Durvalumab Plus Gemcitabine and Cisplatin Versus Gemcitabine and Cisplatin in Biliary Tract Cancer: a Real-World Retrospective, Multicenter Study.

BACKGROUND: The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed cell death ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). OBJECTIVE: The present study investigated for the first time the impact on survival of adding durvalumab to cisplatin/gemcitabine compared with cisplatin/gemcitabine in a real-world setting. PATIENTS AND METHODS: The analyzed population included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab in combination with cisplatin/gemcitabine or with cisplatin/gemcitabine alone. The impact of adding durvalumab to chemotherapy in terms of overall survival (OS) and progression free survival (PFS) was investigated with univariate and multivariate analysis. RESULTS: Overall, 563 patients were included in the analysis: 213 received cisplatin/gemcitabine alone, 350 received cisplatin/gemcitabine plus durvalumab. At the univariate analysis, the addition of durvalumab was found to have an impact on survival, with a median OS of 14.8 months versus 11.2 months [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.50-0.80, p = 0.0002] in patients who received cisplatin/gemcitabine plus durvalumab compared to those who received cisplatin/gemcitabine alone. At the univariate analysis for PFS, the addition of durvalumab to cisplatin/gemcitabine demonstrated a survival impact, with a median PFS of 8.3 months and 6.0 months (HR 0.57, 95% CI 0.47-0.70, p < 0.0001) in patients who received cisplatin/gemcitabine plus durvalumab and cisplatin/gemcitabine alone, respectively. The multivariate analysis confirmed that adding durvalumab to cisplatin/gemcitabine is an independent prognostic factor for OS and PFS, with patients > 70 years old and those affected by locally advanced disease experiencing the highest survival benefit. Finally, an exploratory analysis of prognostic factors was performed in the cohort of patients who received durvalumab: neutrophil-lymphocyte ratio (NLR) and disease stage were to be independent prognostic factors in terms of OS. The interaction test highlighted NLR ≤ 3, Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 0, and locally advanced disease as positive predictive factors for OS on cisplatin/gemcitabine plus durvalumab. CONCLUSION: In line with the results of the TOPAZ-1 trial, adding durvalumab to cisplatin/gemcitabine has been confirmed to confer a survival benefit in terms of OS and PFS in a real-world setting of patients with advanced BTC.

The Italian Rare Biliary tract Cancer initiative (IRaBiCa): A multicentric observational study of Gruppo Oncologico dell'Italia Meridionale (GOIM) in collaboration with Gruppo Italiano Colangiocarcinoma (GICO).

INTRODUCTION: About 90% of cholangiocarcinomas are adenocarcinomas with glandular or tubular structures lined by epithelial cells, with no bile production and with a variable degree of differentiation, arising in the background of desmoplastic stroma. The remaining 10% is represented by rarer histological variants of which there is little knowledge regarding the biological behavior, molecular characterization, and sensitivity to the various possible therapies, including molecular-based treatments. Such rare tumors are described only in case reports or small retrospective series because of their exclusion from clinical trials. This national initiative, here presented, aims to address the following knowledge gap: a) how much does histological diversity translate into clinical manifestation variety? b) are those chemotherapy regimens, recommended for conventional biliary tract cancers, potentially active in rare variants?Therefore, epidemiological, pathological, and clinical characterization of series of rare biliary histotypes/variants, for which therapeutic and follow-up data are available, will be collected. METHODS: An Italian task force on rare tumors of the biliary tract (IRaBiCa) has been created, whose initiative is a multicenter retrospective study involving 34 Italian cancer centers.Clinical data from approximately 100 patients will be collected and analyzed. Continuous variables will be presented as median ± standard deviation, while categorical variables will be expressed in terms of frequency. Kaplan-Maier analyses will be used to compare disease free, progression free and overall survival, according to the different histotypes. CONCLUSIONS: We expect to gather novel data on rare histotypes of biliary tract cancer that will be useful to support their molecular and immunological characterization.

HSV1 microRNAs in glioblastoma development: an in silico study.

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor. Recent findings highlighted the significance of viral microRNAs (miRs) in regulating post-transcriptional mRNA expression in various human conditions. Although HSV1 encodes viral miRs and affects the central nervous system, no study investigated the roles of HSV1-encoding miRs in GBM development. This study applied in silico approaches to investigate whether HSV1-encoding miRs are involved in GBM development and, if so, how they regulate tumor-suppressive/oncogenes expression in GBM. This study leveraged bioinformatics approaches to identify the potential effect of HSV1 miRs in GBM development. The GSE158284, GSE153679, and GSE182109 datasets were analyzed to identify differentially expressed genes in GBM tissues and cell lines using the limma package in the R software. The GSE182109 dataset was analyzed to determine gene expression at the single-cell levels using the Seurat package in the R software. The TCGA-GTEX, GDSC, CTRP, immunogenetic, and enrichment analyses were performed to study the impact of identified viral HSV1 miRs targets in GBM development. hsv1-miR-H6-3p is upregulated in GBM and can be responsible for EPB41L1 and SH3PXD2A downregulation in GBM tissues. Also, hsv1-miR-H1-5p is upregulated in GBM and can decrease the expression of MELK, FZD2, NOVA1, TMEM97, PTPRZ1, and PDGFC in GBM development. The single-cell RNA sequencing analyses have demonstrated that MELK, FZD2, NOVA1, TMEM97, PTPRZ1, and PDGFC are expressed in astrocytes residing in the GBM microenvironment. This study provides novel insights into the potential roles of HSV1 miRs in GBM pathogenesis and offers a reference for further studies on the significance of HSV1 miRs in GBM development.

Mapping the landscape of immunonutrition and cancer research: a comprehensive bibliometric analysis on behalf of NutriOnc Research Group.

The ongoing global health challenge of cancer is driving the pursuit of innovative avenues for prevention, treatment, and enhanced outcomes. The convergence of nutrition and immune modulation, known as immunonutrition, is ready to act as a catalyst for transformative change in cancer research and therapy. Our study employs a bibliometric analysis to uncover the evolving trends within immunonutrition and cancer research across the past 25 years. Bibliometric data, including authors, journals, affiliations, and countries, were analyzed using the Bibliometrix R package. Clustering algorithms were applied to keywords to identify thematic areas and their evolution. A total of 489 documents were analyzed, showing an annual growth rate of 8.7%, with a collaboration index of 5.41, highlighting comprehensive multidisciplinary involvement within this landscape. Core authors demonstrated sustained productivity, while occasional authors indicated widespread interest. The Medical University of Warsaw led in institutional contributions. Country-wise, Italy, France, and the USA emerged as forerunners in fostering research productivity. Key journals like 'Clinical Nutrition' served as beacons, emphasizing the multidimensional nature of this topic. The analysis highlighted growing research output and several collaborations, indicating the importance of immunoenriched nutrition in cancer treatment. The interplay of core authors and diversified engagement harmoniously accentuates the cross-disciplinary nature of this burgeoning field. International collaboration facilitated knowledge exchange. Prominent documents shaped the field, emphasizing the significance of nutritional interventions. Thematic clusters revealed varied focuses, including pharmaconutrients, surgical approaches, inflammation, and specific cancers. The expanding research output suggests further development, particularly in exploring immunoenriched nutrition's impact on cancer types and patient populations. The multidisciplinary nature and international collaborations enhance the field's progress. Gaps in research underscore the need for original studies and personalized approaches. This study guides future research, informing evidence-based nutritional interventions and advancing cancer care practices.

Clinical and Genomic Characterization of Pancreatic Ductal Adenocarcinoma with Signet-Ring/Poorly Cohesive Cells.

Signet-ring cell (SRC)/poorly cohesive cell carcinoma is an aggressive variant of pancreatic ductal adenocarcinoma (PDAC). This study aimed to clarify its clinicopathologic and molecular profiles based on a multi-institutional cohort of 20 cases. The molecular profiles were investigated using DNA and RNA sequencing. The clinicopathologic parameters and molecular alterations were analyzed based on survival indices and using a validation/comparative cohort of 480 conventional PDAC patients. The primary findings were as follows: (1) clinicopathologic features: SRC carcinomas are highly aggressive neoplasms with poor prognosis, and the lungs are elective metastatic sites; (2) survival analysis: a higher SRC component was indicative of poorer prognosis. In particular, the most clinically significant threshold of SRC was 80%, showing statistically significant differences in both disease-specific and disease-free survival; (3) genomic profiles: SRC carcinomas are similar to conventional PDAC with the most common alterations affecting the classic PDAC drivers KRAS (70% of cases), TP53 (55%), SMAD4 (25%), and CDKN2A (20%). EGFR alterations, RET::CCDC6 fusion gene, and microsatellite instability (3 different cases, 1 alteration per case) represent novel targets for precision oncology. The occurrence of SMAD4 mutations was associated with poorer prognosis; (4) pancreatic SRC carcinomas are genetically different from gastric SRC carcinomas: CDH1, the classic driver gene of gastric SRC carcinoma, is not altered in pancreatic SRC carcinoma; (5) transcriptome analysis: the cases clustered into 2 groups, one classical/exocrine-like, and the other squamous-like; and (6) SRC carcinoma-derived organoids can be successfully generated, and their cultures preserve the histologic and molecular features of parental SRC carcinoma. Although pancreatic SRC carcinoma shares similarities with conventional PDAC regarding the most important genetic drivers, it also exhibits important differences. A personalized approach for patients with this tumor type should consider the clinical relevance of histologic determination of the SRC component and the presence of potentially actionable molecular targets.

Impact of COVID-19 pandemic on outpatient visit volume in cancer patients: Results of COMETA multicenter retrospective observational study.

Objective: To evaluate the impact of the COVID-19 pandemic on first and follow-up visits for cancer outpatients. Methods: This is a multicenter retrospective observational study involving three Comprehensive Cancer Care Centers (CCCCs): IFO, including IRE and ISG in Rome, AUSL-IRCCS of Reggio Emilia, and IRCCS Giovanni Paolo II in Bari) and one oncology department in a Community Hospital (Saint'Andrea Hospital, Rome). From 1 January 2020 and 31 December 2021, we evaluated the volume of outpatient consultations (first visits and follow-up), comparing them with the pre-pandemic year (2019). Results were analyzed by quarter according to the Rt (real-time indicator used to assess the evolution of the pandemic). IFO and IRCCS Giovanni Paolo II were "COVID-free" while AUSL-IRCCS RE was a "COVID-mixed" Institute. Depending on the Rt, Sain't Andrea Hospital experienced a "swinging" organizational pathway (COVID-free/ COVID-mixed). Results: Regarding the "first appointments", in 2020 the healthcare facilities operating in the North and Center of Italy showed a downward trend. In 2021, only AUSL-IRCCS RE showed an upward trend. Regarding the "follow-up", only AUSL IRCCS RE showed a slight up-trend in 2020. In 2021, IFO showed an increasing trend, while S. Andrea Hospital showed a negative plateau. Surprisingly, IRCCS Giovanni Paolo II in Bari showed an uptrend for both first appointment and follow-ups during pandemic and late pandemic except for the fourth quarter of 2021. Conclusions: During the first pandemic wave, no significant difference was observed amongst COVID-free and COVID-mixed Institutes and between CCCCs and a Community Hospital. In 2021 ("late pandemic year"), it has been more convenient to organize COVID-mixed pathway in the CCCCs rather than to keep the Institutions COVID-free. A swinging modality in the Community Hospital did not offer positive results in term of visit volumes. Our study about the impact of COVID-19 pandemic on visit volume in cancer outpatients may help health systems to optimize the post-pandemic use of resources and improve healthcare policies.

Rare histotypes of epithelial biliary tract tumors: A literature review.

Adenocarcinoma represents the most frequent biliary tract cancer. However, other rare histotypes can be found in the biliary tract, such as cholangiolocellular carcinoma, cholangiocarcinoma with ductal plate malformation pattern, adenosquamous carcinoma, mucinous carcinoma, signet ring cell carcinoma, clear cell carcinoma, mucoepidermoid carcinoma, lymphoepithelioma-like carcinoma, and sarcomatous cholangiocarcinoma. These cancer types account for less than 10 % of all the already rare biliary tract tumors. Yet, they represent a relevant issue in everyday clinical practice, given the lack of therapeutic recommendations and the overall scarcity of data, mainly deriving from isolated small center-specific cohorts of patients.The shifts of such histotypes from the most common ones reflect genetic and molecular differences, determine changes in clinical aggressiveness, and suggest a possible variability in sensitivity to the standard treatments of biliary adenocarcinomas. The consistency and degree of these variables are still to be solidly demonstrated and investigated. Therefore, this paper aims to review the current literature concerning very infrequent and rare epithelial biliary tract cancers, focusing our attention on the clinical, molecular, and immunohistochemical features of these tumors.

Immunonutrition and prehabilitation in pancreatic cancer surgery: A new concept in the era of ERAS® and neoadjuvant treatment.

Pancreatic cancer (PC) is an aggressive disease, with a growing incidence, and a poor prognosis. Neoadjuvant treatments in PC are highly recommended in borderline resectable and recently in upfront resectable PC. PC is characterized by exocrine insufficiency and nutritional imbalance, leading to malnutrition/sarcopenia. The concept of malnutrition in PC is multifaceted, as the cancer-related alterations create an interplay with adverse effects of anticancer treatments. All these critical factors have a negative impact on the postoperative and oncological outcomes. A series of actions and programs can be implemented to improve resectable and borderline resectable PC in terms of postoperative complications, oncological outcomes and patients' quality of life. A timely nutritional evaluation and the implementation of appropriate evidence-based nutritional interventions in onco-surgical patients should be considered of importance to improve preoperative physical fitness. Unfortunately, nutritional care and its optimization are often neglected in real-world clinical practice. Currently available studies and ERAS® guidelines mostly support the use of pre- or perioperative medical nutrition, including immunonutrition, in order to decrease the rate of postoperative infections and length of hospital stay. Further data also suggest that medical nutrition should be considered proactively in PC patients, to possibly prevent severe malnutrition and its consequences on disease and treatment outcomes. This narrative review summarizes the most recent data related to the role of prehabilitation, ERAS® program, medical nutrition, and the timing of intervention on clinical outcomes of upfront resectable and borderline PC, and their potential implementation within the timeframe of neoadjuvant treatments.

A scoping review on the significance of programmed death-ligand 1-inhibiting microRNAs in non-small cell lung treatment: A single-cell RNA sequencing-based study.

Background: The programmed death-ligand 1 (PD-L1)/PD-1 axis is one of the well-established inhibitory axes in regulating immune responses. Besides the significance of tumor-intrinsic PD-L1 expression in immune evasion, its oncogenic role has been implicated in various malignancies, like non-small cell lung cancer (NSCLC). As small non-coding RNAs, microRNAs (miRs) have pivotal roles in cancer biology. The current study aimed to systematically review the current knowledge about the significance of PD-L1-inhibiting miRs in NSCLC inhibition and their underlying mechanisms. Materials and methods: We conducted the current scoping review based on the PRISMA-ScR statement. We systematically searched Embase, Scopus, Web of Science, PubMed, Ovid, EBSCO, ProQuest, Cochrane Library, African Index Medicus, and Pascal-Francis up to 4 April 2021. We also performed in silico tumor bulk RNA sequencing and single-cell RNA sequencing to further the current knowledge of the non-coding RNA-mediated tumor-intrinsic PD-L1 regulation and the PD-L1/PD-1 axis in NSCLC. Results: The ectopic expression of hsa-miR-194-5p, hsa-miR-326, hsa-miR-526b-3p, hsa-miR-34a-5p, hsa-miR-34c-5p, hsa-miR-138-5p, hsa-miR-377-3p, hsa-let-7c-5p, hsa-miR-200a-3p, hsa-miR-200b-3p, hsa-miR-200c-3p, and hsa-miR-197-3p, as PD-L1-inhibiting miR, inhibits NSCLC development. These PD-L1-inhibiting miRs can substantially regulate the cell cycle, migration, clonogenicity, invasion, apoptosis, tumor chemosensitivity, and host anti-tumoral immune responses. Based on single-cell RNA sequencing results, PD-L1 inhibition might liberate the tumor-infiltrated CD8+ T-cells and dendritic cells (DCs)-mediated anti-tumoral immune responses via disrupting the PD-L1/PD-1 axis. Conclusion: Given the promising preclinical results of these PD-L1-inhibiting miRs in inhibiting NSCLC development, their ectopic expression might improve NSCLC patients' prognosis; however, further studies are needed to translate this approach into clinical practice.

The expression pattern of Immune checkpoints after chemo/radiotherapy in the tumor microenvironment.

As a disease with the highest disease-associated burden worldwide, cancer has been the main subject of a considerable proportion of medical research in recent years, intending to find more effective therapeutic approaches with fewer side effects. Combining conventional methods with newer biologically based treatments such as immunotherapy can be a promising approach to treating different tumors. The concept of "cancer immunoediting" that occurs in the field of the tumor microenvironment (TME) is the aspect of cancer therapy that has not been at the center of attention. One group of the role players of the so-called immunoediting process are the immune checkpoint molecules that exert either co-stimulatory or co-inhibitory effects in the anti-tumor immunity of the host. It involves alterations in a wide variety of immunologic pathways. Recent studies have proven that conventional cancer therapies, such as chemotherapy, radiotherapy, or a combination of them, i.e., chemoradiotherapy, alter the "immune compartment" of the TME. The mentioned changes encompass a wide range of variations, including the changes in the density and immunologic type of the tumor-infiltrating lymphocytes (TILs) and the alterations in the expression patterns of the different immune checkpoints. These rearrangements can have either anti-tumor immunity empowering or immune attenuating sequels. Thus, recognizing the consequences of various chemo(radio)therapeutic regimens in the TME seems to be of great significance in the evolution of therapeutic approaches. Therefore, the present review intends to summarize how chemo(radio)therapy affects the TME and specifically some of the most important, well-known immune checkpoints' expressions according to the recent studies in this field.

CTLA-4 silencing in dendritic cells loaded with colorectal cancer cell lysate improves autologous T cell responses in vitro.

Dendritic cell (DC)-based immunotherapy has increased interest among anti-cancer immunotherapies. Nevertheless, the immunosuppressive mechanisms in the tumor milieu, e.g., inhibitory immune checkpoint molecules, have been implicated in diminishing the efficacy of DC-mediated anti-tumoral immune responses. Therefore, the main challenge is to overcome inhibitory immune checkpoint molecules and provoke efficient T-cell responses to antigens specifically expressed by cancerous cells. Among the inhibitory immune checkpoints, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression on DCs diminishes their maturation and antigen presentation capability. Accordingly, we hypothesized that the expression of CTLA-4 on DCs inhibits the T cell-mediated anti-tumoral responses generated following the presentation of tumor antigens by DCs to T lymphocytes. In this study, we loaded colorectal cancer (CRC) cell lysate on DCs and inhibited the expression of CTLA-4 by small interfering RNA (siRNA) in them to investigate the DCs' functional and phenotypical features, and T-cell mediated responses following DC/T cell co-culture. Our results demonstrated that blockade of CTLA-4 could promote stimulatory properties of DCs. In addition, CTLA-4 silenced CRC cell lysate-loaded DCs compared to the DCs without CTLA-4 silencing resulted in augmented T cell proliferation and cytokine production, i.e., IFN-γ and IL-4. Taken together, our findings suggest CTLA-4 silenced CRC cell lysate-loaded DCs as a promising therapeutic approach however further studies are needed before this strategy can be used in clinical practice.

Genomic characterization of undifferentiated sarcomatoid carcinoma of the pancreas.

Undifferentiated sarcomatoid carcinoma (USC) of the pancreas is a rare but especially aggressive variant of pancreatic ductal adenocarcinoma (PDAC), composed of at least 80% of sarcomatoid cells. This study aimed to elucidate its clinicopathological and molecular features. The study cohort included 10 patients with pancreatic USC. Clinicopathological parameters were determined for each patient. The molecular profile was investigated using next-generation sequencing (NGS). Histologically, all tumors were hypercellular neoplasms with spindle-shaped or sarcomatoid cells. All patients showed vascular and perineural invasion. Most patients had a poor prognosis. NGS showed important similarities with conventional PDAC, including frequent alterations in the classic PDAC drivers, KRAS (100% of cases), TP53 (90%), and CDKN2A (60%). There were also some important distinctions from conventional PDAC: 1) SMAD4, a typical PDAC driver gene, was mutated in only one case (10%); 2) Another distinctive molecular feature was the recurrent KRAS amplification (30% of cases), which is very rare in conventional PDAC. It has been previously reported in another subtype of pancreatic undifferentiated carcinoma, the rhabdoid variant, and may be a key event leading to the acquisition of an undifferentiated phenotype in a subgroup of cases; 3) Lastly, in two different cases, we detected two potentially actionable targets, not belonging to the typical PDAC molecular landscape, such as MCL1 amplification and POLQ mutation. Our study sheds light on this rare tumor type, which shows aggressive biological behavior and few druggable alterations. The most distinctive molecular features of pancreatic USC are the paucity of SMAD4 alterations and recurrent KRAS amplification.

Targeted Therapy of B7 Family Checkpoints as an Innovative Approach to Overcome Cancer Therapy Resistance: A Review from Chemotherapy to Immunotherapy.

It is estimated that there were 18.1 million cancer cases worldwide in 2018, with about 9 million deaths. Proper diagnosis of cancer is essential for its effective treatment because each type of cancer requires a specific treatment procedure. Cancer therapy includes one or more approaches such as surgery, radiotherapy, chemotherapy, and immunotherapy. In recent years, immunotherapy has received much attention and immune checkpoint molecules have been used to treat several cancers. These molecules are involved in regulating the activity of T lymphocytes. Accumulated evidence shows that targeting immune checkpoint regulators like PD-1/PD-L1 and CTLA-4 are significantly useful in treating cancers. According to studies, these molecules also have pivotal roles in the chemoresistance of cancer cells. Considering these findings, the combination of immunotherapy and chemotherapy can help to treat cancer with a more efficient approach. Among immune checkpoint molecules, the B7 family checkpoints have been studied in various cancer types such as breast cancer, myeloma, and lymphoma. In these cancers, they cause the cells to become resistant to the chemotherapeutic agents. Discovering the exact signaling pathways and selective targeting of these checkpoint molecules may provide a promising avenue to overcome cancer development and therapy resistance. Highlights: (1) The development of resistance to cancer chemotherapy or immunotherapy is the main obstacle to improving the outcome of these anti-cancer therapies. (2) Recent investigations have described the involvement of immune checkpoint molecules in the development of cancer therapy resistance. (3) In the present study, the molecular participation of the B7 immune checkpoint family in anticancer therapies has been highlighted. (4) Targeting these immune checkpoint molecules may be considered an efficient approach to overcoming this obstacle.

The Basis and Advances in Clinical Application of Cytomegalovirus-Specific Cytotoxic T Cell Immunotherapy for Glioblastoma Multiforme.

A high percentage of malignant gliomas are infected by human cytomegalovirus (HCMV), and the endogenous expression of HCMV genes and their products are found in these tumors. HCMV antigen expression and its implications in gliomagenesis have emerged as a promising target for adoptive cellular immunotherapy (ACT) strategies in glioblastoma multiforme (GB) patients. Since antigen-specific T cells in the tumor microenvironments lack efficient anti-tumor immune response due to the immunosuppressive nature of glioblastoma, CMV-specific ACT relies on in vitro expansion of CMV-specific CD8+ T cells employing immunodominant HCMV antigens. Given the fact that several hurdles remain to be conquered, recent clinical trials have outlined the feasibility of CMV-specific ACT prior to tumor recurrence with minimal adverse effects and a substantial improvement in median overall survival and progression-free survival. This review discusses the role of HCMV in gliomagenesis, disease prognosis, and recent breakthroughs in harnessing HCMV-induced immunogenicity in the GB tumor microenvironment to develop effective CMV-specific ACT.

Identification of Common and Distinct Pathways in Inflammatory Bowel Disease and Colorectal Cancer: A Hypothesis Based on Weighted Gene Co-Expression Network Analysis.

Patients with inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, are at higher risk to develop colorectal cancer (CRC). However, the underlying mechanisms of this predisposition remain elusive. We performed in-depth comparative computational analyses to gain new insights, including weighted gene co-expression network analysis (WGCNA) and gene ontology and pathway enrichment analyses, using gene expression datasets from IBD and CRC patients. When individually comparing IBD and CRC to normal control samples, we identified clusters of highly correlated genes, differentially expressed genes, and module-trait associations specific for each disease. When comparing IBD to CRC, we identified common hub genes and commonly enriched pathways. Most notably, IBD and CRC share significantly increased expression of five genes (MMP10, LCN2, REG1A, REG3A, and DUOX2), enriched inflammatory and neutrophil activation pathways and, most notably, highly significant enrichment of IL-4 and IL-13 signaling. Thus, our work expands our knowledge about the intricate relationship between IBD and CRC development and provides new rationales for developing novel therapeutic strategies.

The role of immune checkpoint inhibitors in the treatment sequence of advanced gastric or gastro-esophageal junction cancer: A systematic review and meta-analysis of randomized trials.

PURPOSE: This study aimed to clarify the current knowledge on the use of immunotherapy in patients with advanced gastric(G)/gastroesophageal(GEJ) cancers. MATERIALS AND METHODS: A meta-analysis was done to evaluate the efficacy of immune checkpoint inhibitors(ICIs) in G/GEJ cancer both in the unselected population and in that stratified for combined positive score (CPS)≥ 1 and ≥ 10 patients. RESULTS: In the unselected population the result showed 21%(P < 0.00001), and 29%(P < 0.00001) reduction of death and progression risk for patients treated with ICIs compared without ICIs, while in CPS≥ 1 and≥ 10 populations, the result showed a death reduction of 19%(P = 0.001) and 33%(P < 0.00001) respectively, and, and 23% (P < 0.00001) and 43% (P < 0.00001) progression risk reduction respectively, for patients treated with and without ICIs. CONCLUSION: overall survival(OS) and progression free survival(PFS) data obtained in our meta-analysis, are in favor to use ICIs in association with standard first line chemotherapy for G/GEJ cancer patients regardless to CPS status.

Prediction and validation of GUCA2B as the hub-gene in colorectal cancer based on co-expression network analysis: In-silico and in-vivo study.

BACKGROUND: Several serious attempts to treat colorectal cancer have been made in recent decades. However, no effective treatment has yet been discovered due to the complexities of its etiology. METHODS: we used Weighted Gene Co-expression Network Analysis (WGCNA) to identify key modules, hub-genes, and mRNA-miRNA regulatory networks associated with CRC. Next, enrichment analysis of modules has been performed using Cluepedia. Next, quantitative real-time PCR (RT-qPCR) was used to validate the expression of selected hub-genes in CRC tissues. RESULTS: Based on the WGCNA results, the brown module had a significant positive correlation (r = 0.98, p-value=9e-07) with CRC. Using the survival and DEGs analyses, 22 genes were identified as hub-genes. Next, three candidate hub-genes were selected for RT-qPCR validation, and 22 pairs of cancerous and non-cancerous tissues were collected from CRC patients referred to the Gastroenterology and Liver Clinic. The RT-qPCR results revealed that the expression of GUCA2B was significantly reduced in CRC tissues, which is consistent with the results of differential expression analysis. Finally, top miRNAs correlated with GUCA2B were identified, and ROC analyses revealed that GUCA2B has a high diagnostic performance for CRC. CONCLUSIONS: The current study discovered key modules and GUCA2B as a hub-gene associated with CRC, providing references to understand the pathogenesis and be considered a novel candidate to CRC target therapy.

The regulatory role of autophagy-related miRNAs in lung cancer drug resistance.

Autophagy is conserved cellular machinery that degrades un-usable proteins and cellular components and has a crucial role in the pathogenesis and drug resistance of various diseases such as lung cancer (LC). Multiple types of endogenous molecules (i.e. miRNAs) have been found to regulate multiple biological processes, such as autophagy. Dysfunction of these molecules is associated with the onset and progression of a variety of human malignancies. Several studies had shown that some miRNAs could mediate autophagy activity in LC cells, which would affect drug resistance as a major problem in LC therapy. Therefore, identifying the underlying molecular targets of miRNAs and their function in autophagy pathways could develop new treatment interventions for LC patients. In this review, we will summarize the interplay between miRNAs, autophagy, and drug resistance of LC patients, as well as the genes and molecular pathways that are involved.

The cross-talk between tumor-associated macrophages and tumor endothelium: Recent advances in macrophage-based cancer immunotherapy.

Tumor-associated macrophages (TAMs) are among the abundant cell populations of the tumor microenvironment (TME), which have pivotal roles in tumor development, chemoresistance, immune evasion, and metastasis. Growing evidence indicates that TAMs and the cross-talk between TAMs and tumoral endothelial cells can substantially contribute to tumor angiogenesis, which is considered a vital process for cancer development. Besides, tumoral endothelial cells can regulate the leukocyte infiltration to the TME in solid cancers and contribute to immune evasion. Therefore, targeting the immunosuppressive TAMs and the cross-talk between them can be a promising strategy for improving anti-tumoral immune responses. This review aims to summarize the biology of TAMs, their recently identified roles in tumor development/angiogenesis, and recent advances in macrophage-based cancer immunotherapy approaches for treating cancers.