Immune Checkpoint Inhibitors in Esophageal Carcinoma: Assessment of Efficacy Predictors of Response in Clinical Trials.

Esophageal carcinoma (EC) is among the most common causes of cancer-related deaths worldwide. Even with the improvement of multidisciplinary treatment modalities, advanced unresectable EC patients had limited systemic therapeutic options for an extended period. Recently, immune checkpoint inhibitors (ICIs) have been introduced to advanced EC management in both first-line and second-line options, as well as in postoperative settings in resectable EC after preoperative chemoradiation. Herein, the authors present a comprehensive review of clinical trials on administering ICIs in EC patients while discussing reported clinical, molecular, and immune biomarkers and their predictive value for treatment efficacy.

Association of Baseline Tumor-Specific Neoantigens and CD8+ T-Cell Infiltration With Immune-Related Adverse Events Secondary to Immune Checkpoint Inhibitors.

PURPOSE: Recent evidence has shown that higher tumor mutational burden strongly correlates with an increased risk of immune-related adverse events (irAEs). By using an integrated multiomics approach, we further studied the association between relevant tumor immune microenvironment (TIME) features and irAEs. METHODS: Leveraging the US Food and Drug Administration Adverse Event Reporting System, we extracted cases of suspected irAEs to calculate the reporting odds ratios (RORs) of irAEs for cancers treated with immune checkpoint inhibitors (ICIs). TIME features for 32 cancer types were calculated on the basis of the cancer genomic atlas cohorts and indirectly correlated with each cancer's ROR for irAEs. A separate ICI-treated cohort of non-small-cell lung cancer (NSCLC) was used to evaluate the correlation between tissue-based immune markers (CD8+, PD-1/L1+, FOXP3+, tumor-infiltrating lymphocytes [TILs]) and irAE occurrence. RESULTS: The analysis of 32 cancers and 33 TIME features demonstrated a significant association between irAE RORs and the median number of base insertions and deletions (INDEL), neoantigens (r = 0.72), single-nucleotide variant neoantigens (r = 0.67), and CD8+ T-cell fraction (r = 0.51). A bivariate model using the median number of INDEL neoantigens and CD8 T-cell fraction had the highest accuracy in predicting RORs (adjusted r2 = 0.52, P = .002). Immunoprofile assessment of 156 patients with NSCLC revealed a strong trend for higher baseline median CD8+ T cells within patients' tumors who experienced any grade irAEs. Using machine learning, an expanded ICI-treated NSCLC cohort (n = 378) further showed a treatment duration-independent association of an increased proportion of high TIL (>median) in patients with irAEs (59.7% v 44%, P = .005). This was confirmed by using the Fine-Gray competing risk approach, demonstrating higher baseline TIL density (>median) associated with a higher cumulative incidence of irAEs (P = .028). CONCLUSION: Our findings highlight a potential role for TIME features, specifically INDEL neoantigens and baseline-immune infiltration, in enabling optimal irAE risk stratification of patients.

MicroRNAs Associated with Androgen Receptor and Metastasis in Triple-Negative Breast Cancer.

It is crucial to identify novel molecular biomarkers and therapeutic targets for triple-negative breast cancer (TNBC). The androgen receptor (AR) is a regulator of TNBC, acting partially via microRNA molecules (miRNAs). In this study, we used PCR arrays to profile the expression of 84 miRNAs in 24 TNBC tissue samples, which were equally classified according to AR expression and/or metastasis. Several bioinformatics tools were then utilized to determine the potentially affected protein targets and signaling pathways. Seven miRNAs were found to be significantly more highly expressed in association with AR expression, including miR-328-3p and miR-489-3p. Increased expression of miR-205-3p was found to be significantly associated with metastasis. Certain miRNAs were specifically found to be differentially expressed in either metastatic or non-metastatic AR-positive tumors. A gene ontology (GO) analysis indicated biological roles in the regulation of transcription, cellular response to DNA damage, and the transforming growth factor-beta (TGF-beta) signaling pathway. The GO analysis also showed enrichment in kinase and transcription factor activities. The TGF-beta and a number of kinase-dependent pathways were also retrieved using the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. This study offers an understanding of the role of AR in TNBC and further implicates miRNAs in mediating the effects of AR on TNBC.

Clinical and biomarker results from a phase II trial of combined cabozantinib and durvalumab in patients with chemotherapy-refractory colorectal cancer (CRC): CAMILLA CRC cohort.

CAMILLA is a basket trial (NCT03539822) evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Herein, are the phase II colorectal cohort results. 29 patients were evaluable. 100% had confirmed pMMR/MSS tumors. Primary endpoint was met with ORR of 27.6% (95% CI 12.7-47.2%). Secondary endpoints of 4-month PFS rate was 44.83% (95% CI 26.5-64.3%); and median OS was 9.1 months (95% CI 5.8-20.2). Grade≥3 TRAE occurred in 39%. In post-hoc analysis of patients with RAS wild type tumors, ORR was 50% and median PFS and OS were 6.3 and 21.5 months respectively. Exploratory spatial transcriptomic profiling of pretreatment tumors showed upregulation of VEGF and MET signaling, increased extracellular matrix activity and preexisting anti-tumor immune responses coexisting with immune suppressive features like T cell migration barriers in responders versus non-responders. Cabozantinib plus durvalumab demonstrated anti-tumor activity, manageable toxicity, and have led to the activation of the phase III STELLAR-303 trial.

Targeted and Immunotherapy Approaches in HER2-Positive Gastric and Gastroesophageal Junction Adenocarcinoma: A New Era.

HER2-targeted therapy with the HER2 monoclonal antibody trastuzumab has achieved impressive outcomes in the first-line settings of patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma overexpressing HER2. However, considering that a substantial proportion of those patients eventually relapses, as well as the relatively limited performance of those agents in second-line settings, a deeper understanding of resistance mechanisms is needed for enhanced guidance for patients' therapeutic selection in the second-line setting and beyond. In this review, we highlight trastuzumab's (HER2-targeting agent) performance in patients with gastric or GEJ cancer, with insight into mechanisms of resistance. We also discuss the new integration of PD-1 inhibitor pembrolizumab into the trastuzumab for gastric cancer frontline regimen, the latest addition of trastuzumab deruxtecan to the treatment armamentarium, and the potential of pipeline HER2-targeting approaches and combinations in patients with gastric or GEJ adenocarcinoma.

Next generation immuno-oncology biomarkers in gastrointestinal cancer: what does the future hold?

INTRODUCTION: Gastrointestinal (GI) cancers pose a significant health burden worldwide, necessitating advancements in diagnostic and treatment approaches. One promising avenue is the utilization of next-generation biomarkers, which hold the potential to revolutionize GI cancer management. AREAS COVERED: This review explores the latest breakthroughs and expert opinions surrounding the application of next-generation immunotherapy biomarkers. It encompasses various aspects of the currently utilized biomarkers of immunotherapy in the context of GI cancers focusing on microsatellite stable cancers. It explores the promising research on the next generation of biomarkers addressing the challenges associated with integrating them into clinical practice and the need for standardized protocols and regulatory guidelines. EXPERT OPINION: Immune profiling, multiplex immunohistochemistry, analysis of immune cell subsets, and novel genomic and epigenomic markers integrated with machine-learning approaches offer new avenues for identifying robust biomarkers. Liquid biopsy-based approaches, such as circulating tumor DNA (ctDNA) and exosome-based analyses, hold promise for real-time monitoring and early detection of treatment response.

Expression of lymphoid structure-associated cytokine/chemokine gene transcripts in tumor and protein in serum are prognostic of melanoma patient outcomes.

Background: Proinflammatory chemokines/cytokines support development and maturation of tertiary lymphoid structures (TLS) within the tumor microenvironment (TME). In the current study, we sought to investigate the prognostic value of TLS-associated chemokines/cytokines (TLS-kines) expression levels in melanoma patients by performing serum protein and tissue transcriptomic analyses, and to then correlate these data with patients clinicopathological and TME characteristics. Methods: Levels of TLS-kines in patients' sera were quantitated using a custom Luminex Multiplex Assay. The Cancer Genomic Atlas melanoma cohort (TCGA-SKCM) and a Moffitt Melanoma cohort were used for tissue transcriptomic analyses. Associations between target analytes and survival outcomes, clinicopathological variables, and correlations between TLS-kines were statistically analyzed. Results: Serum of 95 patients with melanoma were evaluated; 48 (50%) female, median age of 63, IQR 51-70 years. Serum levels of APRIL/TNFSF13 were positively correlated with levels of both CXCL10 and CXCL13. In multivariate analyses, high levels of serum APRIL/TNFSF13 were associated with improved event-free survival after adjusting for age and stage (HR = 0.64, 95% CI 0.43-0.95; p = 0.03). High expression of APRIL/TNFSF13 tumor transcripts was significantly associated with improved OS in TCGA-SKCM (HR = 0.69, 95% CI 0.52-0.93; p = 0.01) and in Moffitt Melanoma patients (HR = 0.51, 95% CI: 0.32-0.82; p = 0.006). Further incorporation of CXCL13 and CXCL10 tumor transcript levels in a 3-gene index revealed that high APRIL/CXCL10/CXCL13 expression was associated with improved OS in the TCGA SKCM cohort (HR = 0.42, 95% CI 0.19-0.94; p = 0.035). Melanoma differentially expressed genes positively associated with high APRIL/CXCL10/CXCL13 tumor expression were linked to tumor infiltration by a diverse array of proinflammatory immune cell types. Conclusion: Serum protein and tumor transcript levels of APRIL/TNFSF13 are associated with improved survival outcomes. Patients exhibiting high coordinate expression of APRIL/CXCL10/CXCL13 transcripts in their tumors displayed superior OS. Further investigation of TLS-kine expression profiles related to clinical outcomes in larger cohort studies is warranted.

Brief Report: Prognostic Relevance of 3q Amplification in Squamous Cell Carcinoma of the Lung.

Introduction: Amplification of 3q is the most common genetic alteration identified in squamous cell carcinoma of the lung (LUSC), with the most frequent amplified region being 3q26 to 3q28. Methods: In this analysis, we aim to describe the prognostic relevance of 3q amplification by focusing on a minimal common region (MCR) of amplification constituted of 25 genes. We analyzed 511 cases of LUSC from The Cancer Genome Atlas and included 476 in the final analysis. Results: We identified a 25-gene MCR that was amplified in 221 (44.3%) cases and was associated with better disease-specific survival (not reported [NR] versus 9.25 y, 95% confidence interval [CI]: 5.24-NR, log-rank p = 0.011) and a progression-free interval of 8 years (95% CI: 5.1-NR) versus 4.9 years (95% CI: 3.5-NR, log-rank p = 0.020). Multivariable analysis revealed that MCR amplification was associated with improved disease-specific survival and progression-free interval. Conclusions: Amplification of the 25-gene MCR within 3q was present in 44% of this cohort, consisting mainly of Caucasian patients with early stage LUSC. This analysis strongly indicates the prognostic relevance of the 25-gene MCR within 3q. We are further evaluating its prognostic and predictive relevance in a racially diverse patient population with advanced LUSC.

Atrial resection for T4 non-small cell lung cancer with left atrium involvement: a systematic review and meta-analysis of survival.

PURPOSE: Extended resection for non-small cell lung cancer (NSCLC) with T4 left atrium involvement is controversial. We performed a systematic review and meta-analysis to evaluate the short- and long-term outcomes of this treatment strategy. METHODS: We searched the PubMed database for studies on atrial resection in NSCLC patients. The primary investigated outcome was the effectiveness of the surgery represented by survival data and the secondary outcomes were postoperative morbidity, mortality, and recurrence. RESULTS: Our search identified 18 eligible studies including a total of 483 patients. Eleven studies reported median overall survival and 17 studies reported overall survival rates. The estimated pooled 1, 3, 5-year overall survival rates were 69.1% (95% CI 61.7-76.0%), 21.5% (95% CI 12.3-32.3%), and 19.9% (95% CI 13.9-26.6%), respectively. The median overall survival was 24 months (95% CI 17.7-27 months). Most studies reported significant associations between better survival and N0/1 status, complete resection status, and neoadjuvant therapy. CONCLUSION: Extended lung resection, including the left atrium, for NSCLC is feasible with acceptable morbidity and mortality when complete resection is achieved. Lymph node N0/1 status coupled with the use of neoadjuvant therapies is associated with better outcomes.

Transcervical approach to oropharyngeal synovial sarcoma: a case report.

Aim: Synovial sarcomas (SS) are malignant tumors rarely arising in the head and neck region. In most of these cases, the tumor arises in the cervical or hypopharyngeal region, and extremely rarely in the oropharynx. Case report: Herein, we report the case of a 22-year-old male oropharyngeal SS patient presented with breathing difficulty and dysphagia. The management plan included an emergency tracheostomy, followed shortly by transcervical resection of the oropharyngeal sarcoma tumor, the pectoralis major myocutaneous flap was used for pharyngeal reconstruction, followed by adjuvant radiotherapy resulting in more than 5 years disease-free survival. Conclusion: SS arising in the oropharynx are extremely rare. Transcervical resection coupled with adjuvant radiotherapy warrants enhanced locoregional control in advanced oropharyngeal cases.

Stapler Pharyngeal Repair Versus Conventional Suturing After Laryngectomy in Jordanian Laryngeal Cancer Patients.

Background: The use of staplers in surgical repair of the pharynx after laryngectomy has gained traction in recent years, with differing results. Objective: In this study, we compare the use of stapler suturing (SS) after laryngectomy in comparison with the manual suturing (MS) technique in laryngeal cancer patients regarding pharyngocutaneous fistula (PCF) formation, operative time, blood loss, margin status, and length of hospital stay. Methods: We conducted a retrospective cohort study of laryngeal cancer patients undergoing pharyngeal repair after total laryngectomy by either a stapler or manual suturing. Demographic data, stage of disease, postoperative complications, duration of hospital stay, and operative time were collected. Results: A total of 59 laryngeal cancer patients were included, of which 22 underwent SS and 37 had MS. Our cohort was predominantly males (98%), and similar mean ages were observed across both suturing groups (60.5 vs 59.9, P = 0.83). Negative margins were more frequent with SS (100% vs 86.5%, P = 0.13) yet this difference was not statistically significant, whereas preoperative tracheostomy procedure was present more in MS patients (43.2% vs 0, P = 0.003). Lymph node involvement was higher in the manual suturing cohort, yet this difference was statistically insignificant (41.2% vs 25%, P = 0.49). The muscle flap procedure was significantly higher in the MS cohort (70.3% vs 20%, P = 0.001). In both groups, comparable PCF rates were noted (13.3% vs 10.8%) and there was no association between salvage laryngectomy and PCF occurrence in the entire cohort. For surgery details, there was no statistical difference between both groups in blood loss, hospitalization length, or oral feeding start. Only surgical time was significantly lower in the stapler cohort (277 vs 372.6 minutes, P = 0.000). Conclusion: Both suturing techniques did not show any statistically significant difference in PCF rates. However, was markedly reduced with stapler use in comparison to manual suturing. Further randomized studies with larger sample size are needed to validate the role of stapler suturing for pharyngeal repair.

Tumor Molecular and Microenvironment Characteristics in EBV-Associated Malignancies as Potential Therapeutic Targets: Focus on Gastric Cancer.

Although most people are infected with Epstein-Barr Virus (EBV) during their lifetime, only a minority of them develop an EBV-associated malignancy. EBV acts in both direct and indirect ways to transform infected cells into tumor cells. There are multiple ways in which the EBV, host, and tumor environment interact to promote malignant transformation. This paper focuses on some of the mechanisms that EBV uses to transform the tumor microenvironment (TME) of EBV-associated gastric cancer (EBVaGC) for its benefit, including overexpression of Indoleamine 2,3-Dioxygenase 1 (IDO1), synergism between H. pylori and EBV co-infection, and M1 to M2 switch. In this review, we expand on different modalities and combinatorial approaches to therapeutically target this mechanism.

Genomic and Transcriptomic Predictors of Response to Immune Checkpoint Inhibitors in Melanoma Patients: A Machine Learning Approach.

Immune checkpoint inhibitors (ICIs) became one of the most revolutionary cancer treatments, especially in melanoma. While they have been proven to prolong survival with lesser side effects compared to chemotherapy, the accurate prediction of response remains to be an unmet gap. Thus, we aim to identify accurate clinical and transcriptomic biomarkers for ICI response in melanoma. We also provide mechanistic insight into how high-performing markers impose their effect on the tumor microenvironment (TME). Clinical and transcriptomic data were retrieved from melanoma studies administering ICIs from cBioportal and GEO databases. Four machine learning models were developed using random-forest classification (RFC) entailing clinical and genomic features (RFC7), differentially expressed genes (DEGs, RFC-Seq), survival-related DEGs (RFC-Surv) and a combination model. The xCELL algorithm was used to investigate the TME. A total of 212 ICI-treated melanoma patients were identified. All models achieved a high area under the curve (AUC) and bootstrap estimate (RFC7: 0.71, 0.74; RFC-Seq: 0.87, 0.75; RFC-Surv: 0.76, 0.76, respectively). Tumor mutation burden, GSTA3, and VNN2 were the highest contributing features. Tumor infiltration analyses revealed a direct correlation between upregulated genes and CD8+, CD4+ T cells, and B cells and inversely correlated with myeloid-derived suppressor cells. Our findings confirmed the accuracy of several genomic, clinical, and transcriptomic-based RFC models, that could further support the use of TMB in predicting response to ICIs. Novel genes (GSTA3 and VNN2) were identified through RFC-seq and RFC-surv models that could serve as genomic biomarkers after robust validation.

The Crosstalk between Microbiome and Immunotherapeutics: Myth or Reality.

The gut microbiome refers to microorganisms and their genetic material influencing local and systemic inflammation. Inflammation is known to contribute to cancer development, progression, and treatment. Evidence suggests that modulating the gut microbiome may affect responses to various cancer therapies. The gut microbiota has been suggested to have an impact on immunotherapy efficacy, especially the currently widely used immune checkpoint inhibitors in various malignancies. Microbial interventions like fecal microbiota transplantation, various probiotics, or even antibiotics can increase or decrease the tumor's sensitivity to immunotherapy. However, not all tumors react in the same manner, highlighting the tumor microenvironment heterogeneity across tumor types and the influence this has on the crosstalk between the microbiome and therapy outcomes. In this study, we intend to review the association between the gut microbiota and immunotherapy response in cancer patients and the factors regulating this interaction.

An in Depth Look Into Intracranial Abscesses and Empyemas: a Ten-year Experience in a Single Institute.

Background: As the incidence of intracranial infections increase due to diagnostic procedures improvement, more real-life data is needed to reach a more solid informed management approach. Objective: This study aims to describe and analyse clinical features of intracranial abscesses patients treated at a tertiary hospital in North Jordan during a 10-year period. Methods: We retrospectively identified 37 patients treated at King Abdullah University Hospital (KAUH) from 2011 to 2020 in Irbid, North Jordan. Treatment consisted of either aspiration, open craniotomy excision (OCE) or conservative therapy. Extracted variables included demographic data such (age, gender), clinical presentation, lab findings, radiological findings as well as management plan. Retrieved data was compared between the patients who underwent a single operation and those who underwent reoperation after the initial procedure. Results: Thirty-seven patients with 55 intracerebral abscesses were identified, 29 of whom had intraparenchymal brain abscesses, 4 patients had epidural empyema, and 4 had subdural empyema. The mean age was 28.8 (± 20.7) years, with a male predominance (78.4%). Sixteen patients underwent open craniotomy excision (OCE), 14 patients were treated by aspiration and 7 patients were treated conservatively. When comparing the single operation and the reoperation groups, there was no statistically significant difference across variables. Conclusion: Our study presents valuable insight from a tertiary hospital in north Jordan on intracranial abscesses and empyemas. Our findings confirm that good recovery can be established after aspiration or OCE in the majority of patients. Similar results were obtained when comparing the SOP and the ROP groups.

Sentinel Lymph Node Gene Expression Signature Predicts Recurrence-Free Survival in Cutaneous Melanoma.

We sought to develop a sentinel lymph node gene expression signature score predictive of disease recurrence in patients with cutaneous melanoma. Gene expression profiling was performed on SLN biopsies using U133A 2.0 Affymetrix gene chips. The top 25 genes associated with recurrence-free survival (RFS) were selected and a penalized regression function was used to select 12 genes with a non-zero coefficient. A proportional hazards regression model was used to evaluate the association between clinical covariates, gene signature score, and RFS. Among the 45 patients evaluated, 23 (51%) had a positive SLN. Twenty-one (46.7%) patients developed disease recurrence. For the top 25 differentially expressed genes (DEG), 12 non-zero penalized coefficients were estimated (CLGN, C1QTNF3, ADORA3, ARHGAP8, DCTN1, ASPSCR1, CHRFAM7A, ZNF223, PDE6G, CXCL3, HEXIM1, HLA-DRB). This 12-gene signature score was significantly associated with RFS (p < 0.0001) and produced a bootstrap C index of 0.888. In univariate analysis, Breslow thickness, presence of primary tumor ulceration, SLN positivity were each significantly associated with RFS. After simultaneously adjusting for these prognostic factors in relation to the gene signature, the 12-gene score remained a significant independent predictor for RFS (p < 0.0001). This SLN 12-gene signature risk score is associated with melanoma recurrence regardless of SLN status and may be used as a prognostic factor for RFS.

Primary and secondary immune checkpoint inhibitors resistance in colorectal cancer: Key mechanisms and ways to overcome resistance.

Immune checkpoint inhibitors (ICIs) have significantly advanced colorectal cancer treatment in recent years. Antibodies that target the proteins programmed cell death-1 (PD-1), programmed cell death-1 ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are among the ICIs that are currently being used in clinical practice. However, in colorectal cancer, ICI's effectiveness is limited to a fraction of patients with microsatellite instability-high (MSI-H), which only accounts for about 5% of advanced cases. The tumor microenvironment and intrinsic changes in tumor cells are just a couple of the many mechanisms that play a role in ICI primary or secondary resistance. In order to advance precision medicine and broaden the population benefiting from ICI, this paper highlights the main underlying mechanisms of ICIs resistance and suggested techniques to overcome it.

Hepatocellular carcinoma and immunotherapy: Beyond immune checkpoint inhibitors.

Hepatocellular carcinoma (HCC) is one of the deadliest and most common malignancies of the liver. Considering the rich immune background of carcinogenesis in HCC, efforts have been focused on further understanding the role of the immune system in tumor suppression and promotion. The utilization of immunotherapy in HCC has led to encouraging results that has translated to longer survival and better quality of life among patients. The development of novel HCC-tailored regimens such as vaccine therapy and adoptive cellular therapy coupled with a deeper understanding of biomarkers predictive of the response to immunotherapy will lead to better treatment outcomes.

Insight on BRAFV600E mutated colorectal cancer immune microenvironment.

Colorectal cancer (CRC) is the second deadliest malignancy for both sexes. The BRAFV600E mutation, one of the most common driver mutations in CRC, is known for its poor prognosis due to the increased risk of metastasis. The effect of the BRAFV600E mutation on the tumor microenvironment was the topic of the study reported in World Journal of Gastrointestinal Oncology, with special focus on immune status. The authors presented insightful findings that were exclusively based on macrophage polarity and cytokine levels, without investigating other relevant immune elements. A more comprehensive look into the dynamic immune activity of cancer environments will warrant more meaningful practical findings. In this letter, we discuss other significant immune factors and their possible implications on the tumor microenvironment of BRAF-mutated CRC.

The Use of Bruton Tyrosine Kinase Inhibitors in Waldenström's Macroglobulinemia.

The use of Bruton Tyrosine Kinase (BTK) inhibitors in Waldenström's Macroglobulinemia (WM) is evolving. Ibrutinib, a first-generation BTK inhibitor, is currently approved for use in frontline and relapsed/refractory disease. Second-generation BTK inhibitors are being used and studied to improve clinical outcomes and/or safety profile. Zanubrutinib, one such second-generation inhibitor, was recently approved in treatment-naive and refractory/relapsed patients. Here, we review the use of BTK inhibitors in WM in front-line and refractory or relapsed settings. We also highlight common adverse events, the emergence of BTK inhibitors resistance, and future directions of their use.