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World Journal of Gastroenterology Jun 2024In this editorial, we offer a summary of the risk associated with hepatitis B reactivation (HBVr) in the setting of both solid and hematologic malignancies treated with...
In this editorial, we offer a summary of the risk associated with hepatitis B reactivation (HBVr) in the setting of both solid and hematologic malignancies treated with Bruton tyrosine kinase (BTK) inhibitors, with insights derived from current studies. Furthermore, we emphasize the critical need for a framework regarding robust risk evaluation in patients undergoing such treatments. This framework is essential for identifying those at increased risk of HBVr, enabling healthcare providers to implement proactive measures to prevent reactivation and ensure the safe administration of BTK inhibitor therapy.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Virus Activation; Hepatitis B virus; Protein Kinase Inhibitors; Antiviral Agents; Hepatitis B; Risk Assessment; Hepatitis B, Chronic; Hematologic Neoplasms; Tyrosine Kinase Inhibitors
PubMed: 38899330
DOI: 10.3748/wjg.v30.i21.2748 -
World Journal of Clinical Cases Jun 2024Function-preserving pancreatectomy can improve the long-term quality of life of patients with benign or low-grade malignant tumors, such as intraductal papillary...
BACKGROUND
Function-preserving pancreatectomy can improve the long-term quality of life of patients with benign or low-grade malignant tumors, such as intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms. However, there is limited literature on laparoscopic spleen-preserving total pancreatectomy (L-SpTP) due to technical difficulties.
CASE SUMMARY
Patient 1 was a 51-year-old male diagnosed with IPMN based on preoperative imaging, showing solid nodules in the pancreatic head and diffuse dilation of the main pancreatic duct with atrophy of the distal pancreas. We performed L-SpTP with preservation of the splenic vessels, and the postoperative pathology report revealed IPMN with invasive carcinoma. Patient 2 was a 60-year-old male with multiple cystic lesions in the pancreatic head and body. L-SpTP was performed, and intraoperatively, the splenic vein was injured and required ligation. Postoperative pathology revealed a mucinous cystic tumor of the pancreas with low-grade dysplasia. Both patients were discharged on postoperative day 7, and there were no major complications during the perioperative period.
CONCLUSION
We believe that L-SpTP is a safe and feasible treatment for low-grade malignant pancreatic tumors, but more case studies are needed to evaluate its safety, efficacy, and long-term outcomes.
PubMed: 38898831
DOI: 10.12998/wjcc.v12.i17.3206 -
Clinical and Translational Science Jun 2024SAR439459 (SAR'459), a "second-generation" human anti-transforming growth factor beta (TGFβ) monoclonal antibody, enhances the activity of immune checkpoint inhibitors.... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of SAR439459, a TGFβ inhibitor, as monotherapy and in combination with cemiplimab in patients with advanced solid tumors: Findings from a phase 1/1b study.
SAR439459 (SAR'459), a "second-generation" human anti-transforming growth factor beta (TGFβ) monoclonal antibody, enhances the activity of immune checkpoint inhibitors. In this phase I/Ib study, we evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of SAR'459 ± cemiplimab (intravenous) in patients with advanced solid tumors. Increasing doses of SAR'459 were administered every 2 or 3 weeks (Q2W, Q3W) alone (Part 1A) or with 3 mg/kg cemiplimab Q2W or 350 mg Q3W (Part 1B). In Part 2A (dose expansion), melanoma patients were randomly (1:1) administered 22.5 or 7.5 mg/kg SAR'459. In Part 2B (dose expansion), 22.5 mg/kg SAR'459 and 350 mg cemiplimab Q3W were administered. The primary end points were maximum tolerated dose (MTD) or maximum administered dose (MAD; Part 1), preliminary antitumor activity (Part 2B), and optimal monotherapy dose (Part 2A). Twenty-eight and 24 patients were treated in Parts 1A and 1B, respectively; MTD was not reached, MAD was 15 (Q2W) and 22.5 mg/kg (Q3W) alone and in combination, respectively. Fourteen and 95 patients, including 14 hepatocellular carcinoma (HCC) patients, were treated in Parts 2A and 2B, respectively. The population PK model yielded satisfactory goodness-of-fit plots and adequately described the observed data by a two-compartment PK model with linear elimination. Objective responses were not observed in Parts 1 and 2A. In Part 2B, objective response rate was 8.4% and 7.1% across tumor types and the HCC cohort, respectively. The most frequent treatment-emergent adverse effects were hemorrhagic events (43.5%), keratoacanthoma (6.8%), and skin neoplasms (6.2%). Fatal bleeding occurred in 21.4% HCC patients despite the implementation of mitigation measures. SAR'459 monotherapy and combination with cemiplimab appeared relatively safe and tolerable in limited number of patients in dose escalation. However, the study was discontinued due to the unclear efficacy of SAR'459 and bleeding risk, particularly in HCC patients.
Topics: Humans; Antibodies, Monoclonal, Humanized; Male; Female; Middle Aged; Aged; Adult; Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Maximum Tolerated Dose; Dose-Response Relationship, Drug; Transforming Growth Factor beta; Drug Administration Schedule; Aged, 80 and over; Treatment Outcome
PubMed: 38898592
DOI: 10.1111/cts.13854 -
Cell Communication and Signaling : CCS Jun 2024Killer cell lectin-like receptor G1 (KLRG1) is an immune checkpoint receptor expressed predominantly in NK and T-cell subsets that downregulates the activation and... (Review)
Review
Killer cell lectin-like receptor G1 (KLRG1) is an immune checkpoint receptor expressed predominantly in NK and T-cell subsets that downregulates the activation and proliferation of immune cells and participates in cell-mediated immune responses. Accumulating evidence has demonstrated the importance of KLRG1 as a noteworthy disease marker and therapeutic target that can influence disease onset, progression, and prognosis. Blocking KLRG1 has been shown to effectively mitigate the effects of downregulation in various mouse tumor models, including solid tumors and hematologic malignancies. However, KLRG1 inhibitors have not yet been approved for human use, and the understanding of KLRG1 expression and its mechanism of action in various diseases remains incomplete. In this review, we explore alterations in the distribution, structure, and signaling pathways of KLRG1 in immune cells and summarize its expression patterns and roles in the development and progression of autoimmune diseases, infectious diseases, and cancers. Additionally, we discuss the potential applications of KLRG1 as a tool for tumor immunotherapy.
Topics: Humans; Receptors, Immunologic; Lectins, C-Type; Animals; Neoplasms; Biomarkers; Signal Transduction; Autoimmune Diseases; Immunotherapy
PubMed: 38898461
DOI: 10.1186/s12964-024-01714-7 -
Scientific Reports Jun 2024Cancer cells recruit neutrophils from the bloodstream into the tumor tissue, where these immune cells promote the progression of numerous solid tumors. Studies in mice...
Cancer cells recruit neutrophils from the bloodstream into the tumor tissue, where these immune cells promote the progression of numerous solid tumors. Studies in mice suggest that blocking neutrophil recruitment to tumors by inhibition of neutrophil chemokine receptor CXCR2 could be a potential immunotherapy for pancreatic cancer. Yet, the mechanisms by which neutrophils promote tumor progression in humans, as well as how CXCR2 inhibition could potentially serve as a cancer therapy, remain elusive. In this study, we developed a human cell-based microphysiological system to quantify neutrophil-tumor spheroid interactions in both "separated" and "contact" scenarios. We found that neutrophils promote the invasion of tumor spheroids through the secretion of soluble factors and direct contact with cancer cells. However, they promote the proliferation of tumor spheroids solely through direct contact. Interestingly, treatment with AZD-5069, a CXCR2 inhibitor, attenuates invasion and proliferation of tumor spheroids by blocking direct contact with neutrophils. Our findings also show that CXCR2 inhibition reduces neutrophil migration toward tumor spheroids. These results shed new light on the tumor-promoting mechanisms of human neutrophils and the tumor-suppressive mechanisms of CXCR2 inhibition in pancreatic cancer and may aid in the design and optimization of novel immunotherapeutic strategies based on neutrophils.
Topics: Receptors, Interleukin-8B; Humans; Pancreatic Neoplasms; Neutrophils; Immunotherapy; Cell Line, Tumor; Spheroids, Cellular; Cell Proliferation; Disease Progression; Neutrophil Infiltration; Microphysiological Systems; Benzamides; Cyclobutanes
PubMed: 38898176
DOI: 10.1038/s41598-024-64780-4 -
Scientific Reports Jun 2024Central nervous system tumors have resisted effective chemotherapy because most therapeutics do not penetrate the blood-tumor-brain-barrier. Nanomedicines between...
Central nervous system tumors have resisted effective chemotherapy because most therapeutics do not penetrate the blood-tumor-brain-barrier. Nanomedicines between ~ 10 and 100 nm accumulate in many solid tumors by the enhanced permeability and retention effect, but it is controversial whether the effect can be exploited for treatment of brain tumors. PLX038A is a long-acting prodrug of the topoisomerase 1 inhibitor SN-38. It is composed of a 15 nm 4-arm 40 kDa PEG tethered to four SN-38 moieties by linkers that slowly cleave to release the SN-38. The prodrug was remarkably effective at suppressing growth of intracranial breast cancer and glioblastoma (GBM), significantly increasing the life span of mice harboring them. We addressed the important issue of whether the prodrug releases SN-38 systemically and then penetrates the brain to exert anti-tumor effects, or whether it directly penetrates the blood-tumor-brain-barrier and releases the SN-38 cargo within the tumor. We argue that the amount of SN-38 formed systemically is insufficient to inhibit the tumors, and show by PET imaging that a close surrogate of the 40 kDa PEG carrier in PLX038A accumulates and is retained in the GBM. We conclude that the prodrug penetrates the blood-tumor-brain-barrier, accumulates in the tumor microenvironment and releases its SN-38 cargo from within. Based on our results, we pose the provocative question as to whether the 40 kDa nanomolecule PEG carrier might serve as a "Trojan horse" to carry other drugs past the blood-tumor-brain-barrier and release them into brain tumors.
Topics: Animals; Brain Neoplasms; Irinotecan; Blood-Brain Barrier; Mice; Prodrugs; Humans; Cell Line, Tumor; Female; Xenograft Model Antitumor Assays; Glioblastoma; Camptothecin
PubMed: 38898077
DOI: 10.1038/s41598-024-64186-2 -
Cancer Medicine Jun 2024Improved survival rates have been observed in castration-resistant prostate cancer (CRPC) due to advancements in treatment options. However, individuals with brain...
PURPOSE
Improved survival rates have been observed in castration-resistant prostate cancer (CRPC) due to advancements in treatment options. However, individuals with brain metastases still have limited therapeutic options and an unfavorable prognosis. Therefore, there is an urgent need to explore new therapeutic avenues, such as antibody-drug conjugates (ADCs), which have demonstrated significant clinical activity against active brain metastases in solid tumors. Our objective was to determine the expression levels of the ADC targets Trop-2 and NECTIN-4 in cerebral metastasized CRPC (mCRPC).
METHODS
Immunohistochemical staining of Trop-2 and NECTIN-4 with evaluation of H-score was performed in CRPC brain metastases (n = 31). Additionally, we examined Trop-2 protein expression in prostate cancer cell lines and studied their responsiveness to the anti-Trop-2 ADC Sacituzumab govitecan (SG) in vitro.
RESULTS
Our analysis revealed that most patients exhibited moderate to strong Trop-2 expression [n = 27/31 with H-score ≥100, median H-score 220 (IQR 180-280)], while NECTIN-4 was absent in all cerebral metastases. Mechanistically, we demonstrated that the efficacy of SG depends on Trop-2 expression levels in vitro. Overexpression of Trop-2 in Trop-2-negative PC-3 cells led to sensitization to SG, whereas CRISPR-Cas9-mediated knockdown of Trop-2 in Trop-2-expressing DU-145 cells conferred resistance to SG.
CONCLUSION
The substantial expression of Trop-2 in cerebral metastases, along with our preclinical in vitro results, supports the efficacy of SG in treating cerebral mCRPC. Thus, our results extend the understanding of the potential of ADCs in prostate cancer treatment and provide an additional treatment strategy for the challenging subset of patients with cerebral metastases.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Immunoconjugates; Cell Adhesion Molecules; Antigens, Neoplasm; Brain Neoplasms; Antibodies, Monoclonal, Humanized; Camptothecin; Cell Line, Tumor; Nectins
PubMed: 38895886
DOI: 10.1002/cam4.7320 -
Cancers Jun 2024This study addresses the critical need for the accurate diagnosis and management of intraductal papillary mucinous neoplasms (IPMNs), which are pancreatic cystic...
Navigating Intraductal Papillary Mucinous Neoplasm Management through Fukuoka Consensus vs. European Evidence-Based Guidelines on Pancreatic Cystic Neoplasms-A Study on Two European Centers.
This study addresses the critical need for the accurate diagnosis and management of intraductal papillary mucinous neoplasms (IPMNs), which are pancreatic cystic neoplasm types holding a substantial potential for malignancy. It evaluates the diagnostic effectiveness of the Fukuoka consensus guidelines and the European evidence-based guidelines in detecting high-grade dysplasia/invasive carcinoma in IPMNs, utilizing a retrospective analysis of 113 patients from two European medical centers. The methods include a comparative analysis of clinical, radiological, and endoscopic ultrasonography data, alongside an assessment of guideline-driven diagnostic performance. The results demonstrate that both guidelines offer similar accuracy in identifying severe disease stages in IPMNs, with certain clinical markers-such as jaundice, solid mass presence, and an increase in CA 19-9 levels-being pivotal in predicting the need for surgical intervention. This study concludes that while both guidelines provide valuable frameworks for IPMN management, there is an inherent need for further research to refine these protocols and improve patient-specific treatment strategies. This research contributes to the ongoing discourse on optimizing diagnostic and treatment paradigms for pancreatic cystic neoplasms, aiming to enhance clinical outcomes and patient care in this challenging medical field.
PubMed: 38893274
DOI: 10.3390/cancers16112156 -
International Journal of Molecular... Jun 2024The autonomic nervous system plays an integral role in motion and sensation as well as the physiologic function of visceral organs. The nervous system additionally plays... (Review)
Review
The autonomic nervous system plays an integral role in motion and sensation as well as the physiologic function of visceral organs. The nervous system additionally plays a key role in primary liver diseases. Until recently, however, the impact of nerves on cancer development, progression, and metastasis has been unappreciated. This review highlights recent advances in understanding neuroanatomical networks within solid organs and their mechanistic influence on organ function, specifically in the liver and liver cancer. We discuss the interaction between the autonomic nervous system, including sympathetic and parasympathetic nerves, and the liver. We also examine how sympathetic innervation affects metabolic functions and diseases like nonalcoholic fatty liver disease (NAFLD). We also delve into the neurobiology of the liver, the interplay between cancer and nerves, and the neural regulation of the immune response. We emphasize the influence of the neuroimmune axis in cancer progression and the potential of targeted interventions like neurolysis to improve cancer treatment outcomes, especially for hepatocellular carcinoma (HCC).
Topics: Humans; Liver Neoplasms; Neuroimmunomodulation; Animals; Carcinoma, Hepatocellular; Liver; Non-alcoholic Fatty Liver Disease; Autonomic Nervous System
PubMed: 38892423
DOI: 10.3390/ijms25116237 -
International Journal of Molecular... Jun 2024Breast cancers (BCs) are solid tumors composed of heterogeneous tissues consisting of cancer cells and an ever-changing tumor microenvironment (TME). The TME includes,... (Review)
Review
Breast cancers (BCs) are solid tumors composed of heterogeneous tissues consisting of cancer cells and an ever-changing tumor microenvironment (TME). The TME includes, among other non-cancer cell types, immune cells influencing the immune context of cancer tissues. In particular, the cross talk of immune cells and their interactions with cancer cells dramatically influence BC dissemination, immunoediting, and the outcomes of cancer therapies. Tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) represent prominent immune cell populations of breast TMEs, and they have important roles in cancer immunoescape and dissemination. Therefore, in this article we review the features of TILs, TAMs, and MDSCs in BCs. Moreover, we highlight the mechanisms by which these immune cells remodel the immune TME and lead to breast cancer metastasis.
Topics: Humans; Tumor Microenvironment; Breast Neoplasms; Myeloid-Derived Suppressor Cells; Female; Tumor-Associated Macrophages; Lymphocytes, Tumor-Infiltrating; Neoplasm Metastasis; T-Lymphocytes; Animals
PubMed: 38892411
DOI: 10.3390/ijms25116224