The role of neck dissection in management of patients with clinically apparent parotid metastatic melanoma - systematic review.

Patients with cutaneous melanoma with metastatic deposits in the parotid gland have poor prognosis due to the high risk of developing distant metastasis. In the era of effective immunotherapy, there is no consensus amongst head and neck surgeons about the extent of neck dissection required for patients presenting with clinically apparent parotid metastasis. This review aims to determine the incidence and pattern of occult neck disease for patients with parotid metastasis reported in literature to help guide clinicians on the extent of neck dissection required. The systematic review search was conducted using PubMed, EMBASE and Medline, using PRISMA guidelines. The inclusion criteria include cases treated with parotidectomy and neck dissection for patients with parotid melanoma metastasis. A narrative synthesis was carried out due to heterogeneity of studies. A total of 14 studies was included. We found no study reporting on outcomes with surgery and adjuvant immunotherapy in this cohort of patients. The incidence of distant metastasis reported was variable but remains high for patients with parotid metastasis. Patients with parotid and neck involvement have poorer prognosis than patients with parotid only metastatic disease. The effect and extent of neck dissection in patients with clinically apparent parotid nodes remains unclear in the era of effective immunotherapy. There is a need for further well-designed studies evaluating the outcomes for such patients following surgery and adjuvant immunotherapy.

ERCC1 abundance is an indicator of DNA repair-apoptosis decision upon DNA damage.

DNA repair is essential for successful propagation of genetic material and fidelity of transcription. Nucleotide excision repair (NER) is one of the earliest DNA repair mechanisms, functionally conserved from bacteria to human. The fact that number of NER genes vary significantly between prokaryotes and metazoans gives the insight that NER proteins have evolved to acquire additional functions to combat challenges associated with a diploid genome, including being involved in the decision between DNA repair and apoptosis. However, no direct association between apoptosis and NER proteins has been shown to date. In this study, we induced apoptosis with a variety of agents, including oxaliplatin, doxorubicin and TRAIL, and observed changes in the abundance and molecular weight of NER complex proteins. Our results showed that XPA, XPC and ERCC1 protein levels change during DNA damage-induced apoptosis. Among these, ERCC1 decrease was observed as a pre-mitochondria depolarisation event which marks the "point of no return" in apoptosis signalling. ERCC1 decrease was due to proteasomal degradation upon lethal doses of oxaliplatin exposure. When ERCC1 protein was stabilised using proteasome inhibitors, the pro-apoptotic activity of oxaliplatin was attenuated. These results explain why clinical trials using proteasome inhibitors and platinum derivatives showed limited efficacy in carcinoma treatment and also the importance of how deep understanding of DNA repair mechanisms can improve cancer therapy.

Mesenchymal-epithelial transition and AXL inhibitor TP-0903 sensitise triple-negative breast cancer cells to the antimalarial compound, artesunate.

Triple-negative breast cancer (TNBC) is a difficult-to-treat, aggressive cancer type. TNBC is often associated with the cellular program of epithelial-mesenchymal transition (EMT) that confers drug resistance and metastasis. EMT and reverse mesenchymal-epithelial transition (MET) programs are regulated by several signaling pathways which converge on a group of transcription factors, EMT- TFs. Therapy approaches could rely on the EMT reversal to sensitise mesenchymal tumours to compounds effective against epithelial cancers. Here, we show that the antimalarial ROS-generating compound artesunate (ART) exhibits higher cytotoxicity in epithelial than mesenchymal breast cancer cell lines. Ectopic expression of EMT-TF ZEB1 in epithelial or ZEB1 depletion in mesenchymal cells, respectively, reduced or increased ART-generated ROS levels, DNA damage and apoptotic cell death. In epithelial cells, ZEB1 enhanced expression of superoxide dismutase 2 (SOD2) and glutathione peroxidase 8 (GPX8) implicated in ROS scavenging. Although SOD2 or GPX8 levels were unaffected in mesenchymal cells in response to ZEB1 depletion, stable ZEB1 knockdown enhanced total ROS. Receptor tyrosine kinase AXL maintains a mesenchymal phenotype and is overexpressed in TNBC. The clinically-relevant AXL inhibitor TP-0903 induced MET and synergised with ART to generate ROS, DNA damage and apoptosis in TNBC cells. TP-0903 reduced the expression of GPX8 and SOD2. Thus, TP-0903 and ZEB1 knockdown sensitised TNBC cells to ART, likely via different pathways. Synergistic interactions between TP-0903 and ART indicate that combination approaches involving these compounds can have therapeutic prospects for TNBC treatment.

Epithelial to mesenchymal transition influences fibroblast phenotype in colorectal cancer by altering miR-200 levels in extracellular vesicles.

Colorectal cancer (CRC) with a mesenchymal gene expression signature has the greatest propensity for distant metastasis and is characterised by the accumulation of cancer-associated fibroblasts in the stroma. We investigated whether the epithelial to mesenchymal transition status of CRC cells influences fibroblast phenotype, with a focus on the transfer of extracellular vesicles (EVs), as a controlled means of cell-cell communication. Epithelial CRC EVs suppressed TGF-ß-driven myofibroblast differentiation, whereas mesenchymal CRC EVs did not. This was driven by miR-200 (miR-200a/b/c, -141), which was enriched in epithelial CRC EVs and transferred to recipient fibroblasts. Ectopic miR-200 expression or ZEB1 knockdown, in fibroblasts, similarly suppressed myofibroblast differentiation. Supporting these findings, there was a strong negative correlation between miR-200 and myofibroblastic markers in a cohort of CRC patients in the TCGA dataset. This was replicated in mice, by co-injecting epithelial or mesenchymal CRC cells with fibroblasts and analysing stromal markers of myofibroblastic phenotype. Fibroblasts from epithelial tumours contained more miR-200 and expressed less ACTA2 and FN1 than those from mesenchymal tumours. As such, these data provide a new mechanism for the development of fibroblast heterogeneity in CRC, through EV-mediated transfer of miRNAs, and provide an explanation as to why CRC tumours with greater metastatic potential are CAF rich.

AXL Receptor in Cancer Metastasis and Drug Resistance: When Normal Functions Go Askew.

The TAM proteins TYRO3, AXL, and MER are receptor tyrosine kinases implicated in the clearance of apoptotic debris and negative regulation of innate immune responses. AXL contributes to immunosuppression by terminating the Toll-like receptor signaling in dendritic cells, and suppressing natural killer cell activity. In recent years, AXL has been intensively studied in the context of cancer. Both molecules, the receptor, and its ligand GAS6, are commonly expressed in cancer cells, as well as stromal and infiltrating immune cells. In cancer cells, the activation of AXL signaling stimulates cell survival and increases migratory and invasive potential. In cells of the tumour microenvironment, AXL pathway potentiates immune evasion. AXL has been broadly implicated in the epithelial-mesenchymal plasticity of cancer cells, a key factor in drug resistance and metastasis. Several antibody-based and small molecule AXL inhibitors have been developed and used in preclinical studies. AXL inhibition in various mouse cancer models reduced metastatic spread and improved the survival of the animals. AXL inhibitors are currently being tested in several clinical trials as monotherapy or in combination with other drugs. Here, we give a brief overview of AXL structure and regulation and discuss the normal physiological functions of TAM receptors, focusing on AXL. We present a theory of how epithelial cancers exploit AXL signaling to resist cytotoxic insults, in order to disseminate and relapse.

Adverse reactions associated with perioral rejuvenation using laser, fat and hyaluronic acid: systematic review.

Perioral rejuvenation is carried out by surgical and non-surgical tools. The common procedures are laser resurfacing and volumanisation using alloplastic fillers or autogenous fat. Nonetheless, any such procedures are associated with complications. To evaluate a concise presentation of complications and safety associated with different perioral rejuvenation treatments including laser ablation, fat grafting and hyaluronic acid injections. A systematic literature review of all the relevant studies and case reports on complications and adverse reactions associated with laser ablation, administration of fillers and fat for the rejuvenation of perioral region. Twelve articles passed the inclusion criteria (as per PRISMA guidelines) and were scrupulously analysed. Four publications evaluated complications associated with laser resurfacing, five were related to filler augmentation and three were related to fat administration. The results concluded that all three aesthetic treatments are associated with mild to moderate complications. Severe complications are rare but can arise. Clinicians should be mindful of possible complications and able to recognise adverse events so that remedies could be executed with minimal delay. Training and supervision are essential components of ensuring provision of safe aesthetic treatment, and lack of regulation is a concern.

The ZEB2-dependent EMT transcriptional programme drives therapy resistance by activating nucleotide excision repair genes ERCC1 and ERCC4 in colorectal cancer.

Resistance to adjuvant chemotherapy is a major clinical problem in the treatment of colorectal cancer (CRC). The aim of this study was to elucidate the role of an epithelial to mesenchymal transition (EMT)-inducing protein, ZEB2, in chemoresistance of CRC, and to uncover the underlying mechanism. We performed IHC for ZEB2 and association analyses with clinical outcomes on primary CRC and matched CRC liver metastases in compliance with observational biomarker study guidelines. ZEB2 expression in primary tumours was an independent prognostic marker of reduced overall survival and disease-free survival in patients who received adjuvant FOLFOX chemotherapy. ZEB2 expression was retained in 96% of liver metastases. The ZEB2-dependent EMT transcriptional programme activated nucleotide excision repair (NER) pathway largely via upregulation of the ERCC1 gene and other components in NER pathway, leading to enhanced viability of CRC cells upon oxaliplatin treatment. ERCC1-overexpressing CRC cells did not respond to oxaliplatin in vivo, as assessed using a murine orthotopic model in a randomised and blinded preclinical study. Our findings show that ZEB2 is a biomarker of tumour response to chemotherapy and risk of recurrence in CRC patients. We propose that the ZEB2-ERCC1 axis is a key determinant of chemoresistance in CRC.

Recent advances in the management of cutaneous malignant melanoma: our case cohort.

Decades of research into the management of cutaneous malignant melanoma have proven it to be a 'tough nut to crack', and its incidence has continued to increase over the last 30 years. Surgery remains a gold standard for early-stage melanoma with five-year survival of 98% for stage I disease, and 90% for stage II. Nonetheless, patients with stage III disease are at a higher risk, resulting in local recurrence as well as distant metastasis. Research regarding the control of metastatic malignant melanoma of the head and neck has evolved. Currently the search is on to understand metastatic malignant melanoma as a heterogeneous disease both at the molecular and clinical level. This paper focuses on the latest systemic therapy for metastatic disease of the head and neck, including cytotoxic chemotherapy, immunotherapy, and target therapy. The new eighth edition of tumour staging, and the sequelae for malignant melanoma, sentinel lymph node biopsy (SLNB), surgical intervention, and its benefits and shortfalls, are discussed. Also, the outcome of our cohort series of patients with metastatic cutaneous malignant melanoma who were treated with systemic combination therapy in Dorset is presented.

The synthesis of biologically active indolocarbazole natural products.

Covering: up to 2020The indolocarbazoles, in particular indolo[2,3-a]pyrrolo[3,4-c]carbazole derivatives, are an important class of natural products that exhibit a wide range of biological activities. There has been a plethora of synthetic approaches to this family of natural products, leading to advances in chemical methodology, as well as affording access to molecular scaffolds central to protein kinase drug discovery programmes. In this review, we compile and summarise the synthetic approaches to the indolo[2,3-a]pyrrolo[3,4-c]carbazole derivatives, spanning the period from their isolation in 1980 up to 2020. The selected natural products include indolocarbazoles not functionalised at indolic nitrogen, pyranosylated indolocarbazoles, furanosylated indolocarbazoles and disaccharideindolocarbazoles.

Evolution of surgical modalities in the management of rhinophyma: our experience.

Rhinophyma is a progressive disease of the nose, which is characterised by skin thickening and sebaceous hyperplasia. Patients with rhinophyma are often stigmatised due to worsening disfigurement of their nose. This can also result in functional impairment such as reduced nasal patency. Severe cases of rhinophyma are best managed with varied surgical interventions, as there is no clear 'gold standard' treatment that has been described. We present our experiences in the management of rhinophyma and the evolution of treatment modalities that have been employed over a nine-year period.

Importance of anatomical site in the metastases of auricular cutaneous squamous cell carcinoma: an observational study.

Malignancies of the auricular skin tend to metastasise to preauricular, parotid, facial, and level II (possibly to levels IV and V) lymph nodes in an unpredictable manner. Over the years, we have observed that this pattern of metastasis is commonly linked to lesions that involve the lower half of the ear. To find conclusive evidence based on this hypothetical observation, we retrospectively studied 108 patients who presented with squamous cell carcinoma (SCC) of the ear, and looked at the exact auricular site of the lesion at presentation, incidence of metastasis, nodal involvement, treatment, and survival outcome. The literature was reviewed extensively to ensure detailed presentation of the lymphatic drainage pathway. The pattern of spread and outcome were evaluated. This study has shown that there is a significant correlation between anatomical position and risk of metastasis, and that lesions of the lower half of the ear are more prone to metastasis. These patients therefore may warrant early imaging, possible sentinel node biopsy, or even selective neck dissection with simultaneous primary excision.

Outcome of eminectomy combined with discectomy and silastic interpositional graft for temporomandibular joint dysfunction: a retrospective study of 20 years.

Internal derangement of the temporomandibular joint (TMJ) is usually treated conservatively, but about 5% require surgical treatment. We designed a retrospective study to assess the long-term outcomes of eminectomy combined with discectomy and silastic interpositional graft in 44 patients who had chronic TMJ dysfunction that had not responded to traditional conservative treatment and arthrocentesis. The maximum mouth opening, pain score, Wilkes stage, and clinical dysfunction index were measured before, and two years after, operation. All the patients showed significant improvement in mouth opening and reduced pain scores (p<0.0001 in each case). There were no long-term operative complications, and postoperative magnetic resonance scans showed that the silastic interpositional graft was in a stable position with no evidence of degenerative changes on the surfaces of the joint and no lymphadenopathy.

Loss of the branched-chain amino acid transporter CD98hc alters the development of colonic macrophages in mice.

Comprehensive development is critical for gut macrophages being essential for the intestinal immune system. However, the underlying mechanisms of macrophage development in the colon remain elusive. To investigate the function of branched-chain amino acids in the development of gut macrophages, an inducible knock-out mouse model for the branched-chain amino acid transporter CD98hc in CX3CR1+ macrophages was generated. The relatively selective deletion of CD98hc in macrophage populations leads to attenuated severity of chemically-induced colitis that we assessed by clinical, endoscopic, and histological scoring. Single-cell RNA sequencing of colonic lamina propria macrophages revealed that conditional deletion of CD98hc alters the "monocyte waterfall"-development to MHC II+ macrophages. The change in the macrophage development after deletion of CD98hc is associated with increased apoptotic gene expression. Our results show that CD98hc deletion changes the development of colonic macrophages.

WITHDRAWN: Re: Management of seborrhoeic keratosis and actinic keratosis with an erbium: Yag laser-experience with 547 patients.

This letter has been superseded by the retraction (http://dx.doi.org/10.1016/j.ijom.2020.01.023) of the original article and has therefore been withdrawn. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Protein kinase C inhibitors override ZEB1-induced chemoresistance in HCC.

Epithelial-mesenchymal transition (EMT) is a process by which tumour cells lose epithelial characteristics, become mesenchymal and highly motile. EMT pathways also induce stem cell features and resistance to apoptosis. Identifying and targeting this pool of tumour cells is a major challenge. Protein kinase C (PKC) inhibition has been shown to eliminate breast cancer stem cells but has never been assessed in hepatocellular cancer (HCC). We investigated ZEB family of EMT inducer expression as a biomarker for metastatic HCC and evaluated the efficacy of PKC inhibitors for HCC treatment. We showed that ZEB1 positivity predicted patient survival in multiple cohorts and also validated as an independent biomarker of HCC metastasis. ZEB1-expressing HCC cell lines became resistant to conventional chemotherapeutic agents and were enriched in CD44high/CD24low cell population. ZEB1- or TGFß-induced EMT increased PKCα abundance. Probing public databases ascertained a positive association of ZEB1 and PKCα expression in human HCC tumours. Inhibition of PKCα activity by small molecule inhibitors or by PKCA knockdown reduced viability of mesenchymal HCC cells in vitro and in vivo. Our results suggest that ZEB1 expression predicts survival and metastatic potential of HCC. Chemoresistant/mesenchymal HCC cells become addicted to PKC pathway and display sensitivity to PKC inhibitors such as UCN-01. Stratifying patients according to ZEB1 and combining UCN-01 with conventional chemotherapy may be an advantageous chemotherapeutic strategy.

ZEB1 and IL-6/11-STAT3 signalling cooperate to define invasive potential of pancreatic cancer cells via differential regulation of the expression of S100 proteins.

BACKGROUND: S100 proteins have been implicated in various aspects of cancer, including epithelial-mesenchymal transitions (EMT), invasion and metastasis, and also in inflammatory disorders. Here we examined the impact of individual members of this family on the invasion of pancreatic ductal adenocarcinoma (PDAC) cells, and their regulation by EMT and inflammation. METHODS: Invasion of PDAC cells was analysed in zebrafish embryo xenografts and in transwell invasion assays. Expression and regulation of S100 proteins was studied in vitro by immunoblotting, quantitative PCR and immunofluorescence, and in pancreatic lesions by immunohistochemistry. RESULTS: Whereas the expression of most S100 proteins is characteristic for epithelial PDAC cell lines, S100A4 and S100A6 are strongly expressed in mesenchymal cells and upregulated by ZEB1. S100A4/A6 and epithelial protein S100A14 respectively promote and represses cell invasion. IL-6/11-STAT3 pathway stimulates expression of most S100 proteins. ZEB1 synergises with IL-6/11-STAT3 to upregulate S100A4/A6, but nullifies the effect of inflammation on S100A14 expression. CONCLUSION: EMT/ZEB1 and IL-6/11-STAT3 signalling act independently and congregate to establish the expression pattern of S100 proteins, which drives invasion. Although ZEB1 regulates expression of S100 family members, these effects are masked by IL-6/11-STAT3 signalling, and S100 proteins cannot be considered as bona fide EMT markers in PDAC.

ETS1 is coexpressed with ZEB2 and mediates ZEB2-induced epithelial-mesenchymal transition in human tumors.

Epithelial-mesenchymal transition (EMT) is an embryonic program that is reactivated in cancer and regulates the invasion and metastasis of tumor cells. Zinc finger E-box binding homeobox 2 (ZEB2) induces EMT by upregulating matrix metalloproteinases (MMP), yet MMP genes lack ZEB2 binding motif in their promoters. Recently, expression of MMPs was associated to the activation of ETS1 transcription factor; however, a link between ZEB2 and ETS proto-oncogene 1, transcription factor (ETS1) remains to be elucidated. Hence, we investigated the transcriptional regulation of ETS1 by ZEB2 after our initial observation that ZEB2 and ETS1 are coexpressed in hepatocellular carcinoma cells (HCCs). Chromatin immunoprecipitation and luciferase reporter assays clearly showed that ZEB2 binds to E-box sequences on the promoter of ETS1. Elevated expression of ETS1 was found in DLD-ZEB2 and A431-ZEB2 inducible systems, and knockdown of ZEB2 caused an explicit downregulation of ETS1 in shZEB2-SNU398 and shZEB2-SK-HEP-1 cells. Repression of ETS1 expression in ZEB2-induced conditions substantially impaired the migration and invasive capacities of DLD1 cells. Mechanistically, knockdown of ETS1 in ZEB2-expressing cells resulted in the downregulation of established ZEB2 targets TWIST and MMP9. Correlation analyses in HCC lines, cancer complementary DNA arrays, and The Cancer Genome Atlas RNA-sequencing data set revealed that ZEB2 and ETS1 are coexpressed, and their expressions in human tumors show a highly significant positive correlation. Our results demonstrated that ZEB2 acts as an upstream regulator of ETS1 and, in turn, ETS1 maintains ZEB2-induced EMT. These findings add another level of complexity to the understanding of ZEB2 in the invasion and metastasis of cancer cells, and put ZEB2/ETS1 axis as a novel therapeutic target in human malignancies.

Activity of IL-12/15/18 primed natural killer cells against hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is common, but remains difficult to treat. Natural killer (NK) cells are cells of the innate immune system that have potent anti-cancer activity. Recent work has shown that stimulation with IL-12/15/18 leads to the generation of NK cells with enhanced functional and putative "memory" properties. We have investigated the activity of these NK cells against HCC cell lines in vitro and in a mouse model. METHODS: NK cells from healthy donors or individuals with HCC were activated with IL-12/15/18 in vitro and tested for cytotoxic activity against a panel of human HCC cell lines. IL-12/15/18 primed murine NK cells were then infused into a murine model of spontaneously arising HCC to test for anti-tumor activity. RESULTS: NK cells from patients and healthy controls had similar expression levels of activating and inhibitory NK cell receptors. However, proliferation of NK cells from HCC patients was weaker than healthy controls in response to IL-12/15/18 and IL-2 (p < 0.001 at day 9). In vitro, NK cells from both groups of individuals killed HCC targets to similar levels and this was unrelated to NKG2D expression. In a spontaneous model of HCC, IL-12/15/18 activated NK cells trafficked to the liver and resulted in lower levels of spontaneous HCC formation (p < 0.01). CONCLUSION: Cytokine-primed NK cells from patients with HCC have similar levels of activity against HCC cell lines as those from healthy controls. This type of activated NK cell has immunotherapeutic potential against hepatocellular carcinoma.