YSL-12, a novel microtubule-destabilizing agent, exerts potent anti-tumor activity against colon cancer in vitro and in vivo

Abstract

Purpose

Microtubules play a central role in various fundamental cell functions and thus become an attractive target for cancer therapy. A novel compound YSL-12 is a combretastatin A-4 (CA-4) analogue with more stability. We investigated its anti-tumor activity and mechanisms in vitro and in vivo for the first time.

Methods

Cytotoxicity was evaluated by MTT method. In vitro microtubule polymerization assay was performed using a fluorescence-based method by multifunction fluorescence microplate reader. Intracellular microtubule network was detected by immunofluorescence method. Cell cycle analysis and apoptosis were measured by flow cytometry. Metabolic stability was recorded by liquid chromatography–ultraviolet detection and liquid chromatography–mass spectrometry. In vivo anti-tumor activity was assessed using HT-29 colon carcinoma xenografts established in BALB/c nude mice.

Results

YSL-12 displayed nanomolar-level cytotoxicity against various human cancer cell lines. A high selectivity toward normal cells and potent activity toward drug-resistant cells were also observed. YSL-12 was identified as tubulin polymerization inhibitor evidenced by effectively inhibits tubulin polymerization and heavily disrupted microtubule networks in living HT-29 cells. YSL-12 displayed potent disruption effect of pre-established tumor vasculature in vitro. In addition, YSL-12 treatment also caused cell cycle arrest in the G₂/M phase and induced cell apoptosis in a dose-dependent manner. In vitro metabolic stability study revealed YSL-12 displayed considerable better stability than CA-4 in liver microsomes. In vivo, YSL-12 delayed tumor growth with 69.4 % growth inhibition.

Conclusions

YSL-12 is a promising microtubule inhibitor that has great potential for the treatment of colon carcinoma in vitro and in vivo and worth being a candidate for further development of cancer therapy.

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Potential Role of TRAIL in Metastasis of Mutant KRAS Expressing Lung Adenocarcinoma

Abstract

Apo2L/tumor necrosis factor (TNF)-α-related apoptosis-inducing ligand (TRAIL, TNFSF10) is an important cytokine in the tumor microenvironment and plays a major role in the balance of cell survival/death pathways. Bioinformatic analyses of 839 adenocarcinoma (AC) and 356 squamous cell lung carcinoma patient data (SCC) by cBioPortal (genomic analyses) shows that TRAIL expression leads to differential outcomes of disease free survival in AC and SCC. Oncomine datamining (transcript analyses) reveal that TRAIL is upregulated in 167 SCC as compared to 350 AC patients from six data sets. Genomic analyses using cBioPortal revealed high rates of KRAS mutation in AC accompanied by higher incidence of metastasis and increased amplifications of TRAIL gene in SCC. Bioinformatic analyses of an additional lung cancer patient database also showed that risk of disease progression was significantly increased with high TRAIL expression in AC (461 samples). In vitro studies demonstrated that TRAIL increased phosphorylation of ERK only in adenocarcinoma cell lines with mutant KRAS. This was associated with increased migration that was abrogated by MEK inhibitor PD98059. Effects of increased migration induced by TRAIL persisted even after exposure to ionizing radiation with suppression of DNA damage response. These results help understand the role of TRAIL signaling in metastasis which is essential to develop strategies to revert these signals into pro-apoptotic pathways.

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In Italy anti-asthmatic drug prescription is not always a reliable proxy of asthma

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Progesterone Receptors, Pathological Complete Response and Early Outcome for Locally Advanced Breast Cancer – a Single Centre Study. (PPLB – 01)

Abstract

Neoadjuvant chemotherapy (NACT) for locally advanced breast cancer (LABC), apart from increasing breast conservation rates, also provides an opportunity to assess tumour response to chemotherapy, with Pathological Complete Response (pCR) described as an independent prognostic factor and a surrogate marker for better outcome and survival. Our primary aim was to identify clinical and pathological factors associated with pCR following NACT in patients with LABC treated at our institution. Our secondary aim was to analyze the impact of pCR and associated factors on disease free survival (DFS) and overall survival (OS). A retrospective analysis of LABC patients treated with NACT between Jun 2011 and Dec 2013. Clinical and histological variables were analyzed for association with pCR (no invasive or in situ carcinoma in breast or axillary lymph nodes). Kaplan-Meier curves and Cox regression model was used for survival analysis. All values were twosided, and statistical significance was defined as p < 0.05. 240 patients were included. The median tumor size was 6 cm, with T4 disease in 49.8 %. 45 % of tumors were of low grade (G1 + G2) and 53.8 % of high grade (G3). Estrogen Receptor (ER) was positive in 70.8 %, progesterone receptor (PR) in 53.3 % and Her2 in 38.8 %. The preferred NACT regimen was sequential anthracycline and taxane and 88.8 % of patients received this regimen. Of 93 potential Her2 Positive patients, only 23 received trastuzumab. Overall 23.2 % patients had pCR. At median follow up of 21 months (range, 3–42), 16.3 % of patients had recurrent disease, and 6.7 % had died. High tumor grade (p = 0.04), PR negative status (p < 0.01) and trastuzumab treatment (p = 0.01) were significant predictors of pCR in univariate analysis. On multivariate analysis PR negativity (OR 3.2, 95 % CI = 1.6 to 6.04, p = 0.001) and Trastuzumab use (OR 0.24, 95 % CI = 0.1 to 0.6, p = 0.004) were significant. Patients with pCR had positive associations with survival (p < .02,OS& .02,DFS) and interestingly PR positivity had positive association with DFS (p = 0.02) in Kaplan-Meier curves. On Cox regression, PR positivity (HR = 0.3, p < 0.01) and pCR (HR = 0.2, p < 0.01) correlated with DFS, though not with early OS. for the PR positive patients were paradoxical. Though less likely to have pCR (15 %, vs 32 % if PR negative), they had better DFS (p = 0.02), and achieving pCR had no survival benefit in this group. In contrast, PR negative patients, irrespective of ER status, had a high pCR rate, and achieving pCR had survival advantage (p < 0.05,DFS& p < 0.02,OS). PR negative patients without pCR had the worst DFS (p < 0.01) among all. High grade and Trastuzumab treatment as predictors of pCR, and pCR as a surrogate marker for survival are well recognized, and are supported by our findings. In present cohort, PR negativity showed prognostic importance independent of ER status. However these results were derived from sub-group, post-hoc analysis of data from a pre-existing cohort, without 'a-priori' hypothesis for survival analysis in relation to PR. These "hypothesis generating" results need confirmation by a well-designed prospective cohort or a randomized trial.

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Isolation and characterization of Zika virus imported to China using C6/36 mosquito cells

Abstract

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Multipotent mesenchymal stromal cells are fully permissive for human cytomegalovirus infection

Abstract

Congenital human cytomegalovirus (HCMV) infection is a leading infectious cause of birth defects. Previous studies have reported birth defects with multiple organ maldevelopment in congenital HCMV-infected neonates. Multipotent mesenchymal stromal cells (MSCs) are a group of stem/progenitor cells that are multi-potent and can self-renew, and they play a vital role in multi-organ formation. Whether MSCs are susceptible to HCMV infection is unclear. In this study, MSCs were isolated from Wharton's jelly of the human umbilical cord and identified by their plastic adherence, surface marker pattern, and differentiation capacity. Then, the MSCs were infected with the HCMV Towne strain, and infection status was assessed via determination of viral entry, replication initiation, viral protein expression, and infectious virion release using western blotting, immunofluorescence assays, and plaque forming assays. The results indicate that the isolated MSCs were fully permissive for HCMV infection and provide a preliminary basis for understanding the pathogenesis of HCMV infection in non-nervous system diseases, including multi-organ malformation during fetal development.

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Relation between aerobic fitness and brain structures in amnestic mild cognitive impairment elderly

Abstract

Mild cognitive impairment (aMCI) is a clinical condition, with high risk to develop Alzheimer's disease. Physical exercise may have positive effect on cognition and brain structure in older adults. However, it is still under research whether these influences are true on aMCI subjects with low Ab_42 and high total tau in cerebrospinal fluid (CSF), which is considered a biomarker for AD. Therefore, we aimed to investigate a possible relation between aerobic fitness (AF) and gray matter (GM) volume and AF and white matter (WM) integrity in aMCI with a CSF biomarker. Twenty-two participants with aMCI acquired the images on a 3.0-T MRI. AF was assessed by a graded exercise test on a treadmill. Voxel-based morphometry and tract-based spatial statistic methods were used to analyze the GM volume and WM microstructural integrity, respectively. We correlated AF and GM volume and WM integrity in aMCI (p < 0.05, FWE corrected, cluster with at least five voxels). There was a positive relation between AF and GM volume mostly in frontal superior cortex. In WM integrity, AF was positively correlated with fractional anisotropy and negatively correlated with mean diffusivity and radial diffusivity, all in the same tracts that interconnect frontal, temporal, parietal, and occipital areas (longitudinal fasciculus, fronto-occipital fasciculus, and corpus callosum). These results suggest that aerobic fitness may have a positive influence on protection of brain even in aMCI CSF biomarker, a high-risk population to convert to AD.

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TDRG1 regulates chemosensitivity of seminoma TCam-2 cells to cisplatin via PI3K/Akt/mTOR signaling pathway and mitochondria-mediated apoptotic pathway.

TDRG1 regulates chemosensitivity of seminoma TCam-2 cells to cisplatin via PI3K/Akt/mTOR signaling pathway and mitochondria-mediated apoptotic pathway.

Cancer Biol Ther. 2016 Apr 22;:0

Authors: Gan Y, Wang Y, Tan Z, Zhou J, Kitazawa R, Jiang X, Tang Y, Yang J

Abstract
We previously identified TDRG1 (testis developmental related gene 1), a novel gene with exclusive expression in testis, promoted the proliferation and progression of cultured human seminoma cells through PI3K/Akt/mTOR signaling. As increasing evidence reveal that aberrant activation of this signaling is involved in cisplatin resistance. Then, in this study, we further explored whether TDRG1 regulated the chemosensitivity of seminoma TCam-2 cells to cisplatin. Our researches showed TDRG1 could regulate the viability of TCam-2 cells following cisplatin treatment in vitro through control of both cell apoptosis and cell cycle. Mechanistically, we observed TDRG1 positively regulated the expression levels of the key elements in PI3K/Akt/mTOR pathway including p-PI3K, p-Akt and p-mTOR and also affected the translocation of nuclear p-Akt in TCam-2 cells during cisplatin treatment. Meanwhile, the levels of Bad, cytochrome c, caspase-9 ratio (activated/total), caspase-3 ratio (activated/total) and cleaved-PARP were negatively modulated by TDRG1, which meant the involvement of mitochondria-mediated apoptotic pathway. Furthermore, we found the effect of TDRG1 knockdown or TDRG1 overexpression could be reversed by IGF-1, a PI3K signaling activator, or LY294002, a inhibitor of this pathway, respectively. Similar effects of TDRG1 on cisplatin chemosensitivity and associated molecular mechanism were also confirmed in vivo by employing xenograft assays. In addition, the positive correlation between TDRG1 and p-PI3K, or p-Akt, was found in tumor tissues from seminoma patients. In conclusion, we uncover that TDRG1 regulates chemosensitivity of TCam-2 cells to cisplatin through PI3K/Akt/mTOR signaling and mitochondria-mediated apoptotic pathway both in vitro and in vivo.

PMID: 27104982 [PubMed - as supplied by publisher]

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Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer.

Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer.

Cancer Biol Ther. 2016 Apr 22;:0

Authors: Sunakawa Y, Yang D, Moran M, Astrow SH, Tsuji A, Stephens C, Zhang W, Cao S, Takahashi T, Denda T, Shimada K, Kochi M, Nakamura M, Kotaka M, Segawa Y, Masuishi T, Takeuchi M, Fujii M, Nakajima T, Ichikawa W, Lenz HJ

Abstract
Several studies have reported that epidermal growth factor receptor (EGFR)-related molecules may serve as predictors of cetuximab treatment for metastatic colorectal cancer (mCRC), such as EGFR gene copy number (GCN), expression of two ligands of EGFR, amphiregulin (AREG) and epiregulin (EREG), and EGFR CA simple sequence repeat 1 (CA-SSR1) polymorphism; however, these biomarkers still remain not useful in clinical practice since they have been evaluated using cohorts with patients treated in various settings of chemotherapy. We therefore analyzed associations of mRNA expression of AREG and EREG, EGFR GCN, and CA-SSR1 polymorphism [short (S;≤19) / long (L;≥20)] with clinical outcomes in 77 Japanese patients with KRAS exon 2 wild-type mCRC enrolled in phase II trials of FOLFOX (n=28/57, UMIN000004197) or SOX (n=49/67, UMIN000007022) plus cetuximab as first-line therapy. High AREG expression correlated with significantly better progression-free survival (median 11.6 vs. 6.6 months, HR 0.52, P=0.037); moreover, it remained statistically significant in multivariate analysis (HR: 0.48, P=0.027). S/S genotype of CA-SSR1 predicted severe skin toxicity (P=0.040). Patients with both AREG-low and EGFR low-GCN had significantly shorter overall survival than the others (median 22.2 vs. 42.8 months, HR 2.34, P=0.042). The multivariate analysis showed that molecular status with both AREG-low and EGFR low-GCN was a predictor of worse survival (P=0.006). In conclusion, AREG mRNA expression and EGFR CA-SSR1 polymorphism predict survival and skin toxicity, respectively, of initial chemotherapy with cetuximab. Our results also suggest potential prognostic value of the combined assessment of AREG and EGFR GCN for first-line cetuximab treatment.

PMID: 27104867 [PubMed - as supplied by publisher]

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GUCY2C Ligand Replacement to Prevent Colorectal Cancer.

GUCY2C Ligand Replacement to Prevent Colorectal Cancer.

Cancer Biol Ther. 2016 Apr 22;:0

Authors: Blomain ES, Pattison AM, Waldman SA

Abstract
Despite advances in screening and prevention strategies, colorectal cancer (CRC) remains the second-leading cause of cancer-related death in the United States. Given this continued public health burden of CRC, there is a clear need for improved disease prevention. CRC initiates and progresses over decades, canonically proceeding via a series of stepwise molecular events that turn a normal epithelium into a dysfunctional epithelium, then subsequently into an adenoma, and finally an invasive adenocarcinoma. An emerging paradigm suggests that guanylyl cyclase C (GUCY2C) functions as a tumor suppressor in the intestine, and that the loss of hormone ligands for this receptor causes epithelial dysfunction and represents an important step in the disease process. In that context, GUCY2C ligand replacement therapy has been proposed as a strategy to prevent colorectal cancer, a translational opportunity that is underscored by the recent regulatory approval of the oral GUCY2C ligand linaclotide (Linzess™, Forest Laboratories and Ironwood Pharmaceuticals, Inc.).

PMID: 27104761 [PubMed - as supplied by publisher]

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Bortezomib-related Neuropathy masking CNS relapse in Multiple Myeloma; A unique case report and review of the Literature.

Bortezomib-related Neuropathy masking CNS relapse in Multiple Myeloma; A unique case report and review of the Literature.

Cancer Biol Ther. 2016 Apr 22;:0

Authors: Abid MB, De Mel S, Abid MA, Bing TK, Joo CW

Abstract
BACKGROUND: Neuropathy is a common adverse effect of bortezomib. Isolated central nervous system (CNS) relapse in MM remains exceedingly rare and carries a dismal prognosis. We present an unusual case of bortezomib related neuropathy masking a CNS relapse of MM.
PRESENTATION: A 57-year-old female was diagnosed with standard-risk MM with clinical and cytogenetic features not typically associated with CNS involvement. She was treated with four cycles of bortezomib/cyclophosphamide/dexamethasone (VCD) and achieved a VGPR, after which she underwent an autologous stem cell transplant (ASCT) followed by bortezomib maintenance. Six months after ASCT she developed symptoms suggestive of peripheral neuropathy which was attributed to bortezomib. However the symptoms persisted despite discontinuation of bortezomib. Imaging and cerebrospinal fluid analysis subsequently confirmed a CNS relapse.
DISCUSSION: CNS involvement in MM (CNS-MM) is uncommon and is considered an aggressive disease. Recently published literature has reported biomarkers with prognostic potential. However, isolated CNS relapse is even less common; an event which carries a very poor prognosis. Given the heterogeneous neurologic manifestations associated with MM, clinical suspicion may be masked by confounding factors such as bortezomib-based therapy. The disease may further remain incognito if the patient does not exhibit any of the high risk features and biomarkers associated with CNS involvement.
CONCLUSION: In the era of proteasome inhibitor (PI)/immunomodulator (IMID)-based therapy for MM which carries neurologic adverse effects, it is prudent to consider CNS relapse early. This case further highlights the need for more robust biomarkers to predict CNS relapse and use of newer novel agents which demonstrate potential for CNS penetration.

PMID: 27105248 [PubMed - as supplied by publisher]

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Role of EZH2 histone methyltrasferase in melanoma progression and metastasis.

Role of EZH2 histone methyltrasferase in melanoma progression and metastasis.

Cancer Biol Ther. 2016 Apr 22;:0

Authors: Mahmoud F, Shields B, Makhoul I, Hutchins LF, Shalin SC, Tackett AJ

Abstract
There is accumulating evidence that the histone methyltransferase enhancer of zeste homologue 2 (EZH2), the main component of the polycomb-repressive complex 2 (PRC2), is involved in melanoma progression and metastasis. Novel drugs that target and reverse such epigenetic changes may find a way into the management of patients with advanced melanoma. We provide a comprehensive up-to-date review of the role and biology of EZH2 on gene transcription, senescence/apoptosis, melanoma microenvironment, melanocyte stem cells, the immune system, and micro RNA. Furthermore, we discuss EZH2 inhibitors as potential anti-cancer therapy.

PMID: 27105109 [PubMed - as supplied by publisher]

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TDRG1 regulates chemosensitivity of seminoma TCam-2 cells to cisplatin via PI3K/Akt/mTOR signaling pathway and mitochondria-mediated apoptotic pathway.

TDRG1 regulates chemosensitivity of seminoma TCam-2 cells to cisplatin via PI3K/Akt/mTOR signaling pathway and mitochondria-mediated apoptotic pathway.

Cancer Biol Ther. 2016 Apr 22;:0

Authors: Gan Y, Wang Y, Tan Z, Zhou J, Kitazawa R, Jiang X, Tang Y, Yang J

Abstract
We previously identified TDRG1 (testis developmental related gene 1), a novel gene with exclusive expression in testis, promoted the proliferation and progression of cultured human seminoma cells through PI3K/Akt/mTOR signaling. As increasing evidence reveal that aberrant activation of this signaling is involved in cisplatin resistance. Then, in this study, we further explored whether TDRG1 regulated the chemosensitivity of seminoma TCam-2 cells to cisplatin. Our researches showed TDRG1 could regulate the viability of TCam-2 cells following cisplatin treatment in vitro through control of both cell apoptosis and cell cycle. Mechanistically, we observed TDRG1 positively regulated the expression levels of the key elements in PI3K/Akt/mTOR pathway including p-PI3K, p-Akt and p-mTOR and also affected the translocation of nuclear p-Akt in TCam-2 cells during cisplatin treatment. Meanwhile, the levels of Bad, cytochrome c, caspase-9 ratio (activated/total), caspase-3 ratio (activated/total) and cleaved-PARP were negatively modulated by TDRG1, which meant the involvement of mitochondria-mediated apoptotic pathway. Furthermore, we found the effect of TDRG1 knockdown or TDRG1 overexpression could be reversed by IGF-1, a PI3K signaling activator, or LY294002, a inhibitor of this pathway, respectively. Similar effects of TDRG1 on cisplatin chemosensitivity and associated molecular mechanism were also confirmed in vivo by employing xenograft assays. In addition, the positive correlation between TDRG1 and p-PI3K, or p-Akt, was found in tumor tissues from seminoma patients. In conclusion, we uncover that TDRG1 regulates chemosensitivity of TCam-2 cells to cisplatin through PI3K/Akt/mTOR signaling and mitochondria-mediated apoptotic pathway both in vitro and in vivo.

PMID: 27104982 [PubMed - as supplied by publisher]

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Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer.

Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer.

Cancer Biol Ther. 2016 Apr 22;:0

Authors: Sunakawa Y, Yang D, Moran M, Astrow SH, Tsuji A, Stephens C, Zhang W, Cao S, Takahashi T, Denda T, Shimada K, Kochi M, Nakamura M, Kotaka M, Segawa Y, Masuishi T, Takeuchi M, Fujii M, Nakajima T, Ichikawa W, Lenz HJ

Abstract
Several studies have reported that epidermal growth factor receptor (EGFR)-related molecules may serve as predictors of cetuximab treatment for metastatic colorectal cancer (mCRC), such as EGFR gene copy number (GCN), expression of two ligands of EGFR, amphiregulin (AREG) and epiregulin (EREG), and EGFR CA simple sequence repeat 1 (CA-SSR1) polymorphism; however, these biomarkers still remain not useful in clinical practice since they have been evaluated using cohorts with patients treated in various settings of chemotherapy. We therefore analyzed associations of mRNA expression of AREG and EREG, EGFR GCN, and CA-SSR1 polymorphism [short (S;≤19) / long (L;≥20)] with clinical outcomes in 77 Japanese patients with KRAS exon 2 wild-type mCRC enrolled in phase II trials of FOLFOX (n=28/57, UMIN000004197) or SOX (n=49/67, UMIN000007022) plus cetuximab as first-line therapy. High AREG expression correlated with significantly better progression-free survival (median 11.6 vs. 6.6 months, HR 0.52, P=0.037); moreover, it remained statistically significant in multivariate analysis (HR: 0.48, P=0.027). S/S genotype of CA-SSR1 predicted severe skin toxicity (P=0.040). Patients with both AREG-low and EGFR low-GCN had significantly shorter overall survival than the others (median 22.2 vs. 42.8 months, HR 2.34, P=0.042). The multivariate analysis showed that molecular status with both AREG-low and EGFR low-GCN was a predictor of worse survival (P=0.006). In conclusion, AREG mRNA expression and EGFR CA-SSR1 polymorphism predict survival and skin toxicity, respectively, of initial chemotherapy with cetuximab. Our results also suggest potential prognostic value of the combined assessment of AREG and EGFR GCN for first-line cetuximab treatment.

PMID: 27104867 [PubMed - as supplied by publisher]

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GUCY2C Ligand Replacement to Prevent Colorectal Cancer.

GUCY2C Ligand Replacement to Prevent Colorectal Cancer.

Cancer Biol Ther. 2016 Apr 22;:0

Authors: Blomain ES, Pattison AM, Waldman SA

Abstract
Despite advances in screening and prevention strategies, colorectal cancer (CRC) remains the second-leading cause of cancer-related death in the United States. Given this continued public health burden of CRC, there is a clear need for improved disease prevention. CRC initiates and progresses over decades, canonically proceeding via a series of stepwise molecular events that turn a normal epithelium into a dysfunctional epithelium, then subsequently into an adenoma, and finally an invasive adenocarcinoma. An emerging paradigm suggests that guanylyl cyclase C (GUCY2C) functions as a tumor suppressor in the intestine, and that the loss of hormone ligands for this receptor causes epithelial dysfunction and represents an important step in the disease process. In that context, GUCY2C ligand replacement therapy has been proposed as a strategy to prevent colorectal cancer, a translational opportunity that is underscored by the recent regulatory approval of the oral GUCY2C ligand linaclotide (Linzess™, Forest Laboratories and Ironwood Pharmaceuticals, Inc.).

PMID: 27104761 [PubMed - as supplied by publisher]

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Pluripotency markers are differentially induced by MEK inhibition in thyroid and melanoma BRAFV600E cell lines

10.1080/15384047.2016.1139230<br/>Emma R. Dorris

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Decreased MicroRNA-26a expression causes cisplatin resistance in human non-small cell lung cancer

10.1080/15384047.2015.1095405<br/>Yong Yang

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Bortezomib-related Neuropathy masking CNS relapse in Multiple Myeloma; A unique case report and review of the Literature.

Bortezomib-related Neuropathy masking CNS relapse in Multiple Myeloma; A unique case report and review of the Literature.

Cancer Biol Ther. 2016 Apr 22;:0

Authors: Abid MB, De Mel S, Abid MA, Bing TK, Joo CW

Abstract
BACKGROUND: Neuropathy is a common adverse effect of bortezomib. Isolated central nervous system (CNS) relapse in MM remains exceedingly rare and carries a dismal prognosis. We present an unusual case of bortezomib related neuropathy masking a CNS relapse of MM.
PRESENTATION: A 57-year-old female was diagnosed with standard-risk MM with clinical and cytogenetic features not typically associated with CNS involvement. She was treated with four cycles of bortezomib/cyclophosphamide/dexamethasone (VCD) and achieved a VGPR, after which she underwent an autologous stem cell transplant (ASCT) followed by bortezomib maintenance. Six months after ASCT she developed symptoms suggestive of peripheral neuropathy which was attributed to bortezomib. However the symptoms persisted despite discontinuation of bortezomib. Imaging and cerebrospinal fluid analysis subsequently confirmed a CNS relapse.
DISCUSSION: CNS involvement in MM (CNS-MM) is uncommon and is considered an aggressive disease. Recently published literature has reported biomarkers with prognostic potential. However, isolated CNS relapse is even less common; an event which carries a very poor prognosis. Given the heterogeneous neurologic manifestations associated with MM, clinical suspicion may be masked by confounding factors such as bortezomib-based therapy. The disease may further remain incognito if the patient does not exhibit any of the high risk features and biomarkers associated with CNS involvement.
CONCLUSION: In the era of proteasome inhibitor (PI)/immunomodulator (IMID)-based therapy for MM which carries neurologic adverse effects, it is prudent to consider CNS relapse early. This case further highlights the need for more robust biomarkers to predict CNS relapse and use of newer novel agents which demonstrate potential for CNS penetration.

PMID: 27105248 [PubMed - as supplied by publisher]

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Role of EZH2 histone methyltrasferase in melanoma progression and metastasis.

Role of EZH2 histone methyltrasferase in melanoma progression and metastasis.

Cancer Biol Ther. 2016 Apr 22;:0

Authors: Mahmoud F, Shields B, Makhoul I, Hutchins LF, Shalin SC, Tackett AJ

Abstract
There is accumulating evidence that the histone methyltransferase enhancer of zeste homologue 2 (EZH2), the main component of the polycomb-repressive complex 2 (PRC2), is involved in melanoma progression and metastasis. Novel drugs that target and reverse such epigenetic changes may find a way into the management of patients with advanced melanoma. We provide a comprehensive up-to-date review of the role and biology of EZH2 on gene transcription, senescence/apoptosis, melanoma microenvironment, melanocyte stem cells, the immune system, and micro RNA. Furthermore, we discuss EZH2 inhibitors as potential anti-cancer therapy.

PMID: 27105109 [PubMed - as supplied by publisher]

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TDRG1 regulates chemosensitivity of seminoma TCam-2 cells to cisplatin via PI3K/Akt/mTOR signaling pathway and mitochondria-mediated apoptotic pathway.

TDRG1 regulates chemosensitivity of seminoma TCam-2 cells to cisplatin via PI3K/Akt/mTOR signaling pathway and mitochondria-mediated apoptotic pathway.

Cancer Biol Ther. 2016 Apr 22;:0

Authors: Gan Y, Wang Y, Tan Z, Zhou J, Kitazawa R, Jiang X, Tang Y, Yang J

Abstract
We previously identified TDRG1 (testis developmental related gene 1), a novel gene with exclusive expression in testis, promoted the proliferation and progression of cultured human seminoma cells through PI3K/Akt/mTOR signaling. As increasing evidence reveal that aberrant activation of this signaling is involved in cisplatin resistance. Then, in this study, we further explored whether TDRG1 regulated the chemosensitivity of seminoma TCam-2 cells to cisplatin. Our researches showed TDRG1 could regulate the viability of TCam-2 cells following cisplatin treatment in vitro through control of both cell apoptosis and cell cycle. Mechanistically, we observed TDRG1 positively regulated the expression levels of the key elements in PI3K/Akt/mTOR pathway including p-PI3K, p-Akt and p-mTOR and also affected the translocation of nuclear p-Akt in TCam-2 cells during cisplatin treatment. Meanwhile, the levels of Bad, cytochrome c, caspase-9 ratio (activated/total), caspase-3 ratio (activated/total) and cleaved-PARP were negatively modulated by TDRG1, which meant the involvement of mitochondria-mediated apoptotic pathway. Furthermore, we found the effect of TDRG1 knockdown or TDRG1 overexpression could be reversed by IGF-1, a PI3K signaling activator, or LY294002, a inhibitor of this pathway, respectively. Similar effects of TDRG1 on cisplatin chemosensitivity and associated molecular mechanism were also confirmed in vivo by employing xenograft assays. In addition, the positive correlation between TDRG1 and p-PI3K, or p-Akt, was found in tumor tissues from seminoma patients. In conclusion, we uncover that TDRG1 regulates chemosensitivity of TCam-2 cells to cisplatin through PI3K/Akt/mTOR signaling and mitochondria-mediated apoptotic pathway both in vitro and in vivo.

PMID: 27104982 [PubMed - as supplied by publisher]

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Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer.

Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer.

Cancer Biol Ther. 2016 Apr 22;:0

Authors: Sunakawa Y, Yang D, Moran M, Astrow SH, Tsuji A, Stephens C, Zhang W, Cao S, Takahashi T, Denda T, Shimada K, Kochi M, Nakamura M, Kotaka M, Segawa Y, Masuishi T, Takeuchi M, Fujii M, Nakajima T, Ichikawa W, Lenz HJ

Abstract
Several studies have reported that epidermal growth factor receptor (EGFR)-related molecules may serve as predictors of cetuximab treatment for metastatic colorectal cancer (mCRC), such as EGFR gene copy number (GCN), expression of two ligands of EGFR, amphiregulin (AREG) and epiregulin (EREG), and EGFR CA simple sequence repeat 1 (CA-SSR1) polymorphism; however, these biomarkers still remain not useful in clinical practice since they have been evaluated using cohorts with patients treated in various settings of chemotherapy. We therefore analyzed associations of mRNA expression of AREG and EREG, EGFR GCN, and CA-SSR1 polymorphism [short (S;≤19) / long (L;≥20)] with clinical outcomes in 77 Japanese patients with KRAS exon 2 wild-type mCRC enrolled in phase II trials of FOLFOX (n=28/57, UMIN000004197) or SOX (n=49/67, UMIN000007022) plus cetuximab as first-line therapy. High AREG expression correlated with significantly better progression-free survival (median 11.6 vs. 6.6 months, HR 0.52, P=0.037); moreover, it remained statistically significant in multivariate analysis (HR: 0.48, P=0.027). S/S genotype of CA-SSR1 predicted severe skin toxicity (P=0.040). Patients with both AREG-low and EGFR low-GCN had significantly shorter overall survival than the others (median 22.2 vs. 42.8 months, HR 2.34, P=0.042). The multivariate analysis showed that molecular status with both AREG-low and EGFR low-GCN was a predictor of worse survival (P=0.006). In conclusion, AREG mRNA expression and EGFR CA-SSR1 polymorphism predict survival and skin toxicity, respectively, of initial chemotherapy with cetuximab. Our results also suggest potential prognostic value of the combined assessment of AREG and EGFR GCN for first-line cetuximab treatment.

PMID: 27104867 [PubMed - as supplied by publisher]

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GUCY2C Ligand Replacement to Prevent Colorectal Cancer.

GUCY2C Ligand Replacement to Prevent Colorectal Cancer.

Cancer Biol Ther. 2016 Apr 22;:0

Authors: Blomain ES, Pattison AM, Waldman SA

Abstract
Despite advances in screening and prevention strategies, colorectal cancer (CRC) remains the second-leading cause of cancer-related death in the United States. Given this continued public health burden of CRC, there is a clear need for improved disease prevention. CRC initiates and progresses over decades, canonically proceeding via a series of stepwise molecular events that turn a normal epithelium into a dysfunctional epithelium, then subsequently into an adenoma, and finally an invasive adenocarcinoma. An emerging paradigm suggests that guanylyl cyclase C (GUCY2C) functions as a tumor suppressor in the intestine, and that the loss of hormone ligands for this receptor causes epithelial dysfunction and represents an important step in the disease process. In that context, GUCY2C ligand replacement therapy has been proposed as a strategy to prevent colorectal cancer, a translational opportunity that is underscored by the recent regulatory approval of the oral GUCY2C ligand linaclotide (Linzess™, Forest Laboratories and Ironwood Pharmaceuticals, Inc.).

PMID: 27104761 [PubMed - as supplied by publisher]

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[Expensive cancer drugs funding is undergoing turbulent times].

[Expensive cancer drugs funding is undergoing turbulent times].

Bull Cancer. 2016 Apr;103(4):313-4

Authors: Bay JO, L'Allemain G, Vignot S

PMID: 27102881 [PubMed - in process]

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The medico-legal value of consensus statements

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Pediatric Radiology Continuing Medical Education Activity

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Ultrasound and MR imaging findings in prenatal diagnosis of craniosynostosis syndromes

Abstract

Background

Craniosynostosis syndromes are uncommonly encountered in the prenatal period. Identification is challenging but important for family counseling and perinatal management.

Objective

This series examines prenatal findings in craniosynostosis syndromes, comparing the complementary roles of US and MRI and emphasizing clues easily missed in the second trimester.

Materials and methods

Six prenatal cases evaluated from 2002 through 2011 were retrospectively reviewed. Referral history, gestational age, and sonographic and MRI findings were reviewed by three pediatric radiologists. Abnormalities of the calvarium, hands, feet, face, airway and central nervous system were compared between modalities.

Results

The diagnosis was Apert syndrome in three, Pfeiffer syndrome in two and Carpenter syndrome in one. The gestational age at evaluation ranged from 21 to 33 weeks. All six were evaluated by MRI and US, with two undergoing repeat evaluation in the third trimester, yielding a total of eight MRIs and US exams. The referral history suggested cloverleaf skull in two cases but did not suggest craniosynostosis syndrome in any case. In four, the referral suggested central nervous system (CNS) findings that were not confirmed by MRI; additional CNS findings were discovered in the remaining two. In four cases, developing turricephaly resulted in a characteristic "lampshade" contour of the fetal head. Hypertelorism and proptosis were present in five, with proptosis better appreciated by MRI. Digit abnormalities were present in all, seen equally well by MRI and US. Lung abnormalities in the second trimester in one fetus resolved by the third trimester.

Conclusion

Prenatal diagnosis of craniosynostosis syndromes is difficult prior to the third trimester. MRI and US have complementary roles in evaluation of these patients.

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No title Article type: Exposure

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Role of percutaneous abscess drainage in the management of young patients with Crohn disease

Abstract

Background

Intra-abdominal abscess is a common complication of Crohn disease in children. Prior studies, primarily in adults, have shown that percutaneous abscess drainage is a safe and effective treatment for this condition; however, the data regarding this procedure and indications in pediatric patients is limited.

Objective

Our aim was to determine the success rate of percutaneous abscess drainage for abscesses related to Crohn disease in pediatric patients with a focus on treatment endpoints that are relevant in the era of biological medical therapy.

Materials and methods

We retrospectively reviewed 25 cases of patients ages ≤20 years with Crohn disease who underwent percutaneous abscess drainage. Technical success was defined as catheter placement within the abscess with reduction in abscess size on post-treatment imaging. Clinical success was defined as (1) no surgery within 1 year of drainage or (2) surgical resection following drainage with no residual abscess at surgery or on preoperative imaging. Multiple clinical parameters were analyzed for association with treatment success or failure.

Results

All cases were classified as technical successes. Nineteen cases were classified as clinical successes (76%), including 7 patients (28%) who required no surgery within 1 year of percutaneous drainage and 12 patients (48%) who had elective bowel resection within 1 year. There was a statistically significant association between resumption of immunosuppressive therapy within 8 weeks of drainage and both clinical success (P < 0.01) and avoidance of surgery after 1 year (P < 0.01).

Conclusion

Percutaneous abscess drainage is an effective treatment for Crohn disease-related abscesses in pediatric patients. Early resumption of immunosuppressive therapy is statistically associated with both clinical success and avoidance of bowel resection, suggesting a role for percutaneous drainage in facilitating prompt initiation of medical therapy and preventing surgical bowel resection.

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Incidental mastoid opacification in children on MRI

Abstract

Background

The opacification the mastoid cavity is frequently reported by radiologists on cross-sectional imaging done for non-otological indications. It is well known that presence of fluid the mastoid does not amount to mastoiditis. This study seeks to provide an evidence-based confirmation of this known finding.

Objective

The purpose of our study was to determine the prevalence of mastoid opacification in children undergoing outpatient brain MRI examination.

Materials and methods

Our study included 515 outpatient children who had brain MRI for indications other than mastoiditis or otitis media from January 2014 to March 2014. Children with history of skull base trauma or radiation were excluded. The age range was 15 days to 18 years. The overall prevalence of mastoid opacification was determined using one sample proportion and exact 95% Clopper-Pearson confidence intervals. The prevalence of mastoid opacification was analyzed based on gender, age and presenting symptoms using chi-square test of association.

Results

One hundred ten children (21.4%) had mastoid opacification. Younger patients tended to have higher opacification rates with the prevalence in children younger than 1 year of age and between 1 and 2 years of age as high as 41.7% (20/48) and 47.5% (38/80), respectively.

Conclusion

The diagnosis of mastoiditis in children should not be based upon a radiologist's report of finding fluid or mucosal thickening in the mastoid air cells as incidental opacification the mastoid is seen frequently.

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Hermes

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MSK1 as a candidate gene for PI3K/mTOR resistance

Glioblastoma (GBM) represents a compelling disease for kinase inhibitor therapy because most of these tumors harbor genetic alterations that result in aberrant activation of growth factor signaling pathways. The PI3K/mammalian target of rapamycin (mTOR) pathway is dysregulated in over 50% of human GBM but remains a challenging clinical target. Inhibitors against PI3K/mTOR mediators have limited clinical efficacy as single agents. We investigated potential bypass mechanisms to PI3K/mTOR inhibition using gene expression profiling before and after PI3K inhibitor treatment by Affymetrix microarrays. Mitogen- and stress-activated protein kinase 1 (MSK1) was markedly induced after PI3K/mTOR inhibitor treatment and disruption of MSK1 by specific shRNAs attenuated resistance to PI3K/mTOR inhibitors in glioma initiating cells (GICs). Further investigation showed that MSK1 phosphorylates β-catenin and regulates its nuclear translocation and transcriptional activity. The depletion of β-catenin potentiated PI3K/mTOR inhibitor-induced cytotoxicity and the inhibition of MSK1 synergized with PI3K/mTOR inhibitors to extend survival in an intracranial animal model and decreased phosphorylation of β-catenin at Ser552. These observations suggest that MSK1/β-catenin signaling serves as an escape survival signal upon PI3K/mTOR inhibition and provides a strong rationale for the combined use of PI3K/mTOR and MSK1/β-catenin inhibition to induce lethal growth inhibition in human GBM.

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Src inhibitor in biliary tract cancer

Src, a non-receptor tyrosine kinase, is involved in a number of cancer-related signaling pathways and aberrantly activated in biliary tract cancer (BTC). This study aimed to elucidate the potential role of Src as a therapeutic target in BTC. We tested bosutinib, an orally active c-Src/Abl kinase inhibitor, alone or in combination with cytotoxic agents using nine human BTC cell lines: SNU-245, SNU-308, SNU-478, SNU-869, SNU-1079, SNU-1196, HuCCT1, TFK-1, and EGI-1. Of these, SNU-308 and SNU-478 were relatively sensitive to bosutinib. Bosutinib abrogated phosphorylation of Src and its downstream molecules, significantly increased G1 cell-cycle arrest and apoptosis. Bosutinib significantly inhibited cell migration and invasion and decreased epithelial-mesenchymal transition markers. Bosutinib combined with gemcitabine or cisplatin showed synergistic anti-proliferative and anti-migratory effects. In addition, this combination further inhibited phosphorylation of Src and its downstream molecules and decreased epithelial-mesenchymal transition marker expression compared with bosutinib alone. We established a SNU-478 xenograft model for in vivo experiments, since SNU-478 was more tumorigenic than SNU-308. Bosutinib combined with gemcitabine or cisplatin showed significantly more potent anti-tumor effects than bosutinib alone. Bosutinib combined with gemcitabine further decreased Ki-67 expression and Src phosphorylation, and further increased TUNEL expression. Our data suggest that Src might be a potential therapeutic target in BTC. Bosutinib demonstrated promising anti-tumor activity alone or in combination with gemcitabine or cisplatin in BTC cells, which supports further clinical development in patients with advanced BTC.

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