CAR-T Cell Therapy in Pancreatic and Biliary Tract Cancers: An Updated Review of Clinical Trials.

BACKGROUND: Pancreatic and biliary tract cancers are digestive system tumors with dismal prognosis and limited treatment options. The effectiveness of conventional surgical interventions, radiation therapy, and systemic therapy is restricted in these cases. Furthermore, clinical trials have shown that immunotherapy using immune checkpoint inhibitors has only demonstrated modest clinical results when applied to patients with pancreatobiliary tumors. This highlights the importance of implementing combination immunotherapy approaches or exploring alternative therapeutic strategies to improve treatment outcomes. MATERIALS AND METHODS: We reviewed the relevant literature on chimeric antigen receptor (CAR)-T cell therapy for pancreatobiliary cancers from PubMed/Medline and ClinicalTrials.gov and retrieved the relevant data accordingly. Attention was additionally given to the examination of grey literature with the aim of obtaining additional details regarding ongoing clinical trials. We mainly focused on abstracts and presentations and e-posters and slides of recent important annual meetings (namely ESMO Immuno-Oncology Congress, ESMO Congress, ASCO Virtual Scientific Program, ASCO Gastrointestinal Cancers Symposium). RESULTS: CAR-T cell therapy has emerged as a promising and evolving treatment approach for pancreatic and biliary tract cancer. This form of adoptive cell therapy utilizes genetic engineering to modify the expression of specific antibodies on the surface of T cells enabling them to target specific cancer-associated antigens and to induce potent anti-tumor activity. The aim of this review is to provide an updated summary of the available evidence from clinical trials that have explored the application of CAR-T cell therapy in treating pancreatobiliary cancers. CONCLUSIONS: While the utilization of CAR-T cell therapy in pancreatobiliary cancers is still in its initial phases with only a limited amount of clinical data available, the field is advancing rapidly, incorporating novel technologies to mitigate potential toxicities and enhance antigen-directed tumor eradication.

Photodynamic Therapy for the Treatment of Basal Cell Carcinoma: A Comprehensive Review of Randomized Controlled Trials.

INTRODUCTION: Basal cell carcinoma (BCC) is the most common skin cancer worldwide and has been reported to have a rising incidence in the last years. Multiple therapeutic modalities are approved for the treatment of BCC, making it difficult for physicians to choose the most suitable option for every patient. Photodynamic therapy (PDT) using either 5-aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) as photosensitizing agents is an established treatment option for low-risk BCC. OBJECTIVES: This review aims to summarize the available evidence from randomized clinical trials (RCTs) that utilize either ALA or MAL PDT and compare it with other treatment modalities. The main outcomes related to the effectiveness, adverse events, cosmetic outcomes and pain sensation, along with data from long-term follow-ups will be presented and discussed. METHODS: Thorough literature searches were conducted through the electronic databases ClinicalTrials. gov and Pubmed/MEDLINE from inception up to 28 March 2023. Only studies in English were included. All relevant data were extracted accordingly from the eligible studies. RESULTS: Eight RCTs included superficial BCC (sBCC) alone, 7 included nodular BCC (nBCC), 2 included both sBCC and nBCC and 1 included BCC of unspecified subtype. Follow-up duration ranged from 3 months to 5 years. Both ALA-PDT and MAL-PDT demonstrated acceptable efficacy, adverse events, cosmetic outcomes and pain sensation while no major differences were observed between them. PDT was less effective than surgery but with better reported cosmetic outcomes. CONCLUSIONS: PDT is a safe and efficacious treatment option for sBCC and to a lesser extent nBCC.

Bimekizumab in psoriasis: a monocentric study evaluating short- and mid-term effectiveness and safety profile in a real-world setting.

INTRODUCTION: Bimekizumab is a humanized monoclonal IgG1 antibody with a unique mechanism of action, as it inhibits both IL17A and IL17F molecules. This dual inhibition is thought to be responsible for its high efficacy in treating chronic plaque psoriasis with rapid onset of action in Randomized Controlled Trials (RCTs). Concerning safety, oral candidiasis was one of the most common drug-related adverse events, commonly mild-to-moderate in severity. Although data from RCTs supporting this efficacy and safety profile of bimekizumab is numerous, results from the real-world setting concerning short- and mid-term treatment effectiveness and safety profile are limited. MATERIALS AND METHODS: An observational, retrospective, monocentric study was conducted at the Psoriasis Outpatient Unit of "A. Sygros" Hospital for Skin and Venereal Diseases, in Athens, Greece, which included 61 adult patients with moderate-to-severe skin psoriasis, who received at least one dosage of bimekizumab. RESULTS: At week 4, 65.7% achieved PASI75, 45.7% PASI90, and 32.4% PASI100. After 16 weeks of treatment, 92.3/76.9/66.7% of the patients achieved PASI75/90/100, respectively. Increased BMI, previous treatment with another IL-17 inhibitor, or previous exposure to another biologic did not seem to influence the possibility of achieving PASI90 and PASI100 at week 16 of bimekizumab treatment in this cohort. Six (9.8%) cases of possibly drug-related AEs were reported, from which four incidences of oral candidiasis. CONCLUSION: Our results confirm that this IL17A/F inhibitor is highly effective, with a tolerability profile similar to the one expected from RCTs.

Nimesulide-Induced Fixed Drug Eruption Followed by Etoricoxib-Induced Fixed Drug Eruption: An Unusual Case Report and Review of the Literature.

Fixed drug eruption (FDE) is a well-recognized, non-immediate, drug hypersensitivity reaction, often attributed to the use of various medications, most commonly non-steroidal anti-inflammatory drugs (NSAIDs) and antibiotics. Cross-reactivity between related NSAIDs in FDE has been reported, but among chemically unrelated NSAIDs, is rare. Herein, we present a rare well-documented case where a patient initially displayed tolerance to etoricoxib after experiencing a nimesulide-induced FDE. Subsequently, the patient developed an etoricoxib-induced FDE, accompanied by the development of bullous lesions. This case report and the literature review on comparable FDE occurrences shed light on the intricate nature of FDEs, suggesting the possibility of cross-reactivity between chemically related and unrelated NSAIDs or the emergence of new drug-specific T cells without cross-reactivity after multiple exposures to a drug in a susceptible patient. Our case underscores the importance of increased awareness and vigilance among both physicians and patients in the realm of personalized medicine. Further research is needed to unravel the intricate mechanisms behind these drug eruptions, improve diagnostic approaches, and enhance patient care.

Cyclin-Dependent Kinase 4/6 Inhibitors as Neoadjuvant Therapy of Hormone Receptor-Positive/HER2-Negative Early Breast Cancer: What do we Know so Far?

The introduction of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors to the treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer is regarded as one of the greatest achievements of the last decades in breast oncology. To date, palbociclib, abemaciclib and ribociclib are the 3 approved CDK4/6 inhibitors that combined with endocrine therapy are now considered as the standard first-line treatment of metastatic HR+/HER2- breast cancer. The great success of these drugs in the setting of metastatic disease and the need to combat the high risk of recurrence have paved the way for a number of clinical trials to explore the use of CDK4/6 inhibitors in the neoadjuvant treatment of early breast cancer. In this review, we summarize the main findings of clinical trials that examined the use of CDK4/6 inhibitors in combination with hormone therapy or chemotherapy as neoadjuvant treatment of hormone receptor-positive and HER2-negative breast cancer. Active clinical trials that investigate different treatment schemes are also briefly presented and current limitations and future goals are discussed.

New Emerging Targets in Cancer Immunotherapy: The Role of B7-H3.

Immune checkpoints (ICs) are molecules implicated in the fine-tuning of immune response via co-inhibitory or co-stimulatory signals, and serve to secure minimized host damage. Targeting ICs with various therapeutic modalities, including checkpoint inhibitors/monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and CAR-T cells has produced remarkable results, especially in immunogenic tumors, setting a paradigm shift in cancer therapeutics through the incorporation of these IC-targeted treatments. However, the large proportion of subjects who experience primary or secondary resistance to available IC-targeted options necessitates further advancements that render immunotherapy beneficial for a larger patient pool with longer duration of response. B7-H3 (B7 Homolog 3 Protein, CD276) is a member of the B7 family of IC proteins that exerts pleiotropic immunomodulatory effects both in physiologic and pathologic contexts. Mounting evidence has demonstrated an aberrant expression of B7-H3 in various solid malignancies, including tumors less sensitive to current immunotherapeutic options, and has associated its expression with advanced disease, worse patient survival and impaired response to IC-based regimens. Anti-B7-H3 agents, including novel mAbs, bispecific antibodies, ADCs, CAR-T cells, and radioimmunotherapy agents, have exhibited encouraging antitumor activity in preclinical models and have recently entered clinical testing for several cancer types. In the present review, we concisely present the functional implications of B7-H3 and discuss the latest evidence regarding its prognostic significance and therapeutic potential in solid malignancies, with emphasis on anti-B7-H3 modalities that are currently evaluated in clinical trial settings. Better understanding of B7-H3 intricate interactions in the tumor microenvironment will expand the oncological utility of anti-B7-H3 agents and further shape their role in cancer therapeutics.

The Effect of High-Intensity Interval Training on Mitochondrial-Associated Indices in Overweight and Obese Adults: A Systematic Review and Meta-Analysis.

BACKGROUND: Obesity is a significant health problem with an increasing incidence, causing a low-grade systemic inflammatory state and being implicated in various chronic diseases. Moreover, obesity has been shown to cause mitochondrial dysfunction through oxidative stress and inflammation, eventually affecting energy metabolism. However, high-intensity interval training (HIIT) can improve mitochondrial efficiency through exercise-induced mitochondrial adaptations. This systematic review and meta-analysis aims to examine the potential effects of HIIT on mitochondrial-associated indices in obese and overweight adults. METHODS: PubMed, Scopus, and Web of Science databases were searched. RESULTS: Twenty-eight eligible studies were included, involving 530 participants. HIIT was found to significantly improve the activity of citrate synthase (CS), cytochrome C (COX-IV), beta-hydroxyacyl CoA-dehydrogenase (ß-HAD), Complexes I-V as well as VO2max in overweight and obese individuals, whereas no significant changes were shown in PGC-1α and SIRT1. Interestingly, subgroup analyses revealed that CS, COX-IV, ß-HAD, and Complexes I-V activity exhibited a significant improvement only in the healthy subgroup. CONCLUSIONS: Overall, HIIT can be utilized to enhance mitochondrial-associated indices in overweight and obese individuals. However, this improvement may be health status dependent.

Beyond CTLA-4 and PD-1 Inhibition: Novel Immune Checkpoint Molecules for Melanoma Treatment.

More than ten years after the approval of ipilimumab, immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 have been established as the most effective treatment for locally advanced or metastatic melanoma, achieving durable responses either as monotherapies or in combinatorial regimens. However, a considerable proportion of patients do not respond or experience early relapse, due to multiple parameters that contribute to melanoma resistance. The expression of other immune checkpoints beyond the PD-1 and CTLA-4 molecules remains a major mechanism of immune evasion. The recent approval of anti-LAG-3 ICI, relatlimab, in combination with nivolumab for metastatic disease, has capitalized on the extensive research in the field and has highlighted the potential for further improvement of melanoma prognosis by synergistically blocking additional immune targets with new ICI-doublets, antibody-drug conjugates, or other novel modalities. Herein, we provide a comprehensive overview of presently published immune checkpoint molecules, including LAG-3, TIGIT, TIM-3, VISTA, IDO1/IDO2/TDO, CD27/CD70, CD39/73, HVEM/BTLA/CD160 and B7-H3. Beginning from their immunomodulatory properties as co-inhibitory or co-stimulatory receptors, we present all therapeutic modalities targeting these molecules that have been tested in melanoma treatment either in preclinical or clinical settings. Better understanding of the checkpoint-mediated crosstalk between melanoma and immune effector cells is essential for generating more effective strategies with augmented immune response.

Bcl-2 pathway inhibition in solid tumors: a review of clinical trials

Due to their key role in the pathogenesis of cancer through the regulation of apoptosis, the B-cell leukemia/lymphoma-2 (BCL-2) family proteins have been an attractive target for cancer therapy for the past decades. Throughout the years, many Bcl-2 family inhibitors have been developed, with Venetoclax being now successfully used in treating hematological malignancies. Although their effectiveness in the treatment of solid tumors is yet to be established, some preclinical evidence indicates their possible clinical application. This review aims to summarize current data from completed clinical trials that used Bcl-2 protein family inhibitors as monotherapy or in combination with other agents for the treatment of solid malignancies. We managed to include clinical trials of various phases which analyze the pharmacokinetics and pharmacodynamics of the drugs, as well as the effectiveness and adverse effects. Active and recruiting clinical trials are also briefly presented and future prospects and challenges are discussed (AU)

Bcl-2 pathway inhibition in solid tumors: a review of clinical trials.

Due to their key role in the pathogenesis of cancer through the regulation of apoptosis, the B-cell leukemia/lymphoma-2 (BCL-2) family proteins have been an attractive target for cancer therapy for the past decades. Throughout the years, many Bcl-2 family inhibitors have been developed, with Venetoclax being now successfully used in treating hematological malignancies. Although their effectiveness in the treatment of solid tumors is yet to be established, some preclinical evidence indicates their possible clinical application. This review aims to summarize current data from completed clinical trials that used Bcl-2 protein family inhibitors as monotherapy or in combination with other agents for the treatment of solid malignancies. We managed to include clinical trials of various phases which analyze the pharmacokinetics and pharmacodynamics of the drugs, as well as the effectiveness and adverse effects. Active and recruiting clinical trials are also briefly presented and future prospects and challenges are discussed.

Comprehensive clinical evaluation of CAR-T cell immunotherapy for solid tumors: a path moving forward or a dead end?

INTRODUCTION: Chimeric Antigen Receptor (CAR)-T cell therapy is a form of adoptive cell therapy that has demonstrated tremendous results in the treatment of hematopoietic malignancies, leading to the US Food and Drug Administration (FDA) approval of four CD19-targeted CAR-T cell products. With the unprecedented success of CAR-T cell therapy in hematological malignancies, hundreds of preclinical studies and clinical trials are currently undergoing to explore the translation of this treatment to solid tumors. However, the clinical experience in non-hematologic malignancies has been less encouraging, with only a few patients achieving complete responses. Tumor-associated antigen heterogeneity, inefficient CAR-T cell trafficking and the immunosuppressive tumor microenvironment are considered as the most pivotal roadblocks in solid tumor CAR-T cell therapy. MATERIALS AND METHODS: We reviewed the relevant literature/clinical trials for CAR-T cell immunotherapy for solid tumors from Pubmed and ClinicalTrials.gov. CONCLUSION: Herein, we provide an update on solid tumor CAR-T cell clinical trials, focusing on the studies with published results. We further discuss some of the key hurdles that CAR-T cell therapy is encountering for solid tumor treatment as well as the strategies that are exploited to overcome these obstacles.

Therapies targeting CGRP signaling for medication overuse headache.

PURPOSE OF REVIEW: Medication overuse headache (MOH) affects more than 60 million individuals worldwide causing enormous personal and social burden. Only repurposed drugs are available for MOH that share limited evidence for efficacy. The preclinical data suggesting that activation of the calcitonin gene-related peptide (CGRP) pathway is involved in headache chronification along with clinical evidence that monoclonal antibodies targeting CGRP (anti-CGRP mAbs) have good efficacy in preventing chronic migraine, triggered this review that aims to summarize the current data on the effectiveness and safety of mAbs against CGRP in MOH. RECENT FINDINGS: Post hoc analyses of phase-3 trials of erenumab, fremanezumab, galcanezumab, and eptinezumab for the prevention of chronic migraine revealed that patients with MOH benefit from the treatment over placebo. Several real-world studies confirm the efficacy of erenumab and galcanezumab in patients with MO. However, all published trials evaluated treatments in patients with chronic migraine with MO collectively, not in patients with MOH exclusively. SUMMARY: The available data indicate that anti-CGRP mAbs represent a good mechanism-based and disease-specific therapeutical option with for MOH as long as detoxification and additional nonpharmaceutical interventions are operated. Future research should focus on long-term-controlled trials in MOH populations exclusively.