blood pressure trajectories for women in the years preceding and following pregnancy and compared life course trajectories of blood pressure for parous and nulliparous women. We linked information on all women who participated in the population-based, longitudinal HUNT Study, Norway with pregnancy information from the Medical Birth Registry of Norway. A total of 23,438 women were included with up to 3 blood pressure measurements per woman. Blood pressure trajectories were compared using a mixed effects linear spline model. Before first pregnancy, women who later gave birth had similar mean blood pressure to women who never gave birth. Women who delivered experienced a drop after their first birth of − 3.32 mmHg (95% CI, − 3.93, − 2.71) and − 1.98 mmHg (95% CI, − 2.43, − 1.53) in systolic and diastolic blood pressure, respectively. Subsequent pregnancies were associated with smaller reductions. These pregnancy-related reductions in blood pressure led to persistent differences in mean blood pressure, and at age 50, parous women still had lower systolic (− 1.93 mmHg; 95% CI, − 3.33, − 0.53) and diastolic (− 1.36 mmHg; 95% CI, − 2.26, − 0.46) blood pressure compared to nulliparous women. The findings suggest that the first pregnancy and, to a lesser extent, successive pregnancies are associated with lasting and clinically relevant reductions in systolic and diastolic blood pressure.

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Improving combination cancer therapy: the CombiPlex® development platform

Future Oncology, Ahead of Print.


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Improving combination cancer therapy: the CombiPlex® development platform

Future Oncology, Ahead of Print.


http://ift.tt/2DyETgH

The impact of parity on life course blood pressure trajectories: the HUNT study in Norway

Abstract

The drop in blood pressure during pregnancy may persist postpartum, but the impact of pregnancy on blood pressure across the life course is not known. In this study we examined blood pressure trajectories for women in the years preceding and following pregnancy and compared life course trajectories of blood pressure for parous and nulliparous women. We linked information on all women who participated in the population-based, longitudinal HUNT Study, Norway with pregnancy information from the Medical Birth Registry of Norway. A total of 23,438 women were included with up to 3 blood pressure measurements per woman. Blood pressure trajectories were compared using a mixed effects linear spline model. Before first pregnancy, women who later gave birth had similar mean blood pressure to women who never gave birth. Women who delivered experienced a drop after their first birth of − 3.32 mmHg (95% CI, − 3.93, − 2.71) and − 1.98 mmHg (95% CI, − 2.43, − 1.53) in systolic and diastolic blood pressure, respectively. Subsequent pregnancies were associated with smaller reductions. These pregnancy-related reductions in blood pressure led to persistent differences in mean blood pressure, and at age 50, parous women still had lower systolic (− 1.93 mmHg; 95% CI, − 3.33, − 0.53) and diastolic (− 1.36 mmHg; 95% CI, − 2.26, − 0.46) blood pressure compared to nulliparous women. The findings suggest that the first pregnancy and, to a lesser extent, successive pregnancies are associated with lasting and clinically relevant reductions in systolic and diastolic blood pressure.

http://ift.tt/2DHFwrW

Long non-coding RNA implicated in the invasion and metastasis of head and neck cancer: possible function and mechanisms

Abstract

Head and neck cancer (HNC) ranks as the 6th most common malignancy across the world. Metastasis is a hallmark of cancer, primarily contributing to the relapse and poor prognosis of HNC. Recently, long noncoding RNAs (lncRNAs), previously considered as non-functional, are increasingly appreciated by scholars to play crucial roles in mediating HNC metastasis. LncRNAs, which are located in the nucleus and cytoplasm, mainly exert their function via epigenetic modification, transcriptional control and translational regulation. As several lncRNAs are presently demonstrated to participate in HNC metastasis, we make a summary of the functions and mechanisms regarding these lncRNAs. As shown in the literature, most lncRNAs appear to promote the metastasis of HNC. Hence, we primarily discuss the lncRNAs involved in enhancing metastasis. Additionally, more studies are needed to understand those lncRNAs without clear mechanisms. Furthermore, we introduced the upstream regulator for the aberrant expression of lncRNAs in HNC. Finally, we concisely addressed future research prospects of lncRNAs, particularly the interplay between lncRNAs and tumor immunity as well as lncRNA-targeted therapeutic techniques, and we introduced clustered regularly interspaced short palindromic repeats (CRISPR)-Display as a possibly transformative tool to study lncRNAs. Although lncRNA research is still in the initial stage, it holds great promise to be applied as a prognosticator of HNC and a therapeutic target to inhibit HNC metastasis, which could significantly enhance the outcome of HNC patients.

http://ift.tt/2rFBJqi

The impact of parity on life course blood pressure trajectories: the HUNT study in Norway

Abstract

The drop in blood pressure during pregnancy may persist postpartum, but the impact of pregnancy on blood pressure across the life course is not known. In this study we examined blood pressure trajectories for women in the years preceding and following pregnancy and compared life course trajectories of blood pressure for parous and nulliparous women. We linked information on all women who participated in the population-based, longitudinal HUNT Study, Norway with pregnancy information from the Medical Birth Registry of Norway. A total of 23,438 women were included with up to 3 blood pressure measurements per woman. Blood pressure trajectories were compared using a mixed effects linear spline model. Before first pregnancy, women who later gave birth had similar mean blood pressure to women who never gave birth. Women who delivered experienced a drop after their first birth of − 3.32 mmHg (95% CI, − 3.93, − 2.71) and − 1.98 mmHg (95% CI, − 2.43, − 1.53) in systolic and diastolic blood pressure, respectively. Subsequent pregnancies were associated with smaller reductions. These pregnancy-related reductions in blood pressure led to persistent differences in mean blood pressure, and at age 50, parous women still had lower systolic (− 1.93 mmHg; 95% CI, − 3.33, − 0.53) and diastolic (− 1.36 mmHg; 95% CI, − 2.26, − 0.46) blood pressure compared to nulliparous women. The findings suggest that the first pregnancy and, to a lesser extent, successive pregnancies are associated with lasting and clinically relevant reductions in systolic and diastolic blood pressure.

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Long non-coding RNA implicated in the invasion and metastasis of head and neck cancer: possible function and mechanisms

Abstract

Head and neck cancer (HNC) ranks as the 6th most common malignancy across the world. Metastasis is a hallmark of cancer, primarily contributing to the relapse and poor prognosis of HNC. Recently, long noncoding RNAs (lncRNAs), previously considered as non-functional, are increasingly appreciated by scholars to play crucial roles in mediating HNC metastasis. LncRNAs, which are located in the nucleus and cytoplasm, mainly exert their function via epigenetic modification, transcriptional control and translational regulation. As several lncRNAs are presently demonstrated to participate in HNC metastasis, we make a summary of the functions and mechanisms regarding these lncRNAs. As shown in the literature, most lncRNAs appear to promote the metastasis of HNC. Hence, we primarily discuss the lncRNAs involved in enhancing metastasis. Additionally, more studies are needed to understand those lncRNAs without clear mechanisms. Furthermore, we introduced the upstream regulator for the aberrant expression of lncRNAs in HNC. Finally, we concisely addressed future research prospects of lncRNAs, particularly the interplay between lncRNAs and tumor immunity as well as lncRNA-targeted therapeutic techniques, and we introduced clustered regularly interspaced short palindromic repeats (CRISPR)-Display as a possibly transformative tool to study lncRNAs. Although lncRNA research is still in the initial stage, it holds great promise to be applied as a prognosticator of HNC and a therapeutic target to inhibit HNC metastasis, which could significantly enhance the outcome of HNC patients.

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Simultaneous detection of single-nucleotide variant, deletion/insertion, and fusion in lung and thyroid carcinoma using cytology specimen and an RNA-based next-generation sequencing assay

BACKGROUND

Molecular testing for epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusion is routinely performed in patients with stage IV lung adenocarcinoma to assess their eligibility for targeted therapy. Fine-needle aspiration (FNA)-derived material frequently is the only pathologic material available. The identification of genomic aberrations in thyroid nodules from FNA smears may help stratify cancer risk and spare patients from a second surgery. In the current study, the authors tested nucleic acid extracted from the cytology smears of lung and thyroid carcinomas for simultaneous detection of single-nucleotide variant, insertion/deletion, and gene fusion using an RNA-based next-generation sequencing assay.

METHODS

A total of 27 cases (17 lung and 10 thyroid carcinomas, the majority of which had known variants) were tested. Areas of interest were scrapped from stained smears using a scalpel. Total nucleic acid was extracted. Gene fusion and mutational analysis was performed using the Comprehensive Thyroid and Lung FusionPlex Assay. Data were analyzed using the analysis pipeline provided by the vendor. Eleven cases with available formalin-fixed, paraffin-embedded (FFPE) tissue were tested in parallel.

RESULTS

Gene fusions were detected in 6 cases; common single-nucleotide variants in EGFR, RAS, and BRAF in 14 cases; and in-frame deletions within EGFR in 3 cases. A concordance rate of 100% was observed between FNA and FFPE tissue.

CONCLUSIONS

Cytology preparations can be a reliable source for the detection of both DNA and RNA aberrations. The ability to simultaneously detect multiple types of genomic variants is crucial for patients with advanced cancer and maximizes the usefulness of cytology specimens. Cancer Cytopathol 2018. © 2018 American Cancer Society.

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All-in-one: The dream and reality of molecular cytopathology testing on routine lung cancer smears

If cytopathologists are used to dedicating 1 or more fine-needle aspiration passes to prepare a tumor-representative cell block, the testing laboratory may strongly rely on anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), and programmed death-ligand 1 (PD-L1) immunocytochemistry assays. Conversely, when sample procurement and diagnostic interpretation are based primarily on smeared material, cytopathologists should promote, in conjunction with the molecular team, ALK and ROS1 RNA-based testing approaches on smears, saving the cell block only for PD-L1 staining. See also pages 000-000.

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Simultaneous detection of single-nucleotide variant, deletion/insertion, and fusion in lung and thyroid carcinoma using cytology specimen and an RNA-based next-generation sequencing assay

BACKGROUND

Molecular testing for epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusion is routinely performed in patients with stage IV lung adenocarcinoma to assess their eligibility for targeted therapy. Fine-needle aspiration (FNA)-derived material frequently is the only pathologic material available. The identification of genomic aberrations in thyroid nodules from FNA smears may help stratify cancer risk and spare patients from a second surgery. In the current study, the authors tested nucleic acid extracted from the cytology smears of lung and thyroid carcinomas for simultaneous detection of single-nucleotide variant, insertion/deletion, and gene fusion using an RNA-based next-generation sequencing assay.

METHODS

A total of 27 cases (17 lung and 10 thyroid carcinomas, the majority of which had known variants) were tested. Areas of interest were scrapped from stained smears using a scalpel. Total nucleic acid was extracted. Gene fusion and mutational analysis was performed using the Comprehensive Thyroid and Lung FusionPlex Assay. Data were analyzed using the analysis pipeline provided by the vendor. Eleven cases with available formalin-fixed, paraffin-embedded (FFPE) tissue were tested in parallel.

RESULTS

Gene fusions were detected in 6 cases; common single-nucleotide variants in EGFR, RAS, and BRAF in 14 cases; and in-frame deletions within EGFR in 3 cases. A concordance rate of 100% was observed between FNA and FFPE tissue.

CONCLUSIONS

Cytology preparations can be a reliable source for the detection of both DNA and RNA aberrations. The ability to simultaneously detect multiple types of genomic variants is crucial for patients with advanced cancer and maximizes the usefulness of cytology specimens. Cancer Cytopathol 2018. © 2018 American Cancer Society.

http://ift.tt/2DD3ggN

All-in-one: The dream and reality of molecular cytopathology testing on routine lung cancer smears

If cytopathologists are used to dedicating 1 or more fine-needle aspiration passes to prepare a tumor-representative cell block, the testing laboratory may strongly rely on anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), and programmed death-ligand 1 (PD-L1) immunocytochemistry assays. Conversely, when sample procurement and diagnostic interpretation are based primarily on smeared material, cytopathologists should promote, in conjunction with the molecular team, ALK and ROS1 RNA-based testing approaches on smears, saving the cell block only for PD-L1 staining. See also pages 000-000.

http://ift.tt/2F7Y41s

Impact of chemotherapy relative dose intensity on cause-specific and overall survival for stage I–III breast cancer: ER+/PR+, HER2- vs. triple-negative

Abstract

Purpose

To investigate the impact of chemotherapy relative dose intensity (RDI) on cause-specific and overall survival for stage I–III breast cancer: estrogen receptor or progesterone receptor positive, human epidermal-growth factor receptor negative (ER+/PR+ and HER2-) vs. triple-negative (TNBC) and to identify the optimal RDI cut-off points in these two patient populations.

Methods

Data were collected by the Louisiana Tumor Registry for two CDC-funded projects. Women diagnosed with stage I–III ER+/PR+, HER2- breast cancer, or TNBC in 2011 with complete information on RDI were included. Five RDI cut-off points (95, 90, 85, 80, and 75%) were evaluated on cause-specific and overall survival, adjusting for multiple demographic variables, tumor characteristics, comorbidity, use of granulocyte-growth factor/cytokines, chemotherapy delay, chemotherapy regimens, and use of hormone therapy. Cox proportional hazards models and Kaplan–Meier survival curves were estimated and adjusted by stabilized inverse probability treatment weighting (IPTW) of propensity score.

Results

Of 494 ER+/PR+, HER2- patients and 180 TNBC patients, RDI < 85% accounted for 30.4 and 27.8%, respectively. Among ER+/PR+, HER2- patients, 85% was the only cut-off point at which the low RDI was significantly associated with worse overall survival (HR = 1.93; 95% CI 1.09–3.40). Among TNBC patients, 75% was the cut-off point at which the high RDI was associated with better cause-specific (HR = 2.64; 95% CI 1.09, 6.38) and overall survival (HR = 2.39; 95% CI 1.04–5.51).

Conclusions

Higher RDI of chemotherapy is associated with better survival for ER+/PR+, HER2- patients and TNBC patients. To optimize survival benefits, RDI should be maintained ≥ 85% in ER+/PR+, HER2- patients, and ≥ 75% in TNBC patients.

http://ift.tt/2rBVLli

Cancers, Vol. 10, Pages 30: Volumetric Modulated Arc (Radio) Therapy in Pets Treatment: The “La Cittadina Fondazione” Experience

Cancers, Vol. 10, Pages 30: Volumetric Modulated Arc (Radio) Therapy in Pets Treatment: The "La Cittadina Fondazione" Experience

Cancers doi: 10.3390/cancers10020030

Authors: Mario Dolera Luca Malfassi Nancy Carrara Sara Finesso Silvia Marcarini Giovanni Mazza Simone Pavesi Massimo Sala Gaetano Urso

Volumetric Modulated Arc Therapy (VMAT) is a modern technique, widely used in human radiotherapy, which allows a high dose to be delivered to tumor volumes and low doses to the surrounding organs at risk (OAR). Veterinary clinics takes advantage of this feature due to the small target volumes and distances between the target and the OAR. Sparing the OAR permits dose escalation, and hypofractionation regimens reduce the number of treatment sessions with a simpler manageability in the veterinary field. Multimodal volumes definition is mandatory for the small volumes involved and a positioning device precisely reproducible with a setup confirmation is needed before each session for avoiding missing the target. Additionally, the elaborate treatment plan must pursue hard constraints and objectives, and its feasibility must be evaluated with a per patient quality control. The aim of this work is to report results with regard to brain meningiomas and gliomas, trigeminal nerve tumors, brachial plexus tumors, adrenal tumors with vascular invasion and rabbit thymomas, in comparison with literature to determine if VMAT is a safe and viable alternative to surgery or chemotherapy alone, or as an adjuvant therapy in pets.

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Cancers, Vol. 10, Pages 30: Volumetric Modulated Arc (Radio) Therapy in Pets Treatment: The “La Cittadina Fondazione” Experience

Cancers, Vol. 10, Pages 30: Volumetric Modulated Arc (Radio) Therapy in Pets Treatment: The "La Cittadina Fondazione" Experience

Cancers doi: 10.3390/cancers10020030

Authors: Mario Dolera Luca Malfassi Nancy Carrara Sara Finesso Silvia Marcarini Giovanni Mazza Simone Pavesi Massimo Sala Gaetano Urso

Volumetric Modulated Arc Therapy (VMAT) is a modern technique, widely used in human radiotherapy, which allows a high dose to be delivered to tumor volumes and low doses to the surrounding organs at risk (OAR). Veterinary clinics takes advantage of this feature due to the small target volumes and distances between the target and the OAR. Sparing the OAR permits dose escalation, and hypofractionation regimens reduce the number of treatment sessions with a simpler manageability in the veterinary field. Multimodal volumes definition is mandatory for the small volumes involved and a positioning device precisely reproducible with a setup confirmation is needed before each session for avoiding missing the target. Additionally, the elaborate treatment plan must pursue hard constraints and objectives, and its feasibility must be evaluated with a per patient quality control. The aim of this work is to report results with regard to brain meningiomas and gliomas, trigeminal nerve tumors, brachial plexus tumors, adrenal tumors with vascular invasion and rabbit thymomas, in comparison with literature to determine if VMAT is a safe and viable alternative to surgery or chemotherapy alone, or as an adjuvant therapy in pets.

http://ift.tt/2DA4wCa

PKN2 in colon cancer cells inhibits M2 phenotype polarization of tumor-associated macrophages via regulating DUSP6-Erk1/2 pathway

Abstract

Background

Protein kinase N2 (PKN2) is a PKC-related serine/threonine-protein kinase. PKN2 is required for tumor cell migration, invasion and apoptosis. However, the functional role of PKN2 in regulating tumor associated macrophages (TAMs) polarization in colon cancer has never been reported.

Methods

PKN2 expression in human colon cancer tissues was examined with immunohistochemistry (IHC). M1/M2 macrophage signatures were evaluated by RT-PCR, IHC and flow cytometry. The effects of PKN2 on tumor growth and TAM polarization were investigated both in vitro and in vivo. PKN2 targeted cytokines/pathway were analyzed by gene expression analysis and further confirmed by PCR, luciferase assay or western blot. Correlations between PKN2 and transcriptional factors for IL4 and IL10 were confirmed by ChIP-qPCR. The catalytic activities of PKN2 and DUSP6 were determined by kinase activity assay. Interactions between PKN2 and DUSP6 were confirmed by Co-IP.

Results

The expression of PKN2 in colon cancer cells predicted a favorable prognosis and was associated with low M2 macrophage content in human colon cancer tissues. PKN2 inhibited tumor growth in mice xenograft model and inhibited M2 phenotype polarization both in vitro and in vivo. Mechanistically, PKN2 suppresses the expression of IL4 and IL10 from colon cancer cells by inhibiting Erk1/2 phosphorylation, which is required for phosphorylation and binding of CREB and Elk-1 to the promoters of IL4 and IL10. DUSP6, which is phosphorylated and activated through direct association with PKN2, suppresses Erk1/2 activation.

Conclusions

The expression of PKN2 in colon cancer cells suppresses tumor associated M2 macrophage polarization and tumor growth. Targeting PKN2 signaling pathway may provide a potential therapeutic strategy for colon cancer.

http://ift.tt/2n86HSm

PKN2 in colon cancer cells inhibits M2 phenotype polarization of tumor-associated macrophages via regulating DUSP6-Erk1/2 pathway

Abstract

Background

Protein kinase N2 (PKN2) is a PKC-related serine/threonine-protein kinase. PKN2 is required for tumor cell migration, invasion and apoptosis. However, the functional role of PKN2 in regulating tumor associated macrophages (TAMs) polarization in colon cancer has never been reported.

Methods

PKN2 expression in human colon cancer tissues was examined with immunohistochemistry (IHC). M1/M2 macrophage signatures were evaluated by RT-PCR, IHC and flow cytometry. The effects of PKN2 on tumor growth and TAM polarization were investigated both in vitro and in vivo. PKN2 targeted cytokines/pathway were analyzed by gene expression analysis and further confirmed by PCR, luciferase assay or western blot. Correlations between PKN2 and transcriptional factors for IL4 and IL10 were confirmed by ChIP-qPCR. The catalytic activities of PKN2 and DUSP6 were determined by kinase activity assay. Interactions between PKN2 and DUSP6 were confirmed by Co-IP.

Results

The expression of PKN2 in colon cancer cells predicted a favorable prognosis and was associated with low M2 macrophage content in human colon cancer tissues. PKN2 inhibited tumor growth in mice xenograft model and inhibited M2 phenotype polarization both in vitro and in vivo. Mechanistically, PKN2 suppresses the expression of IL4 and IL10 from colon cancer cells by inhibiting Erk1/2 phosphorylation, which is required for phosphorylation and binding of CREB and Elk-1 to the promoters of IL4 and IL10. DUSP6, which is phosphorylated and activated through direct association with PKN2, suppresses Erk1/2 activation.

Conclusions

The expression of PKN2 in colon cancer cells suppresses tumor associated M2 macrophage polarization and tumor growth. Targeting PKN2 signaling pathway may provide a potential therapeutic strategy for colon cancer.

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Complete response in advanced breast cancer patient treated with a combination of capecitabine, oral vinorelbine and dasatinib

Abstract

Background

Currently, there are no data available on the best choice of treatment in heavily pretreated patients with advanced breast cancer. However, the combination of oral vinorelbine and capecitabine has been demonstrated to be effective and safe in patients with advanced breast cancer pretreated with anthracycline. Furthermore, some studies assessed the activity of dasatinib, an oral tyrosine kinase inhibitor that inhibits five oncogenic tyrosine kinase families, alone or in combination with different chemotherapy in patients affected with advanced breast cancer.

Case presentation

A patient with metastatic breast cancer, hormone receptor positive and human epidermal grow factor receptor 2 negative, pretreated with epirubicine, taxanes and nab-paclitaxel, was submitted to third line chemotherapy with vinorelbine 60 mg/m² on day 1, 8 plus capecitabine 1000 mg/m² twice daily from day 1 to day 14 every 21 days. The patient was taking also dasatinib 100 mg once daily for chronic myeloid leukemia. The treatment was well tolerated and, after 15 months, computed tomography scan showed a complete response of liver metastases and bone stable disease. After another 28 months, a 18-fluorodeoxyglucose positron emission tomography scan showed a metabolic response of bone metastases without other site of disease.

Conclusions

This is the first case in literature about activity of dasatinib in combination with a chemotherapy schedule of oral vinorelbine and capecitabine in advanced breast cancer. This treatment showed both good tolerability and great activity with a long progression free survival of 54 months.

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Complete response in advanced breast cancer patient treated with a combination of capecitabine, oral vinorelbine and dasatinib

Abstract

Background

Currently, there are no data available on the best choice of treatment in heavily pretreated patients with advanced breast cancer. However, the combination of oral vinorelbine and capecitabine has been demonstrated to be effective and safe in patients with advanced breast cancer pretreated with anthracycline. Furthermore, some studies assessed the activity of dasatinib, an oral tyrosine kinase inhibitor that inhibits five oncogenic tyrosine kinase families, alone or in combination with different chemotherapy in patients affected with advanced breast cancer.

Case presentation

A patient with metastatic breast cancer, hormone receptor positive and human epidermal grow factor receptor 2 negative, pretreated with epirubicine, taxanes and nab-paclitaxel, was submitted to third line chemotherapy with vinorelbine 60 mg/m² on day 1, 8 plus capecitabine 1000 mg/m² twice daily from day 1 to day 14 every 21 days. The patient was taking also dasatinib 100 mg once daily for chronic myeloid leukemia. The treatment was well tolerated and, after 15 months, computed tomography scan showed a complete response of liver metastases and bone stable disease. After another 28 months, a 18-fluorodeoxyglucose positron emission tomography scan showed a metabolic response of bone metastases without other site of disease.

Conclusions

This is the first case in literature about activity of dasatinib in combination with a chemotherapy schedule of oral vinorelbine and capecitabine in advanced breast cancer. This treatment showed both good tolerability and great activity with a long progression free survival of 54 months.

http://ift.tt/2rBqbEd

Optic nerve grey crescent: an assessment using swept-source OCT

Description

Optic nerve head is an area of opening within the scleral canal; pigmentary changes at the margins and around the disc encompass a few important differential diagnoses. Optic nerve head grey crescent is one such clinical entity where it is characterised by bilateral greyish pigmentation of the temporal neuroretinal rims. The appearance is due to an internal extension of Bruch's layer into the peripapillary scleral canal. It was first noted by Shields in 1980 in African-American patients. The pigmentation mainly lies within the optic nerve head; in contrast, the alpha and beta zone lies outside the optic nerve head. The beta zone of peripapillary region is mainly an atrophy of the choroid and retinal layers for a varying degree with underlying visible sclera, whereas the crescent area is an area of encroachment of the peripapillary layers onto the disc. The clinical implication of this clinical entity is...

http://ift.tt/2n81aLz

A mesh masquerading as malignancy: a cancer misdiagnosed

After a positive faecal occult blood test, a 60-year-old woman underwent a screening colonoscopy which identified a malignant-looking ulcer in the ascending colon. Biopsies from the lesion were inconclusive. A subsequent CT scan of the abdomen and pelvis commented on a polypoid lesion in the ascending colon. A colorectal cancer multidisciplinary team discussion concluded that a right hemicolectomy was indicated as the lesion was suspicious for malignancy. Intraoperatively, there was a firm ascending colon mass adherent to the abdominal wall, which was resected with clear margins. There were no other complications, and the patient was discharged without further issues. Histopathology from the retrieved specimen revealed a complete absence of malignancy, but rather, inflamed granulation tissue with 'reaction to foreign birefringent material'—likely to represent a mesh from an incisional hernia repair 9 years previously. The patient is currently recovering well without complication.

http://ift.tt/2DCwJZ2

The effect of a therapeutic lithium level on a stroke-related cerebellar tremor

Lithium is a mood stabiliser used in the treatment of acute mania, bipolar disorder and as augmentation for unipolar major depression. Tremor is a common adverse effect associated with lithium at both therapeutic and toxic serum levels. We present a case of dose-dependent changes in the quality and intensity of a stroke-related, chronic cerebellar tremor with lithium treatment at serum levels within the therapeutic range. On admission, the patient in this case had a baseline fine, postural tremor, which increased in frequency and evolved to include myoclonic jerks once lithium therapy was initiated. Although the patient's serum lithium level was never in the toxic range, his tremor returned to baseline on reduction of his serum lithium level. This case highlights that a pre-existing, baseline tremor may lower the threshold for developing myoclonus. It also suggests that caution may be warranted with lithium therapy in the setting of known cerebellar disease.

http://ift.tt/2n811aZ

Severe systemic inflammatory response syndrome immediately after spinal surgery in a patient with axial gout

We report a 55-year-old man with gouty arthritis who developed a 3-month history of low back pain, gradual lower extremities weakness and urinary incontinence. Lumbar MRI showed an exophytic lesion at L3–L4. Immediately after spinal decompression surgery, he developed fever, disorientation, polyarthritis, acute kidney injury and leucocytosis. He was treated with multiple antimicrobial agents for presumed spinal abscess but did not improve. Multiple body site cultures were negative. Aspiration of the sacroiliac joint revealed the presence of monosodium uric acid crystals. A diagnosis of acute gout was done, and he was treated with high-dose intravenous methylprednisolone and colchicine. Within 48 hours, he had a remarkable clinical improvement. At discharge, neurological and laboratory abnormalities had resolved. Awareness of risk factors for axial gout and a high degree of suspicion are important to establish a prompt diagnosis and treatment to prevent severe complications as seen in this case.

http://ift.tt/2DCXX1L

Parapedicular vertebral augmentation with polymethylmetacrylate for pedicle screw loosening

A 71-year-old man who had a L1/S1 posterior fusion revision surgery complained of increasing back pain 5 weeks after the open surgical procedure. The pain was initially estimated at 9/10 on the visual analog scale (VAS) and thought to be related to a right-sided L2 screw loosening. A right parapedicular vertebroplasty was performed and polymethylmethacrylate cement was instilled around the right pedicle screw, filling the anterior two-thirds of the vertebral body. On postvertebroplasty day 1, the patient had significant improvement in his low back pain. The pain further decreased at 1 and 3 months after the intervention (2/10 on the VAS). Vertebroplasty is a minimally invasive, accessible, effective, and long lasting treatment for compression fractures. We believe that this technique could also be indicated to treat pain related to low grade screw loosening in properly selected patients.

http://ift.tt/2n7Hck4

Left ventricular free-wall rupture that occurred during a cardiopulmonary exercise test

Although exercise testing has become a standard procedure before discharge for patients with acute coronary syndrome, a fatal accident during the test is extremely rare. A 60-year-old man was admitted for a non-ST-segment elevation myocardial infarction. A coronary angiogram showed stenosis at the distal lesion of the circumflex, and a balloon angioplasty was performed. His recovery was smooth, and a cardiopulmonary exercise test was performed 5 days after admission. At 2.5 metabolic equivalents, he suddenly went into cardiac arrest, and percutaneous cardiopulmonary support was initiated. Echocardiography revealed the presence of a large amount of pericardial effusion, and emergency cardiac surgery was performed to repair the free-wall rupture. This highlights the importance of careful monitoring of patients with percutaneous coronary intervention during cardiopulmonary exercise testing.

http://ift.tt/2DzyiH7

Super obesity is not necessarily a contraindication to deep inferior epigastric perforator flap breast reconstruction

The deep inferior epigastric perforator (DIEP) flap is widely recognised as a safe and reliable flap for use as a first-choice option in autologous tissue breast reconstruction. Patients with obesity represent a challenging group for autologous breast reconstruction, as they are at increased risk of developing major and minor complications in comparison with patients with normal weight. We report a 59-year-old woman with super obesity, who presented to our department with right breast skin necrosis after implant reconstruction following mastectomy for right breast cancer. After implant removal and local treatment with both surgical debridement and negative pressure wound therapy, the patient successfully underwent a DIEP flap breast reconstruction. We conclude that super obesity should not be a contraindication to DIEP flap breast reconstruction.

http://ift.tt/2n7GWBC

The curse of relieving pain

A 39-year-old woman with a history of chronic back pain due to spinal haemangiomas, multiple malignancies and depression was brought by Emergency medical servicesS to the emergency centre (EC) after being found unresponsive on the bathroom floor. The patient had an exacerbation of her back pain the previous day for which she admitted to taking double her usual dose of oxycodone, in addition to alprazolam, lorazepam, diphenhydramine and a glass of wine. She reported that she lost consciousness and was down for over 8 hours. In the EC, she complained of right forearm pain which was accompanied by mild diffuse soft-tissue swelling and decreased sensation in the right hand. Radial pulse was intact. Creatine kinase was found to be at 4663 U/L. The patient was found to have acute compartment syndrome and underwent emergent forearm fasciotomy. She eventually regained full function of the right arm.

http://ift.tt/2DCXMn7

Closed gastroschisis with left defect: a rare variant

Description

Gastroschisis is a congenital abdominal wall defect where the intestine, stomach and rarely the other abdominal organs like the ovary, urinary bladder and the liver eviscerate through the defect. It occurs in 4–5 per 10 000 live births and is more common in preterm, low birth weight and female babies. Very rarely, the abdominal wall defect completely closes around the eviscerated bowel resulting in closed gastroschisis (CG). This constitutes 6% of all gastroschisis.1

A 2.2 kg term baby boy delivered at home at 36 weeks of gestation presented on day 1 of life with an eviscerated loop of herniated bowel segment seen to the left of the umbilicus (figure 1). The bowel loop was uncovered, erythematous and congested, butlooked viable; the underlying umbilicus was closed. The child had bilious vomiting and had not passed meconium. The X-ray of the abdomen was suggestive of intestinal obstruction. The child was...

http://ift.tt/2BrsmtQ

Fulminant myocarditis

Description

A previously healthy 36-year-old man presented to the emergency department with dyspnoea after 3 days of fatigue and coughing. He experienced shortness of breath and had 8 hours of fever before admission. His body temperature was 38°C. His ECG showed a wide QRS complex with no signs of acute myocardial infarction (figure 1). Echocardiography demonstrated oedematous left ventricular myocardium and severe, diffusely hypokinetic left ventricular wall motion with estimated ejection fraction of 30%. Intra-aortic balloon pump (IABP) insertion was immediately performed for cardiogenic shock. Meanwhile, he experienced cardiac arrest with ventricular tachycardia. As cardioversion was unsuccessful, peripheral venous-arterial extracorporeal membrane oxygenation (va-ECMO) was initiated, with temporary pacemaker placement and dobutamine administration. Coronary angiography revealed normal coronary arteries. Shortly thereafter, he developed complete ventricular standstill, with no ventricular activity on the ECG and echocardiogram (figure 2 and video 1). Endomyocardial biopsy revealed massive...

http://ift.tt/2n79TOJ

Rare presentation of AICA syndrome

We report a rare presentation of an anterior inferior cerebellar artery (AICA) infarct in a 74-year-old woman with acute-onset nausea, vomiting, vertigo and gait instability long before the full onset of symptoms and a negative MRI on admission. Over the next several days the patient developed left facial weakness, numbness, hypoacusis, and limb and gait ataxia, and was found to have acute infarcts of the left pons and cerebellar peduncle consistent with an AICA syndrome. We discuss this rare stepwise presentation in AICA syndrome and possible underlying pathophysiology. Such patients at risk for cerebrovascular disease should undergo a careful history, exam and follow-up, even with negative MRI findings, as their symptoms may precede a serious vascular event.

http://ift.tt/2BpD8R9

Combination drug chemotherapy and massive skeletal allograft in the management of hydatid disease of femur

Hydatid disease of long bone is a rare presentation. Chemotherapy and surgery constitute the standard treatment of choice. Non-union of a pathological fracture of femur particularly due to hydatid disease has been known to be resistant to treatment. These resistant cases require combination drug chemotherapy and excision of the lesion. Reconstruction of a large skeletal defect following resection of the lesion poses a challenge to the orthopaedic surgeons. We discuss the staged treatment of hydatid disease of shaft of femur with resection and cement spacer application followed by reconstruction using massive skeletal allograft under cover of combination drug chemotherapy.

http://ift.tt/2n5iSQy

Cranial neuropathy and severe pain due to early disseminated Borrelia burgdorferi infection

A 61-year-old man presented to the emergency department in the summer with a right seventh cranial nerve lower motor neuron palsy and worsening paraesthesias for 6 weeks. He had debilitating pain at the scalp and spine. Prior work up was unrevealing. The patient resided in the upper Midwest region of the USA and worked outdoors, optimising the landscape for white tailed deer. Repeat cerebrospinal fluid testing revealed a lymphocytic pleocytosis and positive IgM Lyme serology. Brain MRI demonstrated enhancement of multiple cranial nerves bilaterally. He was diagnosed with early Lyme neuroborreliosis and treated with 28 days of intravenous ceftriaxone. While the painful meningoradiculitis, also known as Bannwarth syndrome, is more commonly seen in Europe, facial palsy is more frequently encountered in the USA. Clinical manifestations of neuroborreliosis are important to recognise as the classic presentation varies by geography and on occasion repeat serological testing may be necessary.

http://ift.tt/2BqaQWL

New drugs and new toxicities: pembrolizumab-induced myocarditis

Pembrolizumab is an immune checkpoint inhibitor that significantly improves clinical outcomes in numerous solid organ malignancies. Despite successful therapeutic responses, this new drug comes with a constellation of adverse reactions. Herein, we chronicle the case of a patient with metastatic non-small-cell lung cancer treated with pembrolizumab. After two cycles, he developed new-onset dyspnoea on exertion. Electrocardiogram showed idioventricular rhythm with diffuse ST-segment elevations. Echocardiography revealed severe biventricular cardiac dysfunction. Based on diagnostic workup and exclusion of probable aetiologies, the patient was diagnosed with pembrolizumab-induced myocarditis. The treatment was initiated with corticosteroids and guideline-conform heart failure therapy. He demonstrated a marked clinical response with resolution of congestive heart failure symptoms. This article summarises the clinical evidence regarding the epidemiology, pathophysiology, clinical features, diagnostic modalities and management of patients with pembrolizumab-associated myocarditis. In addition, it highlights that programmed death receptor-1 inhibition can cause a spectrum of autoimmune adverse events requiring clinical monitoring and periodic screenings.

http://ift.tt/2n73kfa

Delayed presentation of a virilising, pure testosterone-secreting adrenocortical carcinoma with coexistent composite myelolipoma and a venous thrombus extending to the heart

A 40-year-old normotensive woman presented with abnormal facial hair for 4 years and amenorrhoea for 13 years. Hormonal, biochemical and haematological evaluation showed isolated elevation of serum testosterone and free testosterone. Her follicle-stimulating hormone and luteinising hormone were in the premenopausal range. Until recently she had reconciled to early 'menopause' and visited beauty clinics but never sought medical evaluation. Imaging revealed an enhancing left adrenal mass with fat densities and venous thrombus extending through the inferior vena cava to a 7 cm mass in the right atrium. She underwent left kidney-preserving surgery utilising hypothermic cardiopulmonary bypass with early clamping of the pulmonary artery without circulatory arrest. Histology showed adrenocortical carcinoma with composite incidental myelolipoma and neoplastic thrombus. At 2 months, testosterone has normalised and she is doing well. Isolated testosterone-secreting adrenocortical carcinoma with massive venous thrombus is rare as is coincidental composite macroscopic myelolipoma.

http://ift.tt/2BqqMs7

Post-cholecystectomy partial biliary stricture leading to primary intrahepatic calculi

Description

A 40-year-old woman presented with complaints of pain in the right hypochondrium and intermittent high-grade fever with chills for 3 months. She had a history of waxing and waning jaundice for the last 2 months. She had undergone open cholecystectomy 15 years back. Abdominal examination revealed a non-tender hepatomegaly. Blood investigations showed a deranged liver function suggestive of obstructive biliary pathology. Total bilirubin level was raised (4.6 mg/dL) with predominant direct component (3.5 mg/dL). Her serum alkaline phosphatase was elevated (1683 U/L) but transaminase levels were within normal range.

An abdominal ultrasound showed mild hepatomegaly with bilateral intrahepatic biliary radicle dilation. Multiple calculi were present in the intrahepatic bile ducts and a hypoechoic shadow was seen near hilum. In view of suspected mass lesion at hilum, an abdominal CT scan was obtained that showed thickening of the common hepatic duct. Intrahepatic ducts were grossly dilated and were filled with multiple...

http://ift.tt/2n6LdpN

Intracranial myopericytoma: a tumour in a rare location

A 49-year-old female with history of headache, nausea and vomiting with some weeks of evolution, without neurological symptoms. Radiology revealed an expansive lesion near the inferior vermix and cerebellar tonsils, with heterogeneous gadolinium uptake and mass effect on the fourth ventricle, representing a probable extraventricular origin for the lesion. Pathological examination showed a proliferation of oval/spindle cell proliferation with eosinophil cytoplasm and small and monotonous nuclei, without mitoses. The cells had a concentric growth, surrounding thin-walled blood vessels with foci of stromal myxoid degeneration and whorled pattern. The vessels had a haemangiopericytoma pattern and were lined by non-atypical endothelial cells. The tumorous cells expressed vimentin, alpha-smooth actin and heavy-chain caldesmon and were negative for epithelial membrane antigen, protein S100, HMB45, CD34, calponin and desmin, thus providing the final diagnosis of intracranial myopericytoma.

http://ift.tt/2BqiAYZ

Doxycycline sclerotherapy for post-traumatic inguinal lymphocele in a child

Lymphoceles are abnormal collections of lymphatic fluid caused by a disruption in the lymphatic channels and leakage of lymph. This most commonly occurs after surgical procedures, but occasionally lymphoceles may be the result of trauma, more commonly penetrating trauma. Lymphoceles resulting from blunt trauma are rare in both adults and children. In the adult population, there are few published case reports, and management principles vary. To date, there are no reports of traumatic lymphoceles in the paediatric population, and therefore there is no precedent for treatment. Here, we report the case of a young boy who developed an inguinal lymphocele from a bicycle handle bar injury which was successfully treated with doxycycline sclerotherapy.

http://ift.tt/2n87qDC

Extensive skin ulcers in a child with juvenile dermatomyositis

Juvenile dermatomyositis (JDM) is a multisystemic disorder. Vasculitic ulcers in JDM have been reported to involve axilla, elbow or extensor surfaces of other joints. We report a young boy with JDM who presented with extensive cutaneous ulcers involving scrotum, prepuce, gluteal region, neck, bilateral axilla, periumbilical area and bilateral elbows and popliteal fossa. His disease course was marked by several relapses and he required immunosuppression with prednisolone, subcutaneous methotrexate and intravenous cyclophosphamide. His muscle weakness improved and skin ulcers healed after 6 months of intensive immunosuppressive therapy. Children with JDM and ulcers often show increased resistance to immunosuppressive therapy. Extensive cutaneous ulcers in JDM, especially those involving the scrotum, have never been described. Awareness regarding the uncommon manifestations is important to guide appropriate therapy.

http://ift.tt/2BpD8k7

Multiple anomalies in the origin and course of vertebral arteries and aberrant right subclavian artery in a child with moyamoya syndrome

Here we report, for the first time, a combination of five-vessel aortic arch, anomalous origin of the right vertebral artery (VA) from the common carotid artery (CCA), an aberrant right subclavian artery (SCA), and bilateral symmetrical segmental agenesis of VAs.In this case report, we present a patient with moyamoya syndrome (MMS) and Down syndrome (DS) who has bilateral symmetrical segmental agenesis of VAs, left VA originating from aortic arch and anomalous origin of right VA arising from CCA in combination with an aberrant right SCA. Therefore, five vessels are originating from aortic arch. Here, we report, for the first time, a combination of five-vessel aortic arch with an aberrant right SCA and symmetrical segmental agenesis of both VAs. The possible embryological mechanisms of the anomalies as well as an relation with MMS and DS are discussed.

http://ift.tt/2n7jw06

MIR-708 promotes phagocytosis to eradicate T-ALL cells by targeting CD47

Abstract

Immunoevasion is a hallmark of cancer progression, and immune checkpoint blockade has emerged as a promising strategy for cancer treatment. microRNAs (miRNAs) are important negative regulators of gene expression in the immune system. Here, we demonstrate that miR-708 regulates CD47, a transmembrane protein that inhibits phagocytosis in T cell acute lymphoblastic leukemia. miR-708 directly targeted CD47 through binding to 3'UTR and is inversely correlated with CD47 expression. Functional studies showed that restoration of miR-708 expression in the T-ALL cell line is sufficient to promote phagocytosis by macrophages in the absence or presence of the anti-CD47 antibody to eradicate T-ALL cells, and inhibited tumor engraftment in vivo. Together, our findings suggest that miR-708 is a key negative regulator of CD47 and may serve as an attractive candidate for immunotherapy of T-ALL.

from Cancer via ola Kala on Inoreader http://ift.tt/2n6Iyfw
via IFTTT

MIR-708 promotes phagocytosis to eradicate T-ALL cells by targeting CD47

Abstract

Immunoevasion is a hallmark of cancer progression, and immune checkpoint blockade has emerged as a promising strategy for cancer treatment. microRNAs (miRNAs) are important negative regulators of gene expression in the immune system. Here, we demonstrate that miR-708 regulates CD47, a transmembrane protein that inhibits phagocytosis in T cell acute lymphoblastic leukemia. miR-708 directly targeted CD47 through binding to 3'UTR and is inversely correlated with CD47 expression. Functional studies showed that restoration of miR-708 expression in the T-ALL cell line is sufficient to promote phagocytosis by macrophages in the absence or presence of the anti-CD47 antibody to eradicate T-ALL cells, and inhibited tumor engraftment in vivo. Together, our findings suggest that miR-708 is a key negative regulator of CD47 and may serve as an attractive candidate for immunotherapy of T-ALL.

http://ift.tt/2n6Iyfw

Predictive and prognostic clinical and pathological factors of nivolumab efficacy in non-small-cell lung cancer patients

Abstract

Background

Immunotherapy increases overall response rate (ORR) and overall survival (OS) in patients with non-small-cell lung cancer (NSCLC). Prognostic and predictive factors are a high need.

Patients and methods

Retrospective review of NSCLC patients treated with nivolumab was performed. Analyzed variables included age, sex, stage, performance status (PS), location of metastases, presence of tumour-related symptoms and comorbidities, number of metastasis locations, previous chemotherapy, anti-angiogenic and radiotherapy treatments, and analytical data from the standard blood count and biochemistry.

Results

A total of 175 patients were included. Median age was 61.5 years, 73.1% were men, 77.7% were ECOG-PS 0–1, and 86.7% were included with stage IV disease. Histology was non-squamous in 77.1%. Sixty-five received nivolumab in second line (37.1%). Thirty-eight patients had brain metastasis (22%), and 39 (22.3%) liver metastasis and 126 (72%) had more than one metastatic location. The ORR was 15.7% with median Progression free survival (PFS) 2.8 months and median OS 5.81 months. Stage III vs IV and time since the beginning of the previous line of treatment ≥ 6 vs < 6 months were associated with better response. PS 2, time since the previous line of treatment < 6 vs ≥ 6 months, and more than one metastatic location were independently associated with shorter OS in multivariable analysis (7.8 vs 2.7 months, 11.2 vs 4.6 months, and 9.4 vs 5.1 month). Finally, time since the previous treatment < 6 vs ≥ 6 months and more than one metastatic location were independently associated with shorter PFS in multivariable analysis (4.3 vs 2.3 months and 4.7 vs 2.3 months).

Conclusion

Poor PS, short period of time since the previous treatment, and more than one metastatic location were associated with poorer prognostic.

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via IFTTT

Predictive and prognostic clinical and pathological factors of nivolumab efficacy in non-small-cell lung cancer patients

Abstract

Background

Immunotherapy increases overall response rate (ORR) and overall survival (OS) in patients with non-small-cell lung cancer (NSCLC). Prognostic and predictive factors are a high need.

Patients and methods

Retrospective review of NSCLC patients treated with nivolumab was performed. Analyzed variables included age, sex, stage, performance status (PS), location of metastases, presence of tumour-related symptoms and comorbidities, number of metastasis locations, previous chemotherapy, anti-angiogenic and radiotherapy treatments, and analytical data from the standard blood count and biochemistry.

Results

A total of 175 patients were included. Median age was 61.5 years, 73.1% were men, 77.7% were ECOG-PS 0–1, and 86.7% were included with stage IV disease. Histology was non-squamous in 77.1%. Sixty-five received nivolumab in second line (37.1%). Thirty-eight patients had brain metastasis (22%), and 39 (22.3%) liver metastasis and 126 (72%) had more than one metastatic location. The ORR was 15.7% with median Progression free survival (PFS) 2.8 months and median OS 5.81 months. Stage III vs IV and time since the beginning of the previous line of treatment ≥ 6 vs < 6 months were associated with better response. PS 2, time since the previous line of treatment < 6 vs ≥ 6 months, and more than one metastatic location were independently associated with shorter OS in multivariable analysis (7.8 vs 2.7 months, 11.2 vs 4.6 months, and 9.4 vs 5.1 month). Finally, time since the previous treatment < 6 vs ≥ 6 months and more than one metastatic location were independently associated with shorter PFS in multivariable analysis (4.3 vs 2.3 months and 4.7 vs 2.3 months).

Conclusion

Poor PS, short period of time since the previous treatment, and more than one metastatic location were associated with poorer prognostic.

http://ift.tt/2rxKnqL

Risk management adherence following genetic testing for hereditary cancer syndromes: a Singaporean experience

Abstract

Assessing adherence behavior among mutation carriers to cancer risk management guidelines is important for both service improvement and cost-effectiveness analyses, but such real-world data is often lacking. The present study aims to report adherence rates among mutation carriers in a recently established cancer genetics program in Singapore. We conducted a medical chart review of mutation carriers who had attended for genetic counseling and gathered data regarding risk management behavior, including cancer surveillance and/or risk-reducing surgery, and cancers subsequently detected. Of the 52 subjects included in the study, the majority were affected prior to genetic testing (78.8%) and had family history suggestive of a germline mutation (88.5%). The overall adherence rate was 96.2%, including 37 (74.0%) fully-adherent and 13 (26.0%) partially-adherent subjects, with five cancers subsequently detected. Among the 28 BRCA1/2 mutation carriers, adherence to breast cancer risk management was also high (89.3%), although uptake of risk-reducing bilateral salpingo-oophorectomy was not as common (60%). Whilst overall adherence in this cohort was high, BRCA1/2 mutation carriers may require targeted interventions to improve ovarian cancer risk management uptake. Additionally, further education among health professionals and the wider community regarding cancer genetics is needed to ensure the early identification of mutation carriers.

http://ift.tt/2GbsHnW

APC mosaicism in a young woman with desmoid type fibromatosis and familial adenomatous polyposis

Abstract

Familial adenomatous polyposis (FAP) is usually caused by germline mutations in the adenomatous polyposis coli (APC) gene. The classic form is characterized by hundreds to thousands of adenomas in the colorectum and early onset colorectal cancer (CRC) if left untreated. FAP is also associated with multiple extra-colonic manifestations such as gastroduodenal polyps, osteomas, epidermoid cysts, fibromas and desmoids. Most desmoid tumours in FAP patients occur intra-abdominally. Approximately 15–20% of the APC mutations are de novo mutations. Somatic mosaicism has been reported in some sporadic cases of polyposis but is probably an underestimated cause of the disease. This case report presents the detection of a mosaic APC mutation in a 26-year-old woman who as a child had been diagnosed with desmoid type fibromatosis. FAP was suggested when she presented with extensive extra abdominal fibromatosis. Our findings indicate that APC mutations may be suspected in patients presenting with a desmoid regardless of its location. If there is clinical evidence that the patient has FAP, adenomas and colonic mucosa in addition to leukocyte DNA should be included in the screening, preferably using methods that are more sensitive than Sanger sequencing.

http://ift.tt/2rDOykQ

Subsequent anti-VEGF therapy after first-line anti-EGFR therapy improved overall survival of patients with metastatic colorectal cancer

http://ift.tt/2GaQLrf

Predictive and prognostic clinical and pathological factors of nivolumab efficacy in non-small-cell lung cancer patients

Abstract

Background

Immunotherapy increases overall response rate (ORR) and overall survival (OS) in patients with non-small-cell lung cancer (NSCLC). Prognostic and predictive factors are a high need.

Patients and methods

Retrospective review of NSCLC patients treated with nivolumab was performed. Analyzed variables included age, sex, stage, performance status (PS), location of metastases, presence of tumour-related symptoms and comorbidities, number of metastasis locations, previous chemotherapy, anti-angiogenic and radiotherapy treatments, and analytical data from the standard blood count and biochemistry.

Results

A total of 175 patients were included. Median age was 61.5 years, 73.1% were men, 77.7% were ECOG-PS 0–1, and 86.7% were included with stage IV disease. Histology was non-squamous in 77.1%. Sixty-five received nivolumab in second line (37.1%). Thirty-eight patients had brain metastasis (22%), and 39 (22.3%) liver metastasis and 126 (72%) had more than one metastatic location. The ORR was 15.7% with median Progression free survival (PFS) 2.8 months and median OS 5.81 months. Stage III vs IV and time since the beginning of the previous line of treatment ≥ 6 vs < 6 months were associated with better response. PS 2, time since the previous line of treatment < 6 vs ≥ 6 months, and more than one metastatic location were independently associated with shorter OS in multivariable analysis (7.8 vs 2.7 months, 11.2 vs 4.6 months, and 9.4 vs 5.1 month). Finally, time since the previous treatment < 6 vs ≥ 6 months and more than one metastatic location were independently associated with shorter PFS in multivariable analysis (4.3 vs 2.3 months and 4.7 vs 2.3 months).

Conclusion

Poor PS, short period of time since the previous treatment, and more than one metastatic location were associated with poorer prognostic.

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

Predictive and prognostic clinical and pathological factors of nivolumab efficacy in non-small-cell lung cancer patients

Abstract

Background

Immunotherapy increases overall response rate (ORR) and overall survival (OS) in patients with non-small-cell lung cancer (NSCLC). Prognostic and predictive factors are a high need.

Patients and methods

Retrospective review of NSCLC patients treated with nivolumab was performed. Analyzed variables included age, sex, stage, performance status (PS), location of metastases, presence of tumour-related symptoms and comorbidities, number of metastasis locations, previous chemotherapy, anti-angiogenic and radiotherapy treatments, and analytical data from the standard blood count and biochemistry.

Results

A total of 175 patients were included. Median age was 61.5 years, 73.1% were men, 77.7% were ECOG-PS 0–1, and 86.7% were included with stage IV disease. Histology was non-squamous in 77.1%. Sixty-five received nivolumab in second line (37.1%). Thirty-eight patients had brain metastasis (22%), and 39 (22.3%) liver metastasis and 126 (72%) had more than one metastatic location. The ORR was 15.7% with median Progression free survival (PFS) 2.8 months and median OS 5.81 months. Stage III vs IV and time since the beginning of the previous line of treatment ≥ 6 vs < 6 months were associated with better response. PS 2, time since the previous line of treatment < 6 vs ≥ 6 months, and more than one metastatic location were independently associated with shorter OS in multivariable analysis (7.8 vs 2.7 months, 11.2 vs 4.6 months, and 9.4 vs 5.1 month). Finally, time since the previous treatment < 6 vs ≥ 6 months and more than one metastatic location were independently associated with shorter PFS in multivariable analysis (4.3 vs 2.3 months and 4.7 vs 2.3 months).

Conclusion

Poor PS, short period of time since the previous treatment, and more than one metastatic location were associated with poorer prognostic.

http://ift.tt/2rxKnqL