Cancers, Vol. 10, Pages 168: Mechanistic Target of Rapamycin (mTOR) in the Cancer Setting

Cancers, Vol. 10, Pages 168: Mechanistic Target of Rapamycin (mTOR) in the Cancer Setting

Cancers doi: 10.3390/cancers10060168

Authors: James T. Murray Andrew R. Tee

This special issue on mammalian target of rapamycin (mTOR) explores the importance of mTOR in cell growth control and cancer. Cancer cells often exploit mTOR as a mechanism to enhance their capacity to grow. While protein synthesis is by far the best-characterized mTOR-driven process, this special issue also describes a wider array of mTOR-driven biological processes that cancer cells benefit from, including autophagy, cell cycle control, metabolic transformation, angiogenic signaling, and anabolic processes such as nucleotide biosynthesis and ribosomal biogenesis. Other areas of mTOR signaling covered in these reviews delve into cell migration, inflammation, and regulation of transcription factors linked to cancer progression.

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Male patients with resected IIIA-N2 non-small-cell lung cancer may benefit from postoperative radiotherapy: a population-based survival analysis

Future Oncology, Ahead of Print.


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Lymph node ratio has prognostic value related to the number of positive lymph nodes in patients with vulvar cancer

Future Oncology, Ahead of Print.


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TMPRSS2-ERG controls luminal epithelial lineage and antiandrogen sensitivity in PTEN and TP53-mutated prostate cancer

Purpose: Deletions or mutations in PTEN and TP53 tumor suppressor genes have been linked to lineage plasticity in therapy-resistant prostate cancer. Fusion-driven overexpression of the oncogenic transcription factor ERG is observed in approximately 50% of all prostate cancers, many of which also harbor PTEN and TP53 alterations. However, the role of ERG in lineage plasticity of PTEN/TP53-altered tumors is unclear. Understanding the collective effect of multiple mutations within one tumor is essential to combat plasticity-driven therapy resistance. Experimental Design: We generated a Pten-negative/Trp53-mutated/ERG-overexpressing mouse model of prostate cancer and integrated RNA-sequencing with ERG chromatin-immunoprecipitation sequencing (ChIP-seq) to identify pathways regulated by ERG in the context of Pten/Trp53 alteration. We investigated ERG-dependent sensitivity to the antiandrogen enzalutamide and cyclin dependent kinases 4 and 6 (CDK4/6) inhibitor palbociclib in human prostate cancer cell lines, xenografts, and allografted mouse tumors. Trends were evaluated in TCGA, SU2C, and Beltran 2016 published patient cohorts and a human tissue microarray. Results: Transgenic ERG expression in mice blocked Pten/Trp53 alteration-induced decrease of AR expression and downstream luminal epithelial genes. ERG directly suppressed expression of cell cycle-related genes, which induced RB hypophosphorylation and repressed E2F1-mediated expression of mesenchymal lineage regulators, thereby restricting adenocarcinoma plasticity and maintaining antiandrogen sensitivity. In ERG-negative tumors, CDK4/6 inhibition delayed tumor growth. Conclusions: Our studies identify a previously undefined function of ERG to restrict lineage plasticity and maintain antiandrogen sensitivity in PTEN/TP53-altered prostate cancer. Our findings suggest ERG fusion as a biomarker to guide treatment of PTEN/TP53-altered, RB1-intact prostate cancer.

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Glycosyltransferase gene expression identifies a poor prognostic colorectal cancer subtype associated with mismatch repair deficiency and incomplete glycan synthesis

Purpose: We aimed to discover glycosyltransferase gene (glycogene)-derived molecular subtypes of colorectal cancer (CRC) associated with patient outcomes. Experimental Design: Transcriptomic and epigenomic datasets of non-tumor, pre-cancerous, cancerous tissues and cell lines with somatic mutations, mismatch repair status, clinicopathological and survival information, were assembled (n=4223) and glycogene profiles were analyzed. Immunohistochemistry for a glycogene, GALNT6, was conducted in adenoma and carcinoma specimens (n=403). The functional role and cell surface glycan profiles were further investigated by in vitro loss-of-function assays and lectin microarray analysis. Results: We initially developed and validated a 15-glycogene signature that can identify a poor-prognostic subtype, which closely related to deficient mismatch repair (dMMR) and GALNT6 downregulation. The association of decreased GALNT6 with dMMR was confirmed in multiple datasets of tumors and cell lines, and was further recapitulated by immunohistochemistry, where approximately 15% tumors exhibited loss of GALNT6 protein. GALNT6 mRNA and protein was expressed in premalignant/preinvasive lesions but was subsequently downregulated in a subset of carcinomas, possibly through epigenetic silencing. Decreased GALNT6 was independently associated with poor prognosis in the immunohistochemistry cohort and an additional microarray meta-cohort, by multivariate analyses, and its discriminative power of survival was particularly remarkable in stage III patients. GALNT6 silencing in SW480 cells promoted invasion, migration, chemoresistance and increased cell surface expression of a cancer-associated truncated O-glycan, Tn-antigen. Conclusions: The 15-glycogene signature and the expression levels of GALNT6 mRNA and protein each serve as a novel prognostic biomarker, highlighting the role of dysregulated glycogenes in cancer-associated glycan synthesis and poor prognosis.

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Detection of Gastric Cancer with Novel Methylated DNA Markers: Discovery, Tissue Validation, and Pilot Testing in Plasma

Purpose: Gastric adenocarcinoma (GAC) is the third most common cause of cancer mortality worldwide. Accurate and affordable non-invasive detection methods have potential value for screening and surveillance. Herein, we identify novel methylated DNA markers (MDMs) for GAC, validate their discrimination for GAC in tissues from geographically separate cohorts, explore marker acquisition through the oncogenic cascade, and describe distributions of candidate MDMs in plasma from GAC cases and normal controls. Experimental Design: Following discovery by unbiased whole methylome sequencing, candidate MDMs were validated by blinded methylation-specific PCR in archival case-control tissues from U.S. and South Korean patients. Top MDMs were then assayed by an analytically sensitive method (quantitative real-time allele-specific target and signal amplification) in a blinded pilot study on archival plasma from GAC cases and normal controls. Results: Whole methylome discovery yielded novel and highly discriminant candidate MDMs. In tissue, a panel of candidate MDMs detected GAC in 92-100% of U.S. and S. Korean cohorts at 100% specificity. Levels of most MDMs increased progressively from normal mucosa through metaplasia, adenoma, and GAC with variation in points of greatest marker acquisition. In plasma, a 3 marker panel (ELMO1, ZNF569, C13orf18) detected 86% (95% CI 71-95%) of GACs at 95% specificity. Conclusions: Novel MDMs appear to accurately discriminate GAC from normal controls in both tissue and plasma. The point of aberrant methylation during oncogenesis varies by MDM, which may have relevance to marker selection in clinical applications. Further exploration of these MDMs for GAC screening and surveillance is warranted.

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Phase Ib Study of Binimetinib with Paclitaxel in Patients with Platinum-Resistant Ovarian Cancer: Final Results, Potential Biomarkers, and Extreme Responders

Purpose: Epithelial ovarian cancer (EOC) is a molecularly diverse disease. Mitogen-activated protein kinase kinase (MEK) inhibition targets tumors harboring mitogen-activated protein kinase (MAPK) pathway alterations and enhances paclitaxel-induced apoptosis in EOC. This phase Ib study evaluated the MEK inhibitor binimetinib combined with paclitaxel in patients with platinum-resistant EOC. Experimental Design: Patients received intravenous (IV) weekly paclitaxel with oral binimetinib in three different administration schedules. Outcomes were assessed by RECIST and CGIC CA-125 response criteria. Tumor samples were analyzed using next-generation sequencing. Results: Thirty-four patients received ≥1 binimetinib dose. A 30-mg twice daily (BID) continuous or 45-mg BID intermittent binimetinib dose were deemed the recommended phase 2 doses (RP2Ds) in combination with 80 mg/m² IV weekly paclitaxel. Rate of grade 3/4 adverse events was 65%. The best overall response rate was 18%-1 complete (CR) and 4 partial responses (PRs)-among 28 patients with RECIST-measurable disease. Eleven patients achieved stable disease (SD), yielding a clinical benefit rate (CR+PR+SD) of 57%. Response rates, per both RECIST and CA-125 criteria, were highest in the 45-mg BID continuous cohort and lowest in the 45-mg BID intermittent cohort. All 4 evaluable patients with MAPK pathway-altered tumors experienced clinical benefit. Conclusions: The combination of binimetinib and IV weekly paclitaxel was tolerable in this patient population. The RP2D of binimetinib in combination with paclitaxel was 30 mg BID as a continuous or 45 mg BID as an intermittent dose. Although response rates were modest, a higher clinical benefit rate was seen in patients harboring alterations affecting the MAPK pathway.

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Target-Based Screening Against eIF4A1 Reveals the Marine Natural Compound Elatol as a Novel Inhibitor of Translation Initiation with In Vivo Anti-Tumor Activity

Purpose: The DEAD-box RNA helicase eIF4A1 carries out the key enzymatic step of cap-dependent translation initiation and is a well-established target for cancer therapy, but no drug against it has entered evaluation in patients. We identified and characterized a natural compound with broad antitumor activities that emerged from the first target-based screen to identify novel eIF4A1 inhibitors. Experimental Design: We tested potency and specificity of the marine compound elatol vs. eIF4A1 ATPase activity. We also assessed eIF4A1 helicase inhibition, binding between the compound and the target including binding-site mutagenesis, and extensive mechanistic studies in cells. Finally, we determined maximum tolerated dosing in vivo and assessed activity against xenografted tumors. Results: We found elatol is a specific inhibitor of ATP hydrolysis by eIF4A1 in vitro with broad activity against multiple tumor types. The compound inhibits eIF4A1 helicase activity and binds the target with unexpected 2:1 stoichiometry at key sites in its helicase core. Sensitive tumor cells suffer acute loss of translationally regulated proteins, leading to growth arrest and apoptosis. In contrast to other eIF4A1 inhibitors, elatol induces markers of an integrated stress response, likely an off-target effect, but these effects do not mediate its cytotoxic activities. Elatol is less potent in vitro than the well-studied eIF4A1 inhibitor silvestrol but is tolerated in vivo at ~100X relative dosing, leading to significant activity against lymphoma xenografts. Conclusions: Elatol's identification as an eIF4A1 inhibitor with in vivo anti-tumor activities provides proof-of-principle for target-based screening against this highly promising target for cancer therapy.

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SNHG6 acts as a genome-wide hypomethylation trigger via coupling of miR-1297-mediated S-adenosylmethionine-dependent positive feedback loops

Aberrant genome-wide hypomethylation and long non-coding RNA (lncRNA) dysregulation are associated with hepatocarcinogenesis. However, whether a relationship between the two exists remains largely unknown. S-adenosylmethionine (SAMe)-dependent methylation is a critical factor in genomic methylation. We previously found that SNHG6 lncRNA acted as an oncogene in hepatocarcinogenesis and could be considered a potential prognostic indicator for hepatocellular carcinoma (HCC). Here we verify that SNHG6 leads to genome-wide hypomethylation in hepatoma cells and that SNHG6 negatively correlates with the steady-state SAMe concentration in vivo and in vitro. SNHG6 suppressed MAT1A protein expression by activating the miR-1297/FUS pathway to regulate nucleocytoplasmic shuttling of MAT1A mRNA. Additionally, SNHG6 promoted expression of MAT2A by suppressing direct binding of miR-1297 to the MAT2A 3'UTR. SNHG6 regulated steady-state SAMe levels via coupling of two miR-1297-mediated SAMe-dependent positive feedback loops. Interestingly, the effect of SNHG6 on genome-wide methylation was inhibited by exogenous SAMe within a certain concentration range. These results suggest that single lncRNA dysregulation can lead to aberrant genome-wide hypomethylation by inhibiting SAMe production in HCC and that exogenous SAMe may be beneficial in the treatment of HCC.

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Twist1 regulates Vimentin through Cul2 circular RNA to promote EMT in hepatocellular carcinoma

Twist is a critical epithelial-mesenchymal transition (EMT)-inducing transcription factor that increases expression of Vimentin. How Twist1 regulates this expression remains unclear. Here we report that Twist1 regulates Cullin2 (Cul2) circular RNA to increase expression of Vimentin in EMT. Twist1 bound the Cul2 promoter to activate its transcription and selectively promote expression of Cul2 circular RNA (circ-10720), but not mRNA. circ-10720 positively correlated with Twist1, tumor malignance, and poor prognosis in hepatocellular carcinoma (HCC). Twist1 promoted Vimentin expression by increasing levels of circ-10720, which can absorb miRNAs that target Vimentin. circ-10720 knockdown counteracted the tumor-promoting activity of Twist1 in vitro and in patient-derived xenograft (PDX) and DEN-induced TetOn-Twist1 transgenic mouse HCC models. These data unveil a mechanism by which Twist1 regulates Vimentin during EMT. They also provide potential therapeutic targets for HCC treatment and provide new insight for circRNA-based diagnostic and therapeutic strategies.

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The tumor suppressor CIC directly regulates MAPK pathway genes via histone deacetylation

Oligodendrogliomas (ODG) are brain tumors accounting for approximately 10% of all central nervous system cancers. CIC is a transcription factor that is mutated in most patients with ODG; these mutations are believed to be a key oncogenic event in such cancers. Analysis of the Drosophila melanogaster orthologue of CIC, Capicua, indicates that CIC loss phenocopies activation of the EGFR/RAS/MAPK pathway, and studies in mammalian cells have demonstrated a role for CIC in repressing the transcription of the PEA3 subfamily of ETS transcription factors. Here we address the mechanism by which CIC represses transcription and assess the functional consequences of CIC inactivation. Genome-wide binding patterns of CIC in several cell types revealed that CIC target genes were enriched for MAPK effector genes involved in cell cycle regulation and proliferation. CIC binding to target genes was abolished by high MAPK activity, which led to their transcriptional activation. CIC interacted with the SIN3 deacetylation complex and, based on our results, we suggest that CIC functions as a transcriptional repressor through the recruitment of histone deacetylases. Independent single amino acid substitutions found in ODG tumors prevented CIC from binding its target genes. Taken together, our results show that CIC is a transcriptional repressor of genes regulated by MAPK signaling, and that ablation of CIC function leads to increased histone acetylation levels and transcription at these genes, ultimately fueling mitogen-independent tumor growth.

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FGFR1-activated Translation of WNT Pathway Components with Structured 5' UTRs is Vulnerable to Inhibition of EIF4A-dependent Translation Initiation

Cooperativity between WNT and FGF signaling is well documented in embryonic development and cancer progression, but the molecular mechanisms underlying this crosstalk remain elusive. In this study, we interrogated the dynamics of RNA levels, ribosome occupancy, and protein expression as a function of inducible FGF signaling in mouse mammary glands with constitutive WNT hyperactivation. Multi-omics correlation analysis revealed a substantial discrepancy between RNA and ribosome occupancy levels versus protein levels. However, this discrepancy decreased as cells became pre-malignant and dynamically responded to FGF signaling, implicating the importance of stringent gene regulation in non-transformed cells. Analysis of individual genes demonstrated that acute FGF hyperactivation increased translation of many stem cell self-renewal regulators, including WNT signaling components, and decreased translation of genes regulating cellular senescence. WNT pathway components translationally upregulated by FGF signaling had long and structured 5' UTRs with a high frequency of polypurine sequences, several of which harbored (CGG)4 motifs that can fold into either stable G-quadruplexes or other stable secondary structures. The FGF-mediated increase in translation of WNT pathway components was compromised by silvestrol, an inhibitor of EIF4A that clamps EIF4A to polypurine sequences to block 43S scanning and inhibits its RNA-unwinding activity important for translation initiation. Moreover, silvestrol treatment significantly delayed FGF-WNT-driven tumorigenesis. Taken together, these results suggest that FGF signaling selectively enhances translation of structured mRNAs, particularly WNT signaling components, and highlight their vulnerability to inhibitors that target the RNA helicase EIF4A.

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Combined c-Met/Trk inhibition overcomes resistance to CDK4/6 inhibitors in Glioblastoma

Glioblastoma (GBM) is the most common primary brain malignancy and carries an extremely poor prognosis. Recent molecular studies revealed the CDK4/6-Rb-E2F axis and receptor tyrosine kinase (RTK) signaling to be deregulated in most GBM, creating an opportunity to develop more effective therapies by targeting both pathways. Using a phospho-RTK protein array, we found that both c-Met and TrkA-B pathways were significantly activated upon CDK4/6 inhibition in GBM cells. We therefore investigated the efficacy of combined CDK4/6 and c-Met/TrkA-B inhibition against GBM. We show that both c-Met and TrkA-B pathways transactivate each other, and targeting both pathways simultaneously results in more efficient pathway suppression. Mechanistically, inhibition of CDK4/6 drove NF-κB-mediated upregulation of hepatocyte growth factor (HGF), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) that in turn activated both c-Met and TrkA-B pathways. Combining the CDK4/6 inhibitor abemaciclib with the c-Met/Trk inhibitor altiratinib or the corresponding siRNAs induced apoptosis, leading to significant synergy against GBM. Collectively, these findings demonstrate that the activation of c-Met/TrkA-B pathways is a novel mechanism involved in therapeutic resistance of GBM to CDK4/6 inhibition and that dual inhibition of c-Met/Trk with CDK4/6 should be considered in future clinical trials.

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Restraining Network Response to Targeted Cancer Therapies Improves Efficacy and Reduces Cellular Resistance

A key tool of cancer therapy has been targeted inhibition of oncogene addicted pathways. However, efficacy has been limited by progressive emergence of resistance as transformed cells adapt. Here we use Drosophila to dissect response to targeted therapies. Treatment with a range of kinase inhibitors led to hyperactivation of overall cellular networks, resulting in emergent resistance and expression of stem cell markers including Sox2. Genetic and drug screens revealed that inhibitors of histone deacetylases, proteasome, and Hsp90 family of proteins restrained this network hyperactivation. These 'network brake' cocktails, used as adjuncts, prevented emergent resistance and promoted cell death at subtherapeutic doses. Our results highlight a general response of cells-transformed and normal-to targeted therapies that leads to resistance and toxicity. Pairing targeted therapeutics with subtherapeutic doses of broad acting 'network brake' drugs may provide a means of extending therapeutic utility while reducing whole body toxicity.

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Radiotherapy and CD40 activation separately augment immunity to checkpoint blockade in cancer

Immunotherapy in pancreatic ductal adenocarcinoma (PDA) remains a difficult clinical problem despite success in other disease types with immune checkpoint blockade (ICB) and chimeric antigen receptor T cell therapy. Mechanisms driving immunosuppression and poor T cell infiltration in PDA are incompletely understood. Here we use genetically engineered mouse models of PDA that recapitulate hallmarks of human disease to demonstrate that CD40 pathway activation is required for clinical response to radiotherapy (RT) and ICB with αCTLA-4 and αPD-1. The combination of an agonist αCD40 antibody, RT, and dual ICB eradicated irradiated and unirradiated (i.e. abscopal) tumors, generating long-term immunity. Response required T cells and also short-lived myeloid cells and was dependent on the long non-coding RNA myeloid regulator Morrbid. Using unbiased random forest machine learning, we built unique, contextual signatures for each therapeutic component, revealing that (i) RT triggers an early proinflammatory stimulus, ablating existing intratumoral T cells and upregulating MHC class I and CD86 on antigen presenting cells, (ii) αCD40 causes a systemic and intratumoral reorganization of the myeloid compartment, and (iii) ICB increases intratumoral T cell infiltration and improves the CD8 T cell:regulatory T cell ratio. Thus, αCD40 and RT non-redundantly augment anti-tumor immunity in PDA, which is otherwise refractory to ICB, providing a clear rationale for clinical evaluation.

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Specific targeting of MTAP-deleted tumors with a combination of 2'-fluoroadenine and 5'-methylthioadenosine

Homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene is a frequent event in a wide variety of human cancers and is a possible molecular target for therapy. One potential therapeutic strategy to target MTAP-deleted tumors involves combining toxic purine analogs such as 6′-thioguanine (6TG) or 2′-fluoroadenine (2FA) with the MTAP substrate 5′-deoxy-5′-methylthioadenosine (MTA). The rationale is that excess MTA will protect normal MTAP+ cells from purine analog toxicity because MTAP catalyzes the conversion of MTA to adenine, which then inhibits the conversion of purine base analogs into nucleotides. However, in MTAP- tumor cells, no protection takes place because adenine is not formed. Here, we examine the effects of 6TG and 2FA in combination with MTA in vitro and in vivo. In vitro, MTA protected against both 6TG and 2FA toxicity in an MTAP-dependent manner, shifting the IC50 concentration by one to three orders of magnitude. However, in mice, MTA protected against toxicity from 2FA but failed to protect against 6TG. Addition of 100 mg/kg MTA to 20 mg/kg 2FA entirely reversed the toxicity of 2FA in a variety of tissues and the treatment was well tolerated by mice. The 2FA+MTA combination inhibited tumor growth of four different MTAP- human tumor cell lines in mouse xenograft models. Our results suggest that 2FA+MTA may be a promising combination for treating MTAP-deleted tumors.

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Notch-induced myeloid reprogramming in spontaneous pancreatic ductal adenocarcinoma by dual genetic targeting

Despite advances in our understanding of the genetics of pancreatic ductal adenocarcinoma (PDAC), the efficacy of therapeutic regimens targeting aberrant signaling pathways remains highly limited. Therapeutic strategies are greatly hampered by the extensive desmoplasia that comprises heterogeneous cell populations. Notch signaling is a contentious pathway exerting opposite roles in tumorigenesis depending on cellular context. Advanced model systems are needed to gain more insights into complex signaling in the multi-layered tumor microenvironment. In this study, we employed a dual recombinase-based in vivo strategy to modulate Notch signaling specifically in myeloid cells to dissect the tumorigenic role of Notch in PDAC stroma. Pancreas-specific KrasG12D activation and loss of Tp53 was induced using a Pdx1-Flp transgene, while Notch signaling was genetically targeted using a myeloid-targeting Lyz2-Cre strain for either activation of Notch2-IC or deletion of Rbpj. Myeloid-specific Notch activation significantly decreased tumor infiltration by protumorigenic M2 macrophages in spontaneous endogenous PDAC, which translated into significant survival benefit. Further characterization revealed upregulated antigen presentation and cytotoxic T effector phenotype upon Notch-induced M2 reduction. This approach is the first proof-of-concept for genetic targeting and reprogramming of myeloid cells in a complex disease model of PDAC and provides evidence for a regulatory role of Notch signaling in intratumoral immune phenotypes.

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Integrative modeling identifies key determinants of inhibitor sensitivity in breast cancer cell lines

Cancer cell lines differ greatly in their sensitivity to anticancer drugs as a result of different oncogenic drivers and drug resistance mechanisms operating in each cell line. Although many of these mechanisms have been discovered, it remains a challenge to understand how they interact to render an individual cell line sensitive or resistant to a particular drug. To better understand this variability, we profiled a panel of thirty breast cancer cell lines in the absence of drugs for their mutations, copy number aberrations, mRNA and protein expression and protein phosphorylation, and for response to seven different kinase inhibitors. We then constructed a knowledge-based, Bayesian computational model that integrates these data types and estimates the relative contribution of various drug sensitivity mechanisms. The resulting model of regulatory signaling explained the majority of the variability observed in drug response. The model also identified cell lines with an unexplained response, and for these we searched for novel explanatory factors. Among others, we found that 4E-BP1 protein expression - and not just the extent of phosphorylation - was a determinant of mTOR inhibitor sensitivity. We validated this finding experimentally and found that overexpression of 4E-BP1 in cell lines that normally possess low levels of this protein is sufficient to increase mTOR inhibitor sensitivity. Taken together, our work demonstrates that combining experimental characterization with integrative modeling can be used to systematically test and extend our understanding of the variability in anticancer drug response.

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Targeting LGR5 in Colorectal Cancer: therapeutic gold or too plastic?

Targeting LGR5 in Colorectal Cancer: therapeutic gold or too plastic?

Targeting LGR5 in Colorectal Cancer: therapeutic gold or too plastic?, Published online: 30 May 2018; doi:10.1038/s41416-018-0118-6

Targeting LGR5 in Colorectal Cancer: therapeutic gold or too plastic?

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Targeting LGR5 in Colorectal Cancer: therapeutic gold or too plastic?

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Surgical plate fixation of multiple rib fractures: a case report

The healthcare system in developing countries is limited; particularly, medical specialties such as emergency and trauma medicine are underdeveloped. Consequently, trauma injuries sustained in traffic accident...

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Clinicopathological significance of cancer stem cell markers CD44 and ALDH1 expression in breast cancer

Abstract

Background

CD44 and aldehyde dehydrogenase 1 (ALDH1) has been reputed to be cancer stem cell (CSC) markers in breast cancer. Yet, the clinicopathologic and prognostic significance of these markers remain unclear. In this study, we have investigated the expression of these markers and their relation with conventional clinicopathologic tumor characteristic including molecular subtype.

Methods

CD44 and ALDH1 expression were investigated by immunohistochemistry in a series of 157 formalin-fixed paraffin-embedded breast cancer tissues.

Results

Overall, CD44 and ALDH1 are, respectively, detected in 33% (52 of 157) and 7% (10 of 157) of breast cancer cases. We also observed that CD44 expression was associated with histological grade (p = 0.005). For ALDH1, we found that its expression is more frequent with elderly women (> 50 years, p = 0.03). The investigation of relationship between the stem cell phenotype and breast cancer molecular subtype, revealed that CD44 and ALDH1 expression was more frequent in basal-like tumors (p = 0.005). Among the two cancer stem cell markers tested, ALDH1 showed a strong association with the basal marker EGFR (p = 0.05).

Conclusions

These findings suggest that CD44 and ALDH1 play a role in the clinical behavior in breast cancer and might be interesting biomarkers and therapeutic targets.

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Experimental Cancer Drug Metarrestin Targets Metastatic Tumors

Researchers have struggled to develop therapies to treat tumors that have spread to other parts of the body. In a new study, researchers tested whether the experimental drug metarrestin can selectively shrink metastases in mouse models of aggressive pancreatic cancer.

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Stereotactic body radiation therapy (SBRT) in patients with hepatocellular carcinoma and oligometastatic liver disease

To report our experience with SBRT in primary and secondary liver tumors.

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PD-L1-Expressing Radiation-Associated Angiosarcoma after Primary Breast Cancer

Radiation-associated angiosarcoma (RAAS) is a type of radiation-associated sarcoma (RAS) that develops at the previous field of radiation in breast cancer patients. Although several reports have suggested a poor prognosis for RAAS, the 5-year overall survival of RAAS is better than that of cutaneous angiosarcoma (CAS), suggesting that the prognostic factors of RAAS and CAS might be different, at least in part. In this report, we describe a case of RAAS, and employed immunohistochemical (IHC) staining of PD-L1 and MMP9 as well as periostin, IL-4, and CD163. Interestingly, IHC staining revealed that the RAAS in our case was positive for PD-L1 and negative for MMP9. Moreover, the predominant stromal factor of our case was periostin, suggesting that TAMs in the present case was not immunosuppressive, but an inflammatory subtype. These results might explain, at least in part, the better prognosis of RAAS compared to CAS.
Case Rep Oncol 2018;11:330–335

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Small-Cell Carcinoma Transformation of Pulmonary Adenocarcinoma after Osimertinib Treatment: A Case Report

There are various mechanisms underlying the resistance of EGFR-mutant lung adenocarcinoma to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We herein report a case of pulmonary adenocarcinoma with EGFR mutation (exon 19 deletion and T790M) that acquired resistance to osimertinib treatment because of transformation into small-cell lung carcinoma (SCLC). A 67-year-old ex-smoking woman was diagnosed with left upper lobe adenocarcinoma of clinical stage IIIA (cT2bN2M0). She was treated with chemoradiotherapy (cisplatin and vinorelbine plus radiation), gefitinib, cisplatin, and pemetrexed followed by pemetrexed maintenance therapy and erlotinib. Since a sample extracted from the metastatic lung tumor taken obtained via a transbronchial lung biopsy was found to be positive for the T790M mutation at the time of disease progression during erlotinib treatment, she received osimertinib treatment for 15 months until progressive disease. She developed resistance to osimertinib due to the histologic transformation to SCLC. Although the standard chemotherapy of carboplatin and etoposide for SCLC was administered, she died due to metastatic liver failure.
Case Rep Oncol 2018;11:323–329

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Intramammary Metastasis in a Patient with a History of Renal Cell Carcinoma: A Case Report

Intramammary metastasis of renal cell carcinoma (RCC) is extremely rare, accounting for only 1.5% of all intramammary metastases. Distinguishing intramammary metastases from benign tumors and breast cancer is clinically problematic. Some patients undergo excessive surgery after a misdiagnosis of breast cancer instead of a mammary tumor. We performed a core needle biopsy (CNB) of a breast mass that developed in a 71-year-old woman after surgeries for bilateral RCC and breast cancer, leading to a diagnosis of intramammary metastasis of RCC. In this case, the CNB and immunohistochemical examination were critical for reaching a definitive diagnosis. We conclude that, when examining patients with mammary tumors, establishing their history of malignant tumors may help diagnose intramammary metastasis and select the best treatment strategy.
Case Rep Oncol 2018;11:318–322

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MicroRNAs as potential liquid biopsy biomarkers in colorectal Cancer: A systematic review

Publication date: Available online 29 May 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Yuji Toiyama, Yoshinaga Okugawa, James Fleshman, C. Richard Boland, Ajay Goel
Emerging evidence has demonstrated the feasibility of circulating miRNAs as robust non-invasive biomarkers for the diagnosis in colorectal cancer. The use of circulating miRNAs for the early detection of colorectal cancer (CRC) is of particular interest as it can offer a potential complementary approach to screening colonoscopy. However, the development of circulating miRNAs as "liquid biopsy" biomarkers for development into clinical screening tests has been hampered by several issues. In this article, we summarize the status of this field for the clinical utilization of miRNA biomarkers as liquid biopsies in colorectal cancer (CRC) and discuss their applications as screening tests for patients with colorectal adenoma (CRA) and CRC. Herein, we undertook a systematic search for citations in PubMed and the Cochrane Database from January 1, 2002 through December 31, 2017 as electronic sources for this study. All published studies were screened with no restriction on language, date, or country. We used database-specific combinations of the following index terms and text words, including: microRNA, colorectal cancer, serum, plasma, and exosomes. Based upon these searches, we summarize the progress and salient features of the current state of knowledge of miRNA diagnostic biomarkers in CRC, and focuses on the articles that attempt to optimize ideal methodologies to further advance their as liquid biopsies for clinical use. We conclude that the field of noncoding RNAs, particularly for the clinical use of miRNAs as liquid biopsy assays is maturing rapidly, and it is highly promising that these genomic signatures will likely be developed into clinically-viable tests for the early detection and clinical management of patients with colorectal cancer in the not so distant future.



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Thoracic oesophageal cancer as a cause of stridor: a literature review

An 83-year-old woman, with a background of treated squamous cell oesophageal cancer, presented with a 3-week history of stridor. Of note, the patient had no risk factors for oesophageal cancer other than age. Clinical examination was unremarkable apart from stridor. Laboratory investigations, including arterial blood gas on room air, were unremarkable. Radiological examination revealed a 4.5x3.5x3.6 cm mass involving the posterior trachea and invading the tracheal orifice. Oesophagogastroduodenoscopy and rigid bronchoscopy confirmed an extensive tumour arising from the lower oesophagus and invading the trachea, causing 90% airway obstruction for a 6 mm length ending 1.5 cm above the carina. Biopsy revealed a poorly differentiated carcinoma with foci of squamous cell carcinoma. Unfortunately, the patient passed away 2 months after palliative tracheal stent placement.

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Benign acute myositis in an adult patient

The benign acute childhood myositis presents as a marked and painful oedema of leg muscles in the days following a viral illness. This disease is often considered as occurring only in children. We report the case of a 32-year-old patient who presented with severe pain and oedema of both legs associated with motor deficit of lower extremities. He suffered from a grippal syndrome for 4 days. Creatine kinase blood level rose up to 39 394 IU/L (n<200) and a muscle biopsy of left tibialis anterior found necrosisand regeneration of myocytes without inflammatory infiltrates. All clinical and paraclinical abnormalities spontaneously disappeared in a few days. This case illustrates that a disorder similar to benign acute childhood myositis may occur in adult patients. Muscle biopsy might be avoided in typical cases because of the favourable evolution.

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Keratinising squamous cell metaplasia: when is it safe to stop looking?

Keratinising squamous cell metaplasia (KSCM) is an uncommon diagnosis in the West. Patients typically present with lower urinary tract symptoms: haematuria (visible and non-visible), dysuria, urgency and frequency. Investigation is rigid cystoscopy. Abnormal bladder wall tissue should be resected and biopsies sent for histopathology to confirm KSCM. This is a preneoplastic condition with strong associations with squamous cell carcinoma. Due to a significant lag time, annual cystoscopy with multiple biopsies is recommended.

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Acute non-cardiogenic pulmonary oedema due to contralateral pulmonary re-expansion after thoracentesis: an uncommon complication

Description 

An 82-year-old man presented with hypoxaemic respiratory insufficiency due to left-sided pneumonia and lung atelectasis, with a large, long-standing (>7 days) ipsilateral pleural effusion (figure 1A,B). Four hours after draining 1500 mL of transudative pleural fluid, the patient had worsening hypoxaemia and increasing supplemental oxygen necessity (fractional inspired oxygen 60% with high-flow face mask). The left lung had expanded, as noted by normal vesicular lung sounds, while diffuse crackles were exhibited on the right side. The chest radiograph (figure 1C) shows asymmetrical diffuse alveolar opacity in the right lung field, which in this setting relates to non-cardiogenic pulmonary oedema after contralateral pulmonary re-expansion. After 12 days of conservative treatment, the patient was well, his left lung was expanded and his right-sided oedema had completely resolved (figure 1D), with no need for supplemental oxygen.

Figure 1

(A) Chest X-ray showing a left-sided pneumonia and...

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Gastric duplication cyst with elevated CEA level: a case report

Abstract

Gastrointestinal tract duplications are congenital malformations rarely seen in adulthood. Gastric duplications (GD) represent 2–9% of it. Malignant transformation of GD is a rare complication described in the literature. We present the case of a 43-year-old man, who presented an abdominal mass and an elevated CEA level. A total gastrectomy was performed and the histological examination described a gastric duplication cysts (GDC) without malignant transformation. It is not the first case of elevation of CEA in GDC without evidence of malignancy described in the literature. Some authors think that GDC are premalignant lesions that envolve with the time to carcinomas. It is recommend that once the GDC is diagnosed to remove surgically the entire cyst even if the patient is asymptomatic.

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Bleb formation in small unruptured intracranial aneurysm as a predictor of early rupture

Abstract

Small unruptured aneurysms are thought to have a low risk of rupture, but the management of such lesions is still controversial. A 73-year-old man with a small anterior communication artery aneurysm, 4 mm in diameter, while on follow-up, developed an aneurysmal subarachnoid hemorrhage 2 weeks after the detection of a newly emerged bleb on the surface of the aneurysm. In conclusion, the formation of a bleb should be considered as a warning sign of an impending rupture, and treatment should be provided even for patients with small aneurysms.

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Metastatic lobular breast carcinoma to the pancreas: a case report

Abstract

We report a case of a 72-year-old female, with an extensive breast cancer history, who presented with abdominal pain to her general practitioner. Cross-sectional imaging demonstrated a lesion in the head of pancreas, which was not amenable to curative resection. Percutaneous biopsy was obtained, which demonstrated metastatic lobular breast cancer. This rare case highlights how previous medical histories may assist in final pathological diagnosis.

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Pharmacobezoar—a rare case presented as gastric outlet obstruction

Abstract

BEZOARS are retained concretions of indigestible foreign material that accumulate and conglomerate in the gastrointestinal tract, most commonly in the stomach. Prevalence of bezoar is 0.4%. Bezoars are classified in four categories: phytobezoars; trichobezoars; pharmacobezoars; lactobezoars. A 58-year-old man admitted with complains of pain abdomen and recurrent vomiting since last 3 months. Upper GI endoscopic biopsy reported—chronic gastritis with very occasional non-caseating epitheloid granuloma in lamina propria, no evidence of neoplasia? Crohn's disease. Keeping Crohn's as diagnosis patient was given mesalamine 400 mg tid by gastrophyscian. But patient did not respond so the patient was advised surgical management. Repeat UGI endoscopy revealed multiple pills (mesalamine) in the stomach with gastric outlet obstruction (GOO). Around 40 pills were extracted with the help of flower basket, and then patient develope GOO and underwent Laparoscopic gastrojejunostomy and truncal vagotomy.

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Rare case of bleeding nipple hemangioma in a lactating mother

Abstract

Hemangiomas of nipple of the breast are rare lesions and are limited to case reports in the literature. Such pathology in a lactating mother are clearly a hindrance preventing the child from breastfeeding with its benefits. We report a rare case of a bleeding nipple hemangioma in a 24 years old lactating mother with the clinical, imaging and histopathological findings.

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Biliary pancreatitis in a duplicate gallbladder: a case report and review of literature

Abstract

Duplicated gallbladder is a rare congenital anomaly that require special attentions due to its clinical, surgical and diagnostic difficulties. We present a case of a 39-year-old female patient with a duplicated gallbladder who presented with an acute biliary pancreatitis, a case to our knowledge is the first in the literature. A double gallbladder in an abdominal ultrasonography was doubtful, thus a computed tomography scan, a magnetic resonance cholangiopancreatography and an endoscopic retrograde cholangiopancreatography were done that confirmed the double gallbladder. A laparoscopic cholecystectomy with an intraoperative cholangiography was performed safely two months after the acute attack. The histopathological report revealed a Y-shaped type 1 double gallbladder according to the Harlaftis et al. classification.

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Effects of Progressive Additional Lenses on Binocular Vision in Children with Pseudophakia

Binocular vision may be compromised in children after unilateral cataract surgery because the distances at which clear vision is present are different for the two eyes. We believe that wearing progressive additional lenses can be effective in improving the binocular vision in children with pseudophakia.
Case Rep Ophthalmol 2018;9:304–309

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Endophytic-Type Endometrial Cancer with Adenomyosis Successfully Diagnosed with Hysteroscopic Endometrial Biopsy Using an 8.3-mm Operative Resectoscope: A Case Report

In order to diagnose endometrial cancer preoperatively, outpatient endometrial biopsy with a curette is frequently performed owing to its convenience. However, in some cases, gynecologists fail to diagnose endometrial cancer via outpatient endometrial biopsy because of the cancer's distribution in the uterus and its consistency. A 57-year-old Japanese woman (gravida 4 para 4) presented with a 6-month history of light but intermittent postmenopausal vaginal bleeding. A malignant uterine tumor was strongly suspected after imaging using ultrasound examination and magnetic resonance imaging; however, a precise pathological diagnosis was not achieved despite multiple outpatient endometrial biopsies with the aid of office hysteroscopy. Based on an endometrial biopsy obtained using a cutting loop electrode on an 8.3-mm operative resectoscope, we reached a diagnosis of endophytic-type endometrial cancer, which is in accordance with the final pathological diagnosis after abdominal hysterectomy. Three months after her first visit to our hospital, total abdominal hysterectomy and bilateral salpingo-oophorectomy with pelvic/para-aortic lymph node dissection were performed. Macroscopically, the endometrium was atrophic, and there was no obvious mass in the uterine cavity; however, microscopically, the cancer cells mainly existed in the deep myometrium and the final diagnosis was International Federation of Gynecology and Obstetrics (FIGO) stage IB endometrial cancer. Operative biopsy of the uterine endometrium and deep myometrium using hysteroscopy confirmed an accurate preoperative diagnosis of uterine endometrial cancer specifically of the endophytic type.
Case Rep Oncol 2018;11:311–317

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Is there a role for immunotherapy in malignant pleural mesothelioma?

Abstract

Malignant pleural mesothelioma (MPM) is a very aggressive malignancy, mainly caused by asbestos exposure. Patients with MPM have a poor prognosis that remained substantially unchanged in the last few years and limited effective therapeutic options with no recognized second or further-line therapy. In this context, also in view of the positive results observed in other tumor types, immunotherapy could play a relevant role. This review focuses on the most promising immunotherapies being investigated in MPM.

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Establishment of adoptive cell therapy with tumor infiltrating lymphocytes for non-small cell lung cancer patients

Abstract

Adoptive cell therapy (ACT) of tumor infiltration lymphocytes (TIL) yields promising clinical results in metastatic melanoma patients, who failed standard treatments. Due to the fact that metastatic lung cancer has proven to be susceptible to immunotherapy and possesses a high mutation burden, which makes it responsive to T cell attack, we explored the feasibility of TIL ACT in non-small cell lung cancer (NSCLC) patients. Multiple TIL cultures were isolated from tumor specimens of five NSCLC patients undergoing thoracic surgery. We were able to successfully establish TIL cultures by various methods from all patients within an average of 14 days. Fifteen lung TIL cultures were further expanded to treatment levels under good manufacturing practice conditions and functionally and phenotypically characterized. Lung TIL expanded equally well as 103 melanoma TIL obtained from melanoma patients previously treated at our center, and had a similar phenotype regarding PD1, CD28, and 4-1BB expressions, but contained a higher percent of CD4 T cells. Lung carcinoma cell lines were established from three patients of which two possessed TIL cultures with specific in vitro anti-tumor reactivity. Here, we report the successful pre-clinical production of TIL for immunotherapy in the lung cancer setting, which may provide a new treatment modality for patients with metastatic NSCLC. The initiation of a clinical trial is planned for the near future.

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Comparison of Duke Activity Status Index with cardiopulmonary exercise testing in cancer patients

Abstract

Purpose

The Duke Activity Status Index (DASI), a patient-administered questionnaire, is used to quantify functional capacity in patients undergoing cancer surgery.

Methods

This retrospective cohort study assessed whether the DASI was accurate in predicting peak oxygen consumption (pVO₂) that was objectively measured using cardiopulmonary exercise testing (CPET) in 43 consecutive patients scheduled for elective major cancer surgery at a tertiary cancer centre. The primary outcome measured the limits of agreement between DASI-predicted pVO₂ and actual measured pVO₂.

Results

The study population was elderly (median 63 years, interquartile range 18), 58% were male, with the majority having intraabdominal cancer surgery. Although the DASI scores were statistically related to the measured pVO₂ (N = 43, adjusted R² = 0.20, p = 0.002), both the bias (8 ml kg^− 1 min^− 1) and 95% limits of agreement (19.5 to − 3.4 ml kg^− 1 min^− 1) between the predicted and measured pVO₂ were large. Using some of the individual components, recalibrating the intercept and regression coefficient of the total DASI score did not substantially improve its ability to predict the measured pVO₂.

Conclusion

In summary, both the limits of agreement and bias between the measured and DASI-predicted pVO₂ were substantial. The DASI-predicted pVO₂ based on patient's assessment of their functional status could not be considered a reliable surrogate of measured pVO₂ during CPET for the population of patients pending major cancer surgery and cannot, therefore, be used as a triage tool for referral to CPET centres for objective risk assessment.

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Cancers, Vol. 10, Pages 167: Clinical Importance of Epstein–Barr Virus-Associated Gastric Cancer

Cancers, Vol. 10, Pages 167: Clinical Importance of Epstein–Barr Virus-Associated Gastric Cancer

Cancers doi: 10.3390/cancers10060167

Authors: Jun Nishikawa Hisashi Iizasa Hironori Yoshiyama Kanami Shimokuri Yuki Kobayashi Sho Sasaki Munetaka Nakamura Hideo Yanai Kohei Sakai Yutaka Suehiro Takahiro Yamasaki Isao Sakaida

Epstein&ndash;Barr virus-associated gastric carcinoma (EBVaGC) is the most common malignancy caused by EBV infection. EBVaGC has definite histological characteristics similar to gastric carcinoma with lymphoid stroma. Clinically, EBVaGC has a significantly low frequency of lymph node metastasis compared with EBV-negative gastric cancer, resulting in a better prognosis. The Cancer Genome Atlas of gastric adenocarcinomas proposed a molecular classification divided into four molecular subtypes: (1) EBVaGC; (2) microsatellite instability; (3) chromosomal instability; and (4) genomically stable tumors. EBVaGC harbors a DNA methylation phenotype, PD-L1 and PD-L2 overexpression, and frequent alterations in the PIK3CA gene. We review clinical importance of EBVaGC and discuss novel therapeutic applications for EBVaGC.

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