Cancers, Volume 13, Issue 16 (August-2 2021) – 327 articles

Extended colon resection is often performed in advanced ovarian cancer. Restoring intestinal continuity and avoiding stoma creation improve patients’ quality of life postoperatively. We tried to minimize the number of anastomoses, restore intestinal continuity, and avoid stoma creation for 295 patients with stage III/IV ovarian cancer who underwent low anterior rectal resection (LAR) with or without colon resection during cytoreductive surgery. When the remaining colon could not reach the rectal stump after left hemicolectomy with LAR, we used the following techniques for tension-free anastomosis: right colonic transposition, retro-ileal anastomosis through an ileal mesenteric defect, or an additional colic artery division. Rates of stoma creation and rectal anastomotic were 3% (9/295) and 6.6% (19/286), respectively. Among 21 patients in whom the remaining colon did not reach the rectal stump after left hemicolectomy with LAR, 20 underwent tension-free anastomosis, including eight, six, and six patients undergoing right colonic transposition, retro-ileal anastomosis through an ileal mesenteric defect, and an additional colic artery division, respectively. Colorectal anastomosis is feasible for patients with extended colonic resection. Low anastomotic leakage and stoma rates can be achieved with careful attention to colonic mobilization and tension-free anastomosis. Full article

The Hippo pathway is an important signaling pathway modulating growth control and cancer cell proliferation. Dysregulation of the Hippo pathway is a common feature of several types of cancer cells. The modulation of the interaction between yes-associated protein (YAP) and transcriptional enhancer associated domain (TEAD) in the Hippo pathway is considered an attractive target for cancer therapeutic development, although the inhibition of PPI is a challenging task. In order to investigate the hot spots of the YAP and TEAD1 interacting complex, an ab initio Fragment Molecular Orbital (FMO) method was introduced. With the hot spots, pharmacophores for the inhibitor design were constructed, then virtual screening was performed to an in-house library. Next, we performed molecular docking simulations and FMO calculations for screening results to study the binding modes and affinities between PPI inhibitors and TEAD1. As a result of the virtual screening, three compounds were selected as virtual hit compounds. In order to confirm their biological activities, cellular (luciferase activity, proximity ligation assay and wound healing assay in A375 cells, qRT-PCR in HEK 293T cells) and biophysical assays (surface plasmon resonance assays) were performed. Based on the findings of the study, we propose a novel PPI inhibitor BY03 and demonstrate a profitable strategy to analyze YAP–TEAD PPI and discover novel PPI inhibitors. Full article

In recent decades, adoptive cell transfer and checkpoint blockade therapies have revolutionized immunotherapeutic approaches to cancer treatment. Advances in whole exome/genome sequencing and bioinformatic detection of tumour-specific genetic variations and the amino acid sequence alterations they induce have revealed that T cell mediated anti-tumour immunity is substantially directed at mutated peptide sequences, and the identification and therapeutic targeting of patient-specific mutated peptide antigens now represents an exciting and rapidly progressing frontier of personalized medicine in the treatment of cancer. This review outlines the historical identification and validation of mutated peptide neoantigens as a target of the immune system, and the technical development of bioinformatic and experimental strategies for detecting, confirming and prioritizing both patient-specific or “private” and frequently occurring, shared “public” neoantigenic targets. Further, we examine the range of therapeutic modalities that have demonstrated preclinical and clinical anti-tumour efficacy through specifically targeting neoantigens, including adoptive T cell transfer, checkpoint blockade and neoantigen vaccination. Full article

Ultra-high dose rate FLASH proton radiotherapy (F-PRT) has been shown to reduce normal tissue toxicity compared to standard dose rate proton radiotherapy (S-PRT) in experiments using the entrance portion of the proton depth dose profile, while proton therapy uses a spread-out Bragg peak (SOBP) with unknown effects on FLASH toxicity sparing. To investigate, the biological effects of F-PRT using an SOBP and the entrance region were compared to S-PRT in mouse intestine. In this study, 8–10-week-old C57BL/6J mice underwent 15 Gy (absorbed dose) whole abdomen irradiation in four groups: (1) SOBP F-PRT, (2) SOBP S-PRT, (3) entrance F-PRT, and (4) entrance S-PRT. Mice were injected with EdU 3.5 days after irradiation, and jejunum segments were harvested and preserved. EdU-positive proliferating cells and regenerated intestinal crypts were quantified. The SOBP had a modulation (width) of 2.5 cm from the proximal to distal 90%. Dose rates with a SOBP for F-PRT or S-PRT were 108.2 ± 8.3 Gy/s or 0.82 ± 0.14 Gy/s, respectively. In the entrance region, dose rates were 107.1 ± 15.2 Gy/s and 0.83 ± 0.19 Gy/s, respectively. Both entrance and SOBP F-PRT preserved a significantly higher number of EdU + /crypt cells and percentage of regenerated crypts compared to S-PRT. Moreover, tumor growth studies showed no difference between SOBP and entrance for either of the treatment modalities. Full article

Platelets represent the linkage between tissue damage and inflammatory response with a putative role in tumorigenesis. Given the importance of the microenvironment in colon cancer development, we elucidated the eventual role of platelets-cancer cells crosstalk in in vivo colon cancer models. To evaluate the involvement of platelets in intestinal tumorigenesis, we first analyzed if the ablation of β-integrin P-selectin that drives platelets-cell adhesion, would contribute to platelets-colon cancer cell interaction and drive cancer progression. In a xenograft tumor model, we observed that when tumors are inoculated with platelets, the ablation of P-selectin significantly reduced tumor growth compared to control platelets. Furthermore, in genetic models, as well as in chronic colitis-associated colorectal carcinogenesis, P-selectin ablated mice displayed a significant reduction in tumor number and size compared to control mice. Taken together, our data highlights the importance of platelets in the tumor microenvironment for intestinal tumorigenesis. These results support the hypothesis that a strategy aimed to inhibit platelets adhesion to tumor cells are able to block tumor growth and could represent a novel therapeutic approach to colon cancer treatment. Full article

Yes-associated protein (YAP) and TAZ are transcriptional cofactors that sit at the crossroad of several signaling pathways involved in cell growth and differentiation. As such, they play essential functions during embryonic development, regeneration, and, once deregulated, in cancer progression. In this review, we will revise the current literature and provide an overview of how YAP/TAZ control transcription. We will focus on data concerning the modulation of the basal transcriptional machinery, their ability to epigenetically remodel the enhancer–promoter landscape, and the mechanisms used to integrate transcriptional cues from multiple pathways. This reveals how YAP/TAZ activation in cancer cells leads to extensive transcriptional control that spans several hallmarks of cancer. The definition of the molecular mechanism of transcriptional control and the identification of the pathways regulated by YAP/TAZ may provide therapeutic opportunities for the effective treatment of YAP/TAZ-driven tumors. Full article

The pathogen Helicobacter pylori is the first reported bacterial type-1 carcinogen playing a role in the development of human malignancies, including gastric adenocarcinoma. Cancer cell motility is an important process in this scenario, however, the molecular mechanisms are still not fully understood. Here, we demonstrate that H. pylori subverts the actin-binding protein cortactin through its type-IV secretion system and injected oncoprotein CagA, e.g., by inducing tyrosine phosphorylation of cortactin at Y-470, which triggers gastric epithelial cell scattering and motility. During infection of AGS cells, cortactin was discovered to undergo tyrosine dephosphorylation at residues Y-421 and Y-486, which is mediated through inactivation of Src kinase. However, H. pylori also profoundly activates tyrosine kinase Abl, which simultaneously phosphorylates cortactin at Y-470. Phosphorylated cortactin interacts with the SH2-domain of Vav2, a guanine nucleotide exchange factor for the Rho-family of GTPases. The cortactin/Vav2 complex then stimulates a previously unrecognized activation cascade including the small GTPase Rac1, to effect actin rearrangements and cell scattering. We hypothesize that injected CagA targets cortactin to locally open the gastric epithelium in order to get access to certain nutrients. This may disturb the cellular barrier functions, likely contributing to the induction of cell motility, which is important in gastric cancer development. Full article

Keratinocyte carcinomas (KC) include basal cell carcinomas (BCC) and cutaneous squamous cell carcinomas (cSCC) and represents the most common cancer in Europe and North America. Both entities are characterized by a very high mutational burden, mainly UV signature mutations. Predominately mutated genes in BCC belong to the sonic hedgehog pathway, whereas, in cSCC, TP53, CDKN2A, NOTCH1/2 and others are most frequently mutated. In addition, the dysregulation of factors associated with epithelial to mesenchymal transition (EMT) was shown in invasive cSCC. The expression of factors associated with tumorigenesis can be controlled in several ways and include non-coding RNA molecules, such as micro RNAs (miRNA) long noncoding RNAs (lncRNA) and circular RNAs (circRNA). To update findings on circRNA in KC, we reviewed 13 papers published since 2016, identified in a PubMed search. In both BCC and cSCC, numerous circRNAs were identified that were differently expressed compared to healthy skin. Some of them were shown to target miRNAs that are also dysregulated in KC. Moreover, some studies confirmed the biological functions of individual circRNAs involved in cancer development. Thus, circRNAs may be used as biomarkers of disease and disease progression and represent potential targets of new therapeutic approaches for KC. Full article

Membrane-bound CD200 is overexpressed in chronic lymphocytic leukemia (CLL), and there is some evidence that its soluble ectodomain (sCD200) could also be involved in the pathophysiology and the disease. However, very little is known about sCD200’s prognostic significance. sCD200 was tested at diagnosis in 272 patients with CLL and in 78 age- and sex-matched healthy subjects using a specific human CD200 (OX-2 membrane glycoprotein) ELISA kit. A significantly higher concentration of sCD200 was found in CLL patients compared to controls. In our cohort, sCD200 was significantly higher in patients who were older than 66 years, with Binet stage C, unmutated IgVH and unfavorable (del11q or del17p) FISH. Time-to-first treatment and overall survival were significantly shorter in patients with higher sCD200 concentration, using as a cut-off 1281 pg/mL, the median value for sCD200 concentration in the whole CLL cohort. However, the prognostic impact of sCD200 was not confirmed in multivariate analysis. Baseline sCD200 values appeared to have an impact on the response to chemotherapy or chemo-immunotherapy, but not to targeted agents. Collectively, our data show that sCD200 serum levels correlate with more aggressive clinical and biological features and are able to predict a worse prognosis. This work supports the relevant role of CD200 not only as a diagnostic tool but also as a prognostic indicator and a potential therapeutic target in CLL. Full article

Adipose tissue is a component of the tumor microenvironment and is involved in tumor progression. We have previously shown that adipokine adipsin (CFD) functions as an enhancer of tumor proliferation and cancer stem cell (CSC) properties in breast cancers. We established the Cfd-knockout (KO) mice and the mammary adipose tissue-derived stem cells (mADSCs) from them. Cfd-KO in mADSCs significantly reduced their ability to enhance tumorsphere formation of breast cancer patient-derived xenograft (PDX) cells, which was restored by the addition of Cfd in the culture medium. Hepatocyte growth factor (HGF) was expressed and secreted from mADSCs in a Cfd-dependent manner. HGF rescued the reduced ability of Cfd-KO mADSCs to promote tumorsphere formation in vitro and tumor formation in vivo by breast cancer PDX cells. These results suggest that HGF is a downstream effector of Cfd in mADSCs that enhances the CSC properties in breast cancers. Full article

Hepatocellular carcinoma (HCC) remains a serious oncologic issue with still a dismal prognosis. So far, no key molecular mechanism that underlies its pathogenesis has been identified. Recently, by specific molecular approaches, many genetic and epigenetic changes arising during HCC pathogenesis were detected. Epigenetic studies revealed modified methylation patterns in HCC tumors, dysfunction of enzymes engaged in the DNA methylation process, and a set of histone modifications that influence gene expression. HCC cells are also influenced by the disrupted function of non-coding RNAs, such as micro RNAs and long non-coding RNAs. Moreover, a role of liver cancer stem cells in HCC development is becoming evident. The reversibility of epigenetic changes offers the possibility of influencing them and regulating their undesirable effects. All these data can be used not only to identify new therapeutic targets but also to predict treatment response. This review focuses on epigenetic changes in hepatocellular carcinoma and their possible implications in HCC therapy. Full article

Background: in recent years, the management of advanced colorectal cancer (CRC) has been greatly improved with integrated strategies including stereotactic radiation therapy (SRT). The administration of SRT has been demonstrated, particularly in oligo-metastatic (om) CRC, to be a safe and effective option. Interestingly, it has been demonstrated that SRT can induce regression of tumors in non-irradiated regions (“abscopal effect”) through stimulation of anti-tumor immune effects (“radiation-induced immunity”). We have recently shown that lung-limited omCRC is characterized by regression of tumor clones bearing specific key driver gene mutations. Aims: to assess the genetic evolution on tumor cancer cells induced by SRT in lung-limited omCRC. Secondary objectives included descriptions of the abscopal effect, responses’ duration, toxicity, and progression-free survival. A translational research will be performed to evaluate tumor genetic evolution (through liquid biopsies and Next Generation Sequencing), HLA class I repertoire, peripheral immune cells, and cytokine dynamics. Methods: PRELUDE-1 is a prospective translational study. SRT will be administered only to the largest nodule (with a maximum diameter ≤ 25 mm) in omCRC with two or three radiologically evident lesions. The sample size is based on the innovative hypothesis that radiation-induced immunity could induce regression of tumor clones bearing KRAS oncogene mutations. According to the binomial test, considering the frequency of KRAS mutations and assuming a probability of mutant KRAS→wild type KRAS of p₀ = 0.0077, with α = 0.05 and 1-β = 0.60, the final sample size is 25 patients. Full article

To date, extensive efforts to harness immunotherapeutic strategies for the treatment of pancreatic ductal adenocarcinoma (PDAC) have yielded disappointing results in clinical trials. These strategies mainly focused on cancer vaccines and immune checkpoint inhibitors alone or in combination with chemotherapeutic or targeted agents. However, the growing preclinical and clinical data sets from these efforts have established valuable insights into the immunological characteristics of PDAC biology. Most notable are the immunosuppressive role of the tumour microenvironment (TME) and PDAC’s characteristically poor immunogenicity resulting from tumour intrinsic features. Moreover, PDAC tumour heterogeneity has been increasingly well characterized and may additionally limit a “one-fits-all” immunotherapeutic strategy. In this review, we first outline mechanisms of immunosuppression and immune evasion in PDAC. Secondly, we summarize recently published data on preclinical and clinical efforts to establish immunotherapeutic strategies for the treatment of PDAC including diverse combinatorial treatment approaches aiming at overcoming this resistance towards immunotherapeutic strategies. Particularly, these combinatorial treatment approaches seek to concomitantly increase PDAC antigenicity, boost PDAC directed T-cell responses, and impair the immunosuppressive character of the TME in order to allow immunotherapeutic agents to unleash their full potential. Eventually, the thorough understanding of the currently available data on immunotherapeutic treatment strategies of PDAC will enable researchers and clinicians to develop improved treatment regimens and to design innovative clinical trials to overcome the pronounced immunosuppression of PDAC. Full article

Overexpression and amplification of AXL receptor tyrosine kinase (RTK) has been found in several hematologic and solid malignancies. Activation of AXL can enhance tumor-promoting processes such as cancer cell proliferation, migration, invasion and survival. Despite the important role of AXL in cancer development, a deep and quantitative mapping of its temporal dynamic signaling transduction has not yet been reported. Here, we used a TMT labeling-based quantitative proteomics approach to characterize the temporal dynamics of the phosphotyrosine proteome induced by AXL activation. We identified >1100 phosphotyrosine sites and observed a widespread upregulation of tyrosine phosphorylation induced by GAS6 stimulation. We also detected several tyrosine sites whose phosphorylation levels were reduced upon AXL activation. Gene set enrichment-based pathway analysis indicated the activation of several cancer-promoting and cell migration/invasion-related signaling pathways, including RAS, EGFR, focal adhesion, VEGFR and cytoskeletal rearrangement pathways. We also observed a rapid induction of phosphorylation of protein tyrosine phosphatases, including PTPN11 and PTPRA, upon GAS6 stimulation. The novel molecules downstream of AXL identified in this study along with the detailed global quantitative map elucidating the temporal dynamics of AXL activation should not only help understand the oncogenic role of AXL, but also aid in developing therapeutic options to effectively target AXL. Full article

The tumor microenvironment (TME) in breast cancer comprises local factors, cancer cells, immune cells and stromal cells of the local and distant tissues. The interaction between cancer cells and their microenvironment plays important roles in tumor proliferation, propagation and response to therapies. There is increasing research in exploring and manipulating the non-cancerous components of the TME for breast cancer treatment. As the TME is now increasingly recognized as a treatment target, its pathologic assessment has become a critical component of breast cancer management. The latest WHO classification of tumors of the breast listed stromal response pattern/fibrotic focus as a prognostic factor and includes recommendations on the assessment of tumor infiltrating lymphocytes and PD-1/PD-L1 expression, with therapeutic implications. This review dissects the TME of breast cancer, describes pathologic assessment relevant for prognostication and treatment decision, and details therapeutic options that interacts with and/or exploits the TME in breast cancer. Full article

Background: High-grade neuroendocrine tumours and carcinomas (NET/NECs) behave aggressively, typically presenting at an advanced stage. Prognosis is poor, with median survival between 5 and 34 months. The mainstay of treatment is palliative systemic therapy. However, therapy carries a risk of toxicity, which can reduce quality of life. Therefore, accurate prognostic scores for risk stratification of patients with high-grade NET/NECs are needed to help guide patient management to decide whether active treatment is likely to improve overall survival (OS). We aimed to compare the prognostic ability of published prognostic scores to predict OS in a cohort of patients with high-grade NET/NECs of any primary site. Methods: Treatment, biochemical and clinicopathological data were collected retrospectively from 77 patients with high-grade NET/NECs across three hospitals between 2016 and 2020. Variables including performance status (PS), Ki-67, age at diagnosis, previous treatment and presence of liver metastases were recorded. Pre-treatment neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, modified Glasgow prognostic score (mGPS), and gastrointestinal neuroendocrine carcinoma (GI-NEC) score were derived. Univariable and multivariable survival analyses were used to assess prognostic ability. Results: The median age of the cohort was 63 years (range: 31–85); 53% of subjects were female. Grade 3 NETs (G3-NETs) were identified in 32 patients and NECs in 45 patients. The median OS was 13.45 months (range: 0.87–65.37) with no difference observed between G3-NETs and NECs. Univariable analysis revealed that NLR (n = 72, p = 0.049), mGPS (n = 56, p = 0.003), GI-NEC score (n = 27, p = 0.0007) and Ki-67 (n = 66, p = 0.007) were significantly associated with OS. Multivariable analysis confirmed that elevated mGPS (p = 0.046), GI-NEC score (p = 0.036), and Ki-67 (p = 0.02) were independently prognostic for reduced OS across the entire cohort. mGPS was identified as an independent prognostic factor in G3-NETs. Independent predictors of OS in NECs were PS and Ki-67. Conclusions: mGPS, PS and Ki-67 are independent prognostic markers in high-grade NET/NEC patients. Our study supports the use of these prognostic scores for risk stratification of patients with high grade cancers and as useful tools to guide treatment decisions. Full article

An optimal therapeutic regimen for endometrial cancer with extra-uterine metastasis is unavailable. This study aims to improve our understanding of the genomic landscape of advanced endometrial cancer and identify potential therapeutic targets. The clinical and genomic profiles of 81 patients with stage III or IV endometrial cancer were integrated. To identify genomic aberrations associated with clinical outcomes, Cox proportional hazard regression was used. The impacts of the genomic aberrations were validated in vitro and in vivo. The mutation status of MET, U2AF1, BCL9, PPP2R1A, IDH2, CBL, BTK, and CHEK2 were positively correlated with poor clinical outcomes. MET mutations occurred in 30% of the patients who presented with poor overall survival (hazard ratio, 2.606; 95% confidence interval, 1.167~5.819; adjusted p-value, 0.067). Concurrent MET and KRAS mutations presented with the worst outcomes. MET mutations in hepatocyte growth factor (HGF)-binding (58.1%) or kinase (16.2%) domains resulted in differential HGF-induced c-MET phosphorylation. Different types of MET mutations differentially affected tumor growth and displayed different sensitivities to cisplatin and tyrosine kinase inhibitors. MET N375S mutation is a germline variant that causes chemoresistance to cisplatin, with a high incidence in Eastern Asia. This study highlights the ethnic differences in the biology of the disease, which can influence treatment recommendations and the genome-guided clinical trials of advanced endometrial cancer. Full article

This article aimed to analyze concordance of parent- and child-reported child posttraumatic growth (PTG) following pediatric cancer, the influence of the parents’ own level of PTG on the level of concordance and the influence of the parents’ and the child’s own level of PTG on the parents’ proxy reports of PTG in the child. The sample included 127 parent–child dyads. The children provided self-reports of PTG and the parents provided reports of their own as well as the child’s PTG. Overall, the results showed poor parent–child agreement on the child PTG, with the parents proxy-reporting higher levels of PTG than the children. The parents’ proxy reports of the child PTG were the most accurate at the lowest levels of the parents’ own level of PTG. The parents’ own level of PTG was a stronger predictor of the parents’ proxy reports than the child self-reported PTG. The results suggest that parents are not very accurate reporters of PTG in the child; therefore, their reports should be completed with child self-reports whenever possible. Full article

In the last decades, the treatment of primary and secondary bone tumors has faced a slow-down in its development, being mainly based on chemotherapy, radiotherapy, and surgical interventions. However, these conventional therapeutic strategies present a series of disadvantages (e.g., multidrug resistance, tumor recurrence, severe side effects, formation of large bone defects), which limit their application and efficacy. In recent years, these procedures were combined with several adjuvant therapies, with different degrees of success. To overcome the drawbacks of current therapies and improve treatment outcomes, other strategies started being investigated, like carrier-mediated drug delivery, bone substitutes for repairing bone defects, and multifunctional scaffolds with bone tissue regeneration and antitumor properties. Thus, this paper aims to present the types of bone tumors and their current treatment approaches, further focusing on the recent advances in new therapeutic alternatives. Full article

Anaplastic thyroid carcinoma (ATC) is a rare but highly lethal disease. Therefore, its diagnosis at an early stage and a rapid and accurate establishment of a proper treatment strategy is warranted. Tumor glycolysis assessed by ¹⁸fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomography (PET)/computed tomography (CT) is predictive of many cancers despite its limited proven applicability to ATC. We investigated the prognostic capability of [¹⁸F]FDG PET/CT in patients with ATC. Forty patients with ATC were subjected to [¹⁸F]FDG PET/CT for pre-treatment evaluation. The tumor size and stage, overall survival (OS), and PET parameters, including the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were analyzed. The 1-year OS rate was 17.5% with a mean life expectancy of 7.1 months. Distant metastasis was detected solely using PET/CT in 37.5% of cases. High SUVmax, MTV, and TLG were significantly associated with poor prognosis (p < 0.001, p = 0.002, and p < 0.001, respectively). A significant difference (p < 0.001) was observed in OS between patients with a high and low tumor SUVmax. Glucose metabolism assessed by [¹⁸F]FDG PET/CT was significantly associated with the OS of patients with ATC. PET-derived parameters such as SUVmax, MTV, and TLG are useful prognostic biomarkers for ATC. Full article

(1) Background: Aberrant activation of the hedgehog (HH)—GLI pathway in stem-like tumor-initiating cells (TIC) is a frequent oncogenic driver signal in various human malignancies. Remarkable efficacy of anti-HH therapeutics led to the approval of HH inhibitors targeting the key pathway effector smoothened (SMO) in basal cell carcinoma and acute myeloid leukemia. However, frequent development of drug resistance and severe adverse effects of SMO inhibitors pose major challenges that require alternative treatment strategies targeting HH—GLI in TIC downstream of SMO. We therefore investigated members of the casein kinase 1 (CSNK1) family as novel drug targets in HH—GLI-driven malignancies. (2) Methods: We genetically and pharmacologically inhibited CSNK1D in HH-dependent cancer cells displaying either sensitivity or resistance to SMO inhibitors. To address the role of CSNK1D in oncogenic HH signaling and tumor growth and initiation, we quantitatively analyzed HH target gene expression, performed genetic and chemical perturbations of CSNK1D activity, and monitored the oncogenic transformation of TIC in vitro and in vivo using 3D clonogenic tumor spheroid assays and xenograft models. (3) Results: We show that CSNK1D plays a critical role in controlling oncogenic GLI activity downstream of SMO. We provide evidence that inhibition of CSNK1D interferes with oncogenic HH signaling in both SMO inhibitor-sensitive and -resistant tumor settings. Furthermore, genetic and pharmacologic perturbation of CSNK1D decreases the clonogenic growth of GLI-dependent TIC in vitro and in vivo. (4) Conclusions: Pharmacologic targeting of CSNK1D represents a novel therapeutic approach for the treatment of both SMO inhibitor-sensitive and -resistant tumors. Full article

Gliomas are the most common, highly malignant, and deadliest forms of brain tumors. These intra-cranial solid tumors are comprised of both cancerous and non-cancerous cells, which contribute to tumor development, progression, and resistance to the therapeutic regimen. A variety of soluble inflammatory mediators (e.g., cytokines, chemokines, and chemotactic factors) are secreted by these cells, which help in creating an inflammatory microenvironment and contribute to the various stages of cancer development, maintenance, and progression. The major tumor infiltrating immune cells of the tumor microenvironment include TAMs and TANs, which are either recruited peripherally or present as brain-resident macrophages (microglia) and support stroma for cancer cell expansion and invasion. These cells are highly plastic in nature and can be polarized into different phenotypes depending upon different types of stimuli. During neuroinflammation, glioma cells interact with TAMs and TANs, facilitating tumor cell proliferation, survival, and migration. Targeting inflammatory mediators along with the reprogramming of TAMs and TANs could be of great importance in glioma treatment and may delay disease progression. In addition, an inhibition of the key signaling pathways such as NF-κB, JAK/STAT, MAPK, PI3K/Akt/mTOR, and TLRs, which are activated during neuroinflammation and have an oncogenic role in glioblastoma (GBM), can exert more pronounced anti-glioma effects. Full article

Tobacco is the primary etiologic agent in worsened lung squamous cell carcinoma (LUSC) outcomes. Meanwhile, it has been shown that etiologic agents alter enhancer RNAs (eRNAs) expression. Therefore, we aimed to identify the effects of tobacco and electronic cigarette (e-cigarette) use on eRNA expression in relation to LUSC outcomes. We extracted eRNA counts from RNA-sequencing data of tumor/adjacent normal tissue and before/after e-cigarette tissue from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), respectively. Tobacco-mediated LUSC eRNAs were correlated to patient survival, clinical variables, and immune-associated elements. eRNA expression was also correlated to mutation rates through the Repeated Evaluation of Variables Conditional Entropy and Redundance (REVEALER) algorithm and methylated sites through methylationArrayAnalysis. Differential expression analysis was then completed for the e-cigarette data to compare with key tobacco-mediated eRNAs. We identified 684 downregulated eRNAs and 819 upregulated eRNAs associated with tobacco-mediated LUSC, specifically, with the cancer pathological stage. We also observed a decrease in immune cell abundance in tobacco-mediated LUSC. Yet, we found an increased association of eRNA expression with immune cell abundance in tobacco-mediated LUSC. We identified 16 key eRNAs with significant correlations to 8 clinical variables, implicating these eRNAs in LUSC malignancy. Furthermore, we observed that these 16 eRNAs were highly associated with chromosomal alterations and reduced CpG site methylation. Finally, we observed large eRNA expression upregulation with e-cigarette use, which corresponded to the upregulation of the 16 key eRNAs. Our findings provide a novel mechanism by which tobacco and e-cigarette smoke influences eRNA interactions to promote LUSC pathogenesis and provide insight regarding disease progression at a molecular level. Full article

Background: pancreatic cancer (PCa) and biliary tract cancer (BTC) are cancers with a poor prognosis and few effective treatments. One of the reasons for this is late detection. Many researchers are tackling to develop non-invasive biomarkers for cancer, but few are specific for PCa or BTC. In addition, genetic abnormalities occur in cancer tissues, which ultimately affect the expression of various molecules. Therefore, it is important to identify molecules that are altered in PCa and BTC. For this systematic review, a systematic review of Medline and Embase to select biomarker studies of PCa and BTC patients was conducted. Results: after reviewing 72 studies, 79 biomarker candidates were identified, including 22 nucleic acids, 43 proteins, and 14 immune cell types. Of the 72 studies, 61 examined PCa, and 11 examined BTC. Conclusion: PCa and BTC are characterized by nucleic acid, protein, and immune cell profiles that are markedly different from those of healthy subjects. These altered molecules and cell subsets may serve as cancer-specific biomarkers, particularly in blood. Further studies are needed to better understand the diagnosis and prognosis of PCa and BTC. Full article

A decrease in carbohydrate antigen (CA) 19-9 levels has been proposed as a prognostic marker for survival and recurrence in patients with pancreatic cancer. We evaluated the association between duration of reduced CA 19-9 levels during 6 months after treatment and long-term survival for 79 patients with unresectable locally advanced pancreatic cancer (LAPC). We calculated the differences between pretreatment and monthly CA19-9 levels. We categorized 71 patients with decreases in CA19-9 levels into three groups based on the duration of these reduced levels (>2, >3, and >4 months). The cut-off level for long-term (more than 2 years) survival was identified as a 44% reduction from the baseline, using a ROC curve. A reduction duration >2 months was not associated with overall survival (p = 0.1), while >3 months was significantly associated with survival (p =.04). In multivariate analysis, a reduction duration >3 months predicted a good long-term prognosis (odds ratio = 5.75; 95% confidence interval = 1.47–22.36; p < 0.01). In patients with unresectable LAPC, the duration of reduced CA19-9 levels for more than 3 months, rather than the rate of reduction in CA19-9 levels, during 6 months after treatment was significantly associated with good prognosis. Full article

Diagnosing lung cancer requires invasive procedures with high risk of complications. Methylated tumor DNA in bronchial lavage has previously shown potential as a diagnostic biomarker. We aimed to develop and validate methylated HOXA9 in bronchial lavage as a diagnostic biomarker of lung cancer. Participants were referred on suspicion of lung cancer. Ten mL lavage fluid was collected at bronchoscopy for analysis of methylated HOXA9 based on droplet digital PCR according to our previously published method. HOXA9 status was compared with the final diagnosis. The Discovery and Validation cohorts consisted of 101 and 95 consecutively enrolled participants, respectively. In the discovery cohort, the sensitivity and specificity were 73.1% (95% CI 60.9–83.2%) and 85.3% (95% CI 68.9–95.0%), respectively. In the validation cohort, the values were 80.0% (95% CI 66.3–90.0%) and 75.6% (95% CI 60.5–87.1%), respectively. A multiple logistic regression model including age, smoking status, and methylated HOXA9 status resulted in an AUC of 84.9% (95% CI 77.3–92.4%) and 85.9% (95% CI 78.4–93.4%) for the Discovery and Validation cohorts, respectively. Methylated HOXA9 in bronchial lavage holds potential as a supplementary tool in the diagnosis of lung cancer with a clinically relevant sensitivity and specificity. It remained significant when adjusting for age and smoking status. Full article

Pancreatic invasive ductal adenocarcinoma (PDAC) has a poor prognosis, and the detection of PDAC during the early stage is thought to improve prognosis. In this study, we retrospectively investigated pancreatic morphological abnormalities that lead to the early diagnosis of PDAC with computed tomography (CT) imaging. In total, 41 out of 308 patients diagnosed with pancreatic cancer between 2011 and 2017 in our institution were enrolled. As a control group for the group with pancreatic cancer, 4277 patients without pancreato-biliary diseases were enrolled. We retrospectively reviewed and analyzed the clinical data including patient characteristics, the clinical course and preoperative CT imaging with pancreatic morphological features. Out of 41 patients, 24 patients (58.5%) showed local K-shaped constriction of the pancreatic parenchyma “K-sign” on preoperative CT images. Eight patients (19.5%) showed localized fatty change. Out of 4277 control patients, seven patients (0.16%) showed K-sign. “K-sign” may be used for the early diagnosis of PDAC by CT imaging. Full article

Purpose: The survival effect of current smoking-related chronic obstructive pulmonary disease (COPD) and COPD with acute exacerbation (COPDAE) is unclear for patients with rectal adenocarcinoma undergoing curative resection. Methods: We recruited patients with clinical stage I–IIIC rectal adenocarcinoma from the Taiwan Cancer Registry Database who had received surgery. The Cox proportional hazards model was used to analyze all-cause mortality. We categorized the patients into two groups by using propensity score matching based on COPD status to compare overall survival outcomes: Group 1 (current smokers with COPD) and Group 2 (nonsmokers without COPD). Results: In the multivariate Cox regression analyses, the adjusted hazard ratio (aHR; 95% confidence interval (CI)) of all-cause mortality for Group 1 compared with Group 2 was 1.25 (1.04–1.51). The aHRs (95% cis) of all-cause mortality for frequency of ≥1 hospitalizations for COPDAE or ≥2 hospitalizations within 1 year before diagnosis were 1.17 (1.05–1.51) and 1.48 (1.03–2.41) compared with no COPDAE in patients with rectal adenocarcinoma undergoing curative resection. Conclusion: In patients with rectal adenocarcinoma undergoing curative resection, being a current smoker with COPD (Group 1) was associated with worse survival outcomes than being a nonsmoker without COPD (Group 2). Being hospitalized at least once for COPDAE within 1 year before the diagnosis of rectal adenocarcinoma is an independent risk factor for poor overall survival in these patients, and a higher number of hospitalizations for COPDAE within 1 year before diagnosis was associated with poorer survival. Full article

Next Generation Sequencing (NGS)-based methods are high-throughput and cost-effective molecular genetic diagnostic tools. Targeted gene panel and whole exome sequencing (WES) are applied in clinical practice for assessing mutations of pheochromocytoma/paraganglioma (PPGL) associated genes, but the best strategy is debated. Germline mutations of at the least 18 PPGL genes are present in approximately 20–40% of patients, thus molecular genetic testing is recommended in all cases. We aimed to evaluate the analytical and clinical performances of NGS methods for mutation detection of PPGL-associated genes. WES (three different library preparation and bioinformatics workflows) and an in-house, hybridization based gene panel (endocrine-onco-gene-panel- ENDOGENE) was evaluated on 37 (20 WES and 17 ENDOGENE) samples with known variants. After optimization of the bioinformatic workflow, 61 additional samples were tested prospectively. All clinically relevant variants were validated with Sanger sequencing. Target capture of PPGL genes differed markedly between WES platforms and genes tested. All known variants were correctly identified by all methods, but methods of library preparations, sequencing platforms and bioinformatical settings significantly affected the diagnostic accuracy. The ENDOGENE panel identified several pathogenic mutations and unusual genotype–phenotype associations suggesting that the whole panel should be used for identification of genetic susceptibility of PPGL. Full article

Background: Resection of jugular foramen schwannomas (JFSs) with minimal cranial nerve (CN) injury remains difficult. Reoperations in this vital region are associated with severe CN deficits. Methods: We performed a retrospective analysis at a tertiary neurosurgical center of patients who underwent surgery for JFSs between June 2007 and May 2020. We included nine patients (median age 60 years, 77.8% female, 22.2% male). Preoperative symptoms included hearing loss (66.6%), headache (44.4%), hoarseness (33.3%), dysphagia (44.4%), hypoglossal nerve palsy (22.2%), facial nerve palsy (33.3%), extinguished gag reflex (22.2%), and cerebellar dysfunction (44.4%). We observed Type A, B, C, and D tumors in 3, 1, 1, and 4 patients, respectively. A total of 77.8% (7/9) underwent a retrosigmoid approach, and 33.3% (3/9) underwent an extreme lateral infrajugular transcondylar (ELITE) approach. Gross total resection (GTR) was achieved in all cases. The rate of shunt-dependent hydrocephalus was 22.2% (2/9). No further complications requiring surgical intervention occurred during follow-up. The median follow-up time was 16.5 months (range 3–84 months). Conclusions: Considering the satisfying outcome, the GTR of JFSs is feasible in performing well-known skull base approaches. Additional invasive and complicated approaches were not needed. Radiosurgery may be an effective alternative for selected patients. Full article