Evaluation Of Therapeutic Response Research Articles

The Role of Serum IL-23 and Volatile Organic Compound Levels to RECIST 1.1 in The Evaluation of Therapeutic Response in Lung Cancer

The Response Evaluation Criteria in Solid Tumors (RECIST 1.1) is the gold standard for the assessment of lung cancer progression. However, the assessment and diagnosis of early treatment failure is challenging due to the limitations of current tools, as well as the long intervals and unavoidable side effects.This study aims to correlate volatile organic compound (VOC) patterns, serum level of interleukin-23 (IL-23), and RECIST 1.1 to assess chemotherapy response in lung cancer patients at Saiful Anwar Hospital. A prospective observational study was performed to 47 lung cancer patients who received three cycles of platinum-based chemotherapy. Using the Breath Analyzer to measure certain volatile organic compounds (VOCs), the study observed that three of the seven VOCs examined, formaldehyde (CH2O), toluene (C7H8), and hexane (C6H14), showed lower levels after three cycles of chemotherapy. Furthermore, there was a negative correlation between RECIST1.1 and acetone (C3H6O) (p=0.023), while RECIST1.1 and methane (CH4) had a positive correlation (p=0.011). Moreover, a significant positive correlation was observed between IL-23 after-chemotherapy and RECIST 1.1 (p=0.000). According to this study, a correlation exists between methane, IL-23, and RECIST 1.1 after three cycles of chemotherapy. The increase in methane and IL-23 aligns with the disease progression determined by RECIST 1.1. Furthermore, The decrease in acetone after chemotherapy showed a negative correlation with RECIST1.1, consistent with disease progression.Keywords: Volatile Organic Compound, Interleukin-23, RECIST 1.1.

Abstract 2064: Unveiling the correlation between gemtuzumab-ozogamicin efficacy and CD33+ expression in AML primary samples using the novel AML vitroscreen

Abstract Acute myeloid leukemia (AML) poses a significant therapeutic challenge, with a rising incidence in recent times. This clonal hematopoietic disorder of progenitor and stem cells exhibits aggressive behavior, and despite initial remission, recurrence is common1. The conventional shift from chemotherapy to monoclonal antibodies and antibody-drug conjugates (ADCs) has been hindered by the absence of AML-specific antigens. Notably, CD33, expressed strongly in 80-90% of AML cells, has become a target for gemtuzumab-ozogamicin (Mylotarg), the sole FDA approved ADC for AML treatment2. While advancements in understanding AML molecular mechanisms have influenced clinical approaches, the lack of clinically representative models hinders therapeutic progress. Existing models, both in vivo and ex vivo, struggle to capture the heterogeneity and complexity of AML3. Addressing this, we present our proprietary assay, Champions AML VitroScreen®4, designed for testing therapeutic candidates in primary AML samples. Our diverse bank of deeply characterized AML samples encompasses multiple subtypes, allowing evaluation of therapeutic responses through cell viability, proliferation, and clonal composition analyses. To validate our novel assay, we employed the VitroScreen platform to test Mylotarg across various AML subtypes, considering CD33 expression levels. By assessing more than 20 AML models, we determined the IC50 for Mylotarg and observed dose-dependent responses, where sensitivity to the drugh correlated with CD33 expression. Through multiple endpoints, including viability, proliferation, apoptosis, and phenotyping, we categorized primary AML models as responders, low responders, or resistant, establishing a strong positive correlation between Mylotarg sensitivity and CD33 expression. Our innovative approach, utilizing deeply characterized AML patient samples in the AML VitroScreen® platform, facilitates high-throughput drug testing. This system, serving as an ideal clinical translational setting in preclinical research, holds promise for developing tailored therapeutic strategies. Ultimately, this approach could significantly impact patient outcomes by offering improved strategies for both primary and recurrent AML cases. Citation Format: Mara Gilardi, Garima Kaushik, Brandon Walling, Paolo Schiavini, Stefano Cairo, Marianna Zipeto. Unveiling the correlation between gemtuzumab-ozogamicin efficacy and CD33+ expression in AML primary samples using the novel AML vitroscreen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2064.

Abstract 4204: Subcutaneous vs. orthotopic tumor models: A comparative assessment

Abstract The failure of murine tumor models to adequately simulate the native biological milieu and tissue architecture of human malignancies, has fomented much discourse surrounding the discord that exists between experimental outcomes and clinical settings. Orthotopic (OT) models, which are generated by the engraftment of tumor cells or fragments into recipient organs of the same histotype from which they were derived, has the advantage of recapitulating the appropriate vasculature, as well as cellular and stromal components as the site of origin. In the context of immunotherapy, there is increasing evidence that subcutaneous (SC) tumors bear a vastly different immunological profile compared to OT implants, a phenomenon dictated by tissue-specific recruitment of various immune subsets, and subsequently, impacts overall response. Therefore, establishing cancer models that better represent the natural tumor environment is imperative for addressing some of the foibles inherent to preclinical mouse models. To demonstrate the significance of the anatomical site of the tumor, we present a comparative assessment of the MC38 murine colon carcinoma model, in the context of SC and OT settings. In the SC model of MC38, administration of either 5mg/kg anti-mPD1, anti-mPDL1, or anti-mCTLA-4, failed to elicit any notable anti-tumor activity, as evidenced by 0% incidences of complete regressions (CR) and tumor free survivors (TFS) for all three therapeutic agents, and incidences of 11%, 5% and -22% increase in time to progression (ITP), respectively. However, mice bearing OT tumors, exhibited meaningful response to 5mg/kg anti-mPD1 and anti-mPDL1, both evoking incidences of 25% CR, 25% TFS and 108% ITP. Though the anti-mCTLA-4 treated cohort did not produce any CRs or TFS, there was, nonetheless, a 50% incidence of ITP. Taken together, the data clearly illustrates the distinct disparities in response between SC and OT tumors, with respect to immunomodulatory agents. Characterization of immune phenotype within both settings, and interrogation of additional mouse models are ongoing. The exigencies and profound limitations associated with bench to bedside translation have long encumbered the drug development process. Despite staggering financial investment in oncology research, effective treatments for a myriad of cancers remain elusive, and only 3.4% of cancer drug candidates are conferred with clinical approval. Employing modalities that adequately reproduce the molecular and structural frameworks of human tumors, is crucial to better elucidating the natural trajectory of cancer progression, thus facilitating more accurate evaluation of drug activity and therapeutic response in preclinical settings. OT models therefore represent a more disease-relevant preclinical approach compared to their subcutaneous counterparts, as they more reliably preserve the intrinsic infrastructure and complexities of patient tumors in situ. Citation Format: Kerry-Ann Bright, Sheri Barnes, Derrik Germain, Lauren Kucharczyk. Subcutaneous vs. orthotopic tumor models: A comparative assessment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4204.

Applications of Exosome Vesicles in Different Cancer Types as Biomarkers.

One of the biggest challenges in the fight against cancer is early detection. Early diagnosis is vital, but there are some barriers such as economic, cultural, and personal factors. Considering the disadvantages of radiological imaging techniques or serological analysis methods used in cancer diagnosis, such as being expensive, requiring expertise, and being time-consuming, there is a need to develop faster, more reliable, and cost-effective diagnostic methods for use in cancer diagnosis. Exosomes, which are responsible for intercellular communication with sizes ranging from 30-120 nm, are naturally produced biological nanoparticles. Thanks to the cargo contents they carry, they are a potential biomarker to be used in the diagnosis of cancer. Exosomes, defined as extracellular vesicles of endosomal origin, are effective in cancer growth, progression, metastasis, and drug resistance, and changes in microenvironmental conditions during tumor development change exosome secretion. Due to their high cellular activity, tumor cells produce much higher exosomes than healthy cells. Therefore, it is known that the number of exosomes in body fluids is significantly rich compared to other cells and can act as a stand-alone diagnostic biomarker. Cancer- derived exosomes have received great attention in recent years for the early detection of cancer and the evaluation of therapeutic response. In this article, the content, properties, and differences of exosomes detected in common types of cancer (lung, liver, pancreas, ovaries, breast, colorectal), which are the leading causes of cancer-related deaths, are reviewed. We also discuss the potential utility of exosome contents as a biomarker for early detection, which is known to be important in targeted cancer therapy.

Noncoding RNAs and programmed cell death in hepatocellular carcinoma: Significant role of epigenetic modifications in prognosis, chemoresistance, and tumor recurrence rate.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer with a high death rate in the world. The molecular mechanisms related to the pathogenesis of HCC have not been precisely defined so far. Hence, this review aimed to address the potential cross-talk between noncoding RNAs (ncRNAs) and programmed cell death in HCC. All related papers in the English language up to June 2023 were collected and screened. The searched keywords in scientific databases, including Scopus, PubMed, and Google Scholar, were HCC, ncRNAs, Epigenetic, Programmed cell death, Autophagy, Apoptosis, Ferroptosis, Chemoresistance, Tumor recurrence, Prognosis, and Prediction. According to the reports, ncRNAs, comprising long ncRNAs, microRNAs, circular RNAs, and small nucleolar RNAs can affect cell proliferation, migration, invasion, and metastasis, as well as cell death-related processes, such as autophagy, ferroptosis, necroptosis, and apoptosis in HCC by regulating cancer-associated genes and signaling pathways, for example, phosphoinositide 3-kinase/Akt, extracellular signal-regulated kinase/MAPK, and Wnt/β-catenin signaling pathways. It seems that ncRNAs, as epigenetic regulators, can be utilized as biomarkers in diagnosis, prognosis, survival and recurrence rates prediction, chemoresistance, and evaluation of therapeutic response in HCC patients. However, more scientific evidence is suggested to be accomplished to confirm these results.

Evaluation of Therapeutic Response Under Biologic Therapy in Patients with Rheumatoid Arthritis

Biotherapy has revolutionized the therapeutic management of rheumatoid arthritis (RA). The objective of the study was to evaluate and compare the efficacy and tolerance of biological disease modifying antirheumatic drugs (bDMARDs) and conventional disease modifying antirheumatic drugs ( cDMARDs) used in RA.
 It was a retrospective study covering 13 years at the level of the immunology unit of the UHU Hassiba Ben Bouali Blida and functional rehabilitation service of the CHU Frantz Fanon Blida. We identified 1866 records of patients with RA, 75 receiving biotherapy and 71 receiving conventional treatment. The therapeutic response was evaluated by the DAS 28-ESR (disease activity score based on erythrocyte sedimentation rate) and interpreted according to the EULAR (European league against rheumatism) judgements criteria.
 A female predominance of 83%, the average age of RA patients was 49.3 ±13.42 years, the mean starting DAS28-ESR was 5.625± 1.4. 84% of patients initially received MTX (methotrexate) on the front line, the decrease in DAS28-ESR was non- significant, with patients exhibiting intolerance (41%), and (45%) ineffectiveness. The introduction of biotherapy mainly Actemra allowed a decrease of DAS28-ESR of - 1.842±0.3812, a significant decrease according to the criteria of the EULAR. Humira had an adverse efficacy and tolerance profile (including the occurrence of severe adverse effects (AEs)).
 In conclusion, biotherapy is more effective than conventional treatments, while in terms of tolerance data are insufficient to make a judgment on it.
 Keywords: Rheumatoid arthritis – Biotherapy.

The role of hematological coefficients of systemic inflammation in the diagnosis and risk assessment of affective disorders

The review article highlights the problem of using hematological coefficients of systemic inflammation in clinical practice, as well as the results of studies aimed at its use in the diagnosis and evaluation of therapeutic response in the treatment of mood disorders. The contribution of each individual link of the immune system to the pathogenesis of an inflammatory reaction is known, but currently of most interest are neutrophil-lymphocytic (NLR), monocyte-lymphocytic (MLR) and platelet-lymphocytic (PLR) ratios, as well as indices of systemic immune-inflammation (SII, platelet count x number of neutrophils / lymphocytes) and system inflammation response (SIRI, number of neutrophils x number of monocytes / lymphocytes). All coefficients are available for calculation based on a routine complete blood count. The analysis of the literature demonstrates the significance of these ratios, but emphasizes the need for further research. A more detailed study of these ratios will allow achieving their prognostic value and a more objective assessment of their validity and specificity for the diagnosis, prediction of risks and variants of the affective disorders course.

Unraveling the role of miRNAs as biomarkers in Chagas cardiomyopathy: Insights into molecular pathophysiology.

Chagas cardiomyopathy (ChCM) is a severe form of Chagas disease and a major cause of cardiovascular morbidity and mortality. The dysregulation of the immune response leads to cardiac remodeling and functional disruptions, resulting in life-threatening complications. Conventional diagnostic methods have limitations, and therapeutic response evaluation is challenging. MicroRNAs (miRNAs), important regulators of gene expression, show potential as biomarkers for diagnosis and prognosis. This review aims to summarize experimental findings on miRNA expression in ChCM and explore the potential of these miRNAs as biomarkers of Chagas disease. The search was conducted in the US National Library of Medicine MEDLINE/PubMed public database using the terms "Chagas cardiomyopathy" OR "Chagas disease" AND "microRNA" OR "miRNA" OR "miR." Additionally, bioinformatics analysis was performed to investigate miRNA-target interactions and explore enrichment pathways of gene ontology biological processes and molecular functions. The miR-21, miR-146b, miR-146a, and miR-155 consistently exhibited up-regulation, whereas miR-145 was down-regulated in ChCM. These specific miRNAs have been linked to fibrosis, immune response, and inflammatory processes in heart tissue. Moreover, the findings from various studies indicate that these miRNAs have the potential as biomarkers for the disease and could be targeted in therapeutic strategies for ChCM. In this review, we point out miR-21, miR-146b, miR-146a, miR-155, and miR-145-5p role in the complex mechanisms of ChCM. These miRNAs have been shown as potential biomarkers for precise diagnosis, reliable prognostic evaluation, and effective treatment strategies in the ChCM.

An α-Gal antigenic surrogate as a biomarker of treatment evaluation in Trypanosoma cruzi-infected children. A retrospective cohort study.

Proper evaluation of therapeutic responses in Chagas disease is hampered by the prolonged persistence of antibodies to Trypanosoma cruzi measured by conventional serological tests and by the lack of sensitivity of parasitological tests. Previous studies indicated that tGPI-mucins, an α-Gal (α-d-Galp(1→3)-β-d-Galp(1→4)-d-GlcNAc)-rich fraction obtained from T. cruzi trypomastigotes surface coat, elicit a strong and protective antibody response in infected individuals, which disappears soon after successful treatment. The cost and technical difficulties associated with tGPI-mucins preparation, however, preclude its routine implementation in clinical settings. We herein developed a neoglycoprotein consisting of a BSA scaffold decorated with several units of a synthetic α-Gal antigenic surrogate (α-d-Galp(1→3)-β-d-Galp(1→4)-β-d-Glcp). Serological responses to this reagent, termed NGP-Tri, were monitored by means of an in-house enzyme-linked immunosorbent assay (α-Gal-ELISA) in a cohort of 82 T. cruzi-infected and Benznidazole- or Nifurtimox-treated children (3 days to 16 years-old). This cohort was split into 3 groups based on the age of patients at the time of treatment initiation: Group 1 comprised 24 babies (3 days to 5 months-old; median = 26 days-old), Group 2 comprised 31 children (7 months to 3 years-old; median = 1.0-year-old) and Group 3 comprised 26 patients (3 to 16 years-old; median = 8.4 years-old). A second, control cohort (Group 4) included 39 non-infected infants (3 days to 5 months-old; median = 31 days-old) born to T. cruzi-infected mothers. Despite its suboptimal seroprevalence (58.4%), α-Gal-ELISA yielded shorter median time values of negativization (23 months [IC 95% 7 to 36 months] vs 60 months [IC 95% 15 to 83 months]; p = 0.0016) and higher rate of patient negative seroconversion (89.2% vs 43.2%, p < 0.005) as compared to conventional serological methods. The same effect was verified for every Group, when analyzed separately. Most remarkably, 14 out of 24 (58.3%) patients from Group 3 achieved negative seroconversion for α-Gal-ELISA while none of them were able to negativize for conventional serology. Detailed analysis of patients showing unconventional serological responses suggested that, in addition to providing a novel tool to shorten follow-up periods after chemotherapy, the α-Gal-ELISA may assist in other diagnostic needs in pediatric Chagas disease. The tools evaluated here provide the cornerstone for the development of an efficacious, reliable, and straightforward post-therapeutic marker for pediatric Chagas disease.

Prediction of response to neoadjuvant chemo-immunotherapy in patients with esophageal squamous cell carcinoma by a rapid breath test.

Neoadjuvant chemo-immunotherapy combination has shown remarkable advances in the management of esophageal squamous cell carcinoma (ESCC). However, the identification of a reliable biomarker for predicting the response to this chemo-immunotherapy regimen remains elusive. While computed tomography (CT) is widely utilized for response evaluation, its inherent limitations in terms of accuracy are well recognized. Therefore, in this study, we present a novel technique to predict the response of ESCC patients before receiving chemo-immunotherapy by testing volatile organic compounds (VOCs) in exhaled breath. This study employed a prospective-specimen-collection, retrospective-blinded-evaluation design. Patients' baseline breath samples were collected and analyzed using high-pressure photon ionization time-of-flight mass spectrometry (HPPI-TOFMS). Subsequently, patients were categorized as responders or non-responders based on the evaluation of therapeutic response using pathology (for patients who underwent surgery) or CT images (for patients who did not receive surgery). A total of 133 patients were included in this study, with 91 responders who achieved either a complete response (CR) or a partial response (PR), and 42 non-responders who had stable disease (SD) or progressive disease (PD). Among 83 participants who underwent both evaluations with CT and pathology, the paired t-test revealed significant differences between the two methods (p < 0.05). For the breath test prediction model using breath test data from all participants, the validation set demonstrated mean area under the curve (AUC) of 0.86 ± 0.06. For 83 patients with pathological reports, the breath test achieved mean AUC of 0.845 ± 0.123. Since CT has inherent weakness in hollow organ assessment and no other ideal biomarker has been found, our study provided a noninvasive, feasible, and inexpensive tool that could precisely predict ESCC patients' response to neoadjuvant chemo-immunotherapy combination using breath test based on HPPI-TOFMS.

Recent advancements in 18F-FDG PET/CT for the diagnosis, staging, and treatment management of HIV-related lymphoma.

Infection with the Human Immunodeficiency Virus (HIV) is one of the most pressing issues facing public health on a worldwide scale. Currently, HIV-related lymphoma is the most common cause of death among people living with HIV, and warrants more attention. The unique challenges associated with HIV-related lymphoma management derive from the underlying HIV infection and its immunosuppressive effects. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has gained significant prominence in the past few years as a valuable diagnostic and therapeutic instrument for the treatment of HIV-related lymphoma. This review will start with an overview of the subtypes, risk factors, and therapeutic choices for individuals with HIV-related lymphoma. We will then briefly discuss the current application of 18F-FDG PET/CT in the medical management of HIV-related lymphoma patients, followed by the initial staging of the disease, the evaluation of therapeutic response, the prediction of prognostic outcomes, the decision-making process for radiotherapy guided by PET findings, and the distinguishing of various diagnoses.

Patient-Derived Xenografts: Historical Evolution, Immunocompromised Host Models, and Translational Significance.

Patient-derived xenografts (PDXs) represent a critical advancement in preclinical cancer research, wherein human tumor samples are implanted into animal models for evaluation of therapeutic responses. PDXs have emerged as indispensable tools in translational cancer research, facilitating investigation into tumor microenvironments and personalized medicine. This chapter elucidates the historical evolution of PDXs, from early attempts in the eighteenth century to contemporary immunocompromised host models that enhance engraftment success.

Carrageenan-Induced Acute Inflammation on Back-Skin of Mice: Histopathological Features, Number of Inflammatory Cells, and Expression of COX-2, COX-1, and IL-6

Carrageenan is a sulfated polysaccharide obtained from red seaweed (Rhodophyceae) and can trigger inflammatory activation in both humans and laboratory animals. This study aimed to investigate the expression of cyclooxygenase-2 (COX-2), cyclooxygenase-1 (COX-1), and interleukin-6 (IL-6) and the number of inflammatory cells (neutrophil) involved in a carrageenan-induced acute inflammatory model in the back skin of mice. Paraffin blocks from the back skin of female Swiss mice aged 8 weeks were used in this study. The back-skins of 4 groups of 5 mice in each group were subcutaneously injected with 1%, 2%, and 4% carrageenan powder in 0.9% buffer saline and 0.9% buffer saline as control. Skin samples on paraffin blocks were taken 6 hours after carrageenan injection. Furthermore, paraffin blocks were stained with hematoxylin-eosin (HE) to count the number of inflammatory cells. Immunohistochemistry staining using anti-COX-2, COX-1, and IL-6 antibodies was performed to determine the role of inflammatory mediators. The results showed that the number of inflammatory cells (neutrophils) increased significantly following an increase in carrageenan concentrations. The COX-2, COX-1, and IL-6 expressed by inflammatory cells increased significantly at carrageenan concentrations of 1% to 4%. Histopathological features supported the results obtained from the calculation of the number of inflammatory cells and the expression of COX-2, COX-1, and IL-6. The inflammatory markers consisting of COX-2, COX-1, and IL-6 were expressed on the back skin of mice at 6 hours post-injection with 1% to 4% carrageenan. It can be concluded that carrageenan can be used for an acute inflammatory model of the back skin of a mouse. This inflammation model is intended to facilitate the evaluation or measurement of therapeutic and inflammatory responses when test substances are administered topically or transdermal.

Rationale, Development, and Validation of HdxSim, a Clinical Decision Support Tool for Model-Informed Precision Dosing of Hydroxyurea for Children with Sickle Cell Anemia.

Hydroxyurea treatment for children with sickle cell anemia (SCA) is effective and life-saving. Stepwise escalation to maximum tolerated dose (MTD) provides optimal benefits, but is logistically challenging and time-consuming, especially in low-income countries where most people with SCA live. Model-informed precision dosing (MIPD) of hydroxyurea expedites MTD determination and improves outcomes compared with trial-and-error dose adjustments. HdxSim, a user-friendly, online, clinical decision support tool was developed to facilitate hydroxyurea MIPD and evaluated using real-world pharmacokinetic (PK) data. First-dose hydroxyurea PK profiles were analyzed from two clinical trial datasets (Hydroxyurea Study of Long-Term Effects (HUSTLE), NCT00305175 and Therapeutic Response Evaluation and Adherence Trial (TREAT), NCT02286154). Areas under the concentration-time curve (AUC) estimated by HdxSim were compared with those determined using traditional trapezoidal methodology and PK software (MWPharm-DOS). The doses predicted by HdxSim and MWPharm-DOS were compared with the observed clinical MTD. For HUSTLE participants, HdxSim accurately estimated hydroxyurea AUC compared with the trapezoidal method, with < 20% variance. The average (mean ± SD) AUC for TREAT participants estimated with HdxSim (68.6 ± 18.0 mg*hour/L) was lower than MWPharm-DOS (78.6 ± 20.7 mg*hour/L, P = 0.012), but the average recommended doses were not different (425 vs. 423 mg/day, P = 0.97). Moreover, HdxSim was non-inferior to MWPharm-DOS at predicting clinical MTD (absolute difference 3.9 ± 5.8 vs. 4.9 ± 8.2 mg/kg/day, P = 0.19). HdxSim accurately estimates hydroxyurea exposure and is noninferior to traditional PK approaches at predicting the clinical hydroxyurea MTD. Hydroxyurea dosing based on target exposure leads to improved outcomes in children with SCA, and has the potential to make PK-guided hydroxyurea dosing more accessible to this neglected population globally.

Adoptive Therapy with Cytomegalovirus-Specific Cytotoxic T Lymphocytes for Refractory Cytomegalovirus Infection and Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Cytomegalovirus (CMV) infection remains a common complication in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). The rates of refractory CMV infection are reported in allo-HSCT recipients ranging from 19.0% to 50.6%. Patients with refractory CMV infection have a higher incidence of CMV disease and non-relapse mortality than those without refractory CMV infection, and the antiviral drug has limited efficacy. In this study, we retrospectively compared the efficacy and safety of donor and third-party CMV-specific cytotoxic T lymphocytes (CMV-CTLs) in patients with refractory CMV infection and disease after allo-HSCT in the context of the new definitions. Methods: This study examined all consecutive patients who received CMV-CTL therapy for refractory CMV infection and disease after allo-HSCT at our center from January 2017 to September 2021. Refractory CMV infection referred to refractory CMV DNAemia, which was defined by a &amp;gt;1 log 10 increase in CMV DNA levels in blood after at least 2 weeks of appropriately dosed antiviral therapy. Refractory CMV disease referred to refractory CMV end-organ disease, which was defined by a worsening in signs and symptoms or progression into end-organ disease after at least 2 weeks of appropriately dosed antiviral therapy. This study mainly focused on the therapeutic response, overall survival (OS) and safety evaluation. Complete response (CR) was defined as undetectable CMV DNA by quantitative PCR in two consecutive tests coupled with the resolution of clinical signs and symptoms. Results:A total of 53 patients who received CMV-CTL therapy for refractory CMV DNAemia and disease after allo-HSCT were enrolled in this study, including 40 in the donor CMV-CTL group and 13 in the third-party CMV-CTL group. Of the 40 patients with donor CMV-CTLs, 20 were refractory CMV DNAemia, and 20 were refractory CMV end-organ diseases. Of the 13 patients with third-party CMV-CTLs, 7 were refractory CMV DNAemia, and 6 had refractory CMV end-organ diseases. Within 6 weeks of treatment, 26 (65.0%) patients and 9 (69.2%) patients achieved CR in the donor and third-party groups (P=1.00). The CR rates at 6 weeks after the first CMV-CTL infusion were 65.0% (95% CI 49.5%-77.9%) in the donor group and 69.2% (95% CI 42.4%-87.3%) in the third-party group. At the date of statistical analysis (September 30, 2022), 16 patients died in the donor CMV-CTL group and 6 died in the third-party CMV-CTL group. Causes of death were relapse of the primary diseases (n=3; 3 in the donor group), CMV diseases (n=5; 4 in the donor group and 1 in the third-party group), mixed infections (n=9; 6 in the donor group and 3 in the third-party group), bacterial infection (n=4; 2 in each group), and fungal infection (n=1; 1 in the donor group). The OS at 2 year was 59.6% (95%CI 46.1%-77.1%) in the donor group and 53.8% (95% CI 32.6%-89.1%) in the third-party group (P=0.860). Conclusion:This study contributes important information regarding the comparable antiviral efficacy and safety of donor or third-party CMV-CTLs for refractory CMV infection and disease after allo-HSCT.

Serum BLMH and CKM as Potential Biomarkers for Predicting Therapeutic Effects of Deep Brain Stimulation in Parkinson's Disease: A Proteomics Study.

Deep brain stimulation (DBS) is recommended for the treatment of advanced Parkinson's disease (PD), though individual reactions may be different. There are currently no clinically available biomarkers for predicting the responses of PD patients to DBS before surgery. This study aimed to determine serum biomarkers to predict DBS responses in PD. We profiled differentially expressed proteins (DEPs) in serum samples and identified potential biomarkers to predict the therapeutic responses to DBS in PD patients. Ten serum samples were selected from PD patients to identify DEPs via mass spectrometry proteomics; these were then verified by enzyme-linked immunosorbent assay in another 21 serum samples of PD patients. The present study identified 14 DEPs (10 downregulated and four upregulated DEPs) with significantly different levels between non-responders and responders. Most of the DEPs were related to amino acid metabolism and protein modification pathways. Bleomycin hydrolase (BLMH) and creatine kinase M-type (CKM) were found to be significantly downregulated in the responders. Additionally, subsequent logistic regression and receiver operating characteristic analyses were performed to determine the diagnostic performance of candidate proteins. The identified DEPs show potential as biomarkers for the accurate evaluation of DBS therapeutic responses before surgery. Furthermore, assessment of serum BLMH and CKM may be particularly useful for predicting the therapeutic responses to DBS in PD patients.

Miniaturized microscope for non-invasive imaging of leukocyte-endothelial interaction in human microcirculation

We present a miniature oblique back-illumination microscope (mOBM) for imaging the microcirculation of human oral mucosa, enabling real-time, label-free phase contrast imaging of individual leukocytes circulating in the bloodstream, as well as their rolling and adhesion on vascular walls—the initial steps in leukocyte recruitment that is a hallmark of inflammation. Using the mOBM system, we studied the leukocyte-endothelial interactions in healthy and locally inflamed tissue and observed drastic changes in leukocyte movement (velocity and displacement profile). Our findings suggest that real-time imaging of leukocyte dynamics can provide new diagnostic insights (assessment of inflammation, temporal progression of disease, evaluation of therapeutic response, etc.) that are not available using conventional static parameters such as cell number and morphology.

MHealth Monitoring of Treatment of Cutaneous Leishmaniasis Patients: A Community-Based Implementation Study.

Cutaneous leishmaniasis (CL) remains a global health problem. Compelled by the protracted healing process, initial and final outcomes of treatment are determined at 90 and 180 days, respectively, after initiation of treatment. Loss to follow-up during these intervals is substantial. Consequently, the effectiveness of treatment is largely unknown. We conducted an effectiveness-implementation hybrid design study of a community-based mobile health (mHealth) strategy to monitor adherence to anti-leishmanial treatment, adverse drug reactions, and therapeutic response compared with standard of care in two rural communities of Colombia. Three implementation outcomes were evaluated: usability and acceptability by qualitative methods and fidelity using quantitative methods. Fifty-seven patients were prospectively included in the mHealth intervention and 48 in the standard-of-care group. In addition, 24 community health leaders (CHLs), health workers, and patients participated in qualitative evaluations. The intervention significantly increased the proportion of patients having follow-up of therapeutic outcomes 90 and 180 days after initiating treatment from 4.2% (standard of care) to 82.5% (intervention), P < 0.001. The proportion of patients having records of treatment adherence, adverse drug reactions, and therapeutic response also increased significantly (P < 0.001). Fidelity to the intervention (recording of treatment adherence, adverse drug reactions, lesion photographs, and evaluation of therapeutic response) was 70-100%. The app was highly accepted by CHLs, health workers, and patients, who perceived that the app improved case identification and follow-up and met a public health need. Although usability was high, low connectivity affected real-time transmission of data. This community-based mHealth strategy facilitated access to health care for CL in rural areas and knowledge of treatment effectiveness.

Necroptosis in the sarcoma immune microenvironment: From biology to therapy.

Apoptosis resistance remains a major obstacle to treatment failure in sarcoma. Necroptosis is a caspase-independent programmed cell death, investigated as a novel strategy to eradicate anti-apoptotic tumor cells. The process is mediated by the receptor-interacting proteins kinase family and mixed lineage kinase domain-like proteins, which is morphologically similar to necrosis. Recent studies suggest that necroptosis in the tumor microenvironment has pro- or anti-tumor effects on immune response and cancer development. Necroptosis-related molecules display a remarkable value in prognosis prediction and therapeutic response evaluation of sarcoma. Furthermore, the induction of tumor necroptosis has been explored as a feasible therapeutic strategy against sarcoma and to synergize with immunotherapy. This review discusses the dual roles of necroptosis in the immune microenvironment and tumor progression, and explores the potential of necroptosis as a new target for sarcoma treatment.

Biomarkers of fibrosis, inflammation, and extracellular matrix in the phase 3 trial of tocilizumab in systemic sclerosis

Drug development for systemic sclerosis (SSc) benefits from understanding the relationship between disease and circulating biomarkers to enable activities such as patient stratification and evaluation of therapeutic response. We measured biomarkers in serum from SSc patients from a phase 3 trial of tocilizumab (focuSSced) and compared baseline levels with healthy controls (HCs). Several baseline biomarkers appeared elevated in SSc patients compared to HCs, suggesting activation of epithelial damage, inflammation, fibrosis, and extracellular matrix (ECM) remodeling. Baseline correlations among both periostin/COMP and ECM biomarker subsets implicated their participation in fibroblast activation. Tocilizumab treatment modulated serum biomarkers of macrophage activation, inflammation, and ECM turnover, including collagen formation and degradation neoepitopes. Baseline CRP, periostin, and SP-D showed prognostic trends for worsening lung function, and IL-6, COMP, periostin, and Pro-C3 showed prognostic trends for worsening skin thickness. These prognostic results warrant confirmation in additional patient cohorts to verify their utility.