Izhar Bagwan

Colorectal cancer (CRC) remains a significant global health burden. While early-stage CRC has a high survival rate, most patients are diagnosed with advanced disease, necessitating more effective and less toxic therapeutic targets. This review examines recent advancements, challenges, and future directions in targeted therapies for CRC, focusing on HER inhibitors. We assess the efficacy of monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) and explore strategies to overcome resistance mechanisms. Targeted therapies like cetuximab and panitumumab have improved outcomes for CRC patients with wild-type KRAS. However, resistance mechanisms and intra- and inter-tumour heterogeneity limit their effectiveness. Recent advancements include the development of dual TKIs, antibody/drug conjugates (ADCs), bispecific antibodies, and CAR-T cells against HER family members and other targets that are showing promise in preclinical and clinical trials. Targeted therapies have transformed CRC treatment, but more research is needed to overcome some of the current challenges, such as late diagnosis and the heterogenous nature of CRC, as well as the discovery of more reliable biomarkers for response to the therapy and patient selection. Future research should focus on identifying novel biomarkers of diagnostic, prognostic, and predictive value, developing next-generation inhibitors, drug repurposing, and combining small-molecule targeted therapies with immunotherapy. Such advances could ultimately help increase both the treatment options and outcomes for patients with CRC.

Background/Objectives: The aberrant expression and activation of HER family members is a known major oncogenic pathway for the proliferation, progression, and metastasis of a wide range of human malignancies. In this study, our aim was to examine the relative expression and prognostic significance of all members of the HER family, the type III EGFR mutant (EGFRvIII), and the putative stem cell markers CD44 and CD109 in patients with glioblastoma. Methods: The expression levels of wild-type EGFR (wtEGFR), HER2, HER3, HER4, EGFRvIII, CD44, and CD109 were determined in tumour specimens from 80 patients by immunohistochemistry. The staining was scored based on the percentage of positive tumour cells, the intensity, and the cellular location of immunostaining. The association between the expression level of the biomarkers and patient overall survival was evaluated using Chi-squared, Kaplan–Meier survival curves, and log-rank tests. Results: At a cut-off value of ≥5% with positive staining, 46% (wtEGFR), 75% (HER2), 19% (HER3), 71% (HER4), 85% (EGFRvIII), 95% (CD44), and 16% (CD109) of the cases were positive for these biomarkers. Interestingly, at the same cut-off value, the expression of wtEGFR in these patients was accompanied by co-expression with HER2 (35%), HER3 (0%), HER4 (30%), EGFRvIII (36%), CD44 (44%), HER2/EGFRvIII (28%), HER2/CD44 (31%), and EGFRvIII/CD44 (36%). In addition, the expression of EGFRvIII was accompanied by co-expression with HER2 (65%), HER3 (15%), HER4 (63%), CD44 (83%), CD109 (16%), wtEGFR/HER2 (28%), and 55% of the cases had co-expression of EGFRvIII/HER2/HER4/CD44. With the exception of HER2 expression, at cut-off values of ≥5% of tumour cells with positive staining, which was associated with better overall survival [HR = 0.57 (p = 0.038), HR = 0.56 (p = 0.034)], there was no significant association between the expression of other members of the HER family, EGFRvIII, CD44, and CD109 on the overall survival in both univariate and multivariate analysis. Conclusions Our results suggest that the co-expression of different members of the HER family, with EGFRvIII, CD44, and CD109, occurs in patients with glioblastoma. As the results of therapy with EGFR inhibitors have not been encouraging in patients with a brain tumour, further investigation should determine whether the co-expression of such biomarkers can be of predictive value for the response to the therapy with various types of HER inhibitors and their potential as therapeutic targets for co-targeted therapy.

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.

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.

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.

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.

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.

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.

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.

Pancreatic Ductal Adenocarcinoma (PDAC) and biliary-tract cancers (BTC) often present at a late stage, and consequently patients have poor survival-outcomes. Circular RNAs (circRNAs) are non-coding RNA molecules whose role in tumourigenesis has recently been realised. They are stable, conserved and abundant, with tissue-specific expression profiles. Therefore, significant interest has arisen in their use as potential biomarkers for PDAC and BTC. High-throughput methods and more advanced bioinformatic techniques have enabled better profiling and progressed our understanding of how circRNAs may function in the competing endogenous RNA (ceRNA) network to influence the transcriptome in these cancers. Therefore, the aim of this systematic review was to describe the roles of circRNAs in PDAC and BTC, their potential as biomarkers, and their function in the wider ceRNA network in regulating microRNAs and the transcriptome. Medline, Embase, Scopus and PubMed were systematically reviewed to identify all the studies addressing circRNAs in PDAC and BTC. A total of 32 articles were included: 22 considering PDAC, 7 for Cholangiocarcinoma (CCA) and 3 for Gallbladder Cancer (GBC). There were no studies investigating Ampullary Cancer. Dysregulated circRNA expression was associated with features of malignancy in vitro, in vivo, and ex vivo. Overall, there have been very few PDAC and BTC tissues profiled for circRNA signatures. Therefore, whilst the current studies have demonstrated some of their functions in these cancers, further work is required to elucidate their potential role as cancer biomarkers in tissue, biofluids and biopsies.