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Frontiers in Surgery 2024Over the course of nearly six decades since the inception of initial trials involving 5-FU in the treatment of mCRC (metastatic colorectal cancer), our progressive... (Review)
Review
Over the course of nearly six decades since the inception of initial trials involving 5-FU in the treatment of mCRC (metastatic colorectal cancer), our progressive comprehension of the pathophysiology, genetics, and surgical techniques related to mCRC has paved the way for the introduction of novel therapeutic modalities. These advancements not only have augmented the overall survival but have also positively impacted the quality of life (QoL) for affected individuals. Despite the remarkable progress made in the last two decades in the development of chemotherapy, immunotherapy, and target therapies, mCRC remains an incurable disease, with a 5-year survival rate of 14%. In this comprehensive review, our primary goal is to present an overview of mCRC treatment methods following the latest guidelines provided by the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the American Society of Colon and Rectal Surgeons (ASCRS). Emphasis has been placed on outlining treatment approaches encompassing chemotherapy, immunotherapy, targeted therapy, and surgery's role in managing mCRC. Furthermore, our review delves into prospective avenues for developing new therapies, offering a glimpse into the future of alternative pathways that hold potential for advancing the field.
PubMed: 38948479
DOI: 10.3389/fsurg.2024.1398289 -
Frontiers in Pharmacology 2024Pancreatoblastoma (PB), a neoplasm derived from pancreatic follicular cells, primarily affects the pediatric population. Although infrequent in adults, it is associated...
Pancreatoblastoma (PB), a neoplasm derived from pancreatic follicular cells, primarily affects the pediatric population. Although infrequent in adults, it is associated with a considerably worse prognosis. Approximately one-third of patients are diagnosed with metastatic disease, with liver metastases being the most prevalent. Diagnosis relies on histopathological alterations including squamous vesicles, positive staining for CK8/CK18/CK19, and nuclear displacement of β-catenin. Additionally, liver metastases demonstrate substantial enhancement during the arterial phase of a contrast-enhanced computed tomography (CT) scan. Surgical resection serves as the principal therapeutic approach for addressing primary lesions and liver metastatic PB. In instances where surgical intervention is not viable, patients may derive benefits from systemic therapy and radiotherapy. This particular case report presents the clinical details of a 27-year-old female patient diagnosed with PB, who subsequently developed multiple liver metastases following a pancreaticoduodenectomy. Genomic examinations revealed the presence of ERBB2 amplification, RAD54L deletion, low TMB-L, and MSS in the patient. Despite the patient undergoing chemotherapy and Her-2 targeted therapy in conjunction with immunotherapy, no reduction in lesion size was observed until the administration of surufatinib. Subsequently, a notable outcome ensued, where the metastatic lesions were effectively excised via surgical intervention. Surufatinib has demonstrated a progression-free survival (PFS) of no less than 14 months, and the patient's survival has endured for a duration of 33 months. This indicates the potential efficacy of surufatinib as a viable therapeutic alternative for adult patients afflicted with PB.
PubMed: 38948477
DOI: 10.3389/fphar.2024.1361628 -
Frontiers in Pharmacology 2024Genomic profiling has revolutionized therapeutic interventions and the clinical management of liver cancer. However, pathogenetic mechanisms, molecular determinants of...
Genomic profiling has revolutionized therapeutic interventions and the clinical management of liver cancer. However, pathogenetic mechanisms, molecular determinants of recurrence, and predictive biomarkers for first-line treatment (anti-PD-(L)1 plus bevacizumab) in liver cancer remain incompletely understood. Targeted next-generation sequencing (tNGS) (a 603-cancer-gene panel) was applied for the genomic profiling of 232 hepatocellular carcinoma (HCC) and 22 intrahepatic cholangiocarcinoma (ICC) patients, among which 47 unresectable/metastatic HCC patients underwent anti-PD-1 plus bevacizumab therapy. Genomic alterations were estimated for their association with vascular invasion (VI), location of onset, recurrence, overall survival (OS), recurrence-free survival (RFS), and anti-PD-1 plus bevacizumab therapy response. The genomic landscape exhibited that the most commonly altered genes in HCC were , , , , , and , while , , , , , and were frequently altered in ICC; notably, (18.18% vs. 1.29%) and (13.64% vs. 1.29%) alterations were significantly more prevalent in ICC. Comparison analysis demonstrated the distinct clinicopathological/genomic characterizations between Chinese and Western HCC cohorts. Genomic profiling of HCC underlying VI showed that , , , , and were frequently altered in the VI group compared to patients without VIs. Compared to the right hepatic lobes of HCC patients, the left hepatic lobe of HCC patients had superior OS (median OS: 36.77 months vs. unreached, < 0.05). By further comparison, Notch signaling pathway-related alterations were significantly prevalent among the right hepatic lobes of HCC patients. Of note, multivariate Cox regression analysis showed that altered , , , , and , as independent prognostic factors, were significantly correlated with the OS of HCC patients. Furthermore, altered was abundantly enriched in the HCC-recurrent group, and impressively, it was independent of clinicopathological features in predicting RFS (median RFS of altered type vs. wild-type: 5.57 months vs. 22.47 months, < 0.01). Regarding those treated HCC patients, TMB value, altered , and cell cycle-related alterations were identified to be positively associated with the objective response rate (ORR), but alterations were negatively correlated with ORR. In addition, altered and cell cycle signaling were significantly associated with reduced and increased time to progression-free survival (PFS), respectively. Comprehensive genomic profiling deciphered distinct molecular characterizations underlying VI, location of onset, recurrence, and survival time in liver cancer. The identification of novel genetic predictors of response to anti-PD-1 plus bevacizumab in HCC facilitated the development of an evidence-based approach to therapy.
PubMed: 38948469
DOI: 10.3389/fphar.2024.1416295 -
Frontiers in Pharmacology 2024"Kratom" refers to an array of bioactive products derived from , a tree indigenous to Southeast Asia. Most kratom consumers report analgesic and stimulatory effects, and...
BACKGROUND
"Kratom" refers to an array of bioactive products derived from , a tree indigenous to Southeast Asia. Most kratom consumers report analgesic and stimulatory effects, and common reasons for use are to address mental and physical health needs, manage pain, and to reduce use of other substances. Natural-history studies and survey studies suggest that many kratom consumers perceive benefits from those uses, but such studies are unlikely to capture the full range of kratom-use experiences.
METHODS
We collected text data from Reddit posts from 2020-2022 to qualitatively examine conceptualizations, motivations, effects, and consequences associated with kratom use among people posting to social media. Reddit posts mentioning kratom were studied using template thematic analysis, which included collecting descriptions of kratom product types and use practices. Network analyses of coded themes was performed to examine independent relationships among themes, and between themes and product types.
RESULTS
Codes were applied to 329 of the 370 posts that comprised the final sample; 134 posts contained kratom product descriptions. As Reddit accounts were functionally anonymous, demographic estimates were untenable. Themes included kratom physical dependence (tolerance, withdrawal, or use to avoid withdrawal), perceived addiction (net detrimental effects on functioning), and quitting. Extract products were positively associated with reports of perceived addiction, dependence, and experiences of quitting kratom. Many used kratom for energy and self-treatment of pain, fatigue, and problems associated with opioid and alcohol; they perceived these uses as effective. Consumers expressed frustrations about product inconsistencies and lack of product information.
CONCLUSION
As in previous studies, kratom was deemed helpful for some and a hindrance to others, but we also found evidence of notable negative experiences with kratom products that have not been well documented in surveys. Daily kratom use may produce mild-moderate physical dependence, with greater severity being possibly more common with concentrated extracts; however, there are currently no human laboratory studies of concentrated kratom extracts. Such studies, and detailed kratom product information, are needed to help inform consumer decision-making.
PubMed: 38948457
DOI: 10.3389/fphar.2024.1412397 -
World Journal of Hepatology Jun 2024Hepatocellular carcinoma (HCC) is a primary contributor to cancer-related mortality on a global scale. However, the underlying molecular mechanisms are still poorly...
BACKGROUND
Hepatocellular carcinoma (HCC) is a primary contributor to cancer-related mortality on a global scale. However, the underlying molecular mechanisms are still poorly understood. Long noncoding RNAs are emerging markers for HCC diagnosis, prognosis, and therapeutic target. No study of LINC01767 in HCC was published.
AIM
To conduct a multi-omics analysis to explore the roles of LINC01767 in HCC for the first time.
METHODS
DESeq2 Package was used to analyze different gene expressions. Receiver operating characteristic curves assessed the diagnostic performance. Kaplan-Meier univariate and Cox multivariate analyses were used to perform survival analysis. The least absolute shrinkage and selection operator (LASSO)-Cox was used to identify the prediction model. Subsequent to the validation of LINC01767 expression in HCC fresh frozen tissues through quantitative real time polymerase chain reaction, next generation sequencing was performed following LINC01767 over expression (GSE243371), and Gene Ontology/Kyoto Encyclopedia of Genes and Genomes/Gene Set Enrichment Analysis/ingenuity pathway analysis was carried out. experiment in Huh7 cell was carried out.
RESULTS
LINC01767 was down-regulated in HCC with a log fold change = 1.575 and was positively correlated with the cancer stemness. LINC01767 was a good diagnostic marker with area under the curve (AUC) [0.801, 95% confidence interval (CI): 0.751-0.852, = 0.0106] and an independent predictor for overall survival (OS) with hazard ratio = 1.899 (95%CI: 1.01-3.58, = 0.048). LINC01767 nomogram model showed a satisfied performance. The top-ranked regulatory network analysis of LINC01767 showed the regulation of genes participating various pathways. LASSO regression identified the 9-genes model showing a more satisfied performance than 5-genes model to predict the OS with AUC > 0.75. LINC01767 was down-expressed obviously in tumor than para-tumor tissues in our cohort as well as in cancer cell line; the over expression of LINC01767 inhibit cell proliferation and clone formation of Huh7 .
CONCLUSION
LINC01767 was an important tumor suppressor gene in HCC with good diagnostic and prognostic performance.
PubMed: 38948436
DOI: 10.4254/wjh.v16.i6.932 -
Drug and Alcohol Dependence Reports Jun 2024In 2017, three brick and mortar supervised consumption sites (SCS) opened in Montreal, Canada. Opponents argued the sites would attract people who use drugs and reduce...
BACKGROUND
In 2017, three brick and mortar supervised consumption sites (SCS) opened in Montreal, Canada. Opponents argued the sites would attract people who use drugs and reduce local real estate prices.
METHODS
We used interrupted time series and hedonic price models to evaluate the effects of Montreal's SCS on local real estate prices. We linked the Quebec Professional Association of Real Estate Brokers' housing sales data provided by Centris Inc. with census tract data and gentrification scores. Homes sold within 200 m of the SCS locations between 1 January 2014 and 31 December 2021 were included. We adjusted for internal (e.g., number of bed/bathrooms, unit size) and external attributes (e.g., neighbourhood demographics), and included a spatio-temporal lag to account for correlation between sales. For sensitivity analysis we used site-specific dummy variables to better account for unmeasured neighbourhood differences, and repeated analyses using 500 m and 1000 m radii.
RESULTS
We observed a price shock after the opening of the first two SCS in June 2017 (level effect: -10.5%, 95% CI: -19.1%, -1.1%) but prices rose faster month-to-month (trend effect: 1.1%, 95% CI: 0.7%, 1.6%) after implementation. Following the implementation of the third site in November 2017 there was no immediate impact (level effect: 2.4%, 95% CI: -10.4%, 17.0%) but once more prices roses faster (0.9%, 95% CI: 0.4%, 1.5%) thereafter. When we replaced neighbourhood attributes with a site-specific dummy variable, we observed the same pattern. Sales' prices dropped (level effect: -9.6%, 95% CI: -15.0%, -3.8%) but rose faster month-to-month (trend effect: 0.9%, 95% CI: 0.6%, 1.2%) following June 2017's SCS implementations, with no level effect (4.9%, 95% CI: -7.3%, 18.6%) and a positive trend (0.9%, 95% CI: 0.5%, 1.3%) after November 2017's SCS opening. In most 500 m and 1000 m radii models, there were no immediate shocks following SCS opening, however, positive trend effects persisted in all models.
CONCLUSION
Our models suggest homes sold near SCS may experience a price shock immediately post-implementation, with evidence of market recovery in the months that follow.
PubMed: 38948426
DOI: 10.1016/j.dadr.2024.100242 -
World Journal of Experimental Medicine Jun 2024Eribulin is a non-taxane synthetic analogue approved in many countries as third-line treatment for the treatment of patients with metastatic breast cancer. In addition... (Review)
Review
Eribulin is a non-taxane synthetic analogue approved in many countries as third-line treatment for the treatment of patients with metastatic breast cancer. In addition to its mitotic property, eribulin has non-mitotic properties including but not limited to, its ability to induce phenotypic reversal of epithelial to mesenchymal transition, vascular remodelling, reduction in immunosuppressive tumour microenvironment. Since approval, there has been a surge in studies investigating the application of eribulin as an earlier-line treatment and also in combination with other agents such as immunotherapy and targeted therapy across all breast cancer sub-types, including hormone receptor positive, HER2 positive and triple negative breast cancer, many demonstrating promising activity. This review will focus on the application of eribulin in the treatment of metastatic breast cancer across all subtypes including its role as an earlier-line agent, its toxicity profile, and potential future directions.
PubMed: 38948420
DOI: 10.5493/wjem.v14.i2.92558 -
Perspectives on Medical Education 2024The healthcare landscape has a growing emphasis on health promotion (HP), which makes HP important in the training of future physicians. This study employed design-based...
INTRODUCTION
The healthcare landscape has a growing emphasis on health promotion (HP), which makes HP important in the training of future physicians. This study employed design-based research to develop a clerkship focused on HP and to outline design principles for shaping workplace learning environments to promote HP learning.
METHODS
We evaluated a nursing-home clerkship designed at Radboud University Medical Center in the Netherlands, and refined it over three rounds. Data collection involved individual and group interviews with students and supervisors, as well as observations during clerkship-related meetings and activities. These interactions also facilitated the exchange of perspectives between participants and generation of new design ideas, fostering co-creation of the clerkship design. Data were analyzed through iterative thematic inquiry to inform new design choices and develop design principles.
RESULTS
Evolved clerkship designs included an app for capturing practice experiences to discuss in relation to students' professional roles, loosening the strict assessment structure, and collaborative creation of a practice assignment about 'Positive Health'. We constructed four design principles, including: to question and discuss students' professional identity, provide concrete and meaningful assignments, aim for a peer-learner role for supervisors, and foster co-creation of the workplace learning environment.
DISCUSSION
Our design principles support the design of workplace-based learning for HP, a subject that is novel within healthcare practice. We find that co-creation of workplace-based learning, which requires embracing uncertainty, is pivotal in this context, for students, practitioners, and educational institutions.
Topics: Humans; Workplace; Health Promotion; Netherlands; Clinical Clerkship; Learning; Qualitative Research
PubMed: 38948402
DOI: 10.5334/pme.1203 -
Asian Journal of Pharmaceutical Sciences Jun 2024The intrinsic resistance of MRSA coupled with biofilm antibiotic tolerance challenges the antibiotic treatment of MRSA biofilm infections. Phytochemical-based...
The intrinsic resistance of MRSA coupled with biofilm antibiotic tolerance challenges the antibiotic treatment of MRSA biofilm infections. Phytochemical-based nanoplatform is a promising emerging approach for treatment of biofilm infection. However, their therapeutic efficacy was restricted by the low drug loading capacity and lack of selectivity. Herein, we constructed a surface charge adaptive phytochemical-based nanoparticle with high isoliquiritigenin (ISL) loading content for effective treatment of MRSA biofilm. A dimeric ISL prodrug (ISL-G2) bearing a lipase responsive ester bond was synthesized, and then encapsulated into the amphiphilic quaternized oligochitosan. The obtained ISL-G2 loaded NPs possessed positively charged surface, which allowed cis-aconityl-d-tyrosine (CA-Tyr) binding via electrostatic interaction to obtain ISL-G2@TMDCOS-Tyr NPs. The NPs maintained their negatively charged surface, thus prolonging the blood circulation time. In response to low pH in the biofilms, the fast removal of CA-Tyr led to a shift in their surface charge from negative to positive, which enhanced the accumulation and penetration of NPs in the biofilms. Sequentially, the pH-triggered release of d-tyrosine dispersed the biofilm and lipase-triggered released of ISL effectively kill biofilm MRSA. An study was performed on a MRSA biofilm infected wound model. This phytochemical-based system led to ∼2 log CFU (>99 %) reduction of biofilm MRSA as compared to untreated wound ( < 0.001) with negligible biotoxicity in mice. This phytochemical dimer nanoplatform shows great potential for long-term treatment of resistant bacterial infections.
PubMed: 38948398
DOI: 10.1016/j.ajps.2024.100923 -
Infectious Medicine Jun 2024In a retrospective view, this review examines the impact of mucormycosis on health workers and researchers during the COVID era. The diagnostic and treatment challenges... (Review)
Review
In a retrospective view, this review examines the impact of mucormycosis on health workers and researchers during the COVID era. The diagnostic and treatment challenges arising from unestablished underlying pathology and limited case studies add strain to healthcare systems. Mucormycosis, caused by environmental molds, poses a significant threat to COVID-19 patients, particularly those with comorbidities and compromised immune systems. Due to a variety of infectious Mucorales causes and regionally related risk factors, the disease's incidence is rising globally. Data on mucormycosis remains scarce in many countries, highlighting the urgent need for more extensive research on its epidemiology and prevalence. This review explores the associations between COVID-19 disease and mucormycosis pathology, shedding light on potential future diagnostic techniques based on the fungal agent's biochemical components. Medications used in ICUs and for life support in ventilated patients have been reported, revealing the challenge of managing this dual onslaught. To develop more effective treatment strategies, it is crucial to identify novel pharmacological targets through "pragmatic" multicenter trials and registries. In the absence of positive mycology culture data, early clinical detection, prompt treatment, and tissue biopsy are essential to confirm the specific morphologic features of the fungal agent. This review delves into the history, pathogens, and pathogenesis of mucormycosis, its opportunistic nature in COVID or immunocompromised individuals, and the latest advancements in therapeutics. Additionally, it offers a forward-looking perspective on potential pharmacological targets for future drug development.
PubMed: 38948388
DOI: 10.1016/j.imj.2024.100112