BACKGROUND: Minimally invasive oncological resections have become increasingly widespread in the surgical management of cancers. However, the role of minimally invasive surgery (MIS) for gallbladder cancer (GBC) remains unclear. We aim to perform a systematic review and network meta-analysis of existing literature to evaluate the safety and feasibility of laparoscopic and robotic surgery in the management of GBC compared to open surgery (OS) by comparing outcomes.
METHODS: A literature search of the PubMed/MEDLINE (2000 to December 2021) and EMBASE (2000 to December 2021) databases was conducted. The primary outcome studied was overall survival, and secondary outcomes studied were postoperative morbidity, severe complications, incidence of bile leak, length of hospital stay, operation time, R0 resection rate, local recurrence and lymph node yield.
RESULTS: Thirty-two full-text articles met the eligibility criteria and were included in the final analysis with a total of 5883 patients undergoing either OS or MIS (laparoscopic or robotic) for GBC. 1- and 2-stage meta-analyses did not reveal any significant differences between OS, laparoscopic and robotic surgery in terms of overall survival, R0 resection, lymph node harvest, local recurrence and post-operative complications. Patients who underwent OS had significantly longer hospitalization stay and intra-operative blood loss compared to those who underwent laparoscopic or robotic surgery. Network meta-analysis did not reveal any significant differences between post-operative and survival outcomes of laparoscopic vs robotic surgery groups.
CONCLUSIONS: This network meta-analysis suggests that both laparoscopic and robotic surgery are safe and effective approaches in the surgical management of GBC, with post-operative and survival outcomes comparable to OS. An MIS approach may also lead to shorter hospitalization stay, less intraoperative blood loss and post-operative complications compared to OS. There was no obvious benefit of either MIS approach (laparoscopic versus robotic) over the other.

BACKGROUND: The predominant immune cells in solid tumors are M2-like tumor-associated macrophages (M2-like TAMs), which significantly impact the promotion of epithelial-mesenchymal transition (EMT) in tumors, enhancing stemness and facilitating tumor invasion and metastasis. However, the contribution of M2-like TAMs to tumor progression in gallbladder cancer (GBC) is partially known.
METHODS: Immunohistochemistry was used to evaluate the expression of M2-like TAMs and cancer stem cell (CSC) markers in 24 pairs of GBC and adjacent noncancerous tissues from patients with GBC. Subsequently, GBC cells and M2-like TAMs were co-cultured to examine the expression of CSC markers, EMT markers, and migratory behavior. Proteomics was performed on the culture supernatant of M2-like TAMs. The mechanisms underlying the induction of EMT, stemness, and metastasis in GBC by M2-like TAMs were elucidated using proteomics and transcriptomics. GBC cells were co-cultured with undifferentiated macrophages (M0) and analyzed. The therapeutic effect of gemcitabine combined with a chemokine (C-C motif) receptor 2 (CCR2) antagonist on GBC was observed in vivo.
RESULTS: The expression levels of CD68 and CD163 in M2-like TAMs and CD44 and CD133 in gallbladder cancer stem cells (GBCSCs) were increased and positively correlated in GBC tissues compared with those in neighboring noncancerous tissues. M2-like TAMs secreted a significant amount of chemotactic cytokine ligand 2 (CCL2), which activated the MEK/extracellular regulated protein kinase (ERK) pathway and enhanced SNAIL expression after binding to the receptor CCR2 on GBC cells. Activation of the ERK pathway caused nuclear translocation of ELK1, which subsequently led to increased SNAIL expression. GBCSCs mediated the recruitment and polarization of M0 into M2-like TAMs within the GBC microenvironment via CCL2 secretion. In the murine models, the combination of a CCR2 antagonist and gemcitabine efficiently inhibited the growth of subcutaneous tumors in GBC.
CONCLUSIONS: The interaction between M2-like TAMs and GBC cells is mediated by the chemokine CCL2, which activates the MEK/ERK/ELK1/SNAIL pathway in GBC cells, promoting EMT, stemness, and metastasis. A combination of a CCR2 inhibitor and gemcitabine effectively suppressed the growth of subcutaneous tumors. Consequently, our study identified promising therapeutic targets and strategies for treating GBC.

UNASSIGNED: Biliary tract cancer (BTC) is a rare, lethal, heterogeneous group of cancers often diagnosed at an advanced stage. While gemcitabine plus cisplatin is the standard of care for first-line treatment of locally advanced or metastatic BTC, no globally accepted standard of care currently exists for second-line treatment of BTC following chemotherapy. However, the treatment landscape is evolving with approvals for therapies targeting actionable mutations. This study aimed to characterize treatment patterns and survival in patients with locally advanced or metastatic BTC.
UNASSIGNED: Patients with advanced or metastatic BTC in the Surveillance, Epidemiology, and End Results Medicare database between 2010 and 2015 (N = 2063) were included; patients with nonprimary BTC were excluded. Patient and clinical characteristics, line and type of therapy, and overall survival of patients were analyzed.
UNASSIGNED: Only 45.5% (n = 938) of patients initiated systemic therapy within 90 days of diagnosis. The most common event following diagnosis was initiation of first-line therapy, and the most common event following first-line treatment was death. Median survival ranged from 5.0 months for patients receiving second-line fluoropyrimidine to 9.7 months for patients receiving second-line gemcitabine. Duration of therapy ranged from 0.7 months for patients receiving second-line fluoropyrimidine to 3.7 months for patients receiving first-line gemcitabine plus cisplatin therapy.
UNASSIGNED: Overall survival from diagnosis was poor and influenced by age, sex, stage, mobility limitations, comorbidity burden, poverty, and previous cancer. Treatment patterns varied for patients who progressed following first-line therapy, as there was no consensus second-line treatment for locally advanced or metastatic BTC without clinically targetable mutations.

BACKGROUND: Up to 90% of patients undergo inadequate resection for incidentally diagnosed T1b-T3 gallbladder cancer (GBC). We evaluated whether adjuvant therapies (ATs) are associated with prolonged overall survival (OS) for patients undergoing inadequate resection of T1b-T3 GBC.
METHODS: Patients who underwent inadequate resection, defined as simple cholecystectomy, for T1b-T3, Nx-N2, and M0 GBC were identified from the National Cancer Database (2004-2016). Patient characteristics, variables associated with AT use, and OS were described using the chi-square test, multivariable logistical regression, Kaplan-Meier, and Cox proportional hazard models.
RESULTS: Of 1386 patients who met inclusion criteria, most received no AT (64%), 20% received chemotherapy (CT), and 16% received chemoradiotherapy (CRT). Patients who received no AT were generally older (51% ≥ 75 y) and had no comorbidities (65% Charlson Comorbidity Index 0). Among those who received AT, CRT rather than CT, tended to be employed for patients who were older (≥75 y) or had more comorbidities (Charlson Comorbidity Index ≥1). Patients with advanced disease (T3, positive lymph nodes, or positive margins) were more likely to receive CRT. For T1b-T3 GBC, any AT was associated with prolonged median OS compared to no AT (22 months versus 15 mo, P < 0.01). Relative to no AT, CT (hazard ratio 0.76, 95% confidence interval 0.67-0.92) and CRT (0.59, 95% confidence interval 0.49-0.72) were associated with decreased risk of death.
CONCLUSIONS: AT was associated with prolonged OS for patients with inadequately resected T1b-T3 GBC. CRT may have a role in treatment for patients with high-risk disease following inadequate resection of T1b-T3 GBC.

Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system, with poor response to current treatments. Abnormal alternative splicing has been associated with the development of a variety of tumors. Combining the GEO database and GBC mRNA-seq analysis, it is found high expression of the splicing factor polypyrimidine region- binding protein 3 (PTBP3) in GBC. Multi-omics analysis revealed that PTBP3 promoted exon skipping of interleukin-18 (IL-18), resulting in the expression of ΔIL-18, an isoform specifically expressed in tumors. That ΔIL-18 promotes GBC immune escape by down-regulating FBXO38 transcription levels in CD8+T cells to reduce PD-1 ubiquitin-mediated degradation is revealed. Using a HuPBMC mouse model, the role of PTBP3 and ΔIL-18 in promoting GBC growth is confirmed, and showed that an antisense oligonucleotide that blocked ΔIL-18 production displayed anti-tumor activity. Furthermore, that the H3K36me3 promotes exon skipping of IL-18 by recruiting PTBP3 via MRG15 is demonstrated, thereby coupling the processes of IL-18 transcription and alternative splicing. Interestingly, it is also found that the H3K36 methyltransferase SETD2 binds to hnRNPL, thereby interfering with PTBP3 binding to IL-18 pre-mRNA. Overall, this study provides new insights into how aberrant alternative splicing mechanisms affect immune escape, and provides potential new perspectives for improving GBC immunotherapy.

UNASSIGNED: Lymph node involvement is recognized as a prognostic factor for patients with gallbladder cancer. However, the N stage varied from different editions of the American Joint Committee on Cancer (AJCC) TNM Classification. Our objective was to investigate the impact of lymph node involvement on overall survival in elderly patients with non-metastatic gallbladder adenocarcinoma.
UNASSIGNED: Patients older than 65 years with non-metastatic gallbladder adenocarcinoma were identified from the SEER data. We used Cox proportional hazard regression analysis to select the independent risk factor. A nomogram was built to identify the 1-, 3-, and 5-years\' prognostic impact. Univariate and multivariate models were used to examine the correlation of overall survival (OS) with the number of metastatic nodes.
UNASSIGNED: A total of 1,654 patients (706 with and 948 without nodal involvement) were included. Cox proportional hazard regression analyses found that age, gender, tumor size, lymph node involvement, and surgical options were risk factors for the prognosis and were integrated into the nomogram. After adjustment, OS was compromised for patients who receive surgery with nodal involvement [hazard ratio (HR), 2.238; P < 0.01]. Furthermore, after adjustment the presence of more than two metastatic lymph nodes was associated with decreased OS (HR, 3.305; P < 0.01).
UNASSIGNED: Our results suggest that lymph node involvement is associated with compromised survival in elderly patients. A nomogram was developed to predict the prognosis of gallbladder cancer. A change point of more than two metastatic lymph nodes seems to carry prognostic significance, calling for closer monitoring of elderly patients with gallbladder cancer with involvement of increased number of lymph nodes.

BACKGROUND: The effect of neoadjuvant chemotherapy (NACT) in gallbladder cancer (GBC) patients remains controversial. The aim of this study was to assess the impact of NACT on overall survival (OS) and cancer specific survival (CSS) in patients with localized or locoregionally advanced GBC, and to explore possible protective predictors for prognosis.
METHODS: Data for patients with localized or locoregionally advanced GBC (i.e., categories cTx-cT4, cN0-2, and cM0) from 2004 to 2020 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Patients in the NACT and non-NACT groups were propensity score matched (PSM) 1:3, and the Kaplan-Meier method and log-rank test were performed to analyze the impact of NACT on OS and CSS. Univariable and multivariable Cox regression models were applied to identify the possible prognostic factors. Subgroup analysis was conducted to identify patients who would benefit from NACT.
RESULTS: Of the 2676 cases included, 78 NACT and 234 non-NACT patients remained after PSM. In localized or locoregionally advanced GBC patients, the median OS of the NACT and non-NACT was 31 and 16 months (log-rank P < 0.01), and the median CSS of NACT and non-NACT was 32 and 17 months (log-rank P < 0.01), respectively. Longer median OS (31 vs 17 months, log-rank P < 0.01) and CSS (32 vs 20 months, log-rank P < 0.01) was associated with NACT compared with surgery alone. Multivariable Cox regression analysis showed that NACT, stage, and surgery type were prognostic factors for OS and CSS in GBC patients. Subgroup analysis revealed that the survival hazard ratios (HRs) of NACT vs non-NACT for localized or locoregionally advanced GBC patients were significant in most subgroups.
CONCLUSIONS: NACT may provide therapeutic benefits for localized or locoregionally advanced GBC patients, especially for those with advanced stage, node-positive, poorly differentiated or undifferentiated disease. NACT combined with radical surgery was associated with a survival advantage. Therefore, NACT combined with surgery may provide a better treatment option for resectable GBC patients.

BACKGROUND: Cross-species horizontal gene transfer (HGT) involves the transfer of genetic material between different species of organisms. In recent years, mounting evidence has emerged that cross-species HGT does take place and may play a role in the development and progression of diseases.
METHODS: Transcriptomic data obtained from patients with gallbladder cancer (GBC) was assessed for the differential expression of antisense RNAs (asRNAs). The Basic Local Alignment Search Tool (BLAST) was used for cross-species analysis with viral, bacterial, fungal, and ancient human genomes to elucidate the evolutionary cross species origins of these differential asRNAs. Functional enrichment analysis and text mining were conducted and a network of asRNAs targeting mRNAs was constructed to understand the function of differential asRNAs better.
RESULTS: A total of 17 differentially expressed antisense RNAs (asRNAs) were identified in gallbladder cancer tissue compared to that of normal gallbladder. BLAST analysis of 15 of these asRNAs (AFAP1-AS1, HMGA2-AS1, MNX1-AS1, SLC2A1-AS1, BBOX1-AS1, ELFN1-AS1, TRPM2-AS, DNAH17-AS1, DCST1-AS1, VPS9D1-AS1, MIR1-1HG-AS1, HAND2-AS1, PGM5P4-AS1, PGM5P3-AS1, and MAGI2-AS) showed varying degree of similarities with bacterial and viral genomes, except for UNC5B-AS1 and SOX21-AS1, which were conserved during evolution. Two of these 15 asRNAs, (VPS9D1-AS1 and SLC2A1-AS1) exhibited a high degree of similarity with viral genomes (Chikungunya virus, Human immunodeficiency virus 1, Stealth virus 1, and Zika virus) and bacterial genomes including (Staphylococcus sp., Bradyrhizobium sp., Pasteurella multocida sp., and, Klebsiella pneumoniae sp.), indicating potential HGT during evolution.
CONCLUSIONS: The results provide novel evidence supporting the hypothesis that differentially expressed asRNAs in GBC exhibit varying sequence similarity with bacterial, viral, and ancient human genomes, indicating a potential shared evolutionary origin. These non-coding genes are enriched with methylation and were found to be associated with cancer-related pathways, including the P53 and PI3K-AKT signaling pathways, suggesting their possible involvement in tumor development.

UNASSIGNED: The aim was to compare survival for incidental gallbladder cancer (IGBC), respectively, preoperatively suspected gallbladder cancer (GBC), subjected to surgery for different pathological tumour (pT) stages and in different treatment groups in a national cohort.
UNASSIGNED: Data were collected and crosslinked from two national quality registers, SweLiv (2009-2019) and GallRiks (2009-2016). Survival was estimated using Kaplan-Meier analysis. The log-rank test and Cox regression analyses were used to compare groups.
UNASSIGNED: In total, 466 IGBC patients, including 225 who only underwent simple cholecystectomy (SC), and 477 GBC patients were included. Most patients were female, with small differences in mean age between groups. In all IGBC patients compared with GBC patients, an improved 5-year overall survival in pT3 GBC undergoing surgery (GBC 13% vs all IGBC 8%, p < 0.001), was seen. GBC was shown to be an independent predictor for improved survival in pT3 patients (hazard ratio (HR): 0.6; 95% confidence interval (CI): 0.4-0.8, p < 0.001). In addition, in GBC with curative reresection compared with IGBC SC and IGBC with curative resection, an improved 5-year overall survival in pT3 GBC was shown (GBC 20% vs all IGBC 10%, p < 0.001). GBC was an independent predictor for improved survival in pT3 patients with curative resection (HR: 0.4; 95% CI: 0.3-0.7, p < 0.001).
UNASSIGNED: GBC was shown to be an independent predictor for improved survival in pT3 patients, and patients with GBC may benefit from one-stage resection. It is, therefore, reasonable to recommend that radiological suspicion of malignancy should be evaluated at a liver tumour centre to optimize patient outcomes.

Background: Gallbladder cancer (GBC) is a rare entity with a poor prognosis, usually discovered late due to nonspecific symptoms; therefore, over the last years, attention has been focused on identifying the risk factors for developing this malignancy in order to provide an early diagnosis, as well as new prognostic factors in order to modulate the long-term evolution of such cases. The aim of this review is to discuss both major risk factors and prognostic factors in GBC for a better understanding and integration of relevant and currently available information. Methods: A literature search was performed using Cochrane Library, PubMed, Google Scholar, Elsevier, and Web of Science; studies published after the year of 2000, in English, were reviewed. Results: Over time, risk factors associated with the development of GBC have been identified, which outline the profile of patients with this disease. The most important prognostic factors in GBC remain TNM staging, safety margin, and R0 status, along with perineural invasion and lymphovascular invasion. Both the technique and experience of the surgeons and a pathological examination that ensures final staging are particularly important and increase the chances of survival of the patients. Conclusions: improvements in surgical techniques and pathological analyses might provide better and more consistent guidance for medical staff in the management of patients with GBC.