Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

Abstract

In the past 15 years, the proteasome has been validated as an anti-cancer drug target and 20S proteasome inhibitors (such as bortezomib and carfilzomib) have been approved by the FDA for the treatment of multiple myeloma and some other liquid tumors. However, there are shortcomings of clinical proteasome inhibitors, including severe toxicity, drug resistance, and no effect in solid tumors. At the same time, extensive research has been conducted in the areas of natural compounds and old drug repositioning towards the goal of discovering effective, economical, low toxicity proteasome-inhibitory anti-cancer drugs. A variety of dietary polyphenols, medicinal molecules, metallic complexes, and metal-binding compounds have been found to be able to selectively inhibit tumor cellular proteasomes and induce apoptotic cell death in vitro and in vivo, supporting the clinical success of specific 20S proteasome inhibitors bortezomib and carfilzomib. Therefore, the discovery of natural proteasome inhibitors and researching old drugs with proteasome-inhibitory properties may provide an alternative strategy for improving the current status of cancer treatment and even prevention.

http://ift.tt/2ziWAP8

Cholecystokinin receptor antagonist alters pancreatic cancer microenvironment and increases efficacy of immune checkpoint antibody therapy in mice

Abstract

Advanced pancreatic ductal adenocarcinoma (PDAC) has typically been resistant to chemotherapy and immunotherapy; therefore, novel strategies are needed to enhance therapeutic response. Cholecystokinin (CCK) has been shown to stimulate growth of pancreatic cancer. CCK receptors (CCKRs) are present on pancreatic cancer cells, fibroblasts, and lymphocytes. We hypothesized that CCKR blockade would improve response to immune checkpoint antibodies by promoting influx of tumor-infiltrating lymphocytes (TILs) and reducing fibrosis. We examined the effects of CCKR antagonists or immune checkpoint blockade antibodies alone or in combination in murine models of PDAC. Monotherapy with CCKR blockade significantly decreased tumor size and metastases in SCID mice with orthotopic PDAC, and in C57BL/6 mice, it reduced fibrosis and induced the influx of TILs. Immune-competent mice bearing syngeneic pancreatic cancer (Panc02 and mT3-2D) that were treated with the combination of CCK receptor antagonists and immune checkpoint blockade antibodies survived significantly longer with smaller tumors. Tumor immunohistochemical staining and flow cytometry demonstrated that the tumors of mice treated with the combination regimen had a significant reduction in Foxp3+ T-regulatory cells and an increase in CD4+ and CD8+ lymphocytes. Masson's trichrome stain analysis revealed 50% less fibrosis in the tumors of mice treated with CCKR antagonist compared to controls and compared to checkpoint antibody therapy. CCKR antagonists given with immune checkpoint antibody therapy represent a novel approach for improving survival of PDAC. The mechanism by which this combination therapy improves the survival of PDAC may be related to the decreased fibrosis and immune cells of the tumor microenvironment.

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Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

Abstract

In the past 15 years, the proteasome has been validated as an anti-cancer drug target and 20S proteasome inhibitors (such as bortezomib and carfilzomib) have been approved by the FDA for the treatment of multiple myeloma and some other liquid tumors. However, there are shortcomings of clinical proteasome inhibitors, including severe toxicity, drug resistance, and no effect in solid tumors. At the same time, extensive research has been conducted in the areas of natural compounds and old drug repositioning towards the goal of discovering effective, economical, low toxicity proteasome-inhibitory anti-cancer drugs. A variety of dietary polyphenols, medicinal molecules, metallic complexes, and metal-binding compounds have been found to be able to selectively inhibit tumor cellular proteasomes and induce apoptotic cell death in vitro and in vivo, supporting the clinical success of specific 20S proteasome inhibitors bortezomib and carfilzomib. Therefore, the discovery of natural proteasome inhibitors and researching old drugs with proteasome-inhibitory properties may provide an alternative strategy for improving the current status of cancer treatment and even prevention.

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Female gonadal shielding with automatic exposure control increases radiation risks

Abstract

Background

Gonadal shielding remains common, but current estimates of gonadal radiation risk are lower than estimated risks to colon and stomach. A female gonadal shield may attenuate active automatic exposure control (AEC) sensors, resulting in increased dose to colon and stomach as well as to ovaries outside the shielded area.

Objective

We assess changes in dose–area product (DAP) and absorbed organ dose when female gonadal shielding is used with AEC for pelvis radiography.

Materials and methods

We imaged adult and 5-year-old equivalent dosimetry phantoms using pelvis radiograph technique with AEC in the presence and absence of a female gonadal shield. We recorded DAP and mAs and measured organ absorbed dose at six internal sites using film dosimetry.

Results

Female gonadal shielding with AEC increased DAP 63% for the 5-year-old phantom and 147% for the adult phantom. Absorbed organ dose at unshielded locations of colon, stomach and ovaries increased 21–51% in the 5-year-old phantom and 17–100% in the adult phantom. Absorbed organ dose sampled under the shield decreased 67% in the 5-year-old phantom and 16% in the adult phantom.

Conclusion

Female gonadal shielding combined with AEC during pelvic radiography increases absorbed dose to organs with greater radiation sensitivity and to unshielded ovaries. Difficulty in proper use of gonadal shields has been well described, and use of female gonadal shielding may be inadvisable given the risks of increasing radiation.

http://ift.tt/2yA3r9L

Female gonadal shielding with automatic exposure control increases radiation risks

Abstract

Background

Gonadal shielding remains common, but current estimates of gonadal radiation risk are lower than estimated risks to colon and stomach. A female gonadal shield may attenuate active automatic exposure control (AEC) sensors, resulting in increased dose to colon and stomach as well as to ovaries outside the shielded area.

Objective

We assess changes in dose–area product (DAP) and absorbed organ dose when female gonadal shielding is used with AEC for pelvis radiography.

Materials and methods

We imaged adult and 5-year-old equivalent dosimetry phantoms using pelvis radiograph technique with AEC in the presence and absence of a female gonadal shield. We recorded DAP and mAs and measured organ absorbed dose at six internal sites using film dosimetry.

Results

Female gonadal shielding with AEC increased DAP 63% for the 5-year-old phantom and 147% for the adult phantom. Absorbed organ dose at unshielded locations of colon, stomach and ovaries increased 21–51% in the 5-year-old phantom and 17–100% in the adult phantom. Absorbed organ dose sampled under the shield decreased 67% in the 5-year-old phantom and 16% in the adult phantom.

Conclusion

Female gonadal shielding combined with AEC during pelvic radiography increases absorbed dose to organs with greater radiation sensitivity and to unshielded ovaries. Difficulty in proper use of gonadal shields has been well described, and use of female gonadal shielding may be inadvisable given the risks of increasing radiation.

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Correction to: Contribution of the MRPS22 variant and a Down mosaic to the phenotype

Abstract

In the original publication of the article, the title was incorrectly written as "The cerebellum is a common site of affection in Leigh syndrome." The correct title is "Contribution of the MRPS22 variant and a Down mosaic to the phenotype."

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Proline dehydrogenase gene (PRODH) polymorphisms and schizophrenia susceptibility: a meta-analysis

Abstract

Previous studies have been conducted to explore the association between proline dehydrogenase gene (PRODH) polymorphisms and schizophrenia (SZ) susceptibility, but providing the controversial results. Here we performed this meta-analysis to determine whether PRODH variants were associated with SZ risk. Relevant studies were screened by retrieving online database PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI) and SZGene from inception to December 2016. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated based on genotype data or allele frequency to evaluate the strength of this association. For rs372055, eleven studies with 3398 SZ patients and 3171 controls were included and the results indicated that people carrying the T allele was not associated with SZ risk in allele frequency model (C vs T, OR = 1.12, 95%CI = 0.96–1.32). However, results from subgroup analysis showed a significant relationship between rs372055 and SZ risk in dominant genetic model (CC + CT vs TT, OR = 1.26, 95% CI = 1.05–1.50) and heterogeneous model (CT vs TT, OR = 1.26, 95% CI = 1.05–1.52) in Asian, but not in Caucasian. For polymorphisms rs383964, rs450046, rs385440 and rs2870983, no associations were found between these polymorphisms and SZ susceptibility in allele frequency. This meta-analysis suggests that rs372055 (C/T) polymorphism in PRODH gene is associated with increased SZ risk only in Asian.

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Correction to: Contribution of the MRPS22 variant and a Down mosaic to the phenotype

Abstract

In the original publication of the article, the title was incorrectly written as "The cerebellum is a common site of affection in Leigh syndrome." The correct title is "Contribution of the MRPS22 variant and a Down mosaic to the phenotype."

http://ift.tt/2ywW6aG

Proline dehydrogenase gene (PRODH) polymorphisms and schizophrenia susceptibility: a meta-analysis

Abstract

Previous studies have been conducted to explore the association between proline dehydrogenase gene (PRODH) polymorphisms and schizophrenia (SZ) susceptibility, but providing the controversial results. Here we performed this meta-analysis to determine whether PRODH variants were associated with SZ risk. Relevant studies were screened by retrieving online database PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI) and SZGene from inception to December 2016. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated based on genotype data or allele frequency to evaluate the strength of this association. For rs372055, eleven studies with 3398 SZ patients and 3171 controls were included and the results indicated that people carrying the T allele was not associated with SZ risk in allele frequency model (C vs T, OR = 1.12, 95%CI = 0.96–1.32). However, results from subgroup analysis showed a significant relationship between rs372055 and SZ risk in dominant genetic model (CC + CT vs TT, OR = 1.26, 95% CI = 1.05–1.50) and heterogeneous model (CT vs TT, OR = 1.26, 95% CI = 1.05–1.52) in Asian, but not in Caucasian. For polymorphisms rs383964, rs450046, rs385440 and rs2870983, no associations were found between these polymorphisms and SZ susceptibility in allele frequency. This meta-analysis suggests that rs372055 (C/T) polymorphism in PRODH gene is associated with increased SZ risk only in Asian.

http://ift.tt/2grnss6

Desmoplastic Small Round Cell Tumor Presenting as an Ocular Mass: Unusual Localization and Remarkable Surgical Approach

Abstract

Desmoplastic small round cell tumor (DSRCT) is a rare tumor that was first described by Gerald and Rosai in 1989 as a mesenchymal entity. This tumor has a unique translocation t (11:22) (p:13, q:12) resulting in EWS/WT1 gene fusion that is diagnostic for DSCRT. The overall prognosis for desmoplastic small round cell tumor remains extremely poor, with reported rates of death as high as 90%. Although the majority of patients undergo chemotherapy following surgery, the prognosis has been shown to be independent of whether the surgical process preceded or followed chemotherapy. In this review, we provide insights for the management of DSCRT that requires aggressive multimodality therapy.

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Desmoplastic Small Round Cell Tumor Presenting as an Ocular Mass: Unusual Localization and Remarkable Surgical Approach

Abstract

Desmoplastic small round cell tumor (DSRCT) is a rare tumor that was first described by Gerald and Rosai in 1989 as a mesenchymal entity. This tumor has a unique translocation t (11:22) (p:13, q:12) resulting in EWS/WT1 gene fusion that is diagnostic for DSCRT. The overall prognosis for desmoplastic small round cell tumor remains extremely poor, with reported rates of death as high as 90%. Although the majority of patients undergo chemotherapy following surgery, the prognosis has been shown to be independent of whether the surgical process preceded or followed chemotherapy. In this review, we provide insights for the management of DSCRT that requires aggressive multimodality therapy.

http://ift.tt/2xMJzvM

SOCS1 gene therapy improves radiosensitivity and enhances irradiation-induced DNA damage in esophageal squamous cell carcinoma

STAT3 has been implicated recently in radioresistance in cancer. In this study, we investigated the association between STAT3 and radioresistance in esophageal squamous cell carcinoma (ESCC). Strong expression of activated phospho-STAT3 (p-STAT3) was observed in 16/22 ESCC patients with preoperative chemoradiotherapy (CRT), compared to 9/24 patients with surgery alone, where the prognosis of those with CRT was poor. Expression of p-STAT3 and the anti-apoptotic proteins Mcl-1 and survivin was strongly induced in ESCC cells by irradiation. Ectopic STAT3 expression increased radioresistance, whereas expression of the STAT3 negative regulator SOCS1 via an adenoviral vector improved radioresponse. Inhibiting the STAT3-Mcl-1 axis by SOCS1 enhanced DNA damage after irradition and induced apoptosis. Combining SOCS1 with radiotherapy enhanced antitumor responses in a murine xenograft model compared to the individual therapies. Tumor repopulation occurred transiently after treatment by irradiation but not the combination SOCS1/radiotherapy. Tumors subjected to this combination expressed high levels of γ-H2AX and low levels of Ki-67, which was maintained after cessation of treatment. Overall, we demonstrated that inhibiting the STAT3-Mcl-1 signaling axis by ectopic SOCS1 improved radiosensitivity by inducing apoptosis and enhancing DNA damage after radiotherapy, offering a mechanistic rationale for a new ESCC treatment.

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Restoration of natural killer cell anti-metastatic activity by IL-12 and checkpoint blockade

Immune checkpoint therapies target tumor antigen-specific T cells, but less is known about their effects on natural killer (NK) cells, which help control metastasis. In studying the development of lung metastases, we found that NK cells lose their cytotoxic capacity and acquire a molecular signature defined by the expression of co-inhibitory receptors. In an effort to overcome this suppressive mechanism, we evaluated NK cell responses to the immunostimulatory cytokine IL-12. Exposure to IL-12 rescued the cytotoxicity of NK cells but also led to the emergence of an immature NK cell population which expressed high levels of the co-inhibitory molecules PD-1, Lag-3 and TIGIT, thereby limiting NK cell-mediated control of pulmonary metastases. Notably, checkpoint blockade therapy synergized with IL-12 to fully enable tumor control by NK cells, demonstrating that checkpoint blockers are not only applicable to enhance T cell-mediated immunotherapy, but also to restore the tumor-suppressive capacity of NK cells.

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SOCS1 gene therapy improves radiosensitivity and enhances irradiation-induced DNA damage in esophageal squamous cell carcinoma

STAT3 has been implicated recently in radioresistance in cancer. In this study, we investigated the association between STAT3 and radioresistance in esophageal squamous cell carcinoma (ESCC). Strong expression of activated phospho-STAT3 (p-STAT3) was observed in 16/22 ESCC patients with preoperative chemoradiotherapy (CRT), compared to 9/24 patients with surgery alone, where the prognosis of those with CRT was poor. Expression of p-STAT3 and the anti-apoptotic proteins Mcl-1 and survivin was strongly induced in ESCC cells by irradiation. Ectopic STAT3 expression increased radioresistance, whereas expression of the STAT3 negative regulator SOCS1 via an adenoviral vector improved radioresponse. Inhibiting the STAT3-Mcl-1 axis by SOCS1 enhanced DNA damage after irradition and induced apoptosis. Combining SOCS1 with radiotherapy enhanced antitumor responses in a murine xenograft model compared to the individual therapies. Tumor repopulation occurred transiently after treatment by irradiation but not the combination SOCS1/radiotherapy. Tumors subjected to this combination expressed high levels of γ-H2AX and low levels of Ki-67, which was maintained after cessation of treatment. Overall, we demonstrated that inhibiting the STAT3-Mcl-1 signaling axis by ectopic SOCS1 improved radiosensitivity by inducing apoptosis and enhancing DNA damage after radiotherapy, offering a mechanistic rationale for a new ESCC treatment.

http://ift.tt/2yxrkhZ

Restoration of natural killer cell anti-metastatic activity by IL-12 and checkpoint blockade

Immune checkpoint therapies target tumor antigen-specific T cells, but less is known about their effects on natural killer (NK) cells, which help control metastasis. In studying the development of lung metastases, we found that NK cells lose their cytotoxic capacity and acquire a molecular signature defined by the expression of co-inhibitory receptors. In an effort to overcome this suppressive mechanism, we evaluated NK cell responses to the immunostimulatory cytokine IL-12. Exposure to IL-12 rescued the cytotoxicity of NK cells but also led to the emergence of an immature NK cell population which expressed high levels of the co-inhibitory molecules PD-1, Lag-3 and TIGIT, thereby limiting NK cell-mediated control of pulmonary metastases. Notably, checkpoint blockade therapy synergized with IL-12 to fully enable tumor control by NK cells, demonstrating that checkpoint blockers are not only applicable to enhance T cell-mediated immunotherapy, but also to restore the tumor-suppressive capacity of NK cells.

http://ift.tt/2gqLJin

Limitations of high throughput methods for miRNA expression profiles in non-functioning pituitary adenomas

Abstract

Microarray, RT-qPCR based arrays and next-generation-sequencing (NGS) are available high-throughput methods for miRNA profiling (miRNome). Analytical and biological performance of these methods were tested in identification of biologically relevant miRNAs in non-functioning pituitary adenomas (NFPA). miRNome of 4 normal pituitary (NP) and 8 NFPA samples was determined by these platforms and expression of 21 individual miRNAs was measured on 30 (20 NFPA and 10 NP) independent samples. Complex bioinformatics was used. 132 and 137 miRNAs were detected by all three platforms in NP and NFPA, respectively, of which 25 were differentially expressed (fold change > 2). The strongest correlation was observed between microarray and TaqMan-array, while the data obtained by NGS were the most discordant despite of various bioinformatics settings. As a technical validation we measured the expression of 21 selected miRNAs by individual RT-qPCR and we were able to validate 35.1%, 76.2% and 71.4% of the miRNAs revealed by SOLiD, TLDA and microarray result, respectively. We performed biological validation using an extended number of samples (20 NFPAs and 8 NPs). Technical and biological validation showed high correlation (p < 0.001; R = 0.96). Pathway and network analysis revealed several common pathways but no pathway showed the same activation score. Using the 25 platform-independent miRNAs developmental pathways were the top functional categories relevant for NFPA genesis. The difference among high-throughput platforms is of great importance and selection of screening method can influence experimental results. Validation by another platform is essential in order to avoid or to minimalize the platform specific errors.

http://ift.tt/2gs0stl

Limitations of high throughput methods for miRNA expression profiles in non-functioning pituitary adenomas

Abstract

Microarray, RT-qPCR based arrays and next-generation-sequencing (NGS) are available high-throughput methods for miRNA profiling (miRNome). Analytical and biological performance of these methods were tested in identification of biologically relevant miRNAs in non-functioning pituitary adenomas (NFPA). miRNome of 4 normal pituitary (NP) and 8 NFPA samples was determined by these platforms and expression of 21 individual miRNAs was measured on 30 (20 NFPA and 10 NP) independent samples. Complex bioinformatics was used. 132 and 137 miRNAs were detected by all three platforms in NP and NFPA, respectively, of which 25 were differentially expressed (fold change > 2). The strongest correlation was observed between microarray and TaqMan-array, while the data obtained by NGS were the most discordant despite of various bioinformatics settings. As a technical validation we measured the expression of 21 selected miRNAs by individual RT-qPCR and we were able to validate 35.1%, 76.2% and 71.4% of the miRNAs revealed by SOLiD, TLDA and microarray result, respectively. We performed biological validation using an extended number of samples (20 NFPAs and 8 NPs). Technical and biological validation showed high correlation (p < 0.001; R = 0.96). Pathway and network analysis revealed several common pathways but no pathway showed the same activation score. Using the 25 platform-independent miRNAs developmental pathways were the top functional categories relevant for NFPA genesis. The difference among high-throughput platforms is of great importance and selection of screening method can influence experimental results. Validation by another platform is essential in order to avoid or to minimalize the platform specific errors.

http://ift.tt/2gs0stl

An Unusual Progression of Signet-Ring Cell Carcinoma of the Appendix in a Caucasian Woman

http://ift.tt/2ikzSCF

An Unusual Progression of Signet-Ring Cell Carcinoma of the Appendix in a Caucasian Woman

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Cognition and Cancer: Conceptual and Methodological Issues and Future Directions

http://ift.tt/2gNPXgO

Understanding acceptability of and engagement with web-based interventions aiming to improve quality of life in cancer survivors- a synthesis of current research

Abstract

Purpose

This review sought to summarize existing knowledge in order to inform the development of an online intervention that aims to improve quality of life after cancer treatment.

Methods

To inform our intervention, we searched for studies relating to web-based interventions designed to improve QoL in adults who have completed primary treatment for breast, prostate and colorectal cancer (as these are three of the most common cancers and impact a large number of cancer survivors). We included a variety of study designs (qualitative research, feasibility/pilot trials, randomised trials, and process evaluations) and extracted all available information regarding intervention characteristics, experiences, and outcomes. Data were synthesised as textual (qualitative) data and analysed using thematic analysis.

Results

Fifty-seven full text articles were assessed for eligibility and 16 papers describing nine interventions were analysed. Our findings suggest that cancer survivors value interventions that offer content specific to their changing needs and are delivered at the right stage of the cancer trajectory. Social networking features do not always provide added benefit, and behaviour change techniques need to be implemented carefully to avoid potential negative consequences for some users.

Conclusions

Future work should aim to identify appropriate strategies for promoting health behaviour change, as well as the optimal stage of cancer survivorship to facilitate intervention delivery.

Clinical Implications

The development of web-based interventions for cancer survivors requires further exploration to better understand how interventions can be carefully designed to match this group's unique needs and capabilities. User involvement during development may help to ensure that interventions are accessible, perceived as useful, and appropriate for challenges faced at different stages of the cancer survivorship trajectory.

http://ift.tt/2ijjsus

Cognition and Cancer: Conceptual and Methodological Issues and Future Directions

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Understanding acceptability of and engagement with web-based interventions aiming to improve quality of life in cancer survivors- a synthesis of current research

Abstract

Purpose

This review sought to summarize existing knowledge in order to inform the development of an online intervention that aims to improve quality of life after cancer treatment.

Methods

To inform our intervention, we searched for studies relating to web-based interventions designed to improve QoL in adults who have completed primary treatment for breast, prostate and colorectal cancer (as these are three of the most common cancers and impact a large number of cancer survivors). We included a variety of study designs (qualitative research, feasibility/pilot trials, randomised trials, and process evaluations) and extracted all available information regarding intervention characteristics, experiences, and outcomes. Data were synthesised as textual (qualitative) data and analysed using thematic analysis.

Results

Fifty-seven full text articles were assessed for eligibility and 16 papers describing nine interventions were analysed. Our findings suggest that cancer survivors value interventions that offer content specific to their changing needs and are delivered at the right stage of the cancer trajectory. Social networking features do not always provide added benefit, and behaviour change techniques need to be implemented carefully to avoid potential negative consequences for some users.

Conclusions

Future work should aim to identify appropriate strategies for promoting health behaviour change, as well as the optimal stage of cancer survivorship to facilitate intervention delivery.

Clinical Implications

The development of web-based interventions for cancer survivors requires further exploration to better understand how interventions can be carefully designed to match this group's unique needs and capabilities. User involvement during development may help to ensure that interventions are accessible, perceived as useful, and appropriate for challenges faced at different stages of the cancer survivorship trajectory.

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Treatment log files as a tool to identify treatment plan sensitivity to inaccuracies in scanned proton beam delivery

Dose distributions delivered at Gantry 2 at the Paul Scherrer Institut (PSI) can be reconstructed on the patient anatomy based on machine log files. With the present work, the dependency of the log file calculation on the planning optimization technique and on other planning parameters, such as field direction and tumour size, has been investigated. Interestingly, and despite the typically higher modulation of Intensity Modulated Proton Therapy (IMPT) plans, the results for both Single Field Uniform Distribution and IMPT approaches have been found to be similar.

http://ift.tt/2ytsIQL

Patterns of care and outcomes for use of concurrent chemoradiotherapy over radiotherapy alone for anaplastic gliomas

The role of concurrent chemoradiotherapy (CRT) for anaplastic gliomas is undefined and patterns of care are under-reported. To address the knowledge gap, we examined use of CRT for grade III gliomas compared to radiotherapy (RT) alone.

http://ift.tt/2x3VQfM

Toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose- and volume escalation trial

The purpose of this study was to evaluate the safety and efficacy of PET and MRI guided re-irradiation of recurrent high-grade glioma (HGG) and to assess the impact of radiotherapy dose, fractionation and irradiated volume.

http://ift.tt/2yttcGC

Multiple-CT optimization of intensity-modulated proton therapy – Is it possible to eliminate adaptive planning?

We hypothesized that a plan's robustness to anatomical changes can be improved by optimizing with multiple CT scans of a patient. The purpose of this study was to determine whether an intensity modulated proton therapy (IMPT) plan could be developed to meet dose criteria on both planning and adaptive CT plans.

http://ift.tt/2x3jhFY

Patterns and correlates of treatment failure in relation to isodose distribution in non-small cell lung cancer: An analysis of 1522 patients in the modern era

To examine the relationship between radiation dose and tumor control in limited stage non-small cell lung cancer (NSCLC).

http://ift.tt/2ytsF7x

ATR/CHK1 inhibitors and cancer therapy

The cell cycle checkpoint proteins ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR) and its major downstream effector checkpoint kinase 1 (CHK1) prevent the entry of cells with damaged or incompletely replicated DNA into mitosis when the cells are challenged by DNA damaging agents, such as radiation therapy (RT) or chemotherapeutic drugs, that are the major modalities to treat cancer. This regulation is particularly evident in cells with a defective G1 checkpoint, a common feature of cancer cells, due to p53 mutations.

http://ift.tt/2x3jcCa

Widening the spectrum of deletions and molecular mechanisms underlying alpha-thalassemia

Abstract

Inherited deletions of α-globin genes and/or their upstream regulatory elements (MCSs) give rise to α-thalassemia, an autosomal recessive microcytic hypochromic anemia. In this study, multiplex ligation-dependent probe amplification performed with commercial and synthetic engineered probes, Gap-PCR, and DNA sequencing were used to characterize lesions in the sub-telomeric region of the short arm of chromosome 16, possibly explaining the α-thalassemia/HbH disease phenotype in ten patients. We have found six different deletions, in heterozygosity, ranging from approximately 3.3 to 323 kb, two of them not previously described. The deletions fall into two categories: one includes deletions which totally remove the α-globin gene cluster, whereas the other includes deletions removing only the distal regulatory elements and keeping the α-globin genes structurally intact. An indel was observed in one patient involving the loss of the MCS-R2 and the insertion of 39 bp originated from a complex rearrangement spanning the deletion breakpoints. Finally, in another case, no α-globin gene cluster deletion was found and the patient revealed to be a very unusual case of acquired α-thalassemia-myelodysplastic syndrome. This study further illustrates the diversity of genomic lesions and underlying molecular mechanisms leading to α-thalassemia.

http://ift.tt/2ilfd1l

Progression of liver fibrosis can be controlled by adequate chelation in transfusion-dependent thalassemia (TDT)

Abstract

A substantial proportion of patients with transfusion-dependent beta-thalassemia major suffer from chronic liver disease. Iron overload resulting from repeated transfusions and HCV infection has been implicated in the development of liver fibrosis. Hepatic siderosis and fibrosis were assessed in 99 transfusion-dependent thalassemia (TDT) patients using transient elastography (TE) and liver iron concentration (LIC) assessed by T2*MRI at baseline and after 4 years. Data were analyzed retrospectively. At baseline, the overall mean liver stiffness measurement (LSM) was 7.4 ± 3.2 kPa and the mean LIC was 4.81 ± 3.82 mg/g dw (n = 99). Data available at 4 ± 1.5 years showed a significant reduction in LSM (6.6 ± 3.2 kPa, p 0.017) and hepatic siderosis measured by LIC (3.65 ± 3.45 mg/g dw, p 0.001). This result was confirmed when considering patients with iron overload at the time of the first measurement (n = 41) and subjects treated with a stable dose of deferasirox over the entire period of observation (n = 39). A reduction of LSM, yet not statistically significant, was achieved in patients on combined deferoxamine + deferiprone, while the group on deferoxamine (n = 11) remained stable over time. HCV-RNA positivity was found in 33 patients at T0, 20 of which were treated during the observation period. Patients who underwent anti-HCV therapy showed a more evident reduction in LSM (9 ± 3 vs 7 ± 3.1 kPa, p 0.016). Adequate chelation therapy is mandatory in order to prevent liver disease progression in TDT. Patients could benefit from regular non-invasive assessment of liver fibrosis by TE to indirectly monitor treatment adequacy and therapeutic compliance.

http://ift.tt/2gMxVLY

The impact of antimicrobial prophylaxis in morbidity and infections during azacitidine treatment

Abstract

The clinical consequences of the infectious events in patients receiving azacitidine are poorly documented. Likewise, the role of primary antimicrobial prophylaxis is unknown. In this retrospective, single-center study, we compare the impact of prophylaxis on the incidence of infection and morbidity in all consecutive higher-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients, during the first 4 azacitidine cycles. Seventy-six patients, corresponding to 283 azacitidine cycles, were studied. There were infectious events in 43% of the patients. Development of infections led to more hospital admissions, increased red blood cells and platelet requirements, and a delay in subsequent cycles. Median overall survival was comparable between patients with or without infections. In the multivariate analysis, a neutrophil count below 0.5 × 10⁹/L (OR 12.5 [2.6–50]) and antimicrobial prophylaxis (OR 0.1 [0.02–04]) were independent factors for the development of infection. We conclude that infectious events have a significant impact in the early clinical course of azacitidine-treated patients by increasing hospital admissions and transfusion requirements. Antimicrobial prophylaxis may prevent infections, leading to a decreased need for supportive care in these patients with poor outcome.

http://ift.tt/2iizLrp

Relative abundance of β-thalassemia-related mutations in southern China correlates with geographical coordinates

http://ift.tt/2gMxLEm

Life-threatening bleeding episodes in primary immune thrombocytopenia: a single-center retrospective study of 169 inpatients

Abstract

Bleeding is the most important clinical outcome in patients with immune thrombocytopenia (ITP), and the goal of therapy in such cases is to treat or prevent bleeding. The frequency of and risk factors for bleeding events in ITP have only recently been identified in several large-scale studies. However, there is little published information about severe life-threatening bleeding in ITP. To clarify the clinical features of life-threatening bleeding in patients with primary ITP, we systematically reviewed the medical records of all ITP patients that were admitted to our hospital between January 1, 1992, and December 31, 2015. Of 169 consecutive inpatients with primary ITP, 8 suffered life-threatening bleeding (10 episodes: gastrointestinal, 4 cases; pulmonary, 1 case; and intracranial, 5 cases). All of these patients were ≥ 60 years of age and had platelet counts of < 20 × 10⁹/L. The highest incidence of such bleeding was found among elderly patients in their 80s with platelet counts of < 5 × 10⁹/L. Among the patients aged ≥ 60 years with platelet counts of < 20 × 10⁹/L, the background data of the patients with and without life-threatening bleeding episodes were compared. It was shown that the patients in the bleeding group were older than those in the non-bleeding group (80.13 ± 2.31 vs. 73.39 ± 2.51 years, p = 0.0266). Hypertension, diabetes mellitus, anticoagulant use, ITP phase, and sex were not identified as strong risk factors for life-threatening bleeding. Combining age and the platelet count might be a useful way of identifying ITP patients that are at risk of life-threatening bleeding. Most intracranial hemorrhaging (4/5) was spontaneous and multifocal, suggesting that these might be characteristics of ITP-related bleeding in elderly patients.

http://ift.tt/2ijqQWT

Therapeutic decision-making in elderly patients with acute myeloid leukemia: conventional intensive chemotherapy versus hypomethylating agent therapy

Abstract

Standards of care for elderly acute myeloid leukemia (AML) patients unfit for intensive chemotherapy remain undefined. We aimed to compare outcomes of hypomethylating agent (HMA) therapy and intensive chemotherapy (IC) in elderly AML patients and identify the subgroup of patients who are eligible for HMA therapy. We reviewed data on the outcomes of 86 AML patients aged ≥ 65 years, who had undergone treatment between 2010 and 2015. These treatments included IC (25 patients, 29.1%) or therapy using HMA including azacitidine or decitabine (61 patients, 70.9%). The overall response rates were 32 and 19.7%, respectively. Median overall survival (OS) (8 vs. 8 months) and progression-free survival (PFS) (6 vs. 7 months) durations were similar in the two groups. Patients in the HMA group with less than 10% peripheral blood (PB) blasts achieved significantly better OS duration than patients in the IC group (P = 0.043). Patients in the IC group with PB blasts and bone marrow blast of ≥ 10 and ≥ 50%, respectively, achieved better PFS durations than the corresponding patients in the HMA group (P = 0.038). Multivariate analysis identified the hematologic improvement-platelet (HI-P) as an independent prognostic factor for survival in the HMA group (P = 0.005). Our results showed that HMA therapy and IC were associated with similar survival duration in elderly AML patients. This study was noteworthy because it assessed prognostic factors that would help to select elderly patients who could expect actual benefits from undergoing the different therapeutic options available, especially HMA therapy.

http://ift.tt/2gMxAsG

PD-L1 expression correlates with VEGF and microvessel density in patients with uniformly treated classical Hodgkin lymphoma

Abstract

Recent studies have reported the associations between programmed death-ligand 1 (PD-L1) or PD-L2/PD-1 pathways and pro-angiogenic genes including hypoxia-inducible factors (HIFs) and vascular endothelial growth factor (VEGF) in several malignancies. However, no study has examined the relationship or prognostic implication of PD-L1, PD-L2, PD-1, VEGF expression, and microvessel density (MVD) in classical Hodgkin lymphoma (cHL) patients. Diagnostic tissues from 109 patients with doxorubicin, bleomycin, vinblastine, and dacarbazine-treated cHL were evaluated retrospectively by immunohistochemical analysis for PD-L1, PD-L2, PD-1, VEGF expression, and for CD31 expression as a measure of MVD. There was a positive correlation between PD-L1 and VEGF expression (P = 0.008) and additionally between PD-L2 and VEGF expression (P = 0.001). The mean MVD in tumors positive for both PD-L1 and VEGF was significantly (P = 0.022) higher than the mean MVD in tumors negative for both markers. High PD-1 expression group had lower (P = 0.019) 5-year overall survival rate than low PD-1 expression group. Multivariate analysis revealed that PD-1 was an independent prognostic factor for cHL with significance (P = 0.026). However, PD-L1, PD-L2, and VEGF expression had no prognostic impact. Our data confirmed the positive correlations between PD-L1, VEGF, or MVD. Our findings provided evidence supporting new therapeutic approaches including combinations of anti-PD-L1/PD-1 and anti-VEGF therapy in addition to the current standard regimen for cHL.

http://ift.tt/2ijaEVo

Clinical outcomes in patients with diffuse large B cell lymphoma with a partial response to first-line R-CHOP chemotherapy: prognostic value of secondary International Prognostic Index scores and Deauville scores

Abstract

After introducing a rituximab-containing chemoimmunotherapy (R-CHOP) for diffuse large B cell lymphoma (DLBCL), a partial response (PR) which is regarded as treatment failure is still observed. To investigate the prognostic factors for the DLBCL patients with a PR to R-CHOP, we retrospectively evaluated 758 newly diagnosed DLBCL patients. After R-CHOP, 88 (11.6%) achieved a PR. Three-year progression-free and overall survival rates measured from the date of PR achievement (PFS2 and OS2) were 57.4 and 67.8%, respectively. The secondary International Prognostic Index (IPI2) scores after R-CHOP were low (0–1) in 68.2% and high (2–3) in 31.8% of the patients. The Deauville scores from 18-fluorodeoxyglucose positron emission tomography after R-CHOP showed low (2–3) in 58.0% and high (4) in 42.0% of the patients. High IPI2 and high Deauville scores were associated with worse PFS2 (P < 0.001 and P = 0.009) and OS2 (P = 0.013 and P = 0.067). The high-risk group defined by the IPI2 and Deauville scores, whose scores were both high, showed significantly lower 3-year PFS2 (P < 0.001) and OS2 (P = 0.006) rates compared with those of the other groups. In multivariate analyses, the IPI score of ≥ 3 at diagnosis and bone marrow involvement at diagnosis were independent prognostic factors. In addition, high IPI2-Deauville score after R-CHOP was significantly associated with poor PFS2 (P = 0.009) and demonstrated a trend toward inferior OS2. In conclusion, DLBCL patients who partially responded to R-CHOP are still a heterogeneous group, for which IPI2 and Deauville scores should be evaluated for prediction of prognosis.

http://ift.tt/2gMPLOV

Evaluation of the Greek TranQol: a novel questionnaire for measuring quality of life in transfusion-dependent thalassemia patients

Abstract

The aim of our study was to evaluate the Greek version of the transfusion-dependent quality of life (TranQol) questionnaire and report our experience of using this novel disease-specific quality of life (QoL) measure in patients with transfusion-dependent thalassemia (TDT). The TranQol and SF-36v2 questionnaires were administered to 94 adult TDT patients with a mean age of 32.1 years (SD = 7, range = 19–58), recruited from the Adult Thalassemia Unit of Hippokration General Hospital of Thessaloniki, Greece. The TranQol was evaluated in terms of construct validity, reliability, and responsiveness. There was a moderately strong correlation between the TranQol summary and both the SF-36v2 physical and mental component summaries (r = 0.4, p < 0.001 and r = 0.5, p < 0.001, respectively). There was also a moderately strong correlation between the physical health scale of TranQol and the relevant SF-36v2 scales, including physical functioning (r = 0.4, p < 0.001), role-physical (r = 0.6, p < 0.001), and bodily pain (r = 0.5, p < 0.001). TranQol also exhibited good internal consistency (Cronbach's alpha coefficient = 0.9) and excellent test-retest reliability (intra-class correlation coefficient = 0.9). The subgroup of patients that reported a better QoL 1 week after transfusion also demonstrated a significant improvement in their TranQol score. These are the first data regarding the administration of the Greek TranQol in a single thalassemia unit. The psychometric properties of the Greek TranQol confirmed it is a valid, reliable, and responsive to change questionnaire, which can be incorporated into future clinical trials.

http://ift.tt/2ihtnki

Plasma levels of complement activation fragments C3b and sC5b-9 significantly increased in patients with thrombotic microangiopathy after allogeneic stem cell transplantation

Abstract

Transplantation-associated thrombotic microangiopathy (TA-TMA) is an uncommon but severe complication in patients undergoing allogeneic stem cell transplantation (allo-SCT). However, the mechanism is unclear. From 2011 to 2014, 20 patients with TA-TMA, 20 patients without, and 54 patients with various other complications, including veno occlusive disease (VOD), graft-versus-host disease (GVHD), and infection, were recruited in the study. Plasma vWF antigen (vWFAg), vWF activity (vWFAc), and ADAMTS13 activity were determined in these patients by ELISAs and FRETS-vWF73 assay, respectively. Plasma C3b, sC5b-9, and CH50 were also determined by ELISAs. Plasma levels of C3b were significantly increased in patients with either TA-TMA (p < 0.0001) or GVHD (p < 0.01). Plasma sC5b-9 and CH50 levels in patients with TA-TMA were also significantly increased (p < 0.001). Plasma ADAMTS13 activity was lower in patients with VOD, but normal with other complications. Both plasma vWFAg and vWFAc levels were not elevated in patients with TA-TMA or VOD compared with those of other groups. Complement activation likely via an alternative pathway (increased C3b, sC5b-9, and CH50) may play a role in the pathogenesis of TA-TMA. ADAMTS13 activity is reduced in VOD, but the ADAMTS13/vWF axis appears to be unaffected in patients with TA-TMA.

http://ift.tt/2gMZbK1

Somatic mutations of calreticulin in patients with myelodysplastic/myeloproliferative neoplasms-unclassifiable

http://ift.tt/2ihtlca

Effectivity of a modified Sanz risk model for early death prediction in patients with newly diagnosed acute promyelocytic leukemia

Abstract

Early death is the main obstacle for the cure of patients with acute promyelocytic leukemia (APL). We have analyzed risk factors of early death from 526 consecutive newly diagnosed APL patients between 2004 and 2016. The overall incidence of early death was 7.2% (38/526). The peak hazard of early death occurred in the first 0–3 days. Multivariate logistic analysis demonstrated white blood cell (WBC) counts [odds ratio (OR) = 1.039; 95% confidence interval (CI): 1.024–1.055; P < 0.001], age (OR = 1.061; 95% CI: 1.025–1.099; P = 0.001) and platelet counts (OR = 0.971; 95% CI: 0.944–0.999; P = 0.038) were independent risk factors for early death. Furthermore, receiver-operator characteristic (ROC) curve analyses revealed a simple WBC/platelet ratio was significantly more accurate in predicting early death [areas under the ROC curve (AUC) = 0.842, 95% CI: 0.807–0.872) than WBC counts (AUC = 0.793; 95% CI: 0.756–0.827) or Sanz score (AUC = 0.746; 95% CI: 0.706–0.783). We stratified APL patients into four risk subgroups: low risk (WBC ≤ 10 × 10⁹/L, platelet >40 × 10⁹/L), intermediate risk (WBC/platelet <0.2 and age ≤ 60, not in low risk), high risk (WBC/platelet ≥0.2 or age > 60, not in low and ultra-high risk) and ultra-high risk (WBC > 50 × 10⁹/L), the early death rates were 0, 0.6, 12.8, and 41.2%, respectively. In conclusion, we proposed a modified Sanz risk model as a useful predictor of early death risk in patients with APL.

http://ift.tt/2gMnEzi

Predictors of early mortality after rabbit antithymocyte globulin as first-line treatment in severe aplastic anemia

Abstract

Despite being recommended as first-line immunosuppressive therapy in severe aplastic anemia (SAA), horse antithymocyte globulin (ATG) is still unavailable in many countries outside the USA. Rabbit ATG is more lymphocytoxic than horse ATG, and this might result in a higher incidence of severe infections and early mortality. This study was designed to identify the risk factors for early mortality and overall survival (OS) after rabbit ATG in patients with SAA. We retrospectively reviewed 185 patients with SAA who underwent rabbit ATG and cyclosporine. The incidence of death in 3 months following rabbit ATG therapy was 15.1% (28/185). Early mortality was mainly related to infectious complications, despite adequate antibiotic and/or antifungal treatment. Age > 35 years (odds ratio [OR] 5.06, P = 0.001) and baseline absolute neutrophil count (ANC) ≤ 0.1 × 10⁹/L (OR 7.64, P < 0.001) were independent risk factors for early mortality after immunosuppressive therapy with this agent. Hematological response at 6 months was observed in only 29.7% of all patients. OS at 1 year after rabbit ATG was 75.3%; and age > 35 years (OR 1.88, P = 0.03), baseline ANC ≤ 0.1 × 10⁹/L (OR 2.65, P < 0.001), and lack of response to rabbit ATG (OR 11.40, P < 0.001) were independently associated with mortality. Alternative strategies are needed for the treatment of SAA patients in countries were horse ATG is unavailable, particularly for those at high risk for early mortality after rabbit ATG due to a higher age and very low pre-treatment neutrophil count.

http://ift.tt/2ihipuX

Encouraging results with the compassionate use of hydralazine/valproate (TRANSKRIP™) as epigenetic treatment for myelodysplastic syndrome (MDS)

Abstract

The hypomethylating agents azacytidine and decitabine are unaffordable for many patients with MDS. The combination of the DNA methyltransferase inhibitor hydralazine and the histone deacetylase inhibitor valproate has shown preliminary efficacy in MDS. The aim of this study is to evaluate the clinical efficacy and safety of hydralazine/valproate in a case series of MDS patients treated in a compassionate manner. Hydralazine was dosed according to the acetylation genotype of patients (slow acetylators 83 mg daily; fast acetylators 182 mg daily), and valproate was dosed at 30 mg/kg/day. Both drugs were given daily until disease progression. Response and toxicity were evaluated with the International Working Group criteria and CTCAE, version 4, respectively. Survival parameters were estimated with the Kaplan-Meier method. From 2009 to 2012, 14 patients were treated. The median age ± SD was 55.2 ± 19.52 (range 23–87) years. According to the IPSS, cases were graded as intermediate-1 (n = 8/14; 57.2%) or intermediate-2 (n = 6/14; 42.8%). Responses were as follows: five (35.7%) complete response, one (7.1%) partial response, and two (14.28%) became transfusion independent. The mean duration of response ± SD was 60 ± 35.28 months (range 5–94). Three patients progressed to AML. At a median follow-up of 57 months (range 1–106), the median OS was 27 months. At that point, five patients remained on the treatment, one with partial response and four with complete response. The median OS was not reached in the eight patients who saw a clinical benefit from the treatment, in comparison to an OS of 7 months in the six patients who had no treatment. The combination of hydralazine and valproate is safe and effective in MDS, and its further testing is highly desirable.

http://ift.tt/2gOq5kV

A novel heterozygous ALAS2 mutation in a female with macrocytic sideroblastic anemia resembling myelodysplastic syndrome with ring sideroblasts: a case report and literature review

http://ift.tt/2iht6xM

A cross-sectional study on late taste disorders in survivors of allogeneic hematopoietic cell transplantation

Abstract

Taste disorders are one of the most common complications in patients undergoing allogeneic hematopoietic cell transplantation (HCT). They persist in some patients as a late complication 3 months or more after HCT. Therefore, we conducted a cross-sectional study to evaluate the prevalence and predictive factors of late taste disorders, with the help of a self-reporting and closed-ended questionnaire, which was distributed among 91 patients in our institute. The median age at this study was 50 (range, 25–69) years. The median follow-up period was 54 (range, 3–234) months after HCT. Taste disorders were observed in 43 patients (47%). The most frequent form of late taste disorders was reduced appetite in 18 patients (20%). The most frequent form of decline of basic taste was umami, which was observed in 12 patients (13%). Almost all taste disorders were mild in their severity. Multivariate logistic regression analyses showed that the duration of less than 1 year post HCT and the presence of oral chronic graft-versus-host disease are important risk factors for late taste disorders in survivors of HCT. These data suggested that taste disorders usually return to normal levels more than a year after HCT in most recipients.

http://ift.tt/2gMVp3B

Effects of realgar (As 4 S 4 ) on degradation of PML-RARA harboring acquired arsenic-resistance mutations

http://ift.tt/2ihsZCm

Patients with primary breast and primary female genital tract diffuse large B cell lymphoma have a high frequency of MYD88 and CD79B mutations

Abstract

This study is to retrospectively evaluate the prevalence of MYD88 and CD79B mutations and the clinicopathologic characteristics of patients with primary diffuse large B cell lymphoma (DLBCL) of the female genital tract and breast. The characteristics, treatments, and outcomes of 19 patients diagnosed with primary DLBCL of the female genital tract and breast, who had formalin-fixed and paraffin-embedded tissues obtained from diagnostic samples diagnosed between January 2004 and June 2016, were analyzed retrospectively. Nineteen female patients (7 with primary breast and 12 with primary female genital tract DLBCL) were included in this retrospective study. Eleven patients (57.9%) carried a MYD88 mutation, including 10 with MYD8 L265P and 1 with the MYD88 L265S mutation. Seven patients (36.8%) harbored a CD79B mutation, which included two cases with CD79B Y196H, two cases with CD79B Y196N, one case with CD79B Y196D, one case with CD79B Y196F, and one case with CD79B Y196X. Four cases had both MYD88 and CD79B mutations. The clinicopathologic parameters, progression-free survival (PFS), and overall survival (OS) of the MYD88 mutation-carrying group were not significantly different from those of the MYD88 wild-type group except for higher LDH levels. Six patients received cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP), while 13 patients received rituximab plus CHOP, and 13 patients received central nervous system prophylaxis. The median OS and PFS were 73 and 56 months, respectively. Patients with primary breast and primary female genital tract DLBCL have a high frequency of MYD88 and CD79B mutations. The presence of these mutations does not affect survival but may offer additional therapeutic options.

http://ift.tt/2gMYMqX

Durable remission is achievable with localized treatment and reduction of immunosuppression in limited stage EBV-related plasmablastic lymphoma

http://ift.tt/2iiCalM

Uterine intravascular lymphoma as a cause of fever of unknown origin

Abstract

Primary intravascular large B cell lymphoma (IVL) remains a diagnostic challenge because of non-specific clinical, laboratory and imaging findings. The aim of the study was to analyse the major characteristics of IVL with uterine involvement. We retrospectively collected features of IVL with uterine involvement that was proven histologically or demonstrated by significant ¹⁸FDG uptake on ¹⁸FDG-PET/CT. Findings were compared to a comprehensive literature review. Five patients were identified. All of them were admitted for fever of unknown origin (FUO), with haemophagocytic lymphohistiocytosis in three cases. None had gynaecological symptom, contrasting with the literature data. Structural imaging (including whole-body CT scan and pelvic RMI) failed to yield any diagnosis. ¹⁸FDG-PET/CT showed intense uterine uptake in all cases. Endometrial biopsy was performed in three cases and was positive in one. Diagnosis was obtained from coelioscopic iliac adenopathy biopsy in one case and from total hysterectomy in another. Punch biopsy of skin lesions led to diagnosis in the two remaining cases. Bone marrow biopsy was normal in all cases. Clinicians should be aware of potential isolated uterine involvement in IVL, especially in elderly women with FUO. Normal structural imaging does not rule out the diagnosis and ¹⁸FDG-TEP/CT should be performed to guide high-yielding biopsy.

http://ift.tt/2gN3yVx

Hereditary diffuse gastric cancer and lynch syndromes in a BRCA1/2 negative breast cancer patient

Abstract

Introduction

Genetic counseling and testing is recommended for women with a personal and/or family history of breast and other cancers (ovarian, pancreatic, male breast and others). Mutations in the BRCA1 and BRCA2 genes (BRCA1/2) are the most common causes of hereditary breast and ovarian cancer. Additional genetic counseling and testing with a multi-gene panel may be considered in breast cancer patients who tested negative for mutations in these two genes. In about 11% of BRCA1/2-negative patients, further genetic testing reveals pathogenic mutations in other high or moderate cancer risk genes. In 0.2% of cases, an individual may carry pathogenic mutations in more than one high penetrance gene (a double heterozygote). Finding one or more pathogenic mutations is important for cancer prevention in patients and/or their families.

Case presentation

Here we present a case of a breast cancer patient who did not have a pathogenic mutation in BRCA1/2 and had a family history of breast and stomach cancers. On an additional multi-gene panel testing, she was found to carry pathogenic mutations in the CDH1 and PMS2 genes, which cause Hereditary Diffuse Gastric Cancer and Lynch syndromes, respectively. To our knowledge, this is the first description of such a double heterozygote.

Discussion

Clinical manifestations, genetics, and management of both syndromes are reviewed, including prophylactic surgery and screening for unaffected family members. Management challenges for a mutation carrier with advanced breast cancer are discussed. Our case supports the clinical utility of additional multi-gene panel testing for breast cancer patients who do not have a pathogenic mutation in BRCA1/2 genes.

http://ift.tt/2gN0ZTC

Analysis of molecular subtypes for the increased HER2 equivocal cases caused by application of the updated 2013 ASCO/CAP HER2 testing guidelines in breast cancer

Abstract

Purpose

Accurate testing of the status of human epidermal growth factor receptor type 2 (HER2) is a prerequisite for HER2-directed therapy. The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) published joint guideline recommendations for HER2 testing in breast cancer in 2007 and it was updated in 2013. We compared the HER2 gene amplification status based on these two guidelines and analyzed the molecular characteristics of the equivocal cases.

Patients and methods

A total of 1894 patient samples were analyzed for both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). HER2 FISH amplification was examined and re-assessed using 2013 guidelines.

Results

According to the 2013 ASCO/CAP recommendations, 763 (40.3%) cases were classified as HER2 positive compared with 729 (38.5%) cases defined by 2007 guidelines. There was a significant increase of 6.1% in the proportion of HER2 FISH equivocal cases that were interpreted using ASCO/CAP 2013 (7.3%) compared with 2007 (1.2%) guidelines (P < 0.001). Of 138 FISH equivocal cases defined by 2013 guidelines, 125 cases were IHC2+ and 13 cases were IHC1+. These 125 cases included 4 double equivocal cases which were defined as equivocal by both 2007 and 2013 guidelines and 121 cases whose status was changed from negative defined by 2007 guidelines to equivocal defined by 2013 guidelines. Compared with luminal A type and luminal B type respectively, these 121 equivocal cases demonstrated no significant difference with luminal B type in T stage and N stage (P = 0.192, P = 0.421). When we divided the luminal B type into two parts that included HER2 negative cases and HER2 positive cases, the equivocal cases also showed no significant difference with these two subtypes in T stage and N stage.

Conclusions

Our study suggested that implementation of the revised ASCO/CAP 2013 guidelines resulted in an increase of 1.7% in overall HER2 positivity rate and of 6.1% in equivocal cases. Pathological analysis revealed that these equivocal cases exhibit similar biological behavior with luminal B type tumors. Clinical utility data on targeted therapy in equivocal patients should be further investigated.

http://ift.tt/2ihinn0

Erratum to: Peroxisome proliferator-activated receptor gamma activates fas ligand gene promoter inducing apoptosis in human breast cancer cells

http://ift.tt/2gN0Xes

A small-molecule inhibitor of SMAD3 attenuates resistance to anti-HER2 drugs in HER2-positive breast cancer cells

Abstract

Purpose

Resistance against anti-HER2 drugs in HER2-positive breast cancer is a major obstacle to the improving prognosis. Transforming growth factor β (TGFβ) is a cytokine involved in the acquisition of more malignant phenotypes through epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties. The aim of this study was to investigate the effects of TGFβ and its downstream SMAD pathway on resistance to anti-HER2 drugs.

Methods

HER2-positive breast cancer cell lines were stimulated with TGFβ for 14 days. Then, the sensitivity to trastuzumab and lapatinib and the expression levels of various EMT and CSC markers were examined. The correlation of nuclear SMAD3 expression in untreated breast tumor tissues with trastuzumab efficacy in neoadjuvant settings was examined. The effect of a small-molecule inhibitor of SMAD3 (SIS3) on resistance to anti-HER2 drugs was explored.

Results

We found that continuous activation of the TGFβ-SMAD3 pathway induced resistance to anti-HER2 drugs and CSC traits in HER2-positive breast cancer cells. The induction of drug resistance by TGFβ required strong activation of SMAD3. In fact, activated SMAD3 regulated multiple genes that harbor SMAD-binding elements and are involved in trastuzumab resistance. Nuclear SMAD3 expression in tumor tissue was inversely correlated with sensitivity to neoadjuvant treatment with trastuzumab. SIS3 not only prevented the acquisition of resistance to anti-HER2 drugs but also restored trastuzumab sensitivity in trastuzumab-resistant cells.

Conclusions

This study indicates that the TGFβ-SMAD3 pathway plays an important role in the induction and maintenance of resistance to anti-HER2 drugs. Thus, SMAD3 is a potential therapeutic target that can inhibit resistance and restore sensitivity to anti-HER2 drugs.

http://ift.tt/2iiQo6o

Impact of tissue-based genomic profiling on clinical decision making in the management of patients with metastatic breast cancer at academic centers

Abstract

Background

Genomic profiling can identify targetable mutations; however, the impact of tissue-based genomic profiling on clinical decision making for patients with metastatic breast cancer has not been well characterized.

Methods

Patients with stage IV breast cancer who had undergone genomic profiling between 7/2013 and 3/2015 were identified at three academic cancer centers. Genomic analysis was determined to have impacted clinical decision if (A) a patient was enrolled onto a genotype-matched clinical trial or (B) prescribed off-label an FDA-approved therapy targeting an identified mutation. The frequency of mutated genes was determined.

Results

A total of 117 patients with stage IV breast cancer were identified. Median age was 46 (25–75). Fifty-three patients (45%) had ER-positive/HER2-negative disease, 50 (43%) had ER-negative/HER2-negative disease, and 14 (12%) had ER-any/HER2-positive disease. Median number of previous therapies received prior to genomic profiling was 2 (range 0–15), and median follow-up after testing was obtained after 5.8 months (range 0–24.4 months). Commercial reports indicated that 85 (73%) patients had at least one mutation targetable by an FDA-approved medication, and 112 (96%) patients had at least one clinical trial available; however, clinical management was only affected in 11 patients (9%). The most frequent mutations observed were those in TP53, FGF, PI3KCA, MYC, ZNF, FGFR, CCND, ARID1A, GATA3, and MAP; frequencies of these mutations varied by clinical subtype.

Conclusions

Tumor genomic profiling affected clinical management in a minority of patients with metastatic breast cancer, thus these data do not support the routine use of genomic profiling outside of a clinical trial.

http://ift.tt/2gN0Uzi

Comments on “ Primary tumor location predicts the site of local relapse after nipple – areola complex (NAC) sparing mastectomy ” by Cont et al. Breast Cancer Res Treat, 2017

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Breast cancer neoplastic seeding in the setting of image-guided needle biopsies of the breast

Abstract

Purpose

To identify clinicopathologic, technical, and imaging features associated with neoplastic seeding (NS) following image-guided needle breast biopsy.

Methods

We performed an institutional review board-approved retrospective review of patients presenting with a new diagnosis of breast cancer or suspicious breast findings requiring biopsy with subsequent diagnosis of NS. The time from biopsy to NS diagnosis was calculated. Histology, grade, estrogen receptor (ER) status, progesterone receptor (PR) status, HER2 status, T category, and N category were recorded. Biopsy guidance method, needle gauge, and number of passes were reviewed in addition to the mammographic and sonographic features of the primary tumors and the NS.

Results

Eight cases of NS were identified in 4010 patients. The mean time from biopsy to NS diagnosis was 60.8 days. The most frequent histology was invasive ductal carcinoma (7/8). Six cases were grade 3 (75.0%). Five primary breast cancers were ER, PR, and HER2 negative (62.5%). Seven patients underwent biopsy with ultrasound guidance. Multiple-insertion, non-coaxial ultrasound-guided core-needle biopsy was done in 6 cases. Mammographic presentation of NS was focal asymmetry (3/7 cases), mass (1/7), calcifications only (1/7), or occult (2/7). Sonographic presentation of NS was most often a mass (7/8) with irregular shape (5/7) and without circumscribed margins (6/7) and was occult in 1 case (1/8). NS distribution was subdermal and intradermal.

Conclusion

High-grade, triple-negative breast cancers and multiple-insertion, non-coaxial biopsies may be risk factors for NS. NS should be suspected on the basis of the superficial and linear pattern of disease progression in these patients.

http://ift.tt/2gN0SYc

Fatty liver decreases the risk of liver metastasis in patients with breast cancer: a two-center cohort study

Abstract

Background

The influence of hepatic steatosis (HS) on liver metastasis in patients with non-metastatic breast cancer (BC) remains unclear. The aim of this study was to clarify the relationship between HS and liver metastasis in non-metastatic BC patients.

Methods

Patients who underwent treatment for BC at two affiliated hospitals of Southern Medical University, between January 1, 2005 and December 31, 2015, were retrospectively reviewed. BC patients were divided into the study and control groups based on the presence of HS. The association between HS and liver metastasis was analyzed, adjusting for the confounding factors using Cox regression and propensity score case-match analysis.

Results

In total, 1230 female BC patients were included, and 372 (30.2%) patients were diagnosed with HS (at the time of diagnosis BC or before). The cumulative liver metastasis-free survival (MFS) rate was significantly higher in the study group than in the control group (hazard ratio 0.61; 95% confidence interval 0.40–0.94; P = 0.024). On multivariate analysis, HS was an independent protective factor for local liver metastasis (HR 0.55; 0.35–0.86; P = 0.008). After one-to-one matching of the study group (344) with the control group (344), liver MFS remained significantly better in the study group (HR 0.42; 0.26–0.69; P = 0.001).

Conclusion

This study indicated that HS may serve as an independent factor to decrease liver metastasis in patients with BC. Additional prospective studies are necessary to validate this finding.

http://ift.tt/2iibMst

Pharmaceutically treated anxiety but not depression prior to cancer diagnosis predicts the onset of cardiovascular disease among breast cancer survivors

Abstract

Purpose

To examine the associations between pharmaceutically treated anxiety and depression present in the year prior to breast cancer diagnosis and the risk of incident cardiovascular disease (CVD), while controlling for traditional cardiovascular risk factors and clinical characteristics in a population-based observational study.

Methods

Adult 1-year breast cancer survivors (n = 7227), diagnosed between 01-01-1999 and 12-31-2010, with no history of CVD, were selected from the Netherlands Cancer Registry. Drug dispensing data were derived from the PHARMO Database Network and used as proxy for CVD, anxiety, and depression. By multivariable Cox regression analysis, we examined the risk associated with pharmaceutically treated anxiety and depression for developing CVD after cancer diagnosis, adjusting for age, pharmaceutically treated hypertension, hypercholesterolemia, and diabetes mellitus in the year prior to cancer diagnosis, tumor stage, and cancer treatment.

Results

During the 13-year follow-up period, 193 (3%) breast cancer survivors developed CVD. Women pharmaceutically treated for anxiety in the year prior to their cancer diagnosis had a 48% increased hazard for CVD [HR = 1.48; 95% CI 1.05–1.08] after full adjustment. This association was restricted to breast cancer survivors who were 65 years or younger. Depression was not associated with CVD risk [HR = 0.89; 95% CI 0.52–1.53]. Older age [HR = 1.06; 95% CI 1.05–1.08], hypertension [HR = 1.80; 95% CI 1.32–2.46], and hypercholesterolemia [HR = 1.63; 95% CI 1.15–2.33] were associated with an increased hazard for incident CVD, whereas hormone therapy [HR = 0.59; 95% CI 0.42–0.83] was protective.

Conclusions

Anxiety present in the year prior to breast cancer diagnosis increases the risk of incident CVD in 1-year breast cancer survivors, after adjustment for depression, traditional cardiovascular risk factors, and clinical characteristics.

http://ift.tt/2gN0Qj2

A functional BRCA1 coding sequence genetic variant contributes to prognosis of triple-negative breast cancer, especially after radiotherapy

Abstract

Purpose

As a subtype of breast cancer, triple-negative breast cancer (TNBC) shows poor prognosis and high heterogeneity. Precise identification of TNBC subgroups relevant to clinical prognosis is crucial in the design and administration of individualized treatments. This study aimed to evaluate the prognostic value of the functional BRCA1 rs799917 genetic variant in TNBC.

Methods

Associations between the rs799917 polymorphism and progression risk were investigated after genotyping 370 TNBC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox regression. 

Results

We found that the rs799917T allele was associated with a significantly increased risk of disease progression and shortened progression-free survival time (PFS) (P = 0.001 for log-rank test). Notably, TNBC patients with the rs799917 CC genotype showed about 22 months prolonged PFS compared to the TT genotype after radiotherapy (HR 4.44, 95% CI 1.98–9.93; P = 2.9 × 10⁻⁴). Additionally, in overweight patients, the mean PFS of the rs799917TT genotype was 10 months shorter than that of the CC genotype (HR 3.57, 95% CI 1.46–8.73, P = 0.005).

Conclusions

Our findings demonstrate that the functional BRCA1 genetic variant contributes to prognosis of TNBC. Our study also highlights the clinical potential of this polymorphism in the screening of high-risk TNBC patients for recurrence and the possibility of patient-tailored decisions especially during radiotherapy.

http://ift.tt/2igAEk9

Cardiac safety of non-anthracycline trastuzumab-based therapy for HER2-positive breast cancer

Abstract

Purpose

Trastuzumab improves overall survival for women with HER2-positive breast cancer but is associated with cardiotoxicity, especially when administered after anthracyclines. Use of non-anthracycline trastuzumab-based regimens is rising, particularly for patients with low-risk disease or with multiple cardiovascular risk factors. We performed a single-center retrospective cohort study to assess the cardiac safety of trastuzumab without anthracyclines outside of a clinical trial setting.

Methods

A retrospective chart review was conducted of patients with HER2-positive early-stage breast cancer receiving non-anthracycline trastuzumab-based therapy between January 2010 and June 2014. Cardiovascular risk factors, left ventricular ejection fraction (LVEF), and treatment interruption data were collected. The primary outcome was a cardiac event (CE), defined by New York Heart Association class III or IV heart failure or cardiac death. The secondary outcome was a significant asymptomatic decline of LVEF (>10% to <55% or >16% from baseline).

Results

A total of 165 patients were identified with a median age of 59 years (range 32–85 years). Seventy (42%) had hypertension, 52 (32%) had hyperlipidemia, 29 (18%) had diabetes, and 5 (3%) had coronary artery disease. All patients had a LVEF >50% (median 67%; range 50–80%) at baseline. Two (1.2%) patients with multiple cardiovascular risk factors developed a CE. After discontinuation of trastuzumab, both patients had recovery of LVEF to >50% and resolution of heart failure symptoms. Ten (6.1%) patients developed significant asymptomatic LVEF decline during trastuzumab therapy.

Conclusions

The overall incidence of symptomatic heart failure and asymptomatic LVEF decline among patients receiving trastuzumab without anthracyclines remains low. These findings suggest that less intensive cardiac monitoring may be appropriate during trastuzumab therapy without anthracyclines.

http://ift.tt/2gN0LMg

Medical costs of treating breast cancer among younger Medicaid beneficiaries by stage at diagnosis

Abstract

Background

Younger women (aged 18–44 years) diagnosed with breast cancer often face more aggressive tumors, higher treatment intensity, and lower survival rates than older women. In this study, we estimated incident breast cancer costs by stage at diagnosis and by race for younger women enrolled in Medicaid.

Methods

We analyzed cancer registry data linked to Medicaid claims in North Carolina from 2003 to 2008. We used Surveillance, Epidemiology, and End Results (SEER) Summary 2000 definitions for cancer stage. We split breast cancer patients into two cohorts: a younger and older group aged 18–44 and 45–64 years, respectively. We conducted a many-to-one match between patients with and without breast cancer using age, county, race, and Charlson Comorbidity Index. We calculated mean excess total cost of care between breast cancer and non-breast cancer patients.

Results

At diagnosis, younger women had a higher proportion of regional cancers than older women (49 vs. 42%) and lower proportions of localized cancers (44 vs. 50%) and distant cancers (7 vs. 9%). The excess costs of breast cancer (all stages) for younger and older women at 6 months after diagnosis were $37,114 [95% confidence interval (CI) = $35,769–38,459] and $28,026 (95% CI = $27,223–28,829), respectively. In the 6 months after diagnosis, the estimated excess cost was significantly higher to treat localized and regional cancer among younger women than among older women. There were no statistically significant differences in excess costs of breast cancer by race, but differences in treatment modality were present among younger Medicaid beneficiaries.

Conclusions

Younger breast cancer patients not only had a higher prevalence of late-stage cancer than older women, but also had higher within-stage excess costs.

http://ift.tt/2ijcNAz

Diagnosis and treatment delays among elderly breast cancer patients with pre-existing mental illness

Abstract

Purpose

This study aimed to compare diagnosis and treatment delays in elderly breast cancer patients with and without pre-existing mental illness.

Methods

A retrospective cohort study was conducted using the Surveillance, Epidemiology and End Results—Medicare data including 16,636 women 68+ years, who were diagnosed with stage I–IIIa breast cancer in the United States from 2005 to 2007. Mental illness was identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes recorded on inpatient and outpatient claims during the 3 years prior to breast cancer diagnosis. Patients were classified as having no mental illness, anxiety, depression, anxiety and depression, or severe mental illness (bipolar disorder, schizophrenia, and other psychotic disorder). Multivariable binomial regression was used to assess the association between mental illness and delays of ≥60 and ≥90 days after adjustment for confounders.

Results

Patients with comorbid anxiety and depression had an increased risk for diagnosis delay of ≥90 days from symptom recognition (RR 1.11; 95% CI 1.00, 1.23), and those with severe mental illness had an increased risk for initial treatment delay of ≥60 days from diagnosis (RR 1.36; 95% CI 1.06, 1.74). Patients with any mental illness experienced an increased risk for adjuvant chemotherapy delay of ≥90 days from last operation (RR 1.13; 95% CI 1.01, 1.26) and each category of mental illness, except depression, showed a non-significant trend for this association.

Conclusion

Breast cancer patients with mental illness should be closely managed by a cross-functional care team, including a psychiatrist, a primary care physician, and an oncologist, to ensure adequate care is received within an appropriate timeframe.

http://ift.tt/2gNz3yE

21-Gene recurrence score and locoregional recurrence in lymph node-negative, estrogen receptor-positive breast cancer

Abstract

Background/purpose

The 21-gene recurrence score (RS) assay evaluates the likelihood of distant recurrence and benefit of chemotherapy in lymph node-negative, estrogen receptor (ER)-positive, HER2-negative breast cancer patients. The RS categories are associated with the risk of locoregional recurrence (LRR) in some, but not all studies.

Methods

We reviewed the institutional database to identify consecutive female patients with node-negative, ER+/HER2− breast carcinoma tested for the 21-gene RS assay and treated at our center from 2008 to 2013. We collected data on clinicopathologic features, treatment, and outcome. Statistical analysis was performed using SAS version 9.4 or R version 3.3.2.

Results

Of 2326 patients, 60% (1394) were in the low RS group, 33.4% (777) in the intermediate RS group, and 6.6% (155) in the high RS group. Median follow-up was 53 months. A total of 44 LRRs were observed, with a cumulative incidence of 0.17% at 12 months and 1.6% at 48 months. The cumulative incidence of LRR at 48 months was 0.84%, 2.72% and 2.80% for low, intermediate, and high RS groups, respectively (p < 0.01). Univariate analysis showed that the risk of LRR was associated with the RS categories (p < 0.01), T stage (p < 0.01) and lymphovascular invasion (LVI) (p = 0.009). There was no difference in LRR rates by initial local treatment (total mastectomy vs. breast-conserving surgery plus radiation therapy). The RS remained significantly associated with LRR after adjusting for LVI and T stage. Compared to patients with low RS, the risk of LRR was increased more than 4-fold (hazard ratio: 4.61, 95% CI 1.90–11.19, p < 0.01), and 3-fold (hazard ratio: 2.81, 95% CI 1.41–5.56, p < 0.01) for high and intermediate risk categories, respectively.

Conclusions

Our study confirms that RS is significantly associated with the risk of LRR in node-negative, ER+/HER2− breast cancer patients. Our findings suggest that in addition to its value for prognostic stage grouping and decision-making regarding adjuvant systemic therapy, the role of the RS in identifying patients not requiring radiotherapy should be studied.

http://ift.tt/2iiQcnG

Trends in incidence and tumour grade in screen-detected ductal carcinoma in situ and invasive breast cancer

Abstract

Purpose

In a biennial screening mammography programme, we analysed the trends in incidence of screen-detected DCIS and invasive breast cancers in the era of screen-film mammography (SFM) screening, the period of the transition to full-field digital mammography (FFDM) screening and the period of FFDM screening. We also investigated a possible association between the incidence and grading of screen-detected DCIS and invasive breast cancer.

Methods

In the southern part of the Netherlands, FFDM screening gradually replaced SFM screening between May 2009 and April 2010. We included a consecutive series of 484, 422 screens obtained between July 2005 and July 2015 and divided these screens into three groups; SFM-only cohort, transition cohort and FFDM-only cohort.

Results

A total of 3059 referred women were diagnosed with DCIS (n = 623) or invasive breast cancer (n = 2436). The majority of DCIS were high-grade (48.2%), whereas the majority of the invasive breast cancers were low-grade (45.4%) or intermediate-grade (41.6%). The cancer detection rate (CDR) per 1000 screened women showed the same distribution by grade in both groups. The transition to FFDM was characterised by an increased overall detection rate of invasive cancers.

Conclusions

Screening mammography detects mostly high-grade DCIS and low- or intermediate-grade invasive cancers. The grade distribution as well as the CDR in the years after the introduction of FFDM remained stable compared to the era of SFM screening. By diagnosing and treating high-grade DCIS, which otherwise may develop into high-grade invasive carcinoma, our findings provide new evidence for the beneficial value of screening mammography programmes.

http://ift.tt/2gMkjjO

Jagged1 promotes aromatase inhibitor resistance by modulating tumor-associated macrophage differentiation in breast cancer patients

Abstract

Purpose

Endocrine resistance limits the efficacy of anti-estrogen therapies. Notch signaling is involved in modulating tumor-associated macrophage (TAM) differentiation and is upregulated in endocrine-resistant breast cancer cells. Here, we analyzed the role of Jagged1 in the regulation of TAM polarization to investigate whether the Jagged1-Notch pathway promotes the acquisition of aromatase inhibitor (AI) resistance by upregulating TAM infiltration.

Methods

The Jagged1 expression levels and M2 TAM infiltration density, in 203 tumor samples from ER-positive postmenopausal patients, who received AI treatment, were evaluated by immunohistochemical staining and the results were compared with clincopathological parameters and survival. The Jagged1 protein and mRNA levels were analyzed in MCF-7 and long-term endocrine-depleted (LTED) cell lines. The phenotypes of macrophage after macrophages were co-cultured with either MCF-7 or LTED cells, were evaluated using flow cytometry. Cell migration assay was performed to evaluate the mobility of cancer cells. Notch gama secretase inhibitor (GSI) RO4929097 was employed to investigate whether modulation of Notch signaling affects M2 polarization.

Results

In the tumor samples, Jagged1 expression was found to be associated with a large tumor size, high histological grade, lymphatic invasion, and high Ki67 expression. Jagged1 expression was also correlated with reduced disease-free and overall survival and was positively associated with the stromal M2 TAM infiltration density in primary tumor tissues. In AI-resistance patients, M2 TAM infiltration was denser in metastatic lesions than in primary tumors. Higher Jagged1 protein and mRNA levels were also found in LTED cells, which model AI-resistant conditions in patients, compared with MCF-7 cells. Macrophages co-cultured with LTED cells expressed higher levels of M2 marker and IL-10. M2 TAM proportion was reduced when macrophages were pre-treated with GSI before co-culture.

Conclusions

The Jagged1-Notch pathway showed elevated expression in AI-resistant breast cancer cells, resulting in macrophage differentiation towards M2 TAMs and there contributing to the acquisition of AI resistance.

http://ift.tt/2iiQaMA

Letter to the editor: In response to “influence of clinical, societal, and treatment variables on racial difference in ER-/PR- breast cancer survival” by Roseland ME, Schwartz K, Ruterbusch JJ, Lamerato L, Krajenta R, Booza J, Simon MS

http://ift.tt/2gNW1FW

Elevated S100A8 protein expression in breast cancer cells and breast tumor stroma is prognostic of poor disease outcome

Abstract

Purpose

Elevated S100A8 expression has been observed in cancers of the bladder, esophagus, colon, ovary, and breast. S100A8 is expressed by breast cancer cells as well as by infiltrating immune and myeloid cells. Here we investigate the association of elevated S100A8 protein expression in breast cancer cells and in breast tumor stroma with survival outcomes in a cohort of breast cancer patients.

Patients and methods

Tissue microarrays (TMA) were constructed from breast cancer specimens from 417 patients with stage I–III breast cancer treated at the University of Michigan Comprehensive Cancer Center between 2004 and 2006. Representative regions of non-necrotic tumor and distant normal tissue from each patient were used to construct the TMA. Automated quantitative immunofluorescence (AQUA) was used to measure S100A8 protein expression, and samples were scored for breast cancer cell and stromal S100A8 expression. S100A8 staining intensity was assessed as a continuous value and by exploratory dichotomous cutoffs. Associations between breast cancer cell and stromal S100A8 expression with disease-free survival and overall survival were determined using the Kaplan–Meier method and Cox proportional hazard models.

Results

High breast cancer cell S100A8 protein expression (as indicated by AQUA scores), as a continuous measure, was a significant prognostic factor for OS [univariable hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.00–1.55, p = 0.05] in this patient cohort. Exploratory analyses identified optimal S100A8 AQUA score cutoffs within the breast cancer cell and stromal compartments that significantly separated survival curves for the complete cohort. Elevated breast cancer cell and stromal S100A8 expression, indicated by higher S100A8 AQUA scores, significantly associates with poorer breast cancer outcomes, regardless of estrogen receptor status.

Conclusions

Elevated breast cancer cell and stromal S1008 protein expression are significant indicators of poorer outcomes in early stage breast cancer patients. Evaluation of S100A8 protein expression may provide additional prognostic information beyond traditional breast cancer prognostic biomarkers.

http://ift.tt/2gMNhQl

Chemoradiation Therapy for Unresected Extrahepatic Cholangiocarcinoma: A Propensity Score-Matched Analysis

Abstract

Background

Unresected extrahepatic cholangiocarcinoma (uEHCC) remains a deadly disease. Guidelines for uEHCC recommend either chemotherapy alone (CT) or chemoradiotherapy (CRT). This study used the National Cancer Database (NCDB) to compare outcomes for patients treated with CT and those who underwent CRT.

Methods

Patients with initially diagnosed non-metastatic uEHCC from 2004 to 2014 were identified. Using Chi square analysis, patients who underwent CT were compared with those who received CRT. Uni- and multivariate Cox regression analyses were used to compare characteristics related to survival. Propensity score matching and shared frailty analysis were undertaken to correct for baseline differences between the two groups. Additional analyses were performed to compare survival for the minority of patients who underwent surgery and advanced-stage patients.

Results

The study identified 2996 patients with uEHCC. Chemoradiation was associated with better survival (median survival [MS], 14.5 months; hazard ratio [HR] 0.84; p < 0.001) than CT alone (MS, 12.6 months). Induction of CT before CRT was associated with a trend toward decreased risk of death compared with concurrent CRT (HR 0.81; p = 0.051). For the patients able to undergo surgery after initial treatment, MS was 24.5 months (HR 0.38; p < 0.001) versus 12.2 months for those who had no surgery. For these patients, CRT also was associated with better survival (MS, 31.2 months; HR 0.66; p = 0.001) than CT (MS, 22.1 months). Positive margins at surgery yielded survival equivalent to that with no surgery.

Conclusion

Although CRT may be associated with slightly better survival in uEHCC than CT alone, the majority of the benefit was observed for patients able to undergo eventual surgery.

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Long-term Follow-up and Post-relapse Outcome of Patients with Localized Retroperitoneal Sarcoma Treated in the Italian Sarcoma Group-Soft Tissue Sarcoma (ISG-STS) Protocol 0303

Abstract

Background

This study was designed to assess patterns of recurrence and long-term outcomes of patients undergoing surgery for localized retroperitoneal sarcoma (RPS) after neoadjuvant high dose long-infusion ifosfamide (HLI) and radiotherapy (RT).

Methods

Patients received three cycles of HLI (14 g/m²). RT was started in combination with II cycle up to a total dose of 50.4 Gy. Surgery was scheduled 4–6 weeks after the end of RT. The primary endpoint was relapse-free survival (RFS) after surgery. Secondary endpoints were overall survival (OS), crude cumulative incidence of local recurrence (CCI-LR), and distant metastases (CCI-DM). For patients who relapsed, progression-free survival (PFS) and post-relapse OS were estimated. The trial was registered with ITASARC_*II_2004_003.

Results

Between 2003 and 2010, 83 patients were recruited. At a median follow-up of 91.7 months, 42 (56%) of 75 operated patients developed LR (n = 27) or DM (n = 10) or both LR and DM (n = 5) relapse. Seven-year RFS was 46.6% [95% confidence interval (CI) 29.6–52.4]. Thirty-two patients died. Seven-year OS rate was 63.2% (95% CI 42.7–66.0). The corresponding CCI of LR and DM were 37.4% [standard error (SE) 5.5%] and 20.0% (SE 12.6%), respectively. The only factor significantly associated with LR was FNCLCC grading, whereas histological subtype resulted associated with DM. At recurrence, 24 patients (57%) underwent surgery. Two-year post-relapse PFS and OS rates for patients developing LR or DM were 14.8, 41.0, 27.3, and 63.6%, respectively.

Conclusions

LR after neoadjuvant CT-RT for RPS were predominantly infield. While almost one half of relapsed patients underwent further surgery, prognosis was poor.

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via IFTTT

Chemoradiation Therapy for Unresected Extrahepatic Cholangiocarcinoma: A Propensity Score-Matched Analysis

Abstract

Background

Unresected extrahepatic cholangiocarcinoma (uEHCC) remains a deadly disease. Guidelines for uEHCC recommend either chemotherapy alone (CT) or chemoradiotherapy (CRT). This study used the National Cancer Database (NCDB) to compare outcomes for patients treated with CT and those who underwent CRT.

Methods

Patients with initially diagnosed non-metastatic uEHCC from 2004 to 2014 were identified. Using Chi square analysis, patients who underwent CT were compared with those who received CRT. Uni- and multivariate Cox regression analyses were used to compare characteristics related to survival. Propensity score matching and shared frailty analysis were undertaken to correct for baseline differences between the two groups. Additional analyses were performed to compare survival for the minority of patients who underwent surgery and advanced-stage patients.

Results

The study identified 2996 patients with uEHCC. Chemoradiation was associated with better survival (median survival [MS], 14.5 months; hazard ratio [HR] 0.84; p < 0.001) than CT alone (MS, 12.6 months). Induction of CT before CRT was associated with a trend toward decreased risk of death compared with concurrent CRT (HR 0.81; p = 0.051). For the patients able to undergo surgery after initial treatment, MS was 24.5 months (HR 0.38; p < 0.001) versus 12.2 months for those who had no surgery. For these patients, CRT also was associated with better survival (MS, 31.2 months; HR 0.66; p = 0.001) than CT (MS, 22.1 months). Positive margins at surgery yielded survival equivalent to that with no surgery.

Conclusion

Although CRT may be associated with slightly better survival in uEHCC than CT alone, the majority of the benefit was observed for patients able to undergo eventual surgery.

http://ift.tt/2yp8Hx2

Long-term Follow-up and Post-relapse Outcome of Patients with Localized Retroperitoneal Sarcoma Treated in the Italian Sarcoma Group-Soft Tissue Sarcoma (ISG-STS) Protocol 0303

Abstract

Background

This study was designed to assess patterns of recurrence and long-term outcomes of patients undergoing surgery for localized retroperitoneal sarcoma (RPS) after neoadjuvant high dose long-infusion ifosfamide (HLI) and radiotherapy (RT).

Methods

Patients received three cycles of HLI (14 g/m²). RT was started in combination with II cycle up to a total dose of 50.4 Gy. Surgery was scheduled 4–6 weeks after the end of RT. The primary endpoint was relapse-free survival (RFS) after surgery. Secondary endpoints were overall survival (OS), crude cumulative incidence of local recurrence (CCI-LR), and distant metastases (CCI-DM). For patients who relapsed, progression-free survival (PFS) and post-relapse OS were estimated. The trial was registered with ITASARC_*II_2004_003.

Results

Between 2003 and 2010, 83 patients were recruited. At a median follow-up of 91.7 months, 42 (56%) of 75 operated patients developed LR (n = 27) or DM (n = 10) or both LR and DM (n = 5) relapse. Seven-year RFS was 46.6% [95% confidence interval (CI) 29.6–52.4]. Thirty-two patients died. Seven-year OS rate was 63.2% (95% CI 42.7–66.0). The corresponding CCI of LR and DM were 37.4% [standard error (SE) 5.5%] and 20.0% (SE 12.6%), respectively. The only factor significantly associated with LR was FNCLCC grading, whereas histological subtype resulted associated with DM. At recurrence, 24 patients (57%) underwent surgery. Two-year post-relapse PFS and OS rates for patients developing LR or DM were 14.8, 41.0, 27.3, and 63.6%, respectively.

Conclusions

LR after neoadjuvant CT-RT for RPS were predominantly infield. While almost one half of relapsed patients underwent further surgery, prognosis was poor.

http://ift.tt/2gi83a8

A long non-coding RNA HOTTIP expression is associated with disease progression and predicts outcome in small cell lung cancer patients

Abstract

Background

Despite progress in treatment of small cell lung cancer (SCLC), the biology of the tumor still remains poorly understood. Recently, we globally investigated the contributions of lncRNA in SCLC with a special focus on sponge regulatory network. Here we report lncRNA HOTTIP, which is specifically amplified in SCLC, is associated with SCLC proliferation and poor prognosis of patients.

Methods

RT-qPCR was used to investigate the expression of HOTTIP in SCLC tissues and cell lines. The role of HOTTIP in SCLC cell proliferation was demonstrated by CCK8 assay, colony formation assay, flow cytometry analysis and in vivo SCLC xenograft model in nude mice through HOTTIP loss- and gain-of-function effects. Western blot assay was used to evaluate gene expression in cell lines at protein level. RNA pull-down, Mass spectrometry and RNA binding protein immunoprecipitation (RIP) were performed to confirm the molecular mechanism of HOTTIP involved in SCLC progression.

Results

We found that HOTTIP was overexpressed in SCLC tissues, and its expression was correlated with the clinical stage and the shorter survival time of SCLC patients. Moreover, HOTTIP knockdown could impair cell proliferation, affect the cell cycle and inhibit tumor growth of mice, while HOTTIP overexpression might enhance cell proliferation and cell cycle in vitro and in vivo. Mechanistic investigations showed that HOTTIP functions as an oncogene in SCLC progression by sponging miR-574-5p and affecting the expression of polycomb group protein EZH1.

Conclusions

Overall, we identified that HOTTIP was involved in SCLC tumorigenesis through the ceRNA network "HOTTIP/miR-574-5p/EZH1". Our findings not only illuminate how HOTTIP confers an oncogenic function in SCLC pathogenesis, but also underscore a novel gene expression governing hallmarks in the disease.

http://ift.tt/2xLsUcc

The importance of early detection of calcifications associated with breast cancer in screening

Abstract

Purpose

The aim of this study was to assess how often women with undetected calcifications in prior screening mammograms are subsequently diagnosed with invasive cancer.

Methods

From a screening cohort of 63,895 women, exams were collected from 59,690 women without any abnormalities, 744 women with a screen-detected cancer and a prior negative exam, 781 women with a false positive exam based on calcifications, and 413 women with an interval cancer. A radiologist identified cancer-related calcifications, selected by a computer-aided detection system, on mammograms taken prior to screen-detected or interval cancer diagnoses. Using this ground truth and the pathology reports, the sensitivity for calcification detection and the proportion of lesions with visible calcifications that developed into invasive cancer were determined.

Results

The screening sensitivity for calcifications was 45.5%, at a specificity of 99.5%. A total of 68.4% (n = 177) of cancer-related calcifications that could have been detected earlier were associated with invasive cancer when diagnosed.

Conclusions

Screening sensitivity for detection of malignant calcifications is low. Improving the detection of these early signs of cancer is important, because the majority of lesions with detectable calcifications that are not recalled immediately but detected as interval cancer or in the next screening round are invasive at the time of diagnosis.

http://ift.tt/2yqzby6

Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy

Abstract

Background

There is an unmet need to determine factors predictive of clinical benefit, to guide therapeutic sequencing and selection in metastatic RCC (mRCC). We evaluated clinical factors such as the neutrophil lymphocyte ratio (NLR) and duration of prior anti-vascular endothelial growth factor (VEGF) inhibitors, as predictors of response rate, progression free survival (PFS) and overall survival (OS) in mRCC patients treated with immune checkpoint inhibitor (ICI).

Methods

Regulatory approval was obtained. A single center retrospective chart review of mRCC patients at Karmanos Cancer Institute, treated with ICI based therapy (PD-1/PD-L1 inhibitors) was conducted. Data were collected on demographics, smoking status, prognostic scoring (Memorial Sloan Kettering and Heng criteria), NLR pretherapy, post 1 and 4 doses of ICI, and duration of prior anti-VEGF therapy ≥6 months or <6.

Results

42 patients were evaluated with median age of 61 years (range, 24-85). Pretherapy NLR < 3 and ≥3 was seen in 19 (45%) and 23 (55%) patients, respectively. 24 (57%) and 18 (43%) patients had prior anti-VEGF inhibitors for a duration of ≥6 months and <6 months, respectively. 12 (29%), 22 (52%) and 8 (19%) patients had favorable, intermediate and poor risk disease based on Heng criteria, respectively. Multivariable analysis showed pretherapy NLR ≥3 was predictive of shorter PFS and OS when treated with ICI with median 3.08 months and 13.50 months, respectively, versus 15.57 months and not reached for NLR < 3 (adjusted p-values =0.003 and 0.025, respectively). Prior anti-VEGF therapy <6 months was predictive of increased likelihood of benefit from ICI therapies (adjusted p = 0.028). The median PFS was 3.72 months and 14.33 months, respectively, in cases with prior anti-VEGF therapy for ≥6 months and <6 months.

Conclusion

Pretherapy NLR <3 and duration of prior anti-VEGF therapy of <6 months, are independent statistically significant predictors of longer PFS and OS with ICI therapy in mRCC. Validation is required in a larger sample size with multi-institutional collaboration.

http://ift.tt/2gpI8AQ

A long non-coding RNA HOTTIP expression is associated with disease progression and predicts outcome in small cell lung cancer patients

Abstract

Background

Despite progress in treatment of small cell lung cancer (SCLC), the biology of the tumor still remains poorly understood. Recently, we globally investigated the contributions of lncRNA in SCLC with a special focus on sponge regulatory network. Here we report lncRNA HOTTIP, which is specifically amplified in SCLC, is associated with SCLC proliferation and poor prognosis of patients.

Methods

RT-qPCR was used to investigate the expression of HOTTIP in SCLC tissues and cell lines. The role of HOTTIP in SCLC cell proliferation was demonstrated by CCK8 assay, colony formation assay, flow cytometry analysis and in vivo SCLC xenograft model in nude mice through HOTTIP loss- and gain-of-function effects. Western blot assay was used to evaluate gene expression in cell lines at protein level. RNA pull-down, Mass spectrometry and RNA binding protein immunoprecipitation (RIP) were performed to confirm the molecular mechanism of HOTTIP involved in SCLC progression.

Results

We found that HOTTIP was overexpressed in SCLC tissues, and its expression was correlated with the clinical stage and the shorter survival time of SCLC patients. Moreover, HOTTIP knockdown could impair cell proliferation, affect the cell cycle and inhibit tumor growth of mice, while HOTTIP overexpression might enhance cell proliferation and cell cycle in vitro and in vivo. Mechanistic investigations showed that HOTTIP functions as an oncogene in SCLC progression by sponging miR-574-5p and affecting the expression of polycomb group protein EZH1.

Conclusions

Overall, we identified that HOTTIP was involved in SCLC tumorigenesis through the ceRNA network "HOTTIP/miR-574-5p/EZH1". Our findings not only illuminate how HOTTIP confers an oncogenic function in SCLC pathogenesis, but also underscore a novel gene expression governing hallmarks in the disease.

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