LRP2 gene variants and their haplotypes strongly influence the risk of developing neural tube defects in the fetus: a family-triad study from South India

Abstract

Neural tube defects (NTDs) are the leading cause of infant deaths worldwide. Lipoprotein related receptor 2 (LRP2) has been shown to play a crucial role in neural tube development in mouse models. However, the role of LRP2 gene in the development of human NTDs is not yet known. In view of this, family-based triad approach has been followed considering 924 subjects comprising 124 NTD case-parent trios and 184 control-parent trios diagnosed at Institute of Genetics and Hospital for Genetic Diseases, Hyderabad. Blood and tissue samples were genotyped for rs3755166 (−G759A) and rs2544390 (C835T) variants of LRP2 gene for their association with NTDs. Assessment of maternal-paternal genotype incompatibility risk for NTD revealed 3.77-folds risk with a combination of maternal GA and paternal GG genotypes (GAxGG = GA,p < 0.001), while CT genotypes of both the parents showed 4.19-folds risk for NTDs (CTxCT = CT,p = 0.009). Haplotype analysis revealed significant risk of maternal A-T (OR = 4.48,p < 0.001) and paternal G-T haplotypes (OR = 5.22,p < 0.001) for NTD development. Further, linkage analysis for parent-of-origin effects (POE) also revealed significant transmission of maternal 'A' allele (OR = 2.33,p = 0.028) and paternal 'T' allele (OR = 6.00,p = 0.016) to NTDs. Analysis of serum folate and active-B12 levels revealed significant association with LRP2 gene variants in the causation of NTDs. In conclusion, the present family-based triad study provides the first report on association of LRP2 gene variants with human NTDs.

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LRP2 gene variants and their haplotypes strongly influence the risk of developing neural tube defects in the fetus: a family-triad study from South India

Abstract

Neural tube defects (NTDs) are the leading cause of infant deaths worldwide. Lipoprotein related receptor 2 (LRP2) has been shown to play a crucial role in neural tube development in mouse models. However, the role of LRP2 gene in the development of human NTDs is not yet known. In view of this, family-based triad approach has been followed considering 924 subjects comprising 124 NTD case-parent trios and 184 control-parent trios diagnosed at Institute of Genetics and Hospital for Genetic Diseases, Hyderabad. Blood and tissue samples were genotyped for rs3755166 (−G759A) and rs2544390 (C835T) variants of LRP2 gene for their association with NTDs. Assessment of maternal-paternal genotype incompatibility risk for NTD revealed 3.77-folds risk with a combination of maternal GA and paternal GG genotypes (GAxGG = GA,p < 0.001), while CT genotypes of both the parents showed 4.19-folds risk for NTDs (CTxCT = CT,p = 0.009). Haplotype analysis revealed significant risk of maternal A-T (OR = 4.48,p < 0.001) and paternal G-T haplotypes (OR = 5.22,p < 0.001) for NTD development. Further, linkage analysis for parent-of-origin effects (POE) also revealed significant transmission of maternal 'A' allele (OR = 2.33,p = 0.028) and paternal 'T' allele (OR = 6.00,p = 0.016) to NTDs. Analysis of serum folate and active-B12 levels revealed significant association with LRP2 gene variants in the causation of NTDs. In conclusion, the present family-based triad study provides the first report on association of LRP2 gene variants with human NTDs.

https://ift.tt/2KAXug3

Aldo‐keto reductases‐mediated cytotoxicity of 2‐deoxyglucose: A novel anticancer mechanism

Cancer Science, EarlyView.


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Aldo‐keto reductases‐mediated cytotoxicity of 2‐deoxyglucose: A novel anticancer mechanism

Cancer Science, EarlyView.


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UGT1A polymorphisms associated with worse outcome in colorectal cancer patients treated with irinotecan-based chemotherapy

Abstract

Purpose

To investigate the association between UDP-glucuronosyltransferase (UGT)1A polymorphisms and irinotecan-treatment efficacy in a Chinese population with metastatic colorectal cancer (mCRC).

Methods

The present study was based on a prospective multicenter trial of Chinese mCRC patients treated with irinotecan-based chemotherapy (NCT01282658, registered at http://www.clinicaltrials.gov). Fifteen single-nucleotide polymorphisms (SNPs) in four UGT1A genes were selected for genotyping in 164 patients. Kaplan–Meier and Cox regression analyses were used to assess the association between potential signatures and survival outcome.

Results

We found that UGT1A1*28 variant genotype was significantly associated with decreased progression-free survival (PFS) [adjusted hazard ratio (HR), 1.803; 95% confidence interval (CI), 1.217–2.671] and overall survival (OS) (adjusted HR 1.979; 95% CI 1.267–3.091) compared with wild-type genotype. Patients carrying (TA)7 allele showed a median PFS of 7.5 (95% CI 5.5–9.6) months compared with 9.8 (95% CI 8.6–10.9) months for patients with wild-type genotype. Median OSs were 13.3 (95% CI 10.3–16.2), and 20.8 (95% CI 18.7–23.0) months for (TA)6/7 or (TA)7/7, and (TA)6/6 patients, respectively. Similarly but more significantly, the copy number of haplotype III (composed by rs3755321-T, rs3821242-C, rs4124874-G and rs3755319-C) constructed among the selected SNPs also correlated with survival outcome.

Conclusions

UGT1A polymorphisms are predictive of survival outcome of irinotecan-treated Chinese mCRC patients. After validation, UGT1A polymorphisms might be helpful in facilitating stratification of mCRC patients for individualized treatment options.

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UGT1A polymorphisms associated with worse outcome in colorectal cancer patients treated with irinotecan-based chemotherapy

Abstract

Purpose

To investigate the association between UDP-glucuronosyltransferase (UGT)1A polymorphisms and irinotecan-treatment efficacy in a Chinese population with metastatic colorectal cancer (mCRC).

Methods

The present study was based on a prospective multicenter trial of Chinese mCRC patients treated with irinotecan-based chemotherapy (NCT01282658, registered at http://www.clinicaltrials.gov). Fifteen single-nucleotide polymorphisms (SNPs) in four UGT1A genes were selected for genotyping in 164 patients. Kaplan–Meier and Cox regression analyses were used to assess the association between potential signatures and survival outcome.

Results

We found that UGT1A1*28 variant genotype was significantly associated with decreased progression-free survival (PFS) [adjusted hazard ratio (HR), 1.803; 95% confidence interval (CI), 1.217–2.671] and overall survival (OS) (adjusted HR 1.979; 95% CI 1.267–3.091) compared with wild-type genotype. Patients carrying (TA)7 allele showed a median PFS of 7.5 (95% CI 5.5–9.6) months compared with 9.8 (95% CI 8.6–10.9) months for patients with wild-type genotype. Median OSs were 13.3 (95% CI 10.3–16.2), and 20.8 (95% CI 18.7–23.0) months for (TA)6/7 or (TA)7/7, and (TA)6/6 patients, respectively. Similarly but more significantly, the copy number of haplotype III (composed by rs3755321-T, rs3821242-C, rs4124874-G and rs3755319-C) constructed among the selected SNPs also correlated with survival outcome.

Conclusions

UGT1A polymorphisms are predictive of survival outcome of irinotecan-treated Chinese mCRC patients. After validation, UGT1A polymorphisms might be helpful in facilitating stratification of mCRC patients for individualized treatment options.

https://ift.tt/2HRD3d9

Use of cyclin-dependent kinase (CDK) 4/6 inhibitors for hormone receptor-positive, human epidermal growth factor receptor 2-negative, metastatic breast cancer: a roundtable discussion by The Breast Cancer Therapy Expert Group (BCTEG)

Abstract

Purpose

To provide an overview of clinical data supporting the use of cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), metastatic breast cancer (mBC), from the perspective of the practicing oncologist community.

Methods

A recent roundtable discussion was convened by The Breast Cancer Therapy Expert Group (BCTEG) to review existing data on this topic and its impact on their current practice.

Results

Level 1 evidence now supports use of a CDK 4/6 inhibitor in combination with endocrine therapy for patients with HR+, HER2−, mBC. Currently, there are no biomarkers that reliably define patients who will, or will not, benefit from the addition of a CDK 4/6 inhibitor to their endocrine therapy. Additional research is needed to identify the optimal sequencing of CDK 4/6 inhibitors in relation to other therapies as well as the optimal duration of therapy; at present, evidence suggests that use in the upfront setting is better than waiting for a later line of therapy, or adding after endocrine therapy has started.

Conclusions

Thus far, three CDK 4/6 inhibitors—palbociclib, ribociclib, and more recently, abemaciclib—have been approved for use in the setting of HR+, HER2−, mBC.  The degrees to which these agents differ in terms of CDK4/6 affinity, side-effect profiles, dosing, degree of central nervous system (CNS) penetration, optimal use in combination with antiestrogen therapy, and across other subsets of breast cancer, remain an active area of investigation.

https://ift.tt/2ro1UhQ

Statins use and cancer: an update

Future Oncology, Ahead of Print.


https://ift.tt/2waEstR

Gallbladder cancer: a journey of a thousand steps

Future Oncology, Ahead of Print.


https://ift.tt/2rj6lLp

Statins use and cancer: an update

Future Oncology, Ahead of Print.


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Gallbladder cancer: a journey of a thousand steps

Future Oncology, Ahead of Print.


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SETD2 Haploinsufficiency for Microtubule Methylation is an Early Driver of Genomic Instability in Renal Cell Carcinoma

Loss of the short arm of chromosome 3 (3p) occurs early in >95% of clear cell renal cell carcinoma (ccRCC). Nearly ubiquitous 3p loss in ccRCC suggests haploinsufficiency for 3p tumor suppressors as early drivers of tumorigenesis. We previously reported methyltransferase SETD2, which trimethylates H3 histones on lysine 36 (H3K36me3) and is located in the 3p deletion, to also trimethylate microtubules on lysine 40 (αTubK40me3) during mitosis, with αTubK40me3 required for genomic stability. We now show that mono-allelic, Setd2-deficient cells retaining H3K36me3 but not αTubK40me3 exhibit a dramatic increase in mitotic defects and micronuclei count with increased viability compared to bi-allelic loss. In SETD2-inactivated human kidney cells, rescue with a pathogenic SETD2 mutant deficient for microtubule (αTubK40me3) but not histone (H3K36me3) methylation replicated this phenotype. Genomic instability (micronuclei) was also a hallmark of patient-derived cells from ccRCC. These data show the SETD2 tumor suppressor displays a haploinsufficiency phenotype disproportionately impacting microtubule methylation and serves as an early driver of genomic instability.

https://ift.tt/2wh8Liq

SETD2 is recurrently mutated in whole-exome sequenced canine osteosarcoma.

Osteosarcoma (OSA) is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of OSA spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that OSA tumors show a high frequency of somatic copy number alterations (SCNA) affecting key oncogenes and tumor suppressor genes. The across-breed results are similar to what has been observed for human OSA, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported), and eleven significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human OSA. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in OSA. This study points to the likely importance of histone modifications in OSA and highlights the strong genetic similarities between human and dog OSA, suggesting that canine OSA may serve as an excellent model for developing treatment strategies in both species.

https://ift.tt/2jqgKk0

MIR142 loss-of-function mutations derepress ASH1L to increase HOXA gene expression and promote leukemogenesis

Point mutations in the seed sequence of miR-142-3p are present in a subset of AML and in several subtypes of B cell lymphoma. Here we show that mutations associated with AML result both in loss of miR-142-3p function and in decreased miR-142-5p expression. Mir142 loss altered the hematopoietic differentiation of multipotent hematopoietic progenitors, enhancing their myeloid potential while suppressing their lymphoid potential. During hematopoietic maturation, loss of Mir142 increased Ash1l protein expression and consequently resulted in the aberrant maintenance of Hoxa gene expression in myeloid-committed hematopoietic progenitors. Mir142 loss also enhanced the disease-initiating activity of IDH2 mutant hematopoietic cells in mice. Together these data suggest a novel model in which miR-142, through repression of ASH1L activity, plays a key role in suppressing HOXA9/A10 expression during normal myeloid differentiation. AML-associated loss-of-function mutations of MIR142 disrupt this negative signaling pathway, resulting in sustained HOXA9/A10 expression in myeloid progenitors/myeloblasts and ultimately contributing to leukemic transformation.

https://ift.tt/2wgfLfQ

The autotaxin - lysophosphatidic acid axis promotes lung carcinogenesis

Pathogenesis and progression of lung cancer (LC) are governed by complex interactions between the environment and host genetic susceptibility, which is further modulated by genetic and epigenetic changes. Autotaxin (ATX, ENPP2) is a secreted glycoprotein that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor-like phospholipid which is further regulated by phospholipid phosphatases (PLPP). LPA's pleiotropic effects in almost all cell types are mediated through at least six, G-protein coupled LPA receptors (LPAR) that exhibit overlapping specificities, widespread distribution, and differential expression profiles. Here we use both preclinical models of LC and clinical samples (from patients and healthy controls) to investigate the expression levels, activity and biological role of the above components of the ATX/LPA axis in LC. ENPP2 was genetically altered in 8% of LC patients, while increased ATX staining and activity were detected in patient biopsies and sera, respectively. Moreover, PLPP3 expression was consistently downregulated in LC patients. Comparable observations were made in the two most widely used animal models of LC, the carcinogen urethane (URE) -induced and the genetically engineered K-rasG12D-driven models, where genetic deletion of Enpp2 or Lpar1 resulted in disease attenuation, thus confirming a pro-carcinogenic role of LPA signaling in the lung. Expression profiling data analysis suggested that metabolic rewiring may be implicated in the pro-carcinogenic effects of the ATX/LPA axis in K-ras-G12D-driven LC pathogenesis.

https://ift.tt/2riIvzv

SETD2 Haploinsufficiency for Microtubule Methylation is an Early Driver of Genomic Instability in Renal Cell Carcinoma

Loss of the short arm of chromosome 3 (3p) occurs early in >95% of clear cell renal cell carcinoma (ccRCC). Nearly ubiquitous 3p loss in ccRCC suggests haploinsufficiency for 3p tumor suppressors as early drivers of tumorigenesis. We previously reported methyltransferase SETD2, which trimethylates H3 histones on lysine 36 (H3K36me3) and is located in the 3p deletion, to also trimethylate microtubules on lysine 40 (αTubK40me3) during mitosis, with αTubK40me3 required for genomic stability. We now show that mono-allelic, Setd2-deficient cells retaining H3K36me3 but not αTubK40me3 exhibit a dramatic increase in mitotic defects and micronuclei count with increased viability compared to bi-allelic loss. In SETD2-inactivated human kidney cells, rescue with a pathogenic SETD2 mutant deficient for microtubule (αTubK40me3) but not histone (H3K36me3) methylation replicated this phenotype. Genomic instability (micronuclei) was also a hallmark of patient-derived cells from ccRCC. These data show the SETD2 tumor suppressor displays a haploinsufficiency phenotype disproportionately impacting microtubule methylation and serves as an early driver of genomic instability.

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SETD2 is recurrently mutated in whole-exome sequenced canine osteosarcoma.

Osteosarcoma (OSA) is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of OSA spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that OSA tumors show a high frequency of somatic copy number alterations (SCNA) affecting key oncogenes and tumor suppressor genes. The across-breed results are similar to what has been observed for human OSA, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported), and eleven significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human OSA. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in OSA. This study points to the likely importance of histone modifications in OSA and highlights the strong genetic similarities between human and dog OSA, suggesting that canine OSA may serve as an excellent model for developing treatment strategies in both species.

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MIR142 loss-of-function mutations derepress ASH1L to increase HOXA gene expression and promote leukemogenesis

Point mutations in the seed sequence of miR-142-3p are present in a subset of AML and in several subtypes of B cell lymphoma. Here we show that mutations associated with AML result both in loss of miR-142-3p function and in decreased miR-142-5p expression. Mir142 loss altered the hematopoietic differentiation of multipotent hematopoietic progenitors, enhancing their myeloid potential while suppressing their lymphoid potential. During hematopoietic maturation, loss of Mir142 increased Ash1l protein expression and consequently resulted in the aberrant maintenance of Hoxa gene expression in myeloid-committed hematopoietic progenitors. Mir142 loss also enhanced the disease-initiating activity of IDH2 mutant hematopoietic cells in mice. Together these data suggest a novel model in which miR-142, through repression of ASH1L activity, plays a key role in suppressing HOXA9/A10 expression during normal myeloid differentiation. AML-associated loss-of-function mutations of MIR142 disrupt this negative signaling pathway, resulting in sustained HOXA9/A10 expression in myeloid progenitors/myeloblasts and ultimately contributing to leukemic transformation.

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The autotaxin - lysophosphatidic acid axis promotes lung carcinogenesis

Pathogenesis and progression of lung cancer (LC) are governed by complex interactions between the environment and host genetic susceptibility, which is further modulated by genetic and epigenetic changes. Autotaxin (ATX, ENPP2) is a secreted glycoprotein that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor-like phospholipid which is further regulated by phospholipid phosphatases (PLPP). LPA's pleiotropic effects in almost all cell types are mediated through at least six, G-protein coupled LPA receptors (LPAR) that exhibit overlapping specificities, widespread distribution, and differential expression profiles. Here we use both preclinical models of LC and clinical samples (from patients and healthy controls) to investigate the expression levels, activity and biological role of the above components of the ATX/LPA axis in LC. ENPP2 was genetically altered in 8% of LC patients, while increased ATX staining and activity were detected in patient biopsies and sera, respectively. Moreover, PLPP3 expression was consistently downregulated in LC patients. Comparable observations were made in the two most widely used animal models of LC, the carcinogen urethane (URE) -induced and the genetically engineered K-rasG12D-driven models, where genetic deletion of Enpp2 or Lpar1 resulted in disease attenuation, thus confirming a pro-carcinogenic role of LPA signaling in the lung. Expression profiling data analysis suggested that metabolic rewiring may be implicated in the pro-carcinogenic effects of the ATX/LPA axis in K-ras-G12D-driven LC pathogenesis.

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A multicentre, open-label phase II study of I rinotecan, capecitabine ( X eloda®), and O xaliplatin (IXO) as first-line treatment in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma

Summary

Purpose Chemotherapy remains the primary treatment for metastatic gastric/GEJ cancer but optimal agents and schedule remain controversial. This study examined the safety and efficacy of first-line Irinotecan, capecitabine (Xeloda®), and Oxaliplatin (IXO). Patients and Methods Eligible patients with HER2-unamplified/unknown, metastatic gastric/GEJ adenocarcinoma were treated with 21-day cycle IXO at dose level 1 (DL1: Day 1 O-100 mg/m² & I-160 mg/m² IV, Day 2–15 X-1900 mg/m²/day PO divided doses) or modified IXO (mIXO): Day 1 O-85 mg/m² & I-120 mg/m² IV, Day 2–15 X-1425 mg/m²/day PO divided doses). This Bryant and Day two-stage designed study had dual primary endpoints of objective response rate (ORR) and toxicity. Secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results Fifty patients were enrolled and received a median of 7 cycles. After accrual of 9 patients at DL1, evaluable RR was 88% however dose limiting toxicity (DLT) rate was 56% thus doses were adjusted to mIXO. Fifteen patients accrued at mIXO had a RR of 60% and DLT rate of 13% allowing continuation to stage 2. Overall, 48 and 49 patients were evaluable for efficacy and safety, respectively, with ORR of 54% and DLTs in 24% of patients (DL1 = 56%; mIXO = 18%). Disease control rate was 85%. The most frequent grade 3/4 adverse events were diarrhea, neutropenia, fatigue, hypokalemia, and nausea. Median PFS and OS were 7.5 and 13.0 months, respectively, with a median follow-up of 9.7 months. Conclusion mIXO demonstrates promising ORR, PFS, OS, and acceptable toxicity compared to standard triplet regimens. IXO should be evaluated in phase III trials.

https://ift.tt/2Ky3iXS

A multicentre, open-label phase II study of I rinotecan, capecitabine ( X eloda®), and O xaliplatin (IXO) as first-line treatment in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma

Summary

Purpose Chemotherapy remains the primary treatment for metastatic gastric/GEJ cancer but optimal agents and schedule remain controversial. This study examined the safety and efficacy of first-line Irinotecan, capecitabine (Xeloda®), and Oxaliplatin (IXO). Patients and Methods Eligible patients with HER2-unamplified/unknown, metastatic gastric/GEJ adenocarcinoma were treated with 21-day cycle IXO at dose level 1 (DL1: Day 1 O-100 mg/m² & I-160 mg/m² IV, Day 2–15 X-1900 mg/m²/day PO divided doses) or modified IXO (mIXO): Day 1 O-85 mg/m² & I-120 mg/m² IV, Day 2–15 X-1425 mg/m²/day PO divided doses). This Bryant and Day two-stage designed study had dual primary endpoints of objective response rate (ORR) and toxicity. Secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results Fifty patients were enrolled and received a median of 7 cycles. After accrual of 9 patients at DL1, evaluable RR was 88% however dose limiting toxicity (DLT) rate was 56% thus doses were adjusted to mIXO. Fifteen patients accrued at mIXO had a RR of 60% and DLT rate of 13% allowing continuation to stage 2. Overall, 48 and 49 patients were evaluable for efficacy and safety, respectively, with ORR of 54% and DLTs in 24% of patients (DL1 = 56%; mIXO = 18%). Disease control rate was 85%. The most frequent grade 3/4 adverse events were diarrhea, neutropenia, fatigue, hypokalemia, and nausea. Median PFS and OS were 7.5 and 13.0 months, respectively, with a median follow-up of 9.7 months. Conclusion mIXO demonstrates promising ORR, PFS, OS, and acceptable toxicity compared to standard triplet regimens. IXO should be evaluated in phase III trials.

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Mutations of the PDE5A gene confer a survival advantage in patients with colon cancer

Sildenafil is a small molecule that inhibits PDE5. The study of Islam et al validates PDE5 as a colon cancer chemoprevention target in mice (2), as did a second mouse study (3). Our analysis of TCGA data corroborates this finding in humans. Further studies are needed to determine whether sildenafil or other PDE5 inhibitors might be colon cancer preventives or treatments.

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Genomic status of MET potentiates sensitivity to MET and MEK inhibition in NF1-related malignant peripheral nerve sheath tumors

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly resistant sarcomas that occur in up to 13% of individuals with Neurofibromatosis Type 1 (NF1). Genomic analysis of longitudinally collected tumor samples in a case of MPNST disease progression revealed early hemizygous microdeletions in NF1 and TP53, with progressive amplifications of MET, HGF, and EGFR. To examine the role of MET in MPNST progression, we developed mice with enhanced MET expression and Nf1 ablation (Nf1fl/KO;lox-stop-loxMETtg/+;Plp-creERTtg/+; referred to as NF1 MET). NF1-MET mice express a robust MPNST phenotype in the absence of additional mutations. A comparison of NF1-MET MPNSTs with MPNSTs derived from Nf1KO/+;p53R172H;Plp-creERTtg/+ (NF1-P53) and Nf1KO/+;Plp-creERTtg/+ (NF1) mice revealed unique Met, Ras, and PI3K signaling patterns. NF1-MET MPNSTs were uniformly sensitive to the highly selective MET inhibitor, capmatinib, whereas a heterogeneous response to MET inhibition was observed in NF1-P53 and NF1 MPNSTs. Combination therapy of capmatinib and the MEK inhibitor trametinib resulted in reduced response variability, enhanced suppression of tumor growth, and suppressed RAS/ERK and PI3K/AKT signaling. These results highlight the influence of concurrent genomic alterations on RAS effector signaling and therapy response to tyrosine kinase inhibitors. Moreover, these findings expand our current understanding of the role of MET signaling in MPNST progression and identify a potential therapeutic niche for NF1-related MPNSTs.

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Genomic status of MET potentiates sensitivity to MET and MEK inhibition in NF1-related malignant peripheral nerve sheath tumors

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly resistant sarcomas that occur in up to 13% of individuals with Neurofibromatosis Type 1 (NF1). Genomic analysis of longitudinally collected tumor samples in a case of MPNST disease progression revealed early hemizygous microdeletions in NF1 and TP53, with progressive amplifications of MET, HGF, and EGFR. To examine the role of MET in MPNST progression, we developed mice with enhanced MET expression and Nf1 ablation (Nf1fl/KO;lox-stop-loxMETtg/+;Plp-creERTtg/+; referred to as NF1 MET). NF1-MET mice express a robust MPNST phenotype in the absence of additional mutations. A comparison of NF1-MET MPNSTs with MPNSTs derived from Nf1KO/+;p53R172H;Plp-creERTtg/+ (NF1-P53) and Nf1KO/+;Plp-creERTtg/+ (NF1) mice revealed unique Met, Ras, and PI3K signaling patterns. NF1-MET MPNSTs were uniformly sensitive to the highly selective MET inhibitor, capmatinib, whereas a heterogeneous response to MET inhibition was observed in NF1-P53 and NF1 MPNSTs. Combination therapy of capmatinib and the MEK inhibitor trametinib resulted in reduced response variability, enhanced suppression of tumor growth, and suppressed RAS/ERK and PI3K/AKT signaling. These results highlight the influence of concurrent genomic alterations on RAS effector signaling and therapy response to tyrosine kinase inhibitors. Moreover, these findings expand our current understanding of the role of MET signaling in MPNST progression and identify a potential therapeutic niche for NF1-related MPNSTs.

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The role of bisphosphonates or denosumab in light of the availability of new therapies for prostate cancer

Publication date: Available online 3 May 2018
Source:Cancer Treatment Reviews
Author(s): Fred Saad, Cora N Sternberg, Peter FA Mulders, Daniela Niepel, Bertrand F Tombal
Most men with advanced prostate cancer will develop bone metastases, which have a substantial impact on quality of life. Bone metastases can lead to skeletal-related events (SREs), which place a burden on patients and healthcare systems. For men with castration-resistant prostate cancer (CRPC) and bone metastases, the treatment landscape has evolved rapidly over the past few years. The relatively recent approvals of the hormonal agents abiraterone acetate and enzalutamide, second-line chemotherapy cabazitaxel, and the radiopharmaceutical radium-223 dichloride (radium-223), have provided clinicians with a greater choice of treatments. These compounds have benefits in terms of overall survival based on the results of pivotal phase 3 studies. The bisphosphonate zoledronic acid and the RANK ligand inhibitor denosumab are indicated for the prevention of SREs in men with metastatic CRPC but studies of these compounds have not demonstrated a survival benefit. The important question of the role of bisphosphonates or denosumab in combination with these new agents has thus materialised. Current and emerging evidence from clinical studies of abiraterone acetate, enzalutamide and radium-223, suggest that addition of bisphosphonates or denosumab to these new therapies may provide further clinical benefits for patients with prostate cancer and bone metastases. This evidence may help to shape clinical practice but are based largely on post hoc analyses of clinical trial data. It is therefore apparent that further data are required from both clinical studies and real-world settings to enable physicians to understand the efficacy and safety of combination therapy with the new agents plus bisphosphonates or denosumab.



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Diabetes and pancreatic neuroendocrine tumours: which interplays, if any?

Publication date: Available online 2 May 2018
Source:Cancer Treatment Reviews
Author(s): Marco Gallo, Rosaria Maddalena Ruggeri, Giovanna Muscogiuri, Genoveffa Pizza, Antongiulio Faggiano, Annamaria Colao
Pancreatic neuroendocrine tumours (PanNETs) represent an uncommon type of pancreatic neoplasm, whose incidence is increasing worldwide. As per exocrine pancreatic cancer, a relationship seems to exist between PanNETs and glycaemic alterations. Diabetes mellitus (DM) or impaired glucose tolerance often occurs in PanNET patients as a consequence of hormonal hypersecretion by the tumour, specifically affecting glucose metabolism, or due to tumour mass effects. On the other hand, pre-existing DM may represent a risk factor for developing PanNETs and is likely to worsen the prognosis of such patients. Moreover, the surgical and/or pharmacological treatment of the tumour itself may impair glucose tolerance, as well as antidiabetic therapies may impact tumour behaviour and patients outcome. Differently from exocrine pancreatic tumours, few data are available for PanNETs as yet on this issue. In the present review, the bidirectional association between glycaemic disorders and PanNETs has been extensively examined, since the co-existence of both diseases in the same individual represents a further challenge for the clinical management of PanNETs.



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Treatment of Advanced HER2-positive Breast Cancer: 2018 and Beyond

Publication date: Available online 2 May 2018
Source:Cancer Treatment Reviews
Author(s): Noam Pondé, Mariana Brandão, Georges El-Hachem, Emilie Werbrouck, Martine Piccart
In the 1980s the importance of HER2 signalling to the aberrant behaviour of a subset of breast cancer cells was recognized for the first time and, consequently, a hitherto unknown subtype of breast cancer – HER2-positive (HER2+) breast cancer was identified. The development of the anti-HER2 class of drugs, first with trastuzumab, followed closely by lapatinib, pertuzumab, and T-DM1, has improved outcomes dramatically. Nevertheless, metastatic HER2+ breast cancer remains an incurable disease and new therapeutic options are needed. Additionally, the rapid changes in treatment standards 5 years ago have left unanswered numerous questions, including the "real-life" benefit of pertuzumab and T-DM1, since both the CLEOPATRA and EMILIA trials were conducted in populations that no longer exist in practice and, moreover, on the role of endocrine therapy in HER2+ disease. Furthermore, despite significant research efforts, including translational efforts and new imaging techniques, no predictive biomarkers have been clinically validated and therefore a more refined approach to treatment tailoring remains beyond our reach. Finally, a better understanding of resistance to currently existing anti-HER2 agents and of the role played by the microenvironment (e.g. immune system) and of interconnected signalling pathways (e.g. PI3K-mTOR-AKT) is at the core of clinical trials exploring new drugs and new regimens. These include the combination of anti-HER2 agents and anti-PD-1/PDL-1, PI3K inhibitors and CDK 4/6 inhibitors, as well as a host of new panHER inhibitors, drug antibody conjugates and anti-HER antibodies, which may, in coming years further push the boundaries of what we can do for our patients.



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The Role of PARP Inhibition in Triple-Negative Breast Cancer: Unraveling the Wide Spectrum of Synthetic Lethality

Publication date: Available online 2 May 2018
Source:Cancer Treatment Reviews
Author(s): Marios Papadimitriou, Giannis Mountzios, Christos A. Papadimitriou
Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancers and is characterized by a lack of immunohistochemical expression of estrogen receptors (ER), progesterone receptors (PR) and HER2. TNBC is associated with poor long-term outcomes compared with other breast cancer subtypes. Many of these tumors are also basal-like cancers which are characterized by an aggressive biological behavior with a distant recurrence peak observed early at 3 years following diagnosis. Furthermore, metastatic TNBC bears a dismal prognosis with an average survival of 12 months. Although the prevalence of genetic alterations among women with TNBC differs significantly by ethnicity, race and age, BRCA mutations (including both germline mutations and somatic genetic aberrations) are found in up to 20-25% of unselected patients and especially in those of the basal-like immunophenotype. Therefore, defects in the DNA repair pathway could represent a promising therapeutic target for this subgroup of TNBC patients. Poly(ADP-ribose) polymerase (PARP) inhibitors exploit this deficiency through synthetic lethality and have emerged as promising anticancer therapies, especially in BRCA1 or BRCA2 mutation carriers. Several PARP inhibitors are currently being evaluated in the adjuvant, neo-adjuvant, and metastatic setting for the treatment of breast cancer patients with a deficient homologous recombination pathway. In this article, we review the major molecular characteristics of TNBC, the mechanisms of homologous recombination, and the role of PARP inhibition as an emerging therapeutic strategy.



https://ift.tt/2risNUW

Cardiotoxicity associated with radiotherapy in breast cancer: A question-based review with current literatures

Publication date: Available online 2 May 2018
Source:Cancer Treatment Reviews
Author(s): Qian Zhu, Youlia M. Kirova, Lu Cao, Alexandre Arsene-Henry, Jiayi Chen
Radiotherapy is an indispensable unit of multidisciplinary treatment of breast cancer. Although the application of modern techniques has led to a significantly reduction in radiation-induced heart disease, it is still recognized as the leading causes of morbidity and mortality among breast cancer survivors. With the growing number of long-term survivors, it is important to understand the cardiovascular risks associated with radiotherapy. Questions exist regarding the existence or not of a safe radiation threshold dose that the heart (or its substructures) can receive and strategies to minimize risk of radiation. This paper aims to review the current understanding of radiation-induced cardiotoxicity and try to give answers to those unsettled issues based on current literatures.



https://ift.tt/2JMxAok

Metabolomics in breast cancer: a decade in review

Publication date: Available online 3 May 2018
Source:Cancer Treatment Reviews
Author(s): Amelia McCartney, Alessia Vignoli, Laura Biganzoli, Richard Love, Leonardo Tenori, Claudio Luchinat, Angelo Di Leo
Breast cancer (BC) is a heterogeneous disease which has been characterised and stratified by many platforms such as clinicopathological risk factors, genomic assays, computer generated models, and various "-omic" technologies. Genomic, proteomic and transcriptomic analysis in breast cancer research is well established, and metabolomics, which can be considered a downstream manifestation of the former disciplines, is of growing interest. The past decade has seen significant progress made within the field of clinical metabolomic BC research, with several groups demonstrating results with significant promise in the setting of BC screening and biological characterisation, as well as future potential for prognostic metabolomic biomarkers.



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The current evidence for a biomarker-based approach in cancer of unknown primary

Publication date: Available online 2 May 2018
Source:Cancer Treatment Reviews
Author(s): Elie El Rassy, Nicholas Pavlidis
Cancer of unknown primary (CUP) accounts for the seventh to eighth most frequently diagnosed cancer yet its prognosis remains poor with conventional chemotherapy. The spectrum of therapeutic management includes both locoregional and systemic therapy and should intend to offer optimal benefit to favorable CUP patients and palliative care to unfavorable cases. The recent molecular advances have revolutionized the armamentarium of cancer treatments though a biomarker-based approach. Unfortunately, solid data in CUP is lacking in the absence of a CUP-specific driver molecular signature. This prompted us to screen the medical literature for clinical data that evaluates the efficacy and safety of the biomarker-based approach in CUP patients. In this review, we will summarize the available evidence for the applicability of targeted therapies in CUP.



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Renal Cell Carcinoma in one year: going inside the news of 2017

Publication date: Available online 2 May 2018
Source:Cancer Treatment Reviews
Author(s): Claudia Mosillo, Chiara Ciccarese, Davide Bimbatti, Emanuela Fantinel, Alberto Dalla Volta, Iolanda Bisogno, Ilaria Zampiva, Matteo Santoni, Francesco Massar, Matteo Brunelli, Rodolfo Montironi, Giampaolo Tortora, Roberto Iacovelli
Very interesting issues regarding RCC treatment have been raised during 2017. We analysed the main news that may potentially modified clinical practice. Conflicting data came from trials testing targeted therapies in the adjuvant setting, supporting the necessity of further investigations. One of the key goals of RCC research is focused on the first-line therapy, with particular interest focus on immunotherapy combinations. Redefine the standard of care with the aim of improving patients' survival represents an imperative need. Enhancing immunotherapy antitumor activity by combining immune checkpoint inhibitors with anti-angiogenetic therapies is a noteworthy research field, with promising results. In addiction, we analysed in the metastatic setting data about the role of cytoreductive nephrectomy and the possibility of delay the start of first-line therapy after an active surveillance period. Based on recent developments, the paper outlines future prospective of RCC research.



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Tolerability of sequential immune therapy and palliative radiotherapy to the cervical and thoracic spine

Abstract

Background

Use of immune therapy in metastatic cancers is rapidly expanding; however, its combination with commonly prescribed palliative radiation fields and doses is not well studied. To investigate this, we evaluated the toxicity of combined immune therapy and palliative cervical or thoracic spine radiotherapy.

Methods

Patients receiving cervical or thoracic spine radiation were evaluated based on administration of immune therapy within 30 days of radiation, use of 3D conformal or simpler techniques, and minimum 1 follow-up from end of treatment.

Results

Thirty patients were evaluable. Median survival following radiotherapy was 87 days. Pembrolizumab was most commonly combined with radiation (11 patients), then nivolumab (10), ipilimumab (3), and atezoliumab (2). Four patients (13.3%) had grade 3 toxicity requiring hospitalization (vomiting, esophagitis) and 12 patients (40%) had grade 2 toxicity (esophagitis, dysphagia). Ten patients (33.3%) had no toxicity. Three of the 4 patients with grade 3 toxicity received concurrent ipilimumab and nivolumab. Median dose was 30 Gy (range, 20–39) and fractions were 10 (range, 5–15). There was a trend toward increased grade 2+ toxicity with greater number of vertebral levels irradiated, 5.7 ± 3.4, vs. 4.0 ± 1.6 for none/grade 1 (P = .086). Seven of 7 patients exposed to ipilimumab developed grade 2+ toxicity vs 39% in the remaining patients (P = .007 for interaction). Radiation dose, fractionation, and timing of immune therapy were not significant contributors.

Conclusions

Combined immune therapy and radiotherapy for palliation of spine metastases suggests increased toxicity when a greater number of vertebral bodies are irradiated, or when combined immune therapy agents are utilized.

https://ift.tt/2waqKqX

Contouring of prostate tumors on multiparametric MRI: Evaluation of clinical delineations in a multicenter radiotherapy trial

To date no guidelines are available for contouring prostate cancer inside the gland, as visible on multiparametric (mp-) MRI. We assessed inter-institutional differences in interpretation of mp-MRI in the multicenter phase III FLAME trial.

https://ift.tt/2joOBKe

SBRT for pancreatic cancer: In regard of Bohoudi et al.

We read with interest the article of Bohoudi and colleagues [1] focusing on SBRT for pancreatic tumours using shallow inspiration breath hold (SIBH) and MRI-based IGRT. The authors proposed daily on-line adaptive RT with organs at risk (OARs) contour deformation and adjustment within 3 cm from the PTV and plan re-optimization, to reduce the daily variations of the relationship between tumour and duodenum and stomach [2]. We congratulate the authors for the high level of their research. We would like to raise some issues that we think could be of interest for the international SBRT community.

https://ift.tt/2HPw6Ju

Implications of improved diagnostic imaging of small nodal metastases in head and neck cancer: Radiotherapy target volume transformation and dose de-escalation

Diagnostic imaging continues to evolve, and now has unprecedented accuracy for detecting small nodal metastasis. This influences the tumor load in elective target volumes and subsequently has consequences for the radiotherapy dose required to control disease in these volumes.Small metastases that used to remain subclinical and were included in elective volumes, will nowadays be detected and included in high-dose volumes. Consequentially, high-dose volumes will more often contain low-volume disease.

https://ift.tt/2rilBbv

Nintedanib is active in malignant pleural mesothelioma cell models and inhibits angiogenesis and tumor growth in vivo

Purpose: Malignant pleural mesothelioma (MPM) is an aggressive thoracic tumor type with limited treatment options and poor prognosis. The angiokinase inhibitor nintedanib has shown promising activity in the LUME-Meso phase 2 MPM trial and thus is currently being evaluated in the confirmatory LUME-Meso phase 3 trial. However, the anti-MPM potential of nintedanib has not been studied in the preclinical setting. Experimental design: We have examined the antineoplastic activity of nintedanib in various in vitro and in vivo models of human MPM. Results: Nintedanib's target receptors were (co)expressed in all the 20 investigated human MPM cell lines. Nintedanib inhibited MPM cell growth in both short- and long-term viability assays. Reduced MPM cell proliferation and migration and the inhibition of Erk1/2 phosphorylation were also observed upon nintedanib treatment in vitro. Additive effects on cell viability were detected when nintedanib was combined with cisplatin, a drug routinely used for systemic MPM therapy. In an orthotopic mouse model of human MPM, survival of animals receiving nintedanib per os showed a favorable trend, but no significant benefit. Nintedanib significantly reduced tumor burden and vascularization and prolonged the survival of mice when it was administered intraperitoneally. Importantly, unlike bevacizumab, nintedanib demonstrated significant in vivo antivascular and antitumor potential independently of baseline VEGF-A levels. Conclusions: Nintedanib exerts significant antitumor activity in MPM both in vitro and in vivo. These data provide preclinical support for the concept of LUME-Meso trials evaluating nintedanib in patients with unresectable MPM.

https://ift.tt/2KyfFmH

Nintedanib is active in malignant pleural mesothelioma cell models and inhibits angiogenesis and tumor growth in vivo

Purpose: Malignant pleural mesothelioma (MPM) is an aggressive thoracic tumor type with limited treatment options and poor prognosis. The angiokinase inhibitor nintedanib has shown promising activity in the LUME-Meso phase 2 MPM trial and thus is currently being evaluated in the confirmatory LUME-Meso phase 3 trial. However, the anti-MPM potential of nintedanib has not been studied in the preclinical setting. Experimental design: We have examined the antineoplastic activity of nintedanib in various in vitro and in vivo models of human MPM. Results: Nintedanib's target receptors were (co)expressed in all the 20 investigated human MPM cell lines. Nintedanib inhibited MPM cell growth in both short- and long-term viability assays. Reduced MPM cell proliferation and migration and the inhibition of Erk1/2 phosphorylation were also observed upon nintedanib treatment in vitro. Additive effects on cell viability were detected when nintedanib was combined with cisplatin, a drug routinely used for systemic MPM therapy. In an orthotopic mouse model of human MPM, survival of animals receiving nintedanib per os showed a favorable trend, but no significant benefit. Nintedanib significantly reduced tumor burden and vascularization and prolonged the survival of mice when it was administered intraperitoneally. Importantly, unlike bevacizumab, nintedanib demonstrated significant in vivo antivascular and antitumor potential independently of baseline VEGF-A levels. Conclusions: Nintedanib exerts significant antitumor activity in MPM both in vitro and in vivo. These data provide preclinical support for the concept of LUME-Meso trials evaluating nintedanib in patients with unresectable MPM.

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Clinico-pathological Features of PIK3CA Mutation in HER2-Positive Breast Cancer of Indian Population

Abstract

PIK3CA pathway is one of the important signaling pathways in cells, which is involved in cell proliferation, cell survival, motility, and growth. Mutation in PIK3CA gene negatively effects to anti-HER2 therapy in breast cancer patients. PIK3CA gene of HER2-positive breast cancers associated with reduced sensitivity to neoadjuvant therapy. In this study, we assessed the frequency of PIK3CA mutations and influence of PIK3CA mutations on patient survival in a series of HER2-positive breast cancer patients. PIK3CA mutations were assessed by pyrosequencing and next generation sequencing in 107 HER2-positive breast cancer patients of a tertiary Cancer Centre of India from Jan 2012 to Jun 2013 with minimum follow-up of 3 years. We found PIK3CA mutations in 26 tumors (24.2%) of which 5 were in exon 9, 20 were in exon 20, and 1 was in both exon 9 and 20. In exon 9, the mutation c.1634A>G was found in 4 cases and mutation c.1636C>A was found in 2 cases. In exon 20, the mutation c.3140A>G was found in 15 cases and c.3140A>T was found in 6 cases. The outcome between PIK3CA mutated versus PIK3CA wild type was significant showing p value 0.014. Overall survival of mutation and treatment with herceptin, mutation with other chemotherapy treatment in both early breast cancer (EBC), and locally advanced breast cancer (LABC) showed significant p value 0.037 and 0.044 respectively. In conclusion, we identified 24.2% somatic mutation of PIK3CA in HER2-positive breast cancer patients. PIK3CA mutation is significantly associated with ER-positive tumors. The frequency and distribution pattern reported in this study is similar to the global report. Overall survival of PIK3CA mutation is slightly lower but in patients who received herceptin with PIK3CA mutation showed better clinical outcome.

https://ift.tt/2jr0zmH

Clinico-pathological Features of PIK3CA Mutation in HER2-Positive Breast Cancer of Indian Population

Abstract

PIK3CA pathway is one of the important signaling pathways in cells, which is involved in cell proliferation, cell survival, motility, and growth. Mutation in PIK3CA gene negatively effects to anti-HER2 therapy in breast cancer patients. PIK3CA gene of HER2-positive breast cancers associated with reduced sensitivity to neoadjuvant therapy. In this study, we assessed the frequency of PIK3CA mutations and influence of PIK3CA mutations on patient survival in a series of HER2-positive breast cancer patients. PIK3CA mutations were assessed by pyrosequencing and next generation sequencing in 107 HER2-positive breast cancer patients of a tertiary Cancer Centre of India from Jan 2012 to Jun 2013 with minimum follow-up of 3 years. We found PIK3CA mutations in 26 tumors (24.2%) of which 5 were in exon 9, 20 were in exon 20, and 1 was in both exon 9 and 20. In exon 9, the mutation c.1634A>G was found in 4 cases and mutation c.1636C>A was found in 2 cases. In exon 20, the mutation c.3140A>G was found in 15 cases and c.3140A>T was found in 6 cases. The outcome between PIK3CA mutated versus PIK3CA wild type was significant showing p value 0.014. Overall survival of mutation and treatment with herceptin, mutation with other chemotherapy treatment in both early breast cancer (EBC), and locally advanced breast cancer (LABC) showed significant p value 0.037 and 0.044 respectively. In conclusion, we identified 24.2% somatic mutation of PIK3CA in HER2-positive breast cancer patients. PIK3CA mutation is significantly associated with ER-positive tumors. The frequency and distribution pattern reported in this study is similar to the global report. Overall survival of PIK3CA mutation is slightly lower but in patients who received herceptin with PIK3CA mutation showed better clinical outcome.

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Patient Navigation Preferences for Adolescent and Young Adult Cancer Services by Distance to Treatment Location

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


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Patient Navigation Preferences for Adolescent and Young Adult Cancer Services by Distance to Treatment Location

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


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Association of Circulating Tumor Cells With Radiotherapy Benefit and Survival in Early-Stage Breast Cancer

This cohort study determines whether circulating tumor cell status is associated with radiotherapeutic benefit in terms of overall, local recurrence-free, and disease-free survival in patients with early-stage breast cancer.

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Disseminated Lesions in a Patient With a Medical History of Myelodysplastic Syndrome

A man in his 50s with a medical history of myelodysplastic syndrome refractory anemia with excess blasts presented with a 2-month history of nonpruritic infiltrative skin lesions on the left upper chest. What is your diagnosis?

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Testing Ashkenazi Jewish Women for Breast Cancer Mutations in Genes Other Than BRCA1 and BRCA2

To the Editor Walsh et al present data on 1007 Jewish women with breast cancer who were sequenced for 23 candidate genes. There were 111 carriers of a BRCA1 or BRCA2 mutation identified, 29 carriers of a CHEK2 mutation, 1 carrier of an NBN mutation, and 1 carrier of a BRIP1 mutation. The authors use these data to support their position that use of a 23-gene panel is preferable to testing for BRCA1 and BRCA2 alone. We look at the same data and conclude that testing should be limited to BRCA1 and BRCA2.

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Circulating Tumors Cells as a Biomarker of Radiation Benefit

Based on the findings of multiple prospective, randomized, phase 3 clinical trials showing improved local control and disease-free survival and the Early Breast Cancer Trialist's Collaborative Group (EBCTCG) meta-analysis showing overall survival benefit, adjuvant radiation therapy has become the standard of care after breast-conserving surgery (BCS) for patients with early-stage breast cancer. In addition, similar randomized clinical trial data and meta-analyses demonstrate the benefit of postmastectomy radiation therapy for women with axillary node–positive disease. Despite evidence of a benefit from radiation therapy in these unselected populations, no accepted biomarkers are available to predict the benefit from adjuvant radiation therapy for individual patients. In contrast, the development and proven utility of molecularly based gene expression signatures to guide decisions on the use of adjuvant systemic chemotherapy suggest that a risk-adapted, personalized biomarker strategy might also be feasible to predict benefit from radiation. OncotypeDx (Genomic Health), Prosigna (NanoString), MammaPrint (Agendia), EndoPredict (Myriad Genetics), Mammostrat (Clarient Diagnostic Services), and the Breast Cancer Index are examples of gene-expression signatures in early-stage breast cancer; several tests are used in clinical practice to predict the additional benefit of adding chemotherapy to adjuvant endocrine therapy. Studies from multiple groups developing gene expression signatures for a response to radiation therapy have been published, but none are ready for clinical adoption.

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Targetable Genomic Alterations in Adult Patients With Soft-Tissue Sarcomas

This study examines the use of next-generation sequencing for identification of potentially actionable alterations in patients with soft-tissue sarcoma.

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Breast Cancer With a Poor Prognosis Diagnosed After Negative Mammography Results

This study of data from the PROSPR consortium assesses the incidence of and risk factors associated with breast cancer with a poor prognosis after undergoing screening mammography with negative results.

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Testing Ashkenazi Jewish Women for Breast Cancer Mutations in Genes Other Than BRCA1 and BRCA2 —Reply

In Reply Narod et al raise several concerns about our recent suggestion that women of Ashkenazi Jewish (AJ) ancestry consider comprehensive sequencing for inherited predisposition to breast and ovarian cancer. Our data led us to suggest that, given recent advances in sequencing technology and reductions in price, AJ women consider the same complete sequencing for all known breast cancer genes as women of other ancestries.

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Quantification of Long-term Survival Benefit in a Comparative Oncology Clinical Study

This study compares conventional hazard ratios and an alternative, clinically interpretable approach to quantify the long-term survival benefit in patients receiving chemotherapy with immunotherapy.

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Neoadjuvant FOLFIRINOX and Chemoradiotherapy for Resectable Pancreatic Adenocarcinoma

This single-arm, phase 2 clinical trial evaluates the margin-negative resection rate in borderline-resectable pancreatic ductal adenocarcinoma after neoadjuvant FOLFIRINOX (fluorouracil, irinotecan, and oxaliplatin) therapy and individualized chemoradiotherapy.

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Blue Infusion

It was not love that endedin a conception, but a rebelcourse of the self, grown outof control into a universeof its own—new arterioles, sleekknots of veins to feed what is, in essence,more of me, transfixed beneath a bowlmy bones make of my neck, an angrylung fugitive.The treatment room todayappears a darker shade of gray, and the wallsfeel plump with picture frames of riverbeds—an unwanted reminder of a smootherpassing, the endlessness of water bodieslike itinerant souls; being, in a way, a tougher distractionfrom my body's reckless arithmetic.

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Involvement of acute neuroinflammation in postoperative delirium-like cognitive deficits in rats

Abstract

Purpose

The purpose of this study was to investigate the age-, time-, and brain region-dependent postoperative neuroinflammatory trajectory, and its association with neurocognitive outcomes in rats.

Methods

Adult and aged rats were randomly assigned to one of three groups: control, isoflurane anesthesia alone, and isoflurane anesthesia with abdominal surgery. On either postoperative day 2 (early phase) or 7 (late phase), all rats were tested for trace and context fear memory retention after acquisition of trace fear conditioning. Freezing behavior was used as an index of fear memory. Following the cognitive testing, the levels of pro-inflammatory cytokines in several brain regions were measured using enzyme-linked immunosorbent assay (n = 8 in each group).

Results

In the early postoperative period, surgery under isoflurane anesthesia induced acute neuroinflammation along with related trace and context memory dysfunction. Such acute neuroinflammatory responses were comparably observed in both adult and aged animals, whereas the aged rats were more likely to exhibit behavioral changes. On the other hand, in the late postoperative period, neither neuroinflammation in all tested brain regions nor concomitant memory decline were found in adult animals. Significant neuroinflammation was detected only in the hippocampus of aged rats, which was associated with context, but not trace memory dysfunction.

Conclusion

Our findings indicate that surgery-induced acute, transient, brain-wide neuroinflammation may be involved in the pathogenesis of the postoperative delirium-like cognitive deficits in rats. Furthermore, neuroinflammation may convert from acute to chronic in an age- and hippocampal-specific manner, likely resulting in the development of sustained cognitive dysfunction.

https://ift.tt/2HSYoCP

Chronophin regulates active vitamin B6 levels and transcriptomic features of glioblastoma cell lines cultured under non-adherent, serum-free conditions

Abstract

Background

The phosphatase chronophin (CIN/PDXP) has been shown to be an important regulator of glioma cell migration and invasion. It has two known substrates: p-Ser3-cofilin, the phosphorylated form of the actin binding protein cofilin, and pyridoxal 5′-phosphate, the active form of vitamin B6. Phosphoregulation of cofilin, among other functions, plays an important role in cell migration, whereas active vitamin B6 is a cofactor for more than one hundred enzymatic reactions. The role of CIN has yet only been examined in glioblastoma cell line models derived under serum culture conditions.

Results

We found that CIN is highly expressed in cells cultured under non-adherent, serum-free conditions that are thought to better mimic the in vivo situation. Furthermore, the substrates of CIN, p-Ser3-cofilin and active vitamin B6, were significantly reduced as compared to cell lines cultured in serum-containing medium. To further examine its molecular role we stably knocked down the CIN protein with two different shRNA hairpins in the glioblastoma cell lines NCH421k and NCH644. Both cell lines did not show any significant alterations in proliferation but expression of differentiation markers (such as GFAP or TUBB3) was increased in the knockdown cell lines. In addition, colony formation was significantly impaired in NCH644. Of note, in both cell lines CIN knockdown increased active vitamin B6 levels with vitamin B6 being known to be important for S-adenosylmethionine biosynthesis. Nevertheless, global histone and DNA methylation remained unaltered as was chemoresistance towards temozolomide. To further elucidate the role of phosphocofilin in glioblastoma cells we applied inhibitors for ROCK1/2 and LIMK1/2 to our model. LIMK- and ROCK-inhibitor treatment alone was not toxic for glioblastoma cells. However, it had profound, but antagonistic effects in NCH421k and NCH644 under chemotherapy.

Conclusion

In non-adherent glioblastoma cell lines cultured in serum-free medium, chronophin knockdown induces phenotypic changes, e.g. in colony formation and transcription, but these are highly dependent on the cellular background. The same is true for phenotypes observed after treatment with inhibitors for kinases regulating cofilin phosphorylation (ROCKs and LIMKs). Targeting the cofilin phosphorylation pathway might therefore not be a straightforward therapeutic option in glioblastoma.

https://ift.tt/2JOtzQm

Association of genetic polymorphisms CYP2A6*2 rs1801272 and CYP2A6*9 rs28399433 with tobacco-induced lung Cancer: case-control study in an Egyptian population

Abstract

Background

Several studies have reported the role of CYP2A6 genetic polymorphisms in smoking and lung cancer risk with some contradictory results in different populations. The purpose of the current study is to assess the contribution of the CYP2A6*2 rs1801272 and CYP2A6*9 rs28399433 gene polymorphisms and tobacco smoking in the risk of lung cancer in an Egyptian population.

Methods

A case-control study was conducted on 150 lung cancer cases and 150 controls. All subjects were subjected to blood sampling for Extraction of genomic DNA and Genotyping of the CYP2A6 gene SNPs (CYP2A6*2 (1799 T > A) rs1801272 and CYP2A6*9 (− 48 T > G) rs28399433 by Real time PCR.

Results

AC and CC genotypes were detected in CYP2A6*9; and AT genotype in CYP2A6*2. The frequency of CYP2A6*2 and CYP2A6*9 were 0.7% and 3.7% respectively in the studied Egyptian population. All cancer cases with slow metabolizer variants were NSCLC. Non-smokers represented 71.4% of the CYP2A6 variants. There was no statistical significant association between risk of lung cancer, smoking habits, heaviness of smoking and the different polymorphisms of CYP2A6 genotypes.

Conclusion

The frequency of slow metabolizers CYP2A6*2 and CYP2A6*9 are poor in the studied Egyptian population. Our findings did not suggest any association between CYP2A6 genotypes and risk of lung cancer.

https://ift.tt/2rhAomz

Characteristics of Cancer Rehabilitation Fellowship Training Programs in the USA

Abstract

Cancer rehabilitation is emerging as a specialized field within Physical Medicine and Rehabilitation. The purpose of this systemic review is to summarize the various cancer rehabilitation fellowship programs in the USA and the scope of training in this discipline. Currently, four institutions offer such a training program. All of the fellowship directors were contacted about characteristics of their programs. The oldest program has been in existence since 2007. All of these programs are 1 year in duration and have between one and two fellowship positions annually. There have been total of 29 graduates as of July 2017. With regard to cancer rehabilitation care delivery model, all four centers reported inpatient consult teams and outpatient rehabilitation. Outpatient experience included electrodiagnosis, botulin toxin, and ultrasound-guided injections. Three of the four programs also reported the presence of an acute inpatient cancer rehabilitation service. A number of clinical rotations are available at each of the four programs with considerable variation. Comprehensive educational efforts are present in all programs with varying expectations for research.

https://ift.tt/2rjMSJB

Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo

Abstract

Background

Tumor hypoxia is considered an important factor in metastasis and disease relapse. Evofosfamide is a hypoxia-activated prodrug that selectively targets the hypoxic regions of solid tumors. As hypoxia-inducible factor-1α (HIF-1α) is overexpressed in nasopharyngeal carcinoma (NPC) tissues, we performed the present study to evaluate the efficacy profile of evofosfamide in NPC.

Methods

We evaluated the efficacy of evofosfamide as a single agent or combined with cisplatin (DDP) in the NPC cell lines CNE-2, HONE-1 and HNE-1, and in nude mouse xenograft tumor models.

Results

Evofosfamide exhibited hypoxia-selective cytotoxicity in NPC cell lines, with 50% inhibition concentration (IC₅₀) values of 8.33 ± 0.75, 7.62 ± 0.67, and 0.31 ± 0.07 μmol/L under hypoxia in CNE-2, HONE-1 and HNE-1 cells, respectively. The sensitization ranged from ninefold to greater than 300-fold under hypoxia compared with normoxia controls. The combination of evofosfamide with DDP had a synergistic effect on cytotoxicity in the NPC cell lines by combination index values assessment. Cell cycle G2 phase was arrested after treated with 0.05 μmol/L evofosfamide under hypoxia. Histone H2AX phosphorylation (γH2AX) (a marker of DNA damage) expression increased while HIF-1α expression suppressed after evofosfamide treatment under hypoxic conditions. In the HNE-1 NPC xenograft models, evofosfamide exhibited antitumor activity both as a single agent and combined with DDP. Hypoxic regions in xenograft tissue were reduced after both evofosfamide monotherapy and combined therapy with DDP.

Conclusions

Our results present preclinical evidence for targeting the selective hypoxic portion of NPC by evofosfamide as a single agent and combined with DDP and provide rationale for the potential clinical application of evofosfamide for the treatment of nasopharyngeal carcinoma.

https://ift.tt/2w6ttSh

Chronophin regulates active vitamin B6 levels and transcriptomic features of glioblastoma cell lines cultured under non-adherent, serum-free conditions

Abstract

Background

The phosphatase chronophin (CIN/PDXP) has been shown to be an important regulator of glioma cell migration and invasion. It has two known substrates: p-Ser3-cofilin, the phosphorylated form of the actin binding protein cofilin, and pyridoxal 5′-phosphate, the active form of vitamin B6. Phosphoregulation of cofilin, among other functions, plays an important role in cell migration, whereas active vitamin B6 is a cofactor for more than one hundred enzymatic reactions. The role of CIN has yet only been examined in glioblastoma cell line models derived under serum culture conditions.

Results

We found that CIN is highly expressed in cells cultured under non-adherent, serum-free conditions that are thought to better mimic the in vivo situation. Furthermore, the substrates of CIN, p-Ser3-cofilin and active vitamin B6, were significantly reduced as compared to cell lines cultured in serum-containing medium. To further examine its molecular role we stably knocked down the CIN protein with two different shRNA hairpins in the glioblastoma cell lines NCH421k and NCH644. Both cell lines did not show any significant alterations in proliferation but expression of differentiation markers (such as GFAP or TUBB3) was increased in the knockdown cell lines. In addition, colony formation was significantly impaired in NCH644. Of note, in both cell lines CIN knockdown increased active vitamin B6 levels with vitamin B6 being known to be important for S-adenosylmethionine biosynthesis. Nevertheless, global histone and DNA methylation remained unaltered as was chemoresistance towards temozolomide. To further elucidate the role of phosphocofilin in glioblastoma cells we applied inhibitors for ROCK1/2 and LIMK1/2 to our model. LIMK- and ROCK-inhibitor treatment alone was not toxic for glioblastoma cells. However, it had profound, but antagonistic effects in NCH421k and NCH644 under chemotherapy.

Conclusion

In non-adherent glioblastoma cell lines cultured in serum-free medium, chronophin knockdown induces phenotypic changes, e.g. in colony formation and transcription, but these are highly dependent on the cellular background. The same is true for phenotypes observed after treatment with inhibitors for kinases regulating cofilin phosphorylation (ROCKs and LIMKs). Targeting the cofilin phosphorylation pathway might therefore not be a straightforward therapeutic option in glioblastoma.

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Association of genetic polymorphisms CYP2A6*2 rs1801272 and CYP2A6*9 rs28399433 with tobacco-induced lung Cancer: case-control study in an Egyptian population

Abstract

Background

Several studies have reported the role of CYP2A6 genetic polymorphisms in smoking and lung cancer risk with some contradictory results in different populations. The purpose of the current study is to assess the contribution of the CYP2A6*2 rs1801272 and CYP2A6*9 rs28399433 gene polymorphisms and tobacco smoking in the risk of lung cancer in an Egyptian population.

Methods

A case-control study was conducted on 150 lung cancer cases and 150 controls. All subjects were subjected to blood sampling for Extraction of genomic DNA and Genotyping of the CYP2A6 gene SNPs (CYP2A6*2 (1799 T > A) rs1801272 and CYP2A6*9 (− 48 T > G) rs28399433 by Real time PCR.

Results

AC and CC genotypes were detected in CYP2A6*9; and AT genotype in CYP2A6*2. The frequency of CYP2A6*2 and CYP2A6*9 were 0.7% and 3.7% respectively in the studied Egyptian population. All cancer cases with slow metabolizer variants were NSCLC. Non-smokers represented 71.4% of the CYP2A6 variants. There was no statistical significant association between risk of lung cancer, smoking habits, heaviness of smoking and the different polymorphisms of CYP2A6 genotypes.

Conclusion

The frequency of slow metabolizers CYP2A6*2 and CYP2A6*9 are poor in the studied Egyptian population. Our findings did not suggest any association between CYP2A6 genotypes and risk of lung cancer.

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Characteristics of Cancer Rehabilitation Fellowship Training Programs in the USA

Abstract

Cancer rehabilitation is emerging as a specialized field within Physical Medicine and Rehabilitation. The purpose of this systemic review is to summarize the various cancer rehabilitation fellowship programs in the USA and the scope of training in this discipline. Currently, four institutions offer such a training program. All of the fellowship directors were contacted about characteristics of their programs. The oldest program has been in existence since 2007. All of these programs are 1 year in duration and have between one and two fellowship positions annually. There have been total of 29 graduates as of July 2017. With regard to cancer rehabilitation care delivery model, all four centers reported inpatient consult teams and outpatient rehabilitation. Outpatient experience included electrodiagnosis, botulin toxin, and ultrasound-guided injections. Three of the four programs also reported the presence of an acute inpatient cancer rehabilitation service. A number of clinical rotations are available at each of the four programs with considerable variation. Comprehensive educational efforts are present in all programs with varying expectations for research.

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Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo

Abstract

Background

Tumor hypoxia is considered an important factor in metastasis and disease relapse. Evofosfamide is a hypoxia-activated prodrug that selectively targets the hypoxic regions of solid tumors. As hypoxia-inducible factor-1α (HIF-1α) is overexpressed in nasopharyngeal carcinoma (NPC) tissues, we performed the present study to evaluate the efficacy profile of evofosfamide in NPC.

Methods

We evaluated the efficacy of evofosfamide as a single agent or combined with cisplatin (DDP) in the NPC cell lines CNE-2, HONE-1 and HNE-1, and in nude mouse xenograft tumor models.

Results

Evofosfamide exhibited hypoxia-selective cytotoxicity in NPC cell lines, with 50% inhibition concentration (IC₅₀) values of 8.33 ± 0.75, 7.62 ± 0.67, and 0.31 ± 0.07 μmol/L under hypoxia in CNE-2, HONE-1 and HNE-1 cells, respectively. The sensitization ranged from ninefold to greater than 300-fold under hypoxia compared with normoxia controls. The combination of evofosfamide with DDP had a synergistic effect on cytotoxicity in the NPC cell lines by combination index values assessment. Cell cycle G2 phase was arrested after treated with 0.05 μmol/L evofosfamide under hypoxia. Histone H2AX phosphorylation (γH2AX) (a marker of DNA damage) expression increased while HIF-1α expression suppressed after evofosfamide treatment under hypoxic conditions. In the HNE-1 NPC xenograft models, evofosfamide exhibited antitumor activity both as a single agent and combined with DDP. Hypoxic regions in xenograft tissue were reduced after both evofosfamide monotherapy and combined therapy with DDP.

Conclusions

Our results present preclinical evidence for targeting the selective hypoxic portion of NPC by evofosfamide as a single agent and combined with DDP and provide rationale for the potential clinical application of evofosfamide for the treatment of nasopharyngeal carcinoma.

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Analysis of cerebral blood flow and intracranial hypertension in critical patients with non-hepatic hyperammonemia

Abstract

Hyperammonemia in adults is generally associated with cerebral edema, decreased cerebral metabolism, and increased cerebral blood flow. The aim of this study was to evaluate the association between non-hepatic hyperammonemia and intracranial hypertension assessed by Doppler flowmetry and measurement of the optic nerve sheath. A prospective cohort study in critically ill patients hospitalized in intensive care units of a University Hospital between March 2015 and February 2016. Clinical data and severity scores were collected and the Glasgow coma scale was recorded. Serial serum ammonia dosages were performed in all study patients. Transcranial Doppler evaluation was carried out for the first 50 consecutive results of each stratum of ammonemia: normal (<35 μmol/L), mild hyperammonemia (≥35 μmol/L and < 50 μmol/L), moderate hyperammonemia (≥50 μmol/L and < 100 μmol/L), and severe hyperammonemia (≥100 μmol/L). The measurement of the optic nerve sheath was performed at the same time as the Doppler examination if the patient scored less than 8 on the Glasgow coma scale. There was no difference in flow velocity in the cerebral arteries between patients with and without hyperammonemia. Patients with hyperammonemia presented longer ICU stay. Optic nerve sheath thickness was higher in the group with severe hyperammonemia and this group presented an association with intracranial hypertension. Higher mortality was observed in the severe hyperammonemia group. There was an association between severe hyperammonemia and signs of intracranial hypertension. No correlation was found between ammonia levels and cerebral blood flow velocity through the Doppler examination.

https://ift.tt/2IaDjHz

Analysis of cerebral blood flow and intracranial hypertension in critical patients with non-hepatic hyperammonemia

Abstract

Hyperammonemia in adults is generally associated with cerebral edema, decreased cerebral metabolism, and increased cerebral blood flow. The aim of this study was to evaluate the association between non-hepatic hyperammonemia and intracranial hypertension assessed by Doppler flowmetry and measurement of the optic nerve sheath. A prospective cohort study in critically ill patients hospitalized in intensive care units of a University Hospital between March 2015 and February 2016. Clinical data and severity scores were collected and the Glasgow coma scale was recorded. Serial serum ammonia dosages were performed in all study patients. Transcranial Doppler evaluation was carried out for the first 50 consecutive results of each stratum of ammonemia: normal (<35 μmol/L), mild hyperammonemia (≥35 μmol/L and < 50 μmol/L), moderate hyperammonemia (≥50 μmol/L and < 100 μmol/L), and severe hyperammonemia (≥100 μmol/L). The measurement of the optic nerve sheath was performed at the same time as the Doppler examination if the patient scored less than 8 on the Glasgow coma scale. There was no difference in flow velocity in the cerebral arteries between patients with and without hyperammonemia. Patients with hyperammonemia presented longer ICU stay. Optic nerve sheath thickness was higher in the group with severe hyperammonemia and this group presented an association with intracranial hypertension. Higher mortality was observed in the severe hyperammonemia group. There was an association between severe hyperammonemia and signs of intracranial hypertension. No correlation was found between ammonia levels and cerebral blood flow velocity through the Doppler examination.

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Characteristics of Cancer Rehabilitation Fellowship Training Programs in the USA

Abstract

Cancer rehabilitation is emerging as a specialized field within Physical Medicine and Rehabilitation. The purpose of this systemic review is to summarize the various cancer rehabilitation fellowship programs in the USA and the scope of training in this discipline. Currently, four institutions offer such a training program. All of the fellowship directors were contacted about characteristics of their programs. The oldest program has been in existence since 2007. All of these programs are 1 year in duration and have between one and two fellowship positions annually. There have been total of 29 graduates as of July 2017. With regard to cancer rehabilitation care delivery model, all four centers reported inpatient consult teams and outpatient rehabilitation. Outpatient experience included electrodiagnosis, botulin toxin, and ultrasound-guided injections. Three of the four programs also reported the presence of an acute inpatient cancer rehabilitation service. A number of clinical rotations are available at each of the four programs with considerable variation. Comprehensive educational efforts are present in all programs with varying expectations for research.

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Characteristics of Cancer Rehabilitation Fellowship Training Programs in the USA

Abstract

Cancer rehabilitation is emerging as a specialized field within Physical Medicine and Rehabilitation. The purpose of this systemic review is to summarize the various cancer rehabilitation fellowship programs in the USA and the scope of training in this discipline. Currently, four institutions offer such a training program. All of the fellowship directors were contacted about characteristics of their programs. The oldest program has been in existence since 2007. All of these programs are 1 year in duration and have between one and two fellowship positions annually. There have been total of 29 graduates as of July 2017. With regard to cancer rehabilitation care delivery model, all four centers reported inpatient consult teams and outpatient rehabilitation. Outpatient experience included electrodiagnosis, botulin toxin, and ultrasound-guided injections. Three of the four programs also reported the presence of an acute inpatient cancer rehabilitation service. A number of clinical rotations are available at each of the four programs with considerable variation. Comprehensive educational efforts are present in all programs with varying expectations for research.

https://ift.tt/2rjMSJB

Phase 2 trial of bortezomib in combination with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with bortezomib, rituximab, methotrexate, and cytarabine for untreated mantle cell lymphoma

Cancer, EarlyView.


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Phase 2 trial of bortezomib in combination with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with bortezomib, rituximab, methotrexate, and cytarabine for untreated mantle cell lymphoma

Cancer, EarlyView.


https://ift.tt/2rfL1Xo

Comparison of effect of dexmedetomidine and lidocaine on intracranial and systemic hemodynamic response to chest physiotherapy and tracheal suctioning in patients with severe traumatic brain injury

Abstract

Purpose

Chest physiotherapy and tracheal suction cause sympathetic stimulation and increase heart rate (HR), mean arterial pressure (MAP) and intracranial pressure (ICP) which may have deleterious effect in the head injured. We planned to compare the effect of intravenous dexmedetomidine and lidocaine on intracerebral and systemic hemodynamic response to chest physiotherapy (CP) and tracheal suctioning (TS) in patients with severe traumatic brain injury (sTBI).

Methods

Prospective, randomized study in patients with sTBI, 18–60 years of age, undergoing mechanical ventilation and intraparenchymal ICP monitoring. Patients were randomized to receive either iv dexmedetomidine 0.5 mcg/kg (group I; n = 30) or iv lidocaine 2 mg/kg (group II; n = 30) over 10 min. After infusion of test drug, CP with vibrator and manual compression was performed for 2 min and TS was done over next 15–20 s. The hemodynamic response was recorded before, during and at interval of 1 min for 10 min after CP and TS. A 20% change in hemodynamic parameters was considered significant.

Results

The baseline hemodynamic (HR, MAP), intracranial (ICP, CPP) and respiratory (SPO₂, AWP_peak) parameters were normal and comparable in both the groups. After dexmedetomidine infusion, MAP and CPP decreased significantly from baseline value. In group II, there was no significant change in HR, MAP, ICP and CPP. At end of CP and TS, HR, MAP and CPP in group I was lower as compared to group II. During the 10-min observation period following CP and TS, MAP and CPP in group I remained significantly lower as compared to baseline and group II. There was no significant change in value of other measured parameters.

Conclusions

Both dexmedetomidine and lidocaine were effective to blunt rise in HR, MAP and ICP in response to CP and TS in patients with sTBI. However, intravenous dexmedetomidine caused significant decrease in MAP and CPP as compared to the baseline and lidocaine.

https://ift.tt/2w9v0ab

Usefulness of fluorodeoxyglucose positron emission tomography/computed tomography for detection of a neuroblastic nodule in a ganglioneuroblastoma: a case report

Ganglioneuroblastoma, nodular is defined as a composite tumor of biologically distinct clones. The peripheral neuroblastic tumors in this category are characterized by the presence of grossly visible neuroblas...

https://ift.tt/2HMZ0Oz

Renal cell carcinoma with venous extension: prediction of inferior vena cava wall invasion by MRI

Abstract

Background

Renal cell carcinoma (RCC) are accompanied by inferior vena cava (IVC) thrombus in up to 10% of the cases, with surgical resection remaining the only curative option. In case of IVC wall invasion, the operative procedure is more challenging and may even require IVC resection. This study aims to determine the diagnostic performance of contrast-enhanced magnetic resonance imaging (MRI) for the assessment of wall invasion by IVC thrombus in patients with RCC, validated with intraoperative findings.

Methods

Data were collected on 81 patients with RCC and IVC thrombus, who received a radical nephrectomy and vena cava thrombectomy between February 2008 and November 2017. Forty eight patients met the inclusion criteria. Sensitivity and specificity as well as the positive and negative predictive values were calculated for preoperative MRI, based on the assessments of the two readers for visual wall invasion. Furthermore, a logistic regression model was used to determine if there was an association between intraoperative wall adherence and IVC diameter.

Results

Complete occlusion of the IVC lumen or vessel breach could reliably assess IVC wall invasion with a sensitivity of 92.3% (95%-CI: 0.75–0.99) and a specificity of 86.4% (95%-CI: 0.65–0.97) (Fisher-test: p-value< 0.001). The positive predictive value (PPV) was 88.9% (95%-CI: 0.71–0.98) and the negative predictive value reached 90.5% (95%-CI: 0.70–0.99). There was an excellent interobserver agreement for determining IVC wall invasion with a kappa coefficient of 0.90 (95%CI: 0.79–1.00).

Conclusions

The present study indicates that standard preoperative MR imaging can be used to reliably assess IVC wall invasion, evaluating morphologic features such as the complete occlusion of the IVC lumen or vessel breach. Increases in IVC diameter are associated with a higher probability of IVC wall invasion.

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Development and evaluation of oral Cancer quality-of-life questionnaire (QOL-OC)

Abstract

Background

In this study scales and items for the Oral Cancer Quality-of-life Questionnaire (QOL-OC) were designed and the instrument was evaluated.

Methods

The QOL-OC was developed and modified using the international definition of quality of life (QOL) promulgated by the European Organization for Research and Treatment of Cancer (EORTC) and analysis of the precedent measuring instruments. The contents of each item were determined in the context of the specific characteristics of oral cancer. Two hundred thirteen oral cancer patients were asked to complete both the EORTC core quality of life questionnaire (EORTC QLC-C30) and the QOL-OC. Data collected was used to conduct factor analysis, test-retest reliability, internal consistency, and construct validity.

Results

Questionnaire compliance was relatively high. Fourteen of the 213 subjects accepted the same tests after 24 to 48 h demonstrating a high test-retest reliability for all five scales. Overall internal consistency surpasses 0.8. The outcome of the factor analysis coincides substantially with our theoretical conception. Each item shows a higher correlation coefficient within its own scale than the others which indicates high construct validity.

Conclusions

QOL-OC demonstrates fairly good statistical reliability, validity, and feasibility. However, further tests and modification are needed to ensure its applicability to the quality-of-life assessment of Chinese oral cancer patients.

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In vitro antineoplastic effects of auranofin in canine lymphoma cells

Abstract

Background

The orally available gold complex auranofin (AF) has been used in humans, primarily as an antirheumatic/immunomodulatory agent. It has been safely administered to healthy dogs to establish pharmacokinetic parameters for oral administration, and has also been used as a treatment in some dogs with immune-mediated conditions. Multiple in vitro studies have recently suggested that AF may possess antineoplastic properties. Spontaneous canine lymphoma may be a very useful translational model for the study of human lymphoma, prompting the evaluation of AF in canine lymphoma cells.

Methods

We investigated the antineoplastic activity of AF in 4 canine lymphoid tumor derived cell lines through measurements of proliferation, apoptosis, thioredoxin reductase (TrxR) activity and generation of reactive oxygen species (ROS), and detected the effects of AF when combined with conventional cytotoxic drugs using the Chou and Talalay method. We also evaluated the antiproliferative effects of AF in primary canine lymphoma cells using a bioreductive fluorometric assay.

Results

At concentrations that appear clinically achievable in humans, AF demonstrated potent antiproliferative and proapoptotic effects in canine lymphoid tumor cell lines. TrxR inhibition and increased ROS production was observed following AF treatment. Moreover, a synergistic antiproliferative effect was observed when AF was combined with lomustine or doxorubicin.

Conclusions

Auranofin appears to inhibit the growth and initiate apoptosis in canine lymphoma cells in vitro at clinically achievable concentrations. Therefore, this agent has the potential to have near-term benefit for the treatment of canine lymphoma, as well as a translational model for human lymphoma. Decreased TrxR activity and increasing ROS production may be useful biomarkers of drug exposure.

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Pretherapeutic FDG-PET total metabolic tumor volume predicts response to induction therapy in pediatric Hodgkin’s lymphoma

Abstract

Background

Standardized treatment in pediatric patients with Hodgkin's lymphoma (HL) follows risk stratification by tumor stage, erythrocyte sedimentation rate and tumor bulk. We aimed to identify quantitative parameters from pretherapeutic FDG-PET to assist prediction of response to induction chemotherapy.

Methods

Retrospective analysis in 50 children with HL (f:18; m:32; median age, 14.8 [4–18] a) consecutively treated according to EuroNet-PHL-C1 (n = 42) or -C2 treatment protocol (n = 8). Total metabolic tumor volume (MTV) in pretherapeutic FDG-PET was defined using a semi-automated, background-adapted threshold. Metabolic (SUVmax, SUVmean, SUVpeak, total lesion glycolysis [MTV*SUVmean]) and heterogeneity parameters (asphericity [ASP], entropy, contrast, local homogeneity, energy, and cumulative SUV-volume histograms) were derived. Early response assessment (ERA) was performed after 2 cycles of induction chemotherapy according to treatment protocol and verified by reference rating. Prediction of inadequate response (IR) in ERA was based on ROC analysis separated by stage I/II (1 and 26 patients) and stage III/IV disease (7 and 16 patients) or treatment group/level (TG/TL) 1 to 3.

Results

IR was seen in 28/50 patients (TG/TL 1, 6/12 patients; TG/TL 2, 10/17; TG/TL 3, 12/21). Among all PET parameters, MTV best predicted IR; ASP was the best heterogeneity parameter. AUC of MTV was 0.84 (95%-confidence interval, 0.69–0.99) in stage I/II and 0.86 (0.7–1.0) in stage III/IV. In patients of TG/TL 1, AUC of MTV was 0.92 (0.74–1.0); in TG/TL 2 0.71 (0.44–0.99), and in TG/TL 3 0.85 (0.69–1.0). Patients with high vs. low MTV had IR in 86 vs. 0% in TG/TL 1, 80 vs. 29% in TG/TL 2, and 90 vs. 27% in TG/TL 3 (cut-off, > 80 ml, > 160 ml, > 410 ml).

Conclusions

In this explorative study, high total MTV best predicted inadequate response to induction therapy in pediatric HL of all pretherapeutic FDG-PET parameters – in both low and high stages as well as the 3 different TG/TL.

Trial registration

Ethics committee number: EA2/151/16 (retrospectively registered).

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Vemurafenib in Chinese patients with BRAF V600 mutation–positive unresectable or metastatic melanoma: an open-label, multicenter phase I study

Abstract

Background

Melanoma is a rare, deadly disease without effective treatment options in China. Vemurafenib is a selective inhibitor of oncogenic BRAF^V600 kinase approved in more than 90 countries, based on results obtained primarily in Caucasian patients. Limited data are available regarding the efficacy and safety of vemurafenib in Asian patients.

Methods

This phase I study investigated the pharmacokinetics, efficacy, and tolerability of vemurafenib (960 mg twice daily) in Chinese patients with BRAF^V600 mutation–positive unresectable or metastatic melanoma. The study included two cohorts: a pharmacokinetic cohort (n = 20) and an expansion cohort (n = 26).

Results

After 21 days of dosing, vemurafenib demonstrated marked accumulation and relatively constant steady-state exposure over the dosing period. Confirmed best overall response rate was 52.2% (95% CI 37.0–67.1%). Median progression-free survival was 8.3 months (95% CI 5.7–10.9%); median overall survival was 13.5 months (95% CI 12.2%–not estimable). The most common adverse events were dermatitis acneiform, arthralgia, diarrhea, blood cholesterol level increase, blood bilirubin level increase, melanocytic nevus, and alopecia. A total of nine grade 3 or 4 adverse events were reported in seven patients (15.2%).

Conclusion

Overall, vemurafenib showed a favorable benefit-risk profile among Chinese patients. Pharmacokinetics, safety, and efficacy were generally consistent with those reported in Caucasian patients.

Trial registration

ClinicalTrials.gov identification: NCT01910181. Registered 29 July 2013, prospectively registered.

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Renal cell carcinoma with venous extension: prediction of inferior vena cava wall invasion by MRI

Abstract

Background

Renal cell carcinoma (RCC) are accompanied by inferior vena cava (IVC) thrombus in up to 10% of the cases, with surgical resection remaining the only curative option. In case of IVC wall invasion, the operative procedure is more challenging and may even require IVC resection. This study aims to determine the diagnostic performance of contrast-enhanced magnetic resonance imaging (MRI) for the assessment of wall invasion by IVC thrombus in patients with RCC, validated with intraoperative findings.

Methods

Data were collected on 81 patients with RCC and IVC thrombus, who received a radical nephrectomy and vena cava thrombectomy between February 2008 and November 2017. Forty eight patients met the inclusion criteria. Sensitivity and specificity as well as the positive and negative predictive values were calculated for preoperative MRI, based on the assessments of the two readers for visual wall invasion. Furthermore, a logistic regression model was used to determine if there was an association between intraoperative wall adherence and IVC diameter.

Results

Complete occlusion of the IVC lumen or vessel breach could reliably assess IVC wall invasion with a sensitivity of 92.3% (95%-CI: 0.75–0.99) and a specificity of 86.4% (95%-CI: 0.65–0.97) (Fisher-test: p-value< 0.001). The positive predictive value (PPV) was 88.9% (95%-CI: 0.71–0.98) and the negative predictive value reached 90.5% (95%-CI: 0.70–0.99). There was an excellent interobserver agreement for determining IVC wall invasion with a kappa coefficient of 0.90 (95%CI: 0.79–1.00).

Conclusions

The present study indicates that standard preoperative MR imaging can be used to reliably assess IVC wall invasion, evaluating morphologic features such as the complete occlusion of the IVC lumen or vessel breach. Increases in IVC diameter are associated with a higher probability of IVC wall invasion.

https://ift.tt/2KwuwOs

The role of vimentin in the tumor marker Nup88-dependent multinucleated phenotype

Abstract

Background

Nucleoporin Nup88, a component of nuclear pore complexes, is known to be overexpressed in several types of tumor tissue. The overexpression of Nup88 has been reported to promote the early step of tumorigenesis by inducing multinuclei in both HeLa cells and a mouse model. However, the molecular basis of how Nup88 leads to a multinucleated phenotype remains unclear because of a lack of information concerning its binding partners. In this study, we characterize a novel interaction between Nup88 and vimentin. We also examine the involvement of vimentin in the Nup88-dependent multinucleated phenotype.

Methods

Cells overexpressing tagged versions of Nup88, vimentin and their truncations were used in this study. Coprecipitation and GST-pulldown assays were carried out to analyze protein-protein interactions. Vimentin knockdown by siRNA was performed to examine the functional role of the Nup88-vimentin interaction in cells. The phosphorylation status of vimentin was analyzed by immunoblotting using an antibody specific for its phosphorylation site.

Results

Vimentin was identified as a Nup88 interacting partner, although it did not bind to other nucleoporins, such as Nup50, Nup214, and Nup358, in HeLa cell lysates. The N-terminal 541 amino acid residues of Nup88 was found to be responsible for its interaction with vimentin. Recombinant GST-tagged Nup88 bound to recombinant vimentin in a GST-pulldown assay. Although overexpression of Nup88 in HeLa cells was observed mainly at the nuclear rim and in the cytoplasm, colocalization with vimentin was only partially detected at or around the nuclear rim. Disruption of the Nup88-vimentin interaction by vimentin specific siRNA transfection suppressed the Nup88-dependent multinucleated phenotype. An excess amount of Nup88 in cell lysates inhibited the dephosphorylation of a serine residue (Ser83) within the vimentin N-terminal region even in the absence and presence of an exogenous phosphatase. The N-terminal 96 amino acid residues of vimentin interacted with both full-length and the N-terminal 541 residues of Nup88.

Conclusions

Nup88 can affect the phosphorylation status of vimentin, which may contribute to the Nup88-dependent multinucleated phenotype through changing the organization of vimentin.

https://ift.tt/2IeqQmb