HOX and PBX gene dysregulation as a therapeutic target in glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common high-grade malignant brain tumour in adults and arises from the glial cells in the brain. The prognosis of treated GBM remains very poor with 5-year survival rates of 5%, a figure which has not improved over the last few decades. Currently, there is a modest 14-month overall median survival in patients undergoing maximum safe resection plus adjuvant chemoradiotherapy. HOX gene dysregulation is now a widely recognised feature of many malignancies. METHODS: In this study we have focused on HOX gene dysregulation in GBM as a potential therapeutic target in a disease with high unmet need. RESULTS: We show significant dysregulation of these developmentally crucial genes and specifically that HOX genes A9, A10, C4 and D9 are strong candidates for biomarkers and treatment targets for GBM and GBM cancer stem cells. We evaluated a next generation therapeutic peptide, HTL-001, capable of targeting HOX gene over-expression in GBM by disrupting the interaction between HOX proteins and their co-factor, PBX. HTL-001 induced both caspase-dependent and -independent apoptosis in GBM cell lines. CONCLUSION: In vivo biodistribution studies confirmed that the peptide was able to cross the blood brain barrier. Systemic delivery of HTL-001 resulted in improved control of subcutaneous murine and human xenograft tumours and improved survival in a murine orthotopic model.

Mucinous Epithelium in Endometrial Curetting Leading to Diagnostic Conundrum: A Case Report.

Mucinous differentiation of the endometrium can occur in a spectrum of changes ranging from benign (metaplasia) to malignant (adenocarcinomas with mucinous differentiation). A rarer differential which is usually not considered is a teratoma. We present a case of a 55-yr-old woman with history of irregular perimenopausal bleeding. Endometrial curetting revealed proliferative mucinous epithelium on histology raising a possibility of low-grade epithelial mucinous malignancy. Hysterectomy was performed and histologic examination revealed a diagnosis of uterine mature teratoma. Mature cystic teratoma of the lower uterine segment is very rare and presence of just one element such as mucinous epithelium can lead to a misdiagnosis of carcinoma on biopsy or curetting.

HOXB9 Overexpression Promotes Colorectal Cancer Progression and Is Associated with Worse Survival in Liver Resection Patients for Colorectal Liver Metastases.

As is known, HOXB9 is an important factor affecting disease progression and overall survival (OS) in cancer. However, its role in colorectal cancer (CRC) remains unclear. We aimed to explore the role of HOXB9 in CRC progression and its association with OS in colorectal liver metastases (CRLM). We analysed differential HOXB9 expression in CRC using the Tissue Cancer Genome Atlas database (TCGA). We modulated HOXB9 expression in vitro to assess its impact on cell proliferation and epithelial-mesenchymal transition (EMT). Lastly, we explored the association of HOXB9 protein expression with OS, using an institutional patient cohort (n = 110) who underwent liver resection for CRLM. Furthermore, HOXB9 was upregulated in TCGA-CRC (n = 644) vs. normal tissue (n = 51) and its expression levels were elevated in KRAS mutations (p < 0.0001). In vitro, HOXB9 overexpression increased cell proliferation (p < 0.001) and upregulated the mRNA expression of EMT markers (VIM, CDH2, ZEB1, ZEB2, SNAI1 and SNAI2) while downregulated CDH1, (p < 0.05 for all comparisons). Conversely, HOXB9 silencing disrupted cell growth (p < 0.0001). High HOXB9 expression (HR = 3.82, 95% CI: 1.59-9.2, p = 0.003) was independently associated with worse OS in CRLM-HOXB9-expressing patients after liver resection. In conclusion, HOXB9 may be associated with worse OS in CRLM and may promote CRC progression, whereas HOXB9 silencing may inhibit CRC growth.

Descriptive analysis of incidental and operable gallbladder carcinoma cases: a UK centre experience.

Objective: To identify and compare significant or relevant prognostic factors in pre-operatively diagnosed, surgically resectable, gallbladder cancer and in incidentally detected gallbladder cancer cases. Material and methods: Gallbladder resections (October 2009-March 2016) were identified on the histopathology Winpath database. Cases with a final histological diagnosis of gallbladder cancer (GBC) were categorised into: Group A: clinically suspected operable GBC (n = 13). Group B: incidental GBC with staged liver bed resection (n = 5). Group C: incidental GBC without staged liver bed resection (n = 15). The clinicopathological features were analysed in each group separately. Results: The overall incidence of primary (GBC) was 0.66% and all the cases were adenocarcinomas, of which, 6 of 33 (18.2%) were grade 1 and 15 of 33 (45.4%) were grade 3. Male to female ratio is 1:2.3. Of the 33 patients with GBC 14 (42.4%) has died of disease at 18-month follow-up. 15 of 33 had perineural invasion and 10/21 (47.6%) cases showed lymph node matastasis. Six cases had positive surgical margin and 9/15 showed direct liver invasion. Higher stage disease (T3/T4) was seen in 10/14 cases. Conclusion: The prognosis of primary GBC is poor and best clinical outcomes can be achieved with early diagnosis followed by radical cholecystectomy and staged liver resection with negative margins.

A Systematic Review on HOX Genes as Potential Biomarkers in Colorectal Cancer: An Emerging Role of HOXB9.

Emerging evidence shows that Homeobox (HOX) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This review (PROSPERO-CRD42020190953) aims to systematically investigate the role of HOX genes as biomarkers in CRC and the impact of their modulation on tumour growth and progression. The MEDLINE, EMBASE, Web of Science and Cochrane databases were searched for eligible studies exploring two research questions: (a) the clinicopathological and prognostic significance of HOX dysregulation in patients with CRC and (b) the functional role of HOX genes in CRC progression. Twenty-five studies enrolling 3003 CRC patients, showed that aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. A post-hoc meta-analysis on HOXB9 showed that its overexpression was significantly associated with the presence of distant metastases (pooled OR 4.14, 95% CI 1.64-10.43, I2 = 0%, p = 0.003). Twenty-two preclinical studies showed that HOX proteins are crucially related to tumour growth and metastatic potential by affecting cell proliferation and altering the expression of epithelial-mesenchymal transition modulators. In conclusion, HOX proteins may play vital roles in CRC progression and are associated with overall survival. HOXB9 may be a critical transcription factor in CRC.

Primary hepatic solitary fibrous tumor with histologically benign and malignant areas.

Extrapleural solitary fibrous tumor (SFT) is an uncommon mesenchymal neoplasm, presenting most commonly in the intrathoracic sites but which has been reported at numerous extrathoracic locations. The majority of intra-thoracic SFTs are benign, but 10%-15% behave aggressively. We report a case of primary hepatic SFT with histologically benign and malignant areas. A 65-year-old man underwent an abdominal CT scan following a cerebrovascular accident, which demonstrated a sharply demarcated large liver mass with a heterogenous enhancing area and occupying most of the left lobe of the liver. Histological examination following a hemihepatectomy showed an SFT with morphological patterns ranging from benign to malignant areas, including pleomorphism, increased cellularity, herringbone pattern, necrosis and a raised mitotic count. On review of the literature, only an occasional case report with malignant areas in a hepatic SFT was identified. This case highlights that SFT should be included in the differential diagnosis of a hepatic spindle cell lesion, and that on rare occasions, malignant areas can occur in this already uncommon neoplasm.

Expression profiling and significance of VEGF-A, VEGFR2, VEGFR3 and related proteins in endometrial carcinoma.

BACKGROUND: Angiogenesis plays a key role in the progression of various tumors, including endometrial carcinomas. Several cytokines and their associated receptors are shown to be involved, particularly VEGF-A with VEGFR1, -2 and -3. METHODS: The expressions of VEGF-A, VEGFR2 and VEGFR3 were studied in by immunohistochemistry in 76 endometrial carcinoma specimens. VEGFR2 and VEGFR3 receptor expression were also studied by qRT-PCR in 17 tumors in comparison to normal endometrium. The expression profiles were correlated with tumor type, grade, stage, lymphovascular invasion, disease free survival, and the expressions of other cytokine receptors (EGFR, CXCR1 and CXCR2). RESULTS: Immunohistochemically, 63% of endometrial cancers expressed VEGF-A, 55% VEGFR2 and 26% VEGFR3. VEGFR3 was significantly correlated with tumor stage (p=0.02), with a trend towards poorer disease free survival (p=0.09). VEGF-A was significantly correlated with microvessel density (p<0.01). Using qRT-PCR, increased expression of VEGFR2 (17.2-fold) and VEGFR3 (21.9-fold) was seen in endometrial carcinomas compared with normal endometrium, with significant correlations among the expression levels of VEGFR2, VEGFR3, EGFR, CXCR1 and CXCR2. CONCLUSION: Our study suggests that evaluation of VEGFR3 expression in tumors may provide prognostic data, and help identify patients who would best benefit from anti-angiogenic therapeutic agents. This is the first report showing correlations between the expressions levels of the different receptors.

Head and neck mucosal melanoma: radiological considerations and UK imaging guidelines.

PURPOSE: Awareness of head and neck mucosal melanoma (HNMM) is important, as incorrect work-up can impact on the investigation and management of this rare and aggressive cancer. Following on from the 2020 HNMM UK guidelines, we set out the imaging recommendations and their rationale. To illustrate the key imaging characteristics, we also include a case series from our centre. METHODS: All HNMM cases managed at our institution from January 2016 to January 2021 were identified, and the available imaging for each patient was reviewed. For each patient, the age, gender and location of primary tumour was recorded together with key staging and diagnostic imaging parameters. RESULTS: A total of 14 patients were identified. The median age was 65 years with a female to male ratio of 1.33:1. Primary tumours were sinonasal in location in 93% of cases, with 7% of patients having metastatic neck nodes at presentation and 21% of cases having distant metastatic disease at presentation. CONCLUSION: This data set is in general concordance with other published series regarding the sinonasal origin of the vast majority of HNMM tumours along with the proportion of patients with metastatic neck nodes and distant metastases at presentation. We recommend dual-modality imaging with computed tomography (CT) and magnetic resonance imaging (MRI) of primary tumours whenever possible. In the systematic staging of HNMM, positron emission tomography (PET)-CT should be strongly considered, together with MRI of the brain. Pre-biopsy imaging of HNMM tumours is advisable whenever possible.

The Combination of Afatinib With Dasatinib or Miransertib Results in Synergistic Growth Inhibition of Stomach Cancer Cells.

Background: Of various human epidermal growth factor receptor (HER) inhibitors, only the anti-HER2 monoclonal antibody (mAb) Herceptin/trastuzumab and the antibody-drug conjugate trastuzumab deruxtecan (T-Dxd) has been approved for the treatment of patients with stomach cancer. However, the duration of response may be short in many patients, with tumor heterogeneity being one contributing factor. Methods: We investigated the effect of various types of targeted agents on growth in vitro and migration of a panel of human stomach cancer cells (HSCCLs) and the impact of cell proliferation rate on the anti-tumor activities of these agents. We also investigated the association between the cell surface expression of the HER family members, hepatocyte growth factor receptor (c-Met), anaplastic lymphoma kinase (ALK)7 and cancer stem cell markers CD44 and CD133, and the response to the targeted agents. Results: Of the 18 agents examined, the cyclin dependent kinase (CDK) 1/2/5/9 inhibitor dinaciclib was the most effective and inhibited the growth of all human HSCCLs at 50% inhibitory concentration (IC50) values between 9 nM to 23 nM. Of various HER inhibitors, the irreversible pan-HER family inhibitors (e.g., afatinib) were more effective than the reversible dual epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor (TKI) lapatinib and the EGFR-specific TKI erlotinib in inhibiting the growth of HSCCLs. Of agents targeting different downstream cell signaling molecules, dasatinib targeting Ab1/Src/C-Kit, trametinib targeting MERK1/2 and miransertib targeting AKT1/2/3 inhibited growth of majority of HSCCLs, with the IC50 values ranging from 2 nM to 7 µM. Many of these agents were more effective in inhibiting the growth of HSCCLs when they were proliferating at a slower rate. Treatment with neratinib, afatinib, dinaciclib, dasatinib, stattic, miransertib and paclitaxel significantly inhibited migration of stomach cancer cells. Interestingly, treatment with a combination of afatinib and dasatinib or afatinib and miransertib resulted in synergistic and additive growth inhibition of stomach cancer cells. Conclusions: These results suggest that treatment with a combination of these agents may be of therapeutic value in stomach cancer and warrants further investigations.

IgG4-related disease: an analysis of the clinicopathological spectrum: UK centre experience.

AIM: To retrospectively evaluate the characteristic clinicopathological spectrum in patients with suspicion of IgG4-related disease (IgG4RD). METHODS: Winpath histology database from January 2011 to April 2018 identified all suspected IgG4RD cases wherein IgG4 immunohistochemistry was performed. The histology slides were reviewed to categorise cases into Boston criteria groups-highly suggestive of IgG4RD, probable IgG4RD and insufficient evidence. Information regarding clinical data, treatment received, follow-up and serum IgG4 levels was obtained from medical records and AllScripts Patient Administration System (APAS) clinical database. RESULTS: The study included 204 patients and the most common sites of biopsy/resection were pancreas and duodenum. The most common clinical presentation was fibroinflammatory lesion or mass/lump. On histology, 54/204 (26.47%) cases showed typical storiform fibrosis, 65/204 (32.64%) had >10 IgG4+ plasma cells per high power field and only one case showed thrombophlebitis (0.49%). There were 14/204 (6.78%) cases categorised as highly suggestive of IgG4RD; 8 of these showed high serum IgG4 levels and were managed clinically as true IgG4RD. CONCLUSION: Histological diagnosis of IgG4RD remains challenging, as not all characteristic features are always present especially in small biopsies. Due to the novelty of its experience, fear of over diagnosis in the context of malignancy and features overlapping with diseases of similar clinical scenario, diagnosis of IgG4RD has become more puzzling. Further multicentre clinical trials/studies are advisable.

Well Differentiated Liposarcoma Presenting as a Duodenal Polyp: A Case Report and Review of the Literature.

Liposarcoma is the most common malignant soft tissue tumour in adults occurring predominantly in the retroperitoneum and extremities but very rarely within the gastrointestinal tract. We report on a 77-year-old gentleman who presented with a history of melaena and anaemia. On oesophagogastric duodenoscopy a duodenal polyp was identified. Surgical excision was performed and on histology, the duodenal polyp revealed a primary duodenal well differentiated liposarcoma. A literature review confirmed the rarity of primary duodenal liposarcomas, with only four cases previously reported.

Gene of the month: cancer testis antigen gene 1b (NY-ESO-1).

Cancer testis antigen gene 1B (CTAG1B) and its associated gene product; New York oesophageal squamous carcinoma 1 (NY-ESO-1), represent a unique and promising target for cancer immunotherapy. As a member of the cancer testis antigen family (CTA), the protein's restricted expression pattern and ability to elicit spontaneous humoural and cellular immune responses has resulted in a plethora of novel modalities and approaches attempting to harness its immunotherapeutic anti-cancer potential. Here, we discuss the structure and function of CTAG1B/NY-ESO-1 in both health and disease, immunohistochemical detection, as well as the most promising advances in the development of associated anti-cancer therapies. From cancer vaccines to engineered cellular therapy approaches, a multitude of immunotherapies targeting CTA's are coming to the forefront of oncology. Although the efficacy of such approaches have yet to provide convincing evidence of durable response, early phase clinical trial data has resulted in some exciting findings which will have significant potential to act as a platform for future practice changing technologies.

Tonsillar Extraintestinal Enteropathy-Associated T-Cell Lymphoma in a Patient With Celiac Disease.

Enteropathy-associated T-cell lymphoma (EATL) is a rare but serious complication of celiac disease. Diagnosis is challenging. Patients can present with weight loss, abdominal pain, and diarrhea or acutely with bowel perforation or obstruction. Patients often present with advanced disease. Malnutrition further limits treatment options. Early diagnosis is important to start aggressive treatment strategies. However, even with prompt diagnosis, prognosis remains poor with a high mortality rate. We report the first documented case of sole tonsillar involvement, a rare extraintestinal and extranodal site of disease, leading to EATL diagnosis. We also highlight some of the challenges in diagnosing EATL.

A Comprehensive Review of the Current and Future Role of the Microbiome in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second most common cause of cancer death in the USA by 2030, yet progress continues to lag behind that of other cancers, with only 9% of patients surviving beyond 5 years. Long-term survivorship of PDAC and improving survival has, until recently, escaped our understanding. One recent frontier in the cancer field is the microbiome. The microbiome collectively refers to the extensive community of bacteria and fungi that colonise us. It is estimated that there is one to ten prokaryotic cells for each human somatic cell, yet, the significance of this community in health and disease has, until recently, been overlooked. This review examines the role of the microbiome in PDAC and how it may alter survival outcomes. We evaluate the possibility of employing microbiomic signatures as biomarkers of PDAC. Ultimately this review analyses whether the microbiome may be amenable to targeting and consequently altering the natural history of PDAC.

Frontal sinus infection leading to sino-orbital aspergillosis: a case report.

Sino-orbital aspergillosis is an uncommon but aggressive infection. It rarely originates from the frontal sinus due to the complex anatomy of the frontal recess and anteromedial position of its ostium. An 87-year-old man of Nigerian heritage with a history of multiple myeloma, chronic kidney disease and type 2 diabetes, presented to the eye clinic with a right tense swollen eyelid and proptosis. Computed tomography (CT) and magnetic resonance imaging (MRI) scan revealed a right superomedial mass communicating with the frontal sinus and biopsy confirmed an orbital aspergilloma. The patient was successfully treated with debulking surgery and anti-fungal treatment despite developing side effects to the drugs. To improve prognosis, ophthalmologists should be aware of this distinct entity and use a multi-disciplinary approach.

Sarcomatoid Carcinoma Arising in a Gastric Duplication Cyst.

Malignancy arising within a gastric duplication cyst (GDC) is extremely rare; only 15 cases have been reported in the literature. We present a 70-year-old woman who was referred with a history of vague postprandial abdominal discomfort. Subsequent imaging identified a gastric cystic mass. A laparoscopic sleeve gastrectomy of a 90 × 60 × 60-mm cystic mass was performed. Histopathological examination showed the presence of a sarcomatoid carcinoma arising within a GDC. The patient, unfortunately, died 5 months after surgery with metastatic disease. To the best of our knowledge, this is the first case of sarcomatoid carcinoma arising within a GDC.

HER2 Expression Is Predictive of Survival in Cetuximab Treated Patients with RAS Wild Type Metastatic Colorectal Cancer.

The overexpressed HER2 is an important target for treatment with monoclonal antibody (mAb) trastuzumab, only in patients with breast and gastric cancers, and is an emerging therapeutic biomarker in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) mAbs cetuximab and panitumumab. In this study, we investigated the relative expression and predictive value of all human epidermal growth factor receptor (HER) family members in 144 cetuximab-treated patients with wild type RAS mCRC. The relative expression of EGFR and HER2 have also been examined in 21-paired primary tumours and their metastatic sites by immunohistochemistry. Of the 144 cases examined, 25%, 97%, 79%, 48%, and 10% were positive for EGFR, HER2, HER3, and HER4 and all four HER family members, respectively. The expression of EGFR was an indicator of poorer overall survival and the membranous expression of HER2 and HER3 3+ intensity was associated with a shorter progression free survival (PFS). In contrast, the cytoplasmic expression of HER2 was associated with better PFS. In 48% and 71% of the cases, there were discordance in the expression of EGFR or one or more HER family members in paired primary and related metastatic tumours, respectively. Our results implicate the importance of a large prospective investigation of the expression level and predictive value of not only the therapeutic target (i.e., EGFR protein) but also HER2 and other HER family members as therapeutic targets, or for response to therapy with anti-EGFR mAbs and other forms of HER inhibitors, in both the primary tumours and metastatic sites in mCRC.

What is the role of the surgeon in the management of head and neck mucosal melanoma in the immunotherapy era?

INTRODUCTION: The advent of immunotherapy has impacted both the management and, to a lesser extent, the outcomes for patients with head and neck mucosal melanoma. As a consequence, one might expect that the role of the surgeon would be limited to the diagnostic work-up and that systemic therapies would be the mainstay of treatment. METHODS AND RESULTS: Here, we present the surgical aspects of the recently published United Kingdom Head and Neck Mucosal Melanoma Guideline to highlight the continued role of surgeons in the management of this disease. We highlight key areas where surgeons remain the lead clinician and reinforce the multidisciplinary requirement for exemplary patient care. CONCLUSIONS: Despite the advent of immunotherapy, surgeons continue to have a key role to play in this disease. When indicated, it is essential that appropriate surgery is offered by a suitably experienced team.

CDKN2A, NF2, and JUN are dysregulated among other genes by miRNAs in malignant mesothelioma -A miRNA microarray analysis.

Malignant mesothelioma (MM) is an aggressive cancer arising from mesothelial cells, mainly due to former asbestos exposure. Little is known about the microRNA (miRNA) expression of MM. miRNAs are small noncoding RNAs, which play an essential role in the regulation of gene expression. This study was carried out to analyze the miRNA expression profile of 17 MM samples using miRNA microarray. The analysis distinguished the overall miRNA expression profiles of tumor tissue and normal mesothelium. Differentially expressed miRNAs were found in tumor samples compared with normal sample. Twelve of them, let-7b*, miR-1228*, miR-195*, miR-30b*, miR-32*, miR-345, miR-483-3p, miR-584, miR-595, miR-615-3p, and miR-885-3p, were highly expressed whereas the remaining nine, let-7e*, miR-144*, miR-203, miR-340*, miR-34a*, miR-423, miR-582, miR-7-1*, and miR-9, were unexpressed or had severely reduced expression levels. Target genes for these miRNAs include the most frequently affected genes in MM such as CDKN2A, NF2, JUN, HGF, and PDGFA. Many of the miRNAs were located in chromosomal areas known to be deleted or gained in MM such as 8q24, 1p36, and 14q32. Furthermore, we could identify specific miRNAs for each histopathological subtype of MM. Regarding risk factors such as smoking status and asbestos exposure, significantly differentially expressed miRNAs were identified in smokers versus nonsmokers (miR-379, miR-301a, miR-299-3p, miR-455-3p, and miR-127-3p), but not in asbestos-exposed patients versus nonexposed ones. This could be related to the method of assessment of asbestos exposure as asbestos remains to be the main contributor to the development of MM.

Development and application of two novel monoclonal antibodies against overexpressed CD26 and integrin α3 in human pancreatic cancer.

Monoclonal antibody (mAb) technology is an excellent tool for the discovery of overexpressed cell surface tumour antigens and the development of targeting agents. Here, we report the development of two novel mAbs against CFPAC-1 human pancreatic cancer cells. Using ELISA, flow cytometry, immunoprecipitation, mass spectrometry, Western blot and immunohistochemistry, we found that the target antigens recognised by the two novel mAbs KU44.22B and KU44.13A, are integrin α3 and CD26 respectively, with high levels of expression in human pancreatic and other cancer cell lines and human pancreatic cancer tissue microarrays. Treatment with naked anti-CD26 mAb KU44.13A did not have any effect on the growth and migration of cancer cells nor did it induce receptor downregulation. In contrast, treatment with anti-integrin α3 mAb KU44.22B inhibited growth in vitro of Capan-2 cells, increased migration of BxPC-3 and CFPAC-1 cells and induced antibody internalisation. Both novel mAbs are capable of detecting their target antigens by immunohistochemistry but not by Western blot. These antibodies are excellent tools for studying the role of integrin α3 and CD26 in the complex biology of pancreatic cancer, their prognostic and predictive values and the therapeutic potential of their humanised and/or conjugated versions in patients whose tumours overexpress integrin α3 or CD26.