Therapeutic advances of targeting receptor tyrosine kinases in cancer.

Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role in cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression of certain RTKs, are critical in creating environments conducive to tumor development. Following their discovery, extensive research has revealed how RTK dysregulation contributes to oncogenesis, with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation, survival and progression. These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer. As a result, RTKs have emerged as primary targets in anticancer therapeutic development. Over the past two decades, this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors (TKIs), now effectively utilized in treating various cancer types. In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer. We explored the various alterations and overexpression of specific receptors across different malignancies, with special attention dedicated to the examination of current RTK inhibitors, highlighting their role as potential targeted therapies. By integrating the latest research findings and clinical evidence, we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes.

Exploring Novel Frontiers in Cancer Therapy.

Cancer progression and initiation are sustained by a series of alterations in molecular pathways because of genetic errors, external stimuli and other factors, which lead to an abnormal cellular function that can be translated into uncontrolled cell growth and metastasis [...].

Molecular Subtypes and the Role of TP53 in Diffuse Large B-Cell Lymphoma and Richter Syndrome.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy and a heterogeneous entity comprised of several biologically distinct subtypes. Recently, novel genetic classifications of DLBCL have been resolved based on common mutational patterns indicative of distinct pathways of transformation. However, the complicated and costly nature of the novel classifiers has precluded their inclusion into routine practice. In view of this, the status of the TP53 gene, which is mutated or deleted in 20-30% of the cases, has emerged as an important prognostic factor for DLBCL patients, setting itself apart from other predictors. TP53 genetic lesions are particularly enriched in a genetic subtype of DLBCL that shares genomic features with Richter Syndrome, highlighting the possibility of a subset of DLBCL arising from the transformation of an occult chronic lymphocytic leukemia-like malignancy, such as monoclonal B-cell lymphocytosis. Patients with TP53-mutated DLBCL, including those with Richter Syndrome, have a particularly poor prognosis and display inferior responses to standard chemoimmunotherapy regimens. The data presented in this manuscript argue for the need for improved and more practical risk-stratification models for patients with DLBCL and show the potential for the use of TP53 mutational status for prognostication and, in prospect, treatment stratification in DLBCL.

A Review of Key Regulators of Steady-State and Ineffective Erythropoiesis.

Erythropoiesis is initiated with the transformation of multipotent hematopoietic stem cells into committed erythroid progenitor cells in the erythroblastic islands of the bone marrow in adults. These cells undergo several stages of differentiation, including erythroblast formation, normoblast formation, and finally, the expulsion of the nucleus to form mature red blood cells. The erythropoietin (EPO) pathway, which is activated by hypoxia, induces stimulation of the erythroid progenitor cells and the promotion of their proliferation and survival as well as maturation and hemoglobin synthesis. The regulation of erythropoiesis is a complex and dynamic interaction of a myriad of factors, such as transcription factors (GATA-1, STAT5), cytokines (IL-3, IL-6, IL-11), iron metabolism and cell cycle regulators. Multiple microRNAs are involved in erythropoiesis, mediating cell growth and development, regulating oxidative stress, erythrocyte maturation and differentiation, hemoglobin synthesis, transferrin function and iron homeostasis. This review aims to explore the physiology of steady-state erythropoiesis and to outline key mechanisms involved in ineffective erythropoiesis linked to anemia, chronic inflammation, stress, and hematological malignancies. Studying aberrations in erythropoiesis in various diseases allows a more in-depth understanding of the heterogeneity within erythroid populations and the development of gene therapies to treat hematological disorders.

In vivo imaging system (IVIS) therapeutic assessment of tyrosine kinase inhibitor-loaded gold nanocarriers for acute myeloid leukemia: a pilot study.

Acute myeloid leukemia (AML) is a malignancy in the myeloid lineage that is characterized by symptoms like fatigue, bleeding, infections, or anemia, and it can be fatal if untreated. In AML, mutations in tyrosine kinases (TKs) lead to enhanced tumor cell survival. The most frequent mutations in TKs are reported in Fms-like tyrosine kinase 3 (FLT3), Janus kinase 2 (JAK2), and KIT (tyrosine-protein kinase KIT), making these TKs potential targets for TK inhibitor (TKI) therapies in AML. With 30% of the mutations in TKs, mutated FLT3 is associated with poor overall survival and an increased chance of resistance to therapy. FLT3 inhibitors are used in FLT3-mutant AML, and the combination with hypomethylating agents displayed promising results. Midostaurin (MDS) is the first targeted therapy in FLT3-mutant AML, and its combination with chemotherapy showed good results. However, chemotherapies induce several side effects, and an alternative to chemotherapy might be the use of nanoparticles for better drug delivery, improved bioavailability, reduced drug resistance and induced toxicity. The herein study presents MDS-loaded gold nanoparticles and compares its efficacy with MDS alone, on both in vitro and in vivo models, using the FLT3-ITD-mutated AML cell line MV-4-11 Luc2 transfected to express luciferin. Our preclinical study suggests that MDS-loaded nanoparticles have a better tumor inhibitory effect than free drugs on in vivo models by controlling tumor growth in the first half of the treatment, while in the second part of the therapy, the tumor size was comparable to the cohort that was treatment-free.

Anaesthesia Management for Giant Intraabdominal Tumours: A Case Series Study.

BACKGROUND: Due to a lack of randomised controlled trials and guidelines, and only case reports being available in the literature, there is no consensus on how to approach anaesthetic management in patients with giant intraabdominal tumours. METHODS: This study aimed to evaluate the literature and explore the current status of evidence, by undertaking an observational research design with a descriptive account of characteristics observed in a case series referring to patients with giant intraabdominal tumours who underwent anaesthesia. RESULTS: Twenty patients diagnosed with giant intraabdominal tumours were included in the study, most of them women, with the overall pathology being ovarian-related and sarcomas. Most of the patients were unable to lie supine and assumed a lateral decubitus position. Pulmonary function tests, chest X-rays, and thoracoabdominal CT were the most often performed preoperative evaluation methods, with the overall findings that there was no atelectasis or pleural effusion present, but there was bilateral diaphragm elevation. The removal of the intraabdominal tumour was performed under general anaesthesia in all cases. Awake fiberoptic intubation or awake videolaryngoscopy was performed in five cases, while the rest were performed with general anaesthesia with rapid sequence induction. Only one patient was ventilated with pressure support ventilation while maintaining spontaneous ventilation, while the rest were ventilated with controlled ventilation. Hypoxemia was the most reported respiratory complication during surgery. In more than 50% of cases, there was hypotension present during surgery, especially after the induction of anaesthesia and after tumour removal, which required vasopressor support. Most cases involved blood loss with subsequent transfusion requirements. The removal of the tumor requires prolonged surgical and anaesthesia times. Fluid drainage from cystic tumour ranged from 15.7 L to 107 L, with a fluid extraction rate of 0.5-2.5 L/min, and there was no re-expansion pulmonary oedema reported. Following surgery, all the patients required intensive care unit admission. One patient died during hospitalization. CONCLUSIONS: This study contributes to the creation of a certain standard of care when dealing with patients presenting with giant intraabdominal tumour. More research is needed to define the proper way to administer anaesthesia and create practice guidelines.

Predictors for anaemia, blood transfusion and outcome in plastic surgery patients.

OBJECTIVE: In patients undergoing plastic surgery, to identify specific risk factors for anaemia and use of blood products, and assess their impact on patient outcome. METHOD: For this retrospective study, data were analysed from patients who attended the Plastic Surgery Department at our hospital over a three-year period (2018 to 2020). Adult patients who presented with traumatic injuries, oncologic patients who underwent reconstructive procedures, and patients with soft tissue infections (STIs) who required plastic surgery for tissue coverage were included. Demographic and injury data, hospital admission characteristics, surgical procedures, laboratory test results, transfusion events, and in-hospital complications were extracted from patient records. RESULTS: Of the 350 patients included in the study, 228 (65%) presented with trauma, 76 (22%) underwent reconstructive surgery for cancers and 46 (13%) had STIs. In total, 175 (50%) patients developed anaemia, and 37 (11%) received blood transfusions; these were 20 (54%), 5 (14%), and 12 (32%) patients in the trauma, cancer and STI groups, respectively. Associated comorbidities and upper and lower limb surgery were the most significant risk factors for anaemia, while the number of surgeries and NSTIs were identified as risk factors for blood transfusions. Direct wound closure was consistently a protective factor for both anaemia and blood transfusions. Blood transfusions were independently associated with a high risk of sepsis, wound complications, and prolonged hospital stay. CONCLUSION: While transfusions are necessary and even lifesaving in surgical patients, blood is a finite resource and its use may negatively impact patient outcome. Therefore, ongoing research must focus on providing safe and restrictive clinical practices while developing sustainable and accessible alternatives.

ROP-ET: a prospective phase III trial investigating the efficacy and safety of ropeginterferon alfa-2b in essential thrombocythemia patients with limited treatment options.

Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.

Immune therapies of B-cell acute lymphoblastic leukaemia in children and adults.

B-cell acute lymphoblastic leukaemia (B-cell ALL) is a common haematologic cancer in children and adults. About 10 percent of children and 50 percent of adults fail to achieve a histological complete remission or subsequently relapse despite current anti-leukaemia drug therapies and/or haematopoietic cell transplants. Several new immune therapies including monoclonal antibodies and chimeric antigen receptor (CAR)-T-cells are proved safe and effective in this setting. We review data on US Food and Drug Administration (FDA)-approved immune therapies for B-cell ALL in children and adults including blinatumomab, inotuzumab ozogamicin, tisagenlecleucel, and brexucabtagene autoleucel. We also summarize pharmaco-dynamics, pharmaco-kinetics, and pharmaco-economics of these interventions.

Unlocking protein-based biomarker potential for graft-versus-host disease following allogenic hematopoietic stem cell transplants.

Despite the numerous advantages of allogeneic hematopoietic stem cell transplants (allo-HSCT), there exists a notable association with risks, particularly during the preconditioning period and predominantly post-intervention, exemplified by the occurrence of graft-versus-host disease (GVHD). Risk stratification prior to symptom manifestation, along with precise diagnosis and prognosis, relies heavily on clinical features. A critical imperative is the development of tools capable of early identification and effective management of patients undergoing allo-HSCT. A promising avenue in this pursuit is the utilization of proteomics-based biomarkers obtained from non-invasive biospecimens. This review comprehensively outlines the application of proteomics and proteomics-based biomarkers in GVHD patients. It delves into both single protein markers and protein panels, offering insights into their relevance in acute and chronic GVHD. Furthermore, the review provides a detailed examination of the site-specific involvement of GVHD. In summary, this article explores the potential of proteomics as a tool for timely and accurate intervention in the context of GVHD following allo-HSCT.

Understanding DNA Epigenetics by Means of Raman/SERS Analysis for Cancer Detection.

This study delves into the intricate interaction between DNA and nanosystems, exploring its potential implications for biomedical applications. The focus lies in understanding the adsorption geometry of DNA when in proximity to plasmonic nanoparticles, utilizing ultrasensitive vibrational spectroscopy techniques. Employing a combined Raman-SERS analysis, we conducted an in-depth examination to clarify the molecular geometry of interactions between DNA and silver nanoparticles. Our findings also reveal distinctive spectral features regarding DNA samples due to their distinctive genome stability. To understand the subtle differences occurring between normal and cancerous DNA, their thermal stability was investigated by means of SERS measurement performed before and after a thermal treatment at 94 °C. It was proved that thermal treatment did not affect DNA integrity in the case of normal cells. On the other hand, due to epimutation pattern that characterizes cancerous DNA, variations between spectra recorded before and after heat treatment were observed, suggesting genome instability. These findings highlight the potential of DNA analysis using SERS for cancer detection. They demonstrate the applicability of this approach to overcoming challenges associated with low DNA concentrations (e.g., circulating tumor DNA) that occur in biofluids. In conclusion, this research contributes significant insights into the nanoscale behavior of DNA in the presence of nanosystems.

Synergistic Effect of Human Chorionic Gonadotropin and Granulocyte Colony Stimulating Factor in the Mobilization of HSPCs Improves Overall Survival After PBSCT in a Preclinical Murine Model. Are We Far Enough for Therapy?

Strategies to improve hematopoietic stem and progenitor cell (HSPC) mobilization from the bone marrow can have a pivotal role in addressing iatrogenic bone-marrow insufficiency from chemo(radio)therapy and overcoming peripheral blood stem cell transplantation (PBSCT) limitations such as insufficient mobilization. Granulocyte-colony stimulating factor (G-CSF) represents the standard mobilization strategy for HSPC and has done so for more than three decades since its FDA approval. Its association with non-G-CSF agents is often employed for difficult HSPC mobilization. However, obtaining a synergistic effect between the two classes is limited by different timing and mechanisms of action. Based on our previous in vitro results, we tested the mobilization potential of human chorionic gonadotropin (HCG), alone and in combination with G-CSF in vivo in a murine study. Our results show an improved mobilization capability of the combination, which seems to act synergistically in stimulating hematopoiesis. With the current understanding of the dynamics of HSPCs and their origins in more primitive cells related to the germline, new strategies to employ the mobilization of hematopoietic progenitors using chorionic gonadotropins could soon become clinical practice.

Usefulness of Saline Sealing in Preventing Pneumothorax after CT-Guided Biopsies of the Lung.

This study aimed to assess the effectiveness of saline sealing in reducing the incidence of pneumothorax after a CT-guided lung biopsy. This was a retrospective case-control study of patients who underwent CT-guided biopsies for lung tumors using 18 G semiautomatic core needles in conjunction with 17 G coaxial needles. The patients were divided into two consecutive groups: a historical Group A (n = 111), who did not receive saline sealing, and Group B (n = 87), who received saline sealing. In Group B, NaCl 0.9% was injected through the coaxial needle upon its removal. The incidence of pneumothorax and chest tube insertion was compared between the two groups. Multivariate logistic regression was performed to verify the contribution of other pneumothorax risk factors. The study included 198 patients, with 111 in Group A and 87 in Group B. There was a significantly (p = 0.02) higher pneumothorax rate in Group A (35.1%, n = 39) compared to Group B (20.7%, n = 18). The difference regarding chest tube insertion was not significant (p = 0.1), despite a tendency towards more insertions in Group A (5.4%, n = 6), compared to Group B (1.1%, n = 1). Among the risk factors for pneumothorax, only the presence of emphysema (OR = 3.5, p = 0.0007) and belonging to Group A (OR = 2.2, p = 0.02) were significant. Saline sealing of the needle tract after a CT-guided lung biopsy can significantly reduce the incidence of pneumothorax. This technique is safe, readily available, and inexpensive, and should be considered as a routine preventive measure during this procedure.

Rare within Rare: A Girl with Severe Haemophilia A and Turner Syndrome.

A coincidental occurrence of severe haemophilia A and Turner syndrome in a female person is extremely rare (less than 10 cases published). In such challenging cases, a multidisciplinary approach based on medicine of precision with full access to genetic and bio-molecular exploration is indispensable. The article presents an eight-year-old girl, with a family history of haemophilia, without significant disease signs (only post-dental extraction bleeding and a shorter stature). Discordantly, however, the investigations revealed a challenging condition: a genotype of 46,X,i(Xq), with an Isochromosome Xq responsible for the Turner syndrome and simultaneously, for the detrimental transformation, interfering with X chromosome inactivation, of an obligate hemophilia carrier into a severe hemophilia case-two distinct and provocative diseases.

Exploring Therapeutic Avenues in Lung Cancer: The Epigenetic Perspective.

Lung cancer, primarily non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC), is distinguished by its high prevalence and marked mortality rates. Traditional therapeutic approaches, encompassing chemotherapy, radiation, and targeted therapies, frequently show limited efficacy due to acquired resistance and notable side effects. The objective of this review is to introduce a fresh perspective on the therapeutic strategies for lung cancer, emphasizing interventions targeting the epigenetic alterations often seen in this malignancy. This review presents the most recent advancements in the field, focusing on both past and current clinical trials related to the modulation of methylation patterns using diverse molecular agents. Furthermore, an in-depth analysis of the challenges and advantages of these methylation-modifying drugs will be provided, assessing their efficacy as individual treatments and their potential for synergy when integrated with prevailing therapeutic regimens.

Large Intron Inversions in Romanian Patients with Hemophilia A-First Report.

Background and Objectives: Despite the vast heterogeneity in the genetic defects causing hemophilia A (HA), large intron inversions represent a major cause of disease, accounting for almost half of the cases of severe HA worldwide. We investigated the intron 22 and intron 1 inversion status in a cohort of Romanian unrelated patients with severe HA. Moreover, we evaluated the role of these inversions as relative risk factors in inhibitor occurrence. Materials and Methods: Inverse shifting-a polymerase chain reaction method was used to detect the presence of intron 22 and intron 1 inversions in 156 Romanian patients with HA. Results: Intron inversion 22 was found in 41.7% of the patients, while intron 1 inversion was detected in 3.2% of the patients. Overall, large intron inversions represented the molecular defect in 44.9% of the studied patients. Our findings are in accord with previously published reports from Eastern Europe countries and with other international studies. The risk of inhibitor development was higher in patients with inversion 1 compared to the patients with HA without any inversion detected. Conclusions: The current study demonstrates the major causative role of large intron inversions in severe HA in Romanian patients. Moreover, our study confirms the contribution of intron 1 inversion in inhibitor development.

Outcomes of CAR-T Cell Therapy Recipients Admitted to the ICU: In Search for a Standard of Care-A Brief Overview and Meta-Analysis of Proportions.

OBJECTIVE: Our primary objective was to describe the baseline characteristics, main reasons for intensive care unit (ICU) admission, and interventions required in the ICU across patients who received CAR-T cell immunotherapy. The secondary objectives were to evaluate different outcomes (ICU mortality) across patients admitted to the ICU after having received CAR-T cell therapy. MATERIALS AND METHODS: We performed a medical literature review, which included MEDLINE, Embase, and Cochrane Library, of studies published from the inception of the databases until 2022. We conducted a systematic review with meta-analyses of proportions of several studies, including CAR-T cell-treated patients who required ICU admission. Outcomes in the meta-analysis were evaluated using the random-effects model. RESULTS: We included four studies and analyzed several outcomes, including baseline characteristics and ICU-related findings. CAR-T cell recipients admitted to the ICU are predominantly males (62% CI-95% (57-66)). Of the total CAR-T cell recipients, 4% CI-95% (3-5) die in the hospital, and 6% CI-95% (4-9) of those admitted to the ICU subsequently die. One of the main reasons for ICU admission is acute kidney injury (AKI) in 15% CI-95% (10-19) of cases and acute respiratory failure in 10% CI-95% (6-13) of cases. Regarding the interventions initiated in the ICU, 18% CI-95% (13-22) of the CAR-T recipients required invasive mechanical ventilation during their ICU stay, 23% CI-95% (16-30) required infusion of vasoactive drugs, and 1% CI-95% (0.1-3) required renal replacement therapy (RRT). 18% CI-95% (13-22) of the initially discharged patients were readmitted to the ICU within 30 days, and the mean length of hospital stay is 22 days CI-95% (19-25). The results paint a current state of matter in CAR-T cell recipients admitted to the ICU. CONCLUSIONS: To better understand immunotherapy-related complications from an ICU standpoint, acknowledge the deteriorating patient on the ward, reduce the ICU admission rate, advance ICU care, and improve the outcomes of these patients, a standard of care and research regarding CAR-T cell-based immunotherapies should be created. Studies that are looking from the perspective of intensive care are highly warranted because the available literature regarding this area is scarce.