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Background: Cancer-related fatigue (CRF) occurs in nearly all patients with metastatic breast cancer (MBC). Objectives: This real-world analysis aimed to describe the prevalence and importance of fatigue in patients with MBC within 3 months of treatment with single-agent taxane-based chemotherapy during the timeframe of 2020–2022 in the United States and Europe. It was also conducted to assess whether there was a difference in relapsed patients compared to patients diagnosed de novo. Design: Electronic health records were analyzed from approximately 150 million patients to identify patients with MBC who underwent taxane treatment. Results: In 2021, 50,490 patients had MBC, of whom 16,170 were diagnosed de novo and 34,330 experienced relapse. The proportion of patients undergoing taxane-based chemotherapy was 7.5% (n = 1220) and 13.4% (n = 4590), respectively, and the prevalence of any fatigue and CRF was similar between the groups (24.6% versus 25.7% and 6.6% versus 5.4%, respectively). Conclusion: At least one in four patients with MBC undergoing taxane-based treatment will experience fatigue. This highlights the importance of validating screening tools to identify CRF, which is necessary to advance clinical trials aimed at investigating treatment strategies to improve patient-centered outcomes for fatigue. [ABSTRACT FROM AUTHOR]

Although long considered a promising treatment option for type 1 diabetes, pancreatic islet cell transformation has been hindered by immune system rejection of engrafted tissue. The identification of pathways that regulate post-transplant detrimental inflammatory events would improve management and outcome of transplanted patients. Here, we found that CXCR1/ 2 chemokine receptors and their ligands are crucial negative determinants for islet survival after transplantation. Pancreatic islets released abundant CXCR1/ 2 ligands (CXCL1 and CXCL8). Accordingly, intrahepatic CXCL1 and circulating CXCL1 and CXCL8 were strongly induced shortly after islet infusion. Genetic and pharmacological blockade of the CXCL1-CXCR1/2 axis in mice improved intrahepatic islet engraftment and reduced intrahepatic recruitment of polymorphonuclear leukocytes and NKT cells after islet infusion. In humans, the CXCR1/2 allosteric inhibitor reparixin improved outcome in a phase 2 randomized, open-label pilot study with a single infusion of allogeneic islets. These findings indicate that the CXCR1/2-mediated pathway is a regulator of islet damage and should be a target for intervention to improve the efficacy of transplantation., Introduction Achieving long-lasting insulin independence after portal vein islet transplantation has improved, but remains challenging. Nonspecific immune activation (1-6), along with preexisting and transplant-induced auto-and allospecific immune responses (7-9), are [...]

Background: Therapeutic idiotypic (Id) vaccination is an experimental treatment for selected B cell malignancies. A broader use of Id-based vaccination, however, is hampered by the complexity and costs due to the individualized production of protein vaccines. These limitations may be overcome by targeted DNA vaccines encoding stereotyped immunoglobulin V regions of B cell malignancies. We have here investigated whether such vaccines might elicit cross-reactive immune responses thus offering the possibility to immunize subsets of patients with the same vaccine.Methods: Fusion vaccines targeting patient Id to mouse Major Histocompatibility Complex (MHC) class II molecules (chimeric mouse/human) or chemokine receptors (fully human) on antigen-presenting cells (APC) were genetically constructed for two Chronic Lymphocytic Leukemia (CLL) patients and one prototypic stereotyped B-cell receptor (BCR) commonly expressed by Hepatitis C Virus (HCV)-associated Non Hodgkin Lymphoma (NHL). The A20 murine B lymphoma cells were engineered to express prototypic HCV-associated B cell lymphoma BCR. Anti-Id antibody responses were studied against stereotyped and non-stereotyped BCRs on CLL patients' cells as well as transfected A20 cells.Results: DNA vaccination of mice with Id vaccines that target APC elicited increased amounts of antibodies specific for the patient's Id as compared with non targeted control vaccines. Anti-Id antibodies cross-reacted between CLL cells with closely related BCR. A20 cells engineered to express patients' V regions were not tumorigenic in mice, preventing tumor challenge experiments.Conclusions: These findings provide experimental support for use of APC-targeted fusion Id DNA vaccines for the treatment of B cell lymphoma and CLL that express stereotyped BCRs. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a type of neuropathic pain that represents a frequent and serious consequence of chemotherapy agents. Over the last years, significant progress has been achieved in elucidating the underlying pathogenesis of CIPN. The interference of taxanes with microtubule has been proposed as a mechanism that leads to altered axonal transport and to permanent neurological damages. The inflammatory process activated by chemotherapeutic agents has been considered as a potential trigger of nociceptive process in CIPN.In this study we investigated the effect of reparixin, an inhibitor of CXCR1/CXCR2, in suppressing the development of paclitaxel-induced nociception in rats. Moreover, reparixin activity in reversing the neurotoxic effects induced by paclitaxel or GRO/KC in F11 cells was also analyzed.Reparixin administered by continuous infusion ameliorated paclitaxel-induced mechanical and cold allodynia in rats. In F11 cells, reparixin was able to inhibit the increase of acetyladed α-tubulin induced both by paclitaxel and GRO/KC. The subsequent experiments were performed in order to dissect the signal transduction pathways under GRO/KC control, eventually modulated by paclitaxel and/or reparixin. To this aim we found that reparixin significantly counteracted p-FAK, p-JAK2/p-STAT3, and PI3K-p-cortactin activation induced either by paclitaxel or GRO/KC.Overall the present results have identified IL-8/CXCR1/2 pathway as a mechanism involved in paclitaxel-induced peripheral neuropathy. In particular, the obtained data suggest that the inhibition of CXCR1/2 combined with standard taxane therapy, in addition to potentiating the taxane anti-tumor activity can reduce chemotherapy-induced neurotoxicity, thus giving some insight for the development of novel treatments.

Multiple myeloma (MM) remains a difficult-to-cure cancer and less than 20% of patients achieve long-term survival irrespective of the treatment delivered, including high-dose chemotherapy. Thus, new treatment modalities are urgently needed. Myeloma cells produce a monoclonal immunoglobulin (Ig) which is a truly tumor-specific antigen. The tumor-specific antigenic determinants are localized in the variable regions of the monoclonal Ig and are termed idiotopes (Id). Id-vaccination, i.e., vaccination with the autologous monoclonal Ig, has been performed in MM patients in order to elicit tumor-specific immune responses and possibly elimination of myeloma cells. However, clinical trials have not given the promising results obtained in mice. This review focuses on tolerance mechanisms that might hinder Id-specific immune responses in MM patients. New strategies for Id vaccination in MM are discussed.

beta-Defensins are small antimicrobial peptides of the innate immune system produced in response to microbial infection of mucosal tissue and skin. We demonstrate that murine beta-defensin 2 (mDF2beta) acts directly on immature dendritic cells as an endogenous ligand for Toll-like receptor 4 (TLR-4), inducing up-regulation of costimulatory molecules and dendritic cell maturation. These events, in turn, trigger robust, type 1 polarized adaptive immune responses in vivo, suggesting that mDF2beta may play an important role in immunosurveillance against pathogens and, possibly, self antigens or tumor antigens.

Background and Objectives: Cancer vaccines are aimed at inducing tumor-specific immunity by immunizing patients with tumor cells or their antigenic components, known as tumor-associated antigens (TAA). Antigens which are either mutated or selectively or abundantly expressed in malignant, but not in normal, cells are considered as TAA. Each patient's B-cell malignancy is usually derived from a single expanded B-cell clone, which expresses an immunoglobulin (Ig) with a unique idiotype (Id, variable regions of Ig). Therefore, Id can be regarded as a TAA and a potential target in clinical vaccination approaches. Although use of tumor-derived Id as an immunogen to elicit antitumor immunity against B-cell malignancies is an attractive idea, the broader use of idiotypic vaccines has been hampered by the fact that autologous Id is not only a weakly immunogenic, self antigen, but is also patient-specific so that the vaccine must be individually prepared for each patient. In this review we will first summarize the latest data from the clinical tests of experimental idiotypic vaccines and discuss issues relevant to the clinical application of cancer vaccines in general; we will then critically review new trends and achievements in the development of the second generation vaccine formulations., Evidence and Information Sources: The authors of the present review are currently working in the field of B-cell tumor immunotherapy and have contributed original papers to peer-reviewed journals. The material analyzed in the present review includes articles and abstracts published in journals covered by the Science Citation Index and Medline., State of Art: The results from a number of experimental models and clinical trials have demonstrated that vaccination with tumor-derived Id can induce immune responses directed against the tumor. Idiotypic vaccines can be divided into two types, although both are at the experimental stage: traditional and second generation, based on the methods of production and vaccine delivery. Second generation vaccines utilizing genetically engineered protein and DNA formulations have, for the first time, opened up the possibility of streamlining production of simpler and effective custom-made idiotypic vaccines. The use of various adjuvants and exogenous carriers is being replaced by more potent genetic carriers which target Id and various co-stimulatory molecules to professional antigen presenting cells (APC), particularly dendritic cells (DC)., Perspectives: Id is the only widely accepted tumor marker and is a promising therapeutic target for immunotherapy of B-cell malignancies. It has been unequivocally established that Id vaccination of patients with follicular lymphoma administered when patients have minimal residual disease, has antitumor effect and potential to improve the clinical outcome. Consequently, the applicability of Id vaccines for other B-cell malignancies such as chronic lymphocytic leukemia, mantle cell lymphoma and multiple myeloma needs to be tested. Idiotypic vaccines should be tailored to target preferentially various subsets of immune cells, such as DCs, which would up take and properly process and present Id, activating both arms of the immune system, humoral and cellular. Moreover, the vaccine should induce the production of a milieu of inflammatory cytokines and lymphokines at the delivery site to elicit a T helper type 1 (Th1) immune response. Components of the inflammatory response can be used to target DCs in vivo, activating the so-called danger signal for circumventing the poor immunogenicity of self-tumor antigens. For example, chemotactic factors of innate immunity are able to deliver Id to APC and render this otherwise non-immunogenic antigen immunogenic. The strategies developed for Id vaccines can be used as a general strategy for eliciting T-cell immunity to other weakly immunogenic, clinically relevant self-tumor antigens.