Search Results (195)

Cruciferae family vegetables are remarkably high in phytochemicals such as Indole-3-carbinol (I3C) and Diindolylmethane (DIM), which are widely known as nutritional supplements. I3C and DIM have been studied extensively in different types of cancers like breast, prostate, endometrial, colorectal, gallbladder, hepatic, and cervical, as well as cancers in other tissues. In this review, we summarized the protective effects of I3C and DIM against cardiovascular, neurological, reproductive, metabolic, bone, respiratory, liver, and immune diseases, infections, and drug- and radiation-induced toxicities. Experimental evidence suggests that I3C and DIM offer protection due to their antioxidant, anti-inflammatory, antiapoptotic, immunomodulatory, and xenobiotic properties. Apart from the beneficial effects, the present review also discusses the possible toxicities of I3C and DIM that are reported in various preclinical investigations. So far, most of the reports about I3C and DIM protective effects against various diseases are only from preclinical studies; this emphasizes the dire need for large-scale clinical trials on these phytochemicals against human diseases. Further, in-depth research is required to improve the bioavailability of these two phytochemicals to achieve the desirable protective effects. Overall, our review emphasizes that I3C and DIM may become potential drug candidates for combating dreadful human diseases. Full article

Background and Objectives: Gallbladder cancer (GBC) is a biologically aggressive malignancy characterised by poor survival outcomes often attributed to delayed diagnosis due to nonspecific clinical presentations. Paraneoplastic syndromes (PNSs), atypical symptoms caused by cancer itself, may serve as valuable indicators for timely diagnosis, particularly in malignancies with nonspecific features. Understanding the manifestations of PNSs in GBC is, therefore, critical. This systematic review collates case studies documenting the association of PNS with GBC, including subsequent management and clinical outcomes. Materials and Methods: A comprehensive search of PubMed, Embase, CINAHL, Web of Science, and Cochrane Library databases yielded 49 relevant articles. Upon searching other information sources, two more relevant articles were identified via citation sources. Results: The paraneoplastic syndromes were classified according to haematological (leukocytosis), dermatological (inflammatory myositis like dermatomyositis and polymyositis, acanthosis nigricans, Sweet’s syndrome, exfoliative dermatitis), neurological, metabolic (hypercalcemia, hyponatremia), and others (chorea). The analysis included the age, sex, and country of origin of the patient, as well as the time of PNS diagnosis relative to GBC diagnosis. Furthermore, common presenting complaints, investigations, and effectiveness of treatment modalities using survival time were assessed. Conclusions: While PNS management can offer some benefits, oncologic outcomes of GBC are largely poor. The majority of PNS in GBC are reported in advanced stages, and, hence, PNS has a minimal role in early diagnosis. PNS management can improve a patient’s quality of life, and thus recognition and treatment are important considerations in the holistic management of GBC patients. Full article

Gastrointestinal (GI) cancers, which mainly include malignancies of the esophagus, stomach, intestine, pancreas, liver, gallbladder, and bile duct, pose a significant global health burden. Unfortunately, the prognosis for most GI cancers remains poor, particularly in advanced stages. Current treatment options, including targeted and immunotherapies, are less effective compared to those for other cancer types, highlighting an urgent need for novel molecular targets. NEK (NIMA related kinase) kinases are a group of serine/threonine kinases (NEK1-NEK11) that play a role in regulating cell cycle, mitosis, and various physiological processes. Recent studies suggest that several NEK members are overexpressed in human cancers, including gastrointestinal (GI) cancers, which can contribute to tumor progression and drug resistance. Among these, NEK2 stands out for its consistent overexpression in all types of GI cancer. Targeting NEK2 with specific inhibitors has shown promising results in preclinical studies, particularly for gastric and pancreatic cancers. The development and clinical evaluation of NEK2 inhibitors in human cancers have emerged as a promising therapeutic strategy. Specifically, an NEK2 inhibitor, T-1101 tosylate, is currently undergoing clinical trials. This review will focus on the gene expression and functional roles of NEKs in GI cancers, as well as the progress in developing NEK inhibitors. Full article

Background: Biliary tract cancers (BTCs) have distinct tumor biology but share a poor prognosis, with a 5-year-survival-rate of 5–19%. Surgical resection is the only potential cure, but recurrences are common. The role of adjuvant radiotherapy (XRT) remains unclear. Methods: Using the National Cancer Database (2006–2018), we analyzed resected non-metastatic BTCs. Patients who survived beyond 90 days post-surgery were included, while those with R2 resections or neoadjuvant therapy were excluded. Propensity matching was performed based on predictors of adjuvant radiation, age, and sex. Survival outcomes were compared between no adjuvant therapy, chemotherapy alone, and XRT ± chemotherapy. Results: Among 21,275 patients, including 5308 intrahepatic cholangiocarcinoma (IHC), 2689 perihilar cholangiocarcinoma (PHC), 3092 distal cholangiocarcinoma (DCC), and 10,186 gallbladder cancer (GBC) cases, adjuvant XRT did not improve survival for IHC. For PHC and DCC, XRT improved survival over no adjuvant therapy (PHC: 31.2 vs. 26.3 months, p = 0.004; DCC: 33.7 vs. 27.0 months, p = 0.015) but not over chemotherapy alone. For GBC, XRT significantly improved survival compared to both no adjuvant therapy and chemotherapy (30.2 vs. 26.6 and 24.6 months; p = 0.05 and p = 0.001). Conclusions: XRT provides a survival benefit for GBC, especially in node-positive and R1-resected patients. For PHC and DCC, XRT improves outcomes compared to no therapy, but its benefit over chemotherapy is uncertain. No benefit was observed for IHC. Full article

Background: Biliary tract cancers (BTCs), including gallbladder and bile duct cancers, have a poor prognosis. Recent advances in chemotherapy, such as using targeted drugs for specific gene mutations, have improved outcomes. Gemcitabine plus cisplatin chemotherapy has been the standard of care for the primary treatment of BTCs, but secondary treatment had not been established until recently. In recent years, durvalumab plus gemcitabine and cisplatin (GCD) chemotherapy is emerging as a promising regimen, although more evidence is needed for its effectiveness. Methods: This retrospective single-center study involved 44 patients receiving GCD treatment between January 2023 and March 2024 with a median follow-up of 10 months. Outcomes focused on overall survival (OS), progression-free survival (PFS), response rates, and adverse events (AEs). Results: The overall response rate (ORR) was 23%, and the disease control rate (DCR) was 82%. The overall median OS and PFS were 15.3 and 8.0 months, respectively, with patients receiving primary chemotherapy experiencing longer survival compared to a control group. Patients who did not undergo bile duct drainage had statistically different better OS and PFS. Grade 3 or higher AEs occurred in 54.5% of patients, with neutropenia and biliary infections being common. Conclusions: GCD chemotherapy shows potential as an effective treatment for BTCs. The favorable treatment outcome was the response rate, particularly in primary therapy or those cases with no metastasis. Bile duct management is crucial for improving patient outcomes. GCD chemotherapy has a high response rate, PFS, and OS compared to other forms of chemotherapy. Full article

Cholangiocarcinoma (CCA) represents approximately 3% of all gastrointestinal cancers and is a highly heterogeneous and aggressive malignancy originating from the epithelial cells of the biliary tree. CCA is classified by anatomical location into intrahepatic (iCCA), extrahepatic (eCCA), gallbladder cancer (GBC), and ampullary cancers. Although considered a rare tumor, CCA incidence has risen globally, particularly due to the increased diagnosis of iCCA. Genomic and immune profiling studies have revealed significant heterogeneity within CCA, leading to the identification of molecular subtypes and actionable genetic alterations in 40–60% of cases, particularly in iCCA. Among these, FGFR2 rearrangements or fusions (7–15%) and IDH1 mutations (10–20%) are common in iCCA, while HER2 amplifications/overexpression are more frequent in eCCA and GBC. The tumor-immune microenvironment (TIME) of CCAs plays an active role in the pathogenesis and progression of the disease, creating a complex and plastic environment dominated by immune-suppressive populations. Among these, cancer-associated fibroblasts (CAFs) are a key component of the TIME and are associated with worse survival due to their role in maintaining a poorly immunogenic landscape through the deposition of stiff extracellular matrix and release of pro-tumor soluble factors. Improved understanding of CCA tumor biology has driven the development of novel treatments. Combination therapies of cisplatin and gemcitabine with immune checkpoint inhibitors (ICIs) have replaced the decade-long standard doublet chemotherapy, becoming the new standard of care in patients with advanced CCA. However, the survival improvements remain modest prompting research into more effective ways to target the TIME of CCAs. As key mechanisms of immune evasion in CCA are uncovered, novel immune molecules emerge as potential therapeutic targets. Current studies are exploring strategies targeting multiple immune checkpoints, angiogenesis, and tumor-specific antigens that contribute to immune escape. Additionally, the success of ICIs in advanced CCA has led to interest in their application in earlier stages of the disease, such as in adjuvant and neoadjuvant settings. This review offers a comprehensive overview of the immune biology of CCAs and examines how this knowledge has guided clinical drug development, with a focus on both approved and emergent treatment strategies. Full article

Objective: This systematic review and meta-analysis aimed to determine the degree to which pancreaticobiliary maljunction (PBM) increases the risk of different types of biliary cancer (BC). Methods: A systematic review and meta-analysis were carried out using the following databases: PubMed, Embase, Cochrane Library, Scopus, Web of Science, and Science Direct. We systematically searched from inception to April 2024. The search terms included were derived from the keywords “Pancreaticobiliary Maljunction” OR “Anomalous Pancreaticobiliary Junction” AND “Cancer” OR “Malignancy”. Studies that provided data comparing BC rates in relation to PBM presence or vice versa were included. The Newcastle–Ottawa Scale (NOS) was used for quality assessment. The random-effects model was used. Results: Fifteen studies were included with a total sample of 8604 patients, of whom 5015 (58.29%) were female with a mean age of 54.58 years. Patients with PBM had 8.42 (95% CI = 3.57–19.87) more risk of developing any type of BC, with a higher risk of GBC than BDC (OR = 16.91 vs. OR = 3.36, p-value = 0.003). There was a higher risk of having PBM in patients with GBC than BDC only when considering the Asian population (OR = 3.12, 95% CI = 1.09–8.94). Meta-regression analysis revealed that neither mean age (p = 0.087) nor percentage of female patients in the study population (p = 0.197) were statistically associated with the variations in OR for the risk of BC based on the presence of PBM. Conclusions: There is a significant association between PBM and the risk of having BC, mainly GBC when compared to BDC. Most of the studies published reported data from Japanese patients, which limits the generalization of the results. The age of patients and sex were not significantly associated with the relation between PBM and BC. Further prospective studies in broader populations will provide additional details to take measures for screening and early management of PBM and BC. Full article

Pancreatic cancer is associated with high rates of morbidity and mortality. Endoscopic ultrasound (EUS)-guided biopsy has become the standard diagnostic modality per the guidelines. The use of EUS has been growing for providing various treatments in patients with pancreatic cancers: biliary and gallbladder drainage for those with malignant biliary obstruction, gastroenterostomy for malignant gastric outlet obstruction, celiac plexus/ganglia neurolysis for pain control, radiofrequency ablation, placement of fiducial markers, and injection of local chemotherapeutic agents. In this review, we explore the recent clinical studies evaluating the EUS-guided treatments in pancreatic cancer. Full article

Latin Americans have a rich genetic make-up that translates into heterogeneous fractions of the autosomal genome in runs of homozygosity (F_ROH) and heterogeneous types and proportions of indigenous American ancestry. While autozygosity has been linked to several human diseases, very little is known about the relationship between inbreeding, genetic ancestry, and cancer risk in Latin Americans. Chile has one of the highest incidences of gallbladder cancer (GBC) in the world, and we investigated the association between inbreeding, GBC, gallstone disease (GSD), and body mass index (BMI) in 4029 genetically admixed Chileans. We calculated individual F_ROH above 1.5 Mb and weighted polygenic risk scores for GSD, and applied multiple logistic regression to assess the association between homozygosity and GBC risk. We found that homozygosity was due to a heterogeneous mixture of genetic drift and consanguinity in the study population. Although we found no association between homozygosity and overall GBC risk, we detected interactions of F_ROH with sex, age, and genetic risk of GSD that affected GBC risk. Specifically, the increase in GBC risk per 1% F_ROH was 19% in men (p-value = 0.002), 30% in those under 60 years of age (p-value = 0.001), and 12% in those with a genetic risk of GSD above the median (p-value = 0.01). The present study highlighted the complex interplay between inbreeding, genetic ancestry, and genetic risk of GSD in the development of GBC. The applied methodology and our findings underscored the importance of considering the population-specific genetic architecture, along with sex- and age-specific effects, when investigating the genetic basis of complex traits in Latin Americans. Full article

The etiology of gallbladder cancer (GBC) is multifactorial, with chronic inflammation resulting from infections, autoimmune diseases, and lifestyle factors playing a pivotal role. Vitamin D deficiency (VDD) has been implicated in the pathogenesis of autoimmune disorders and various malignancies, including GBC. Research on autoimmune diseases highlights the anti-inflammatory properties of vitamin D, suggesting its potential to mitigate disease progression. In oncology, VDD has similarly been linked to increased inflammation, which may contribute to both the initiation and progression of cancer. A critical component in carcinogenesis, as well as in the immunomodulatory effects of vitamin D in autoimmune conditions, is the balance between T-helper 17 (Th17) cells and regulatory T (Treg) cells. We hypothesize that vitamin D may inhibit epithelial–mesenchymal transition (EMT) in GBC by modulating the spatial distribution of tumor-infiltrating T cells, particularly through the regulation of the Th17/Treg balance at the tumor margins. This Th17/Treg imbalance may act as a mechanistic link between VDD and the progression of GBC carcinogenesis. Investigating the role of an Th17/Treg imbalance as a mediator in VDD-induced EMT in GBC not only provides deeper insights into the pathogenesis of GBC but also sheds light on broader mechanisms relevant to the development of other solid organ cancers, given the expanding recognition of the roles of VDD and Th17/Treg cells in cancer biology. Full article

Dendritic cells (DCs) are known to be major antigen-presenting cells, and lymph nodes (LNs) play an important role in DC-mediated immune response. CD1a is known as a marker of monocyte-derived DCs. The present study focused on the infiltration of CD1a-positive DCs (CD1a-DCs) into regional LNs in 70 cases of gallbladder cancer (GBC). After univariate analyses, the results showed that LN infiltration by CD1a-DCs was associated with unfavorable clinical outcomes in patients with GBC, with all cases categorized in the CD1a-DCs high group had nodal metastasis. LN infiltration by CD1a-DCs was not an independent prognostic factor identified by multivariate analyses. After subgroup analyses of cases with LN metastasis (n = 32), no significant impacts of CD1a-DCs infiltration into metastatic LNs were observed. In contrast, CD1a-DCs infiltration into primary tumors had a significant impact on surgical outcomes. The results of strong confounding between CD1a-DCs and LN metastasis support the theory that CD1a-DCs are developed from monocytes at tumor sites. As the results of previous research focused on CD1a-DCs infiltration into regional LNs of other organs varied, the role and significance of CD1a-DCs infiltration in regional LNs may be different according to the tumor histology or its primary site. Thus, further studies are needed to clarify the role and significance of CD1a-DCs infiltration into regional LNs of solid cancers. Full article

The objective of this study was to evaluate and compare the histopathological, clinical, and treatment characteristics of xanthogranulomatous cholecystitis (XGC) in patients undergoing cholecystectomy at a single center. Aim: We aim to enhance the understanding of its presentation and improve its differential diagnosis from other gallbladder pathologies. Methods: We retrospectively reviewed 6783 cholecystectomy cases performed between January 2015 and January 2023 at the General Surgery Clinic of Haydarpaşa Numune Training and Research Hospital, and a diagnosis of xanthogranulomatous cholecystitis was histopathologically established in 131 patients. In this retrospective study, we examined the clinicopathological characteristics, preoperative imaging methods and findings, histopathological images, surgical procedure methods, and postoperative complications of 131 patients. Results: The study included 131 patients, with ages ranging from 18 to 88 years, of which 74 (56.5%) were female and 57 (43.5%) were male. Ultrasound imaging was performed on 128 patients. Ultrasound imaging revealed wall thickening in 72.7% of cases, hypoechoic nodules in 13.3%, biliary tract pathologies in 10.9%, and adenomyomatosis in 3.1%. A total of 59 cases had MRI. On MRI, wall thickening was observed in 50.8% of cases, biliary tract pathologies in 33.9%, adenomyomatosis in 10.2%, hypoechoic nodules in 3.4%, and hypoechoic nodules + wall thickening (HN + WT) in 1.7%. Histopathological diagnosis was diffuse in 79.4% of cases and focal in 20.6%. In addition to cholecystectomy, non-surgical interventions were not required in 77.1% of the cases, while 11.5% underwent ERCP, 9.2% underwent percutaneous procedures, 1.5% underwent both ERCP and percutaneous procedures, and 0.8% underwent other non-surgical interventions. Of the surgeries, 93.1% were elective and 6.9% were emergency. Postoperative complications were not observed in 84% of the patients; 5.3% experienced surgical complications, 5.3% had surgical site infection, and 5.3% had other complications (pneumonia and urinary infection). The length of hospital stay ranged from 0 to 26 days, with a mean of 5.27 ± 4.59 days and a median of 4 days. Conclusions: Xanthogranulomatous cholecystitis is a rare disease of the gallbladder with no characteristic radiological or clinical findings and can often be confused with gallbladder cancer. Further studies involving larger populations are needed to improve the preoperative diagnosis. Full article

Introduction: Gallbladder cancer (GBC) is a rare and aggressive hepatobiliary malignancy with poor prognosis. The symptoms of GBC are insidious and non-specific in its early stages, and most patients are diagnosed at advanced or late stages. Surgical resection is the only potentially curative treatment for GBC for select patients. There is a lack of robust data for patients with GBC, leading to heterogenous practices in management strategies and outcomes. In this study, we aimed to identify patient characteristics and cumulative overall survival (OS) in patients with GBC who underwent surgical resection with curative intent. Methods: All adult patients (age ≥18 years) with localized or locoregionally advanced GBC who underwent definitive surgery with curative intent at our tertiary institution between 1/2013 and 12/2023 were retrospectively identified. Clinical, laboratory, radiology, histopathology, treatment, and survival data were collected from electronic medical records. Postoperative data included the use of adjuvant chemotherapy or radiotherapy, and patient survival mortality at a cut-off date of 1 February, 2024, calculated from the date of curative surgery. Continuous variables are reported as median and quartile 1 (Q1) and quartile 3 (Q3), while categorical variables are reported as counts and percentages. Results: A total of 94 patients with GBC were included in the study. Median age was 71 (62–77) years and 58 (61.7%) patients were female. Median tumor size was 3.3 (1.9–5.0) cm. Perineural invasion was seen in 48.9% and vascular invasion in 38.3% of patients. A positive surgical margin was present in 50% of the patients, and incidental GBC (IGBC) was seen in 48.9% of patients. Tumor grade was well differentiated in 7.6%, moderately differentiated in 53.3%, and poorly differentiated in 39.1% of the patients. Patients with stage T1a (2.1%) and T1b (11.7%) tumors comprised the minority, and the majority of the tumors were stage T2 (55.3%), followed by T3 (31.9%). A total of 60.6% of patients with GBC underwent adjuvant chemotherapy, and 17% underwent adjuvant radiotherapy after surgical resection. Overall, 62 (66.0%) patients died, and the median OS was 1.88 years. The 1-year OS was 68.7%, 3-year OS was 37.4%, and 5-year OS was 32.2%. A higher absolute median OS was seen in patients who had adjuvant chemotherapy (2.1 years) compared to no chemotherapy (1.9 years); however, this finding was not statistically significant (p = 0.36). The median survival was 2.3 years in IGBC compared to 1.6 years in non-IGBC (p = 0.63). Conclusions: GBC is an aggressive hepatobiliary malignancy that is often diagnosed at advanced stages. Our study showed high rates of local and systemic involvement and high mortality, and the need for prospective and randomized studies on adjuvant therapies to assess their survival benefit. Real-world patient data remain important to identify patients at risk of worse outcomes and to stratify risks prior to surgery. Full article

Background: Ochratoxin A (OTA) is widely recognized for its broad spectrum of toxic effects and is classified as a potential human carcinogen, placed in group 2B by the International Agency for Research on Cancer (IARC). Its presence in food and beverages poses a significant health hazard. Extensive research has documented the efficient absorption and distribution of OTA throughout the body via the bloodstream and tissues, underscoring the associated health risk. Additionally, ongoing studies aim to clarify the link between OTA exposure and carcinogenesis. The obtained results indicate a strong correlation between OTA and renal cell carcinoma (RCC), with potential associations with other malignancies, including hepatocellular carcinoma (HCC), gallbladder cancer (GBC), and squamous cell carcinoma (SCC). OTA is implicated in oxidative stress, lipid peroxidation, apoptosis, DNA damage, adduct formation, miRNA deregulation, and distributions in the cell cycle, all of which may contribute to carcinogenesis. Conclusions: Despite significant research efforts, the topic remains inexhaustible and requires further investigation. The obtained results do not yield definitive conclusions, potentially due to species-specific differences in the animal models used and challenges in extrapolating these results to humans. In our review, we delve deeper into the potential mechanisms underlying OTA-induced carcinogenesis and discuss existing limitations, providing directions for future research. Full article

Malignant lymphoma is an unusual form of gallbladder neoplasm. Almost all these tumors are diffuse large B-cell lymphomas or mucosa-associated lymphoid tissue-type lymphomas. Herein, we present a literature review of gallbladder Burkitt’s lymphoma (BL) cases that includes also an unpublished case in an HIV-infected child, observed by our center. The patient (a five-year-old black female child) attended the Federal Hospital of Lagoa, Rio de Janeiro, Brazil, underwent cholecystectomy, and the postoperative pathological analysis of the gallbladder revealed a diagnosis of BL (EBV-positive). Also, HIV serology was performed and returned positive. She was transferred to the Martagão Gesteira Institute of Pediatrics and Childcare for oncological treatment, dying from sepsis and disease progression about 18 months later. The patient did not undergo ART/cART. Previous cases of gallbladder BL were herein described and analyzed to characterize the clinicopathological features and possible similarities. BL can occur in the gallbladder both in the context of HIV infection and in the pediatric population. A biopsy is mandatory in cases with suggestive findings of lymphoma, and an early diagnosis can change the course of the disease. Furthermore, the case highlights the importance of an early initiation of ART/cART in people living with HIV (PLWH), especially in children. Full article