Therapeutic Response In Patients Research Articles

Molecular subtyping based on immune cell marker genes predicts prognosis and therapeutic response in patients with lung adenocarcinoma

ObjectiveLung adenocarcinoma (LA) is one of the most common malignancies and is responsible for the greatest number of tumor-related deaths. Our research aimed to explore the molecular subtype signatures of LA to clarify the correlation among the immune microenvironment, clinical outcomes, and therapeutic response.MethodsThe LA immune cell marker genes (LICMGs) identified by single-cell RNA sequencing (scRNA-seq) analysis were used to discriminate the molecular subtypes and homologous immune and metabolic traits of GSE72094 LA cases. In addition, the model-building genes were identified from 1441 LICMGs by Cox-regression analysis, and a LA immune difference score (LIDscore) was developed to quantify individual differences in each patient, thereby predicting prognosis and susceptibility to immunotherapy and chemotherapy of LA patients.ResultsPatients of the GSE72094 cohort were divided into two distinct molecular subtypes based on LICMGs: immune activating subtype (Cluster-C1) and metabolically activating subtype (cluster-C2). The two molecular subtypes have distinct characteristics regarding prognosis, clinicopathology, genomics, immune microenvironment, and response to immunotherapy. Among the LICMGs, LGR4, GOLM1, CYP24A1, SFTPB, COL1A1, HLA-DQA1, MS4A7, PPARG, and IL7R were enrolled to construct a LIDscore model. Low-LIDscore patients had a higher survival rate due to abundant immune cell infiltration, activated immunity, and lower genetic variation, but probably the higher levels of Treg cells in the immune microenvironment lead to immune cell dysfunction and promote tumor immune escape, thus decreasing the responsiveness to immunotherapy compared with that of the high-LIDscore patients. Overall, high-LIDscore patients had a higher responsiveness to immunotherapy and a higher sensitivity to chemotherapy than the low-LIDscore group.ConclusionsMolecular subtypes based on LICMGs provided a promising strategy for predicting patient prognosis, biological characteristics, and immune microenvironment features. In addition, they helped identify the patients most likely to benefit from immunotherapy and chemotherapy.

ADC Values for Detecting Bowel Inflammation and Biologic Therapy Response in Patients With Crohn Disease: A Post Hoc Prospective Trial Analysis.

BACKGROUND. New biologic agents for Crohn disease (CD) create a need for noninvasive disease markers. DWI may assess bowel inflammation without contrast agents. OBJECTIVE. The purpose of this study was to evaluate ADC values for identifying bowel inflammation and therapeutic response in patients with CD treated with biologic therapy. METHODS. This study entailed post hoc analysis of prospective trial data. Analysis included 89 patients (median age, 37 years; 49 women, 40 men) with CD treated by biologic therapy who underwent MR enterography (MRE) at baseline and 46 weeks after therapy, from March 2013 to April 2021; 43 patients underwent ileocolonoscopy at both time points. Analysis was conducted at the level of small-bowel and colorectal segments (586 segments analyzed). MR index of activity (MaRIA) score and presence of endoscopic ulcers were determined at both time points. One observer measured bowel wall ADC. Diagnostic performance was evaluated. Dichotomous ADC assessments used a threshold of 1301 × 10-6 mm2/s based on initial ROC analysis; dichotomous MaRIA score assessments used a threshold of 11 (moderate to severe inflammation). A second observer repeated ADC measurements in 15 patients. RESULTS. At baseline, ADC had AUC of 0.92, sensitivity of 78.6%, specificity of 91.4%, and accuracy of 88.2% for detecting segments with MaRIA score 11 or greater. At baseline, AUC for detecting endoscopic ulcers was 0.96 for MaRIA score versus 0.87 for ADC (p < .001); sensitivity, specificity, and accuracy were 70.8%, 90.2%, and 85.1% for ADC and 86.2%, 96.2%, and 93.6% for MaRIA score. At follow-up, ADC had AUC of 0.87, sensitivity of 75.4%, specificity of 83.6%, and accuracy of 80.0% for detecting improvement in MaRIA score to less than 11. At follow-up, AUC for detecting endoscopic ulcer healing was 0.94 for MaRIA score versus 0.84 for ADC (p = .01); sensitivity, specificity, and accuracy were 70.7%, 95.8%, and 84.4% for ADC and 90.2%, 100.0%, and 95.6% for MaRIA score. Interobserver agreement for ADC, based on intraclass correlation coefficient, was 0.70 at baseline and 0.65 at follow-up. CONCLUSION. The findings do not support use of ADC rather than MaRIA scores for detecting biologic therapy response. CLINICAL IMPACT. ADC may have an adjunct role in assessing bowel inflammation in CD, but showed limited performance for detecting biologic therapy response.

Dynamic blood flow imaging with 99mTc-hydroxymethylene diphosphonate as a therapeutic response marker in patients with Raynaud's phenomenon.

We evaluated the predictive value of dynamic blood flow scintigraphy with 99mTc-HDP (hydroxymethylene diphosphonate) for therapeutic response in patients with Raynaud's phenomenon (RP). Eighty patients who underwent dynamic blood flow scintigraphy using the one-hand chilling method were enrolled. We analyzed the quantitative variables as the ratio of chilled fingers to ambient fingers (CAfinger), that of the chilled hand to ambient hand (CAhand), and that of chilled fingers to ambient palm (FPR) (CAFPR) at 15 and 30s after 99mTc-HDP bolus injection. Total cumulative radioactivity counts for 180s were obtained. We evaluated the clinical utility of these quantitative parameters with other clinical variables, including RP severity, therapeutic compliance, types of RP, and scintigraphic interpretation of findings in patients with RP. Fifty-two patients showed poor therapeutic response. There were significant differences between good- and poor-therapeutic responder groups in RP intensity (p = 0.003), CAfinger15s (p = 0.008), CAfinger30s (p = 0.002), CAfinger180s (p = 0.011), CAhand15s (p = 0.008), CAhand30s (p = 0.007), CAhand180s (p = 0.017), CAFPR30s (p = 0.004), and CAFPR180s (p = 0.002). After multivariate logistic regression analysis, only CAfinger30s (p = 0.002) had an independent predictive value of the therapeutic response. 99mTc-HDP dynamic blood flow scintigraphy could be helpful in predicting the therapeutic response in patients with RP.

Reoperation after surgery for bone metastasis of renal cell carcinoma.

The prognosis of metastatic renal cell carcinoma (RCC) has markedly improved with the advent of molecular targeted therapies and immune checkpoint inhibitors. However, the therapeutic response in patients with bone metastasis remains low; therefore, surgery still plays a significant role in treatment of bone metastasis. It is important to maintain quality of life for patients with bone metastasis from RCC and avoid reoperation after surgery for bone metastasis. Therefore, we investigated the risk factors for reoperation after surgery in patients with bone metastasis from RCC. We retrospectively studied 103 bones of 97 patients who underwent surgery for bone metastasis of RCC from 2001 to 2023 at our institutions. Reoperation was performed in 10 (9.7%) of 103 bones. There was no correlation between reoperation-free survival and any of the following variables: preoperative and postoperative radiotherapy, site of bone metastasis, indication for surgery (solitary bone metastasis or impending or pathologic fractures), surgical method (intramedullary nailing fixation, curettage, or en bloc resection), preoperative embolization, or survival. The risk of reoperation for bone metastasis of RCC does not appear to be based on the surgical method.

EEG features in patients with different subtypes of prolonged and chronic endogenous manic-delusional states

The purpose of the study. Analysis of the features of EEG spectral parameters in patients with polymorphic and monomorphic subtypes of prolonged and chronic endogenous manic-delusional states (PEMDS).Materials and methods. A clinical-neurophysiological study was carried out in 76 female patients with monomorphic (group 1, 34 patients) and polymorphic (group 2, 42 patients) subtypes of PEMDS, identified based on clinical-dynamic analysis.Results. In the group 1, compared with the group 2, there were significantly lower values of the spectral power of the pre-treatment EEG in most EEG leads and frequency sub-bands, which reflect a significant deficit in the brain inhibitory systems. In the group 2, the EEG slowdown (in the delta-frequency sub-band) after treatment course, was significantly more pronounced in the frontal-anterotemporal-central cortical zones of the left hemisphere, reflecting a greater increase of the neurophysiological processes of inhibition in these brain areas under the influence of treatment, which leads to an improvement in the clinical condition of patients.Conclusions. The revealed differences in the brain functional activity organization may mediate the features of the clinical picture and therapeutic response in patients with polymorphic and monomorphic subtypes of PEMDS.

Cerebrospinal fluid indices as predictors of treatment response in autoimmune encephalitis.

Cerebrospinal fluid (CSF) indices reflecting intrathecal antibody production and blood-brain barrier impairment are not routinely assessed in patients with autoimmune encephalitis (AE). We aimed to study CSF indices and their association with the prognosis of AE. This retrospective cohort study conducted at Amrita Institute of Medical Sciences (AIMS), Kochi, India, included 60 patients aged more than 18 years with definite/probable/possible AE admitted to the Department of Neurology from August 2016 to November 2021. We introduced a classification of treatment response based on modified Rankin Scale change over time and treatment modalities. In our cohort of 60 patients (six [10%] seropositive cases), a good rapid treatment response was associated with CSF white blood cell count of more than 4 cells/mm3 (OR, 4.57; 95% CI 1.31-15.96; P=.02) and positive immunoglobulin G (IgG) Local Synthesis (OR, 7.27; 95% CI 1.56-33.86; P=.01). Albumin Index had association with a poor Glasgow Coma Scale score at the nadir of the disease (OR, 1.17; 95% CI 1.01-1.34; P=.04). Similar results were yielded in the seronegative cohort. IgG Local Synthesis appeared to be a strong predictor for good rapid treatment response in both univariate and multivariate (adjusted OR, 28.71; 95% CI 2.12-389.22; P= .01) analysis. Time to immunotherapy was reversely correlated with good response overall (in the cohort with outliers removed [N=49]: unadjusted OR 0.97, 95% CI 0.95-0.99; P= .01; adjusted OR 0.97; 95% CI 0.95-0.99; P= .008). CSF indices reflecting intrathecal antibody production and blood-brain barrier impairment appear to be promising predictors of disease severity and therapeutic response in patients with autoimmune encephalitis.

An impaired ubiquitin-proteasome system increases APOBEC3A abundance.

Apolipoprotein B messenger RNA (mRNA) editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases cause genetic instability during cancer development. Elevated APOBEC3A (A3A) levels result in APOBEC signature mutations; however, mechanisms regulating A3A abundance in breast cancer are unknown. Here, we show that dysregulating the ubiquitin-proteasome system with proteasome inhibitors, including Food and Drug Administration-approved anticancer drugs, increased A3A abundance in breast cancer and multiple myeloma cell lines. Unexpectedly, elevated A3A occurs via an ∼100-fold increase in A3A mRNA levels, indicating that proteasome inhibition triggers a transcriptional response as opposed to or in addition to blocking A3A degradation. This transcriptional regulation is mediated in part through FBXO22, a protein that functions in SKP1-cullin-F-box ubiquitin ligase complexes and becomes dysregulated during carcinogenesis. Proteasome inhibitors increased cellular cytidine deaminase activity, decreased cellular proliferation and increased genomic DNA damage in an A3A-dependent manner. Our findings suggest that proteasome dysfunction, either acquired during cancer development or induced therapeutically, could increase A3A-induced genetic heterogeneity and thereby influence therapeutic responses in patients.

Significance of the autoantibody assay in predicting the development of immune-related adverse events in patients receiving atezolizumab plus bevacizumab combination therapy for unresectable hepatocellular carcinoma.

Atezolizumab plus bevacizumab (AB) combination therapy is the first-line treatment for unresectable hepatocellular carcinoma (u-HCC). The management of immune-related adverse events (irAEs) is an important issue associated with achieving a good therapeutic response in patients receiving AB therapy. However, few studies have reported irAE development in patients receiving AB therapy. This study focused on the association between irAE development and autoantibodies at baseline in patients receiving AB therapy. Sixty-one patients receiving AB therapy were enrolled. For autoantibodies, the following antibodies were tested before the start of AB therapy: antinuclear antibodies, rheumatoid factor (RF), anti-thyroglobulin antibodies, thyroid peroxidase antibodies, anti-thyroid stimulating hormone receptor antibodies, and acetylcholine receptor antibodies. A patient was considered to have pre-existing antibodies if any of the listed antibodies were present at baseline. Ten patients (16%) developed irAEs during the observation period. The irAEs included liver injury, hypothyroidism, adrenal insufficiency, adrenocorticotropic hormone deficiency, and rhabdomyolysis. Patients with irAE (n=10) were more likely to be positive for any autoantibody (hazard ratio [HR] 3.7, p=0.047) and RF at baseline (HR 5.4, p=0.035) and to achieve complete response (HR 5.8, p=0.027) than those without. The presence of autoantibodies at baseline was an independent factor associated with irAE development. In the real world, 16% of patients receiving AB therapy for u-HCC developed irAEs. Patients with autoantibodies at baseline are at high risk of developing irAEs and require cautious follow-up.

P350 Clinical characteristics and therapeutic response of patients with adult-onset Multiple Acyl-CoA-Dehydrogenase Deficiency (MADD)

P350 Clinical characteristics and therapeutic response of patients with adult-onset Multiple Acyl-CoA-Dehydrogenase Deficiency (MADD)

Cervical dystonia: ways to achieve long-term treatment eff ects and improve patients’ quality of life

The main treatment for cervical dystonia (CD) is botulinum toxin type A (BTA) injections, but several long-term studies have found that between 19-46% of patients discontinue treatment. Anxiety and depression play a signi fi cant role in reducing the quality of life in patients with CD, according to previous surveys.Aim: to assess the dynamics of CD symptom severity, emotional disturbance, and quality of life in patients under different treatment methods.Material and methods. 61 patients with CD, 16 (26%) men and 45 (74%) women, age 50 [40; 59] years, duration of illness 4 [2; 7] years, age at onset 44 [34; 54] years, were studied. Changes in motor and aff ective disturbances, quality of life in patients with CD were assessed after 2 and 4 months in the context of diff erent treatment methods — BTA monotherapy, antidepressant (AD), combined therapy (AD + AD).Results. Combination therapy (BT + AD) was shown to be superior to BTA monotherapy in long-term follow-up of patients in terms of correction of depression, anxiety, integrative assessment of quality of life and severity of dystonia. After 4 months of treatment, the (BT + AD) subgroup maintained the positive trend achieved in dystonia severity (p &lt; 0.001). At the end of the follow-up period in the BT group, the positive eff ect of therapy had regressed to baseline levels of dystonia severity.Conclusion. To achieve a sustained therapeutic response in patients with CD, diagnosis and appropriate correction of emotional disturbances is necessary. The potential effi cacy of antidepressants in the treatment of motor and sensory symptoms of CD requires further investigation.

Clinical Manifestations, Genetic Variants and Therapeutic Evaluation in Sporadic Chinese Patients with Idiopathic Hypogonadotropic Hypogonadism.

Genetic factors account for a large proportion of idiopathic hypogonadotropic hypogonadism (IHH) etiologies, although not necessarily a complete genetic basis. This study aimed to characterize the clinical presentations, genetic variants, and therapeutic outcomes of patients with sporadic IHH, which may be helpful for genetic counseling and treatment decisions. Eleven Chinese patients with IHH were retrospectively analyzed. Rare genetic variants were evaluated using whole-exome sequencing and bioinformatics analysis and were further classified according to the ACMG-AMP guidelines. The therapeutic responses of patients were further evaluated. Six heterozygous variants of SOX10, WDR11, PROKR2, CHD7 and FGF17 were detected in five Kallmann syndrome (KS) patients, whereas two heterozygous variants of CHD7 and PROKR2 were detected in two normosmic IHH (nIHH) patients. Among these variants, a novel likely pathogenic variant in the SOX10 (c.429-1G>C) was considered to cause the KS phenotype in patient 02, and two potential variants of uncertain significance (VUS) in CHD7 (c.3344G>A and c.7391A>G) possibly contributed to the KS phenotype in patient 05 and the nIHH phenotype in patient 07, which need to be confirmed by further evidence. Additionally, long-term testosterone or estradiol replacement treatment effectively improved the development of sexual characteristics in patients with IHH. Next-generation sequencing is a powerful tool for identifying the molecular etiology and early diagnosis of IHH. Efficient therapeutic outcomes strongly indicate a need for timely treatment.

Serial measurements of SIRS criteria to identify unique phenotypes of sepsis: A Microbiologic Approach

Introduction: The utility of serial scoring systems in identifying distinct sepsis phenotypes remains unknown. Methods: Eligible adults were classified into culture-positive (Cx+) and culture-negative (Cx-) groups alongside pre-defined culture subgroups. Average SIRS &amp; SEP (novel scoring system) scores were calculated at t = 0 and hours 3,6,12 &amp; 24 before and after t = 0. The primary outcome was a difference in SIRS/SEP scores amongst those that were Cx+ or Cx- at any time point. Secondary outcomes were comparing total and component SIRS/SEP scores in microbiologic subgroups over serial time points. Results: 4,701 Cx+ and 3254 Cx- patients met eligibility criteria. Statistically significant differences were seen in the average SIRS score between Cx + and Cx- groups at hours six (Cx+ 1.40+1.04 vs Cx- 1.35+1.01) &amp; 12 (Cx+ 0.95+0.95 vs Cx- 0.90+0.90) after t = 0. The hematologic, urologic, and neurologic subgroups had significant differences at numerous time points before and after T = 0. Similar findings were observed with the SEP scores. Cx+ and Cx- groups (including subgroups) consistently doubled both SIRS/SEP scores before t = 0 with an eventual return to baseline values after T = 0 but at different gradients. Conclusion: Significant differences in SIRS/SEP scores were seen in Cx+ &amp; Cx- patients at sequential time points. This microbiologic approach in homogenous culture cohorts has the potential to identify distinct phenotypes of sepsis efficiently and practically. Consistent increases in SIRS/SEP scores before t = 0 and sequential decreases after t = 0 may allow for early detection, intervention, and provision for real-time monitoring of therapeutic responses in patients with concerns for sepsis.

Evaluating the role of serum uric acid in the risk stratification and therapeutic response of patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD).

Background: Pulmonary arterial hypertension (PAH) is a malignant pulmonary vascular disease that negatively impacts quality of life, exercise capacity, and mortality. This study sought to investigate the relationship between serum uric acid (UA) level and the disease severity and treatment response of patients with PAH and congenital heart disease (PAH-CHD). Methods: This study included 225 CHD patients and 40 healthy subjects. Serum UA was measured in all patients, and UA levels and haemodynamic parameters were re-evaluated in 20 patients who had received PAH-specific drug treatment for at least 7 ± 1month. Results: Serum UA levels were significantly higher in PAH-CHD patients than in CHD patients with a normal pulmonary artery pressure and normal subjects (347.7 ± 105.7μmol/L vs. 278.3 ± 84.6μmol/L; 347.7 ± 105.7μmol/L vs. 255.7 ± 44.5μmol/L, p < 0.05). UA levels in the intermediate and high risk groups were significantly higher than those in the low-risk group (365.6 ± 107.8μmol/L vs. 311.2 ± 82.8μmol/L; 451.6 ± 117.6μmol/L vs. 311.2 ± 82.8μmol/L, p < 0.05). Serum UA levels positively correlated with mean pulmonary arterial pressure, WHO functional class, pulmonary vascular resistance, and NT-proBNP (r = 0.343, 0.357, 0.406, 0.398; p < 0.001), and negatively with mixed venous oxygen saturation (SvO2) and arterial oxygen saturation (SaO2) (r = -0.293, -0.329; p < 0.001). UA significantly decreased from 352.7 ± 97.5 to 294.4 ± 56.8μmol/L (p = 0.001) after PAH-specific drug treatment for at least 6months, along with significant decreases in mean pulmonary arterial pressure and pulmonary vascular resistance and increases in cardiac index and mixed SvO2. Conclusion: Serum UA can be used as a practical and economic biomarker for risk stratification and the evaluation of PAH-specific drug treatment effects for patients with PAH-CHD.

Challenges in Development and Qualification of PCR/dPCR Assays for Gene Therapy Biodistribution and Viral Shedding Assessment

Gene therapies are part of a larger class of advanced therapies that aim to treat disease via delivery of recombinant genetic material. A gene therapy product has two components, the delivery system (viral vector or non-viral) and the transgene (DNA or RNA). These therapies act via replacement of a non-functional gene, silencing of a disease-causing gene, or introduction of a new or modified gene with the goal of generating a therapeutic response in patients. Gene therapy biodistribution and viral vector shedding must be evaluated during non-clinical testing. Polymerase chain reaction (PCR) has emerged as the technique of choice to quantify the gene therapy product and the transferred genetic material in study samples. With increasing numbers of gene therapies in pre-clinical development, there has been a concomitant increase in the use of PCR in bioanalytical laboratories. A major challenge in this space is the lack of formal guidance for the development, characterization, and validation of PCR assays. This article will focus on the opportunities and challenges in developing and characterizing non-GLP, digital PCR assays for AAV gene therapy products. AAV vectors are currently the most common viral delivery system, however many of the insights presented will be applicable to other delivery systems.

Morphometry-based radiomics for predicting therapeutic response in patients with gliomas following radiotherapy.

Gliomas are still considered as challenging in oncologic management despite the developments in treatment approaches. The complete elimination of a glioma might not be possible even after a treatment and assessment of therapeutic response is important to determine the future course of actions for patients with such cancers. In the recent years radiomics has emerged as a promising solution with potential applications including prediction of therapeutic response. Hence, this study was focused on investigating whether morphometry-based radiomics signature could be used to predict therapeutic response in patients with gliomas following radiotherapy. 105 magnetic resonance (MR) images including segmented and non-segmented images were used to extract morphometric features and develop a morphometry-based radiomics signature. After determining the appropriate machine learning algorithm, a prediction model was developed to predict the therapeutic response eliminating the highly correlated features as well as without eliminating the highly correlated features. Then the model performance was evaluated. Tumor grade had the highest contribution to develop the morphometry-based signature. Random forest provided the highest accuracy to train the prediction model derived from the morphometry-based radiomics signature. An accuracy of 86% and area under the curve (AUC) value of 0.91 were achieved for the prediction model evaluated without eliminating the highly correlated features whereas accuracy and AUC value were 84% and 0.92 respectively for the prediction model evaluated after eliminating the highly correlated features. Nonetheless, the developed morphometry-based radiomics signature could be utilized as a noninvasive biomarker for therapeutic response in patients with gliomas following radiotherapy.

Experience with agomelatine therapy for non-psychotic depression with a single and recurrent course

Therapy of depression is a current problem in psychiatry. Agomelatine is not inferior to other modern drugs in terms of antidepressant efficacy (response and remission rates) and is characterized by the best tolerability.Objective: to evaluate the efficacy and safety of agomelatine in the treatment of nonpsychotic depression with a single and recurrent course.Material and methods. Patients (n=37) with a current depressive episode (DE; F32 according to ICD-10), mean age 41.2±2.07 years, were studied. Clinical psychopathological and psychometric methods were used in the study (Hamilton Hospital Depression Scale – HAMD-17; Spielberger–Khanin Anxiety Self-Assessment Scale, Sheehan Anxiety Scale, Clinical Global Impression Scale – CGI-I). A single DE was diagnosed in 62.2% of patients, and recurrent depressive disorder in 37.8%. Stress-related onset of current DE was found in 56.8% of cases, autochthonous in 43.2%.Results. 94.6% of patients were responders, including 68.6% who went into remission. A statistically significant decrease in scores on the HAMD-17 scale was noted in the remission group from the 7th day of agomelatine therapy (p&lt;0.05), in the responder group – from the 14th day of therapy (p&lt;0.05). According to the Sheehan scale, a statistically significant decrease in scores was noted at the end of the first week of therapy (p&lt;0.05), according to the Spielberger–Khanin scale – in the second week (p&lt;0.05) in all patients. According to the CGI-I scale, the condition at the end of therapy improved in 57.1% of patients, significantly in 42.9%. Clinical predictors of therapeutic response in patients with remission included significantly higher frequency of a single DE (p&lt;0.02), moderate severity of current depression (p&lt;0.02), dizziness among autonomic disorders (p&lt;0.01), a significantly lower representation of the melancholic type of depression (p&lt;0.05), a symptom of a gloomy and pessimistic vision of the future (p&lt;0.05), sleep disturbances (p&lt;0.04), a factor of personal significance in the form of a threat in patients with stress-provoked onset of the current DE (p&lt;0.05).Adverse events occurred in the first week of treatment with agomelatine in 14.3% of cases (nausea – 8.6%, headache and dizziness – 2.9% each), they were mild and did not require discontinuation of the drug. Two patients taking agomelatine at a dose of 50 mg discontinued the study: in one case persisted social phobia, increased fatigue, motor retardation, and persistent modern insomnia; in the other case – a pronounced senestoalgic syndrome with cerebral localization.Conclusion. Agomelatine therapy has been shown to be highly effective and well tolerated in nonpsychotic depression.

Circulating tumour DNA (ctDNA) burden quantified through low-pass whole genome sequencing as an early pharmacodynamic biomarker of therapeutic response in patients enrolled on phase 1 trials.

23 Background: Early phase trials are conducted to determine the recommended dose and safety of an investigational therapy. Targeted therapies and immunotherapy may not always have dose-dependent toxicities. Therefore, dose finding is increasingly reliant on optimal biological dosing. Pharmacodynamic biomarkers are increasingly important to demonstrate proof of concept. Using ctDNA allows for dynamic and early tumour assessments compared to imaging. We sought to evaluate ctDNA as an early pharmacodynamic biomarker of therapeutic response. Methods: Patients (pts) enrolled on phase 1 trials at the National Cancer Centre Singapore were prospectively consented to collect serial blood samples at defined timepoints (pre-treatment, mid-cycle 1, end of cycle 1, and with subsequent imaging evaluations). ctDNA burden was quantified using low pass whole genome sequencing (lpWGS) with both established (ichorCNA) and novel (cell-free DNA degradation) bioinformatic analyses of ctDNA burden, and targeted panel sequencing. Early kinetics of ctDNA burden prior to imaging evaluation was evaluated as response (reduction in ctDNA burden) versus progression (increase in ctDNA burden). Results: Between May 2021 to Oct 2022, 68 plasma samples (median 3, range 2-5) were collected from 22 pts. Median age was 56 years (range 37-77) and 73% were male. Pts were enrolled on trials of targeted therapy (55%), immunotherapy (40%) or combinations of both (5%). Common tumour types were lung (36%), colorectal (23%) and pancreatic (9%) cancer. Best response on phase 1 trial as per imaging and RECIST v1.1 was partial response (PR) in 9%, stable disease (SD) in 45%, progressive disease (PD) in 27% and not evaluable (NE; taken off trial early due to toxicity) in 18%. Quantification of ctDNA burden using cell-free DNA fragment length pattern demonstrated enhanced limit of detection in detecting baseline ctDNA compared to cell-free DNA copy number profile based ichorCNA method (100% vs 59%). For pts on targeted therapies, early kinetics of ctDNA burden indicated ctDNA response in 9/13 pts, with subsequent imaging showing PR (n=2), SD (n=2), PD (n=2) or NE (n=3). In the remaining 4/13 pts on targeted therapies with early ctDNA progression, subsequent imaging showed SD (n=3) or NE (n=1). For pts on immunotherapy, early ctDNA progression was seen in 8/10 pts, with subsequent imaging showing SD (n=5) and PD (n=3). Patient enrolment and sample analysis is ongoing to further validate these initial findings and updated data will be presented. Conclusions: Early ctDNA evaluation via lpWGS may represent an early pharmacodynamic biomarker of therapeutic response. ctDNA has the potential to provide early proof of concept, particularly for targeted therapies, that may influence subsequent decisions for dose determination.

Multicenter study of the natural history and therapeutic responses of patients with chikungunya, focusing on acute and chronic musculoskeletal manifestations – a study protocol from the clinical and applied research in Chikungunya (REPLICK network)

BackgroundChikungunya is associated with high morbidity and the natural history of symptomatic infection has been divided into three phases (acute, post-acute, and chronic) according to the duration of musculoskeletal symptoms. Although this classification has been designed to help guide therapeutic decisions, it does not encompass the complexity of the clinical expression of the disease and does not assist in the evaluation of the prognosis of severity nor chronic disease. Thus, the current challenge is to identify and diagnose musculoskeletal disorders and to provide the optimal treatment in order to prevent perpetuation or progression to a potentially destructive disease course.MethodsThe study is the first product of the Clinical and Applied Research Network in Chikungunya (REPLICK). This is a prospective, outpatient department-based, multicenter cohort study in Brazil. Four work packages were defined: i. Clinical research; ii) Translational Science – comprising immunology and virology streams; iii) Epidemiology and Economics; iv) Therapeutic Response and clinical trials design. Scheduled appointments on days 21 (D21) ± 7 after enrollment, D90 ± 15, D120 ± 30, D180 ± 30; D360 ± 30; D720 ± 60, and D1080 ± 60 days. On these visits a panel of blood tests are collected in addition to the clinical report forms to obtain data on socio-demographic, medical history, physical examination and questionnaires devoted to the evaluation of musculoskeletal manifestations and overall health are performed. Participants are asked to consent for their specimens to be maintained in a biobank. Aliquots of blood, serum, saliva, PAXgene, and when clinically indicated to be examined, synovial fluid, are stored at -80° C. The study protocol was submitted and approved to the National IRB and local IRB at each study site.DiscussionStandardized and harmonized patient cohorts are needed to provide better estimates of chronic arthralgia development, the clinical spectra of acute and chronic disease and investigation of associated risk factors. This study is the largest evaluation of the long-term sequelae of individuals infected with CHIKV in the Brazilian population focusing on musculoskeletal manifestations, mental health, quality of life, and chronic pain. This information will both define disease burden and costs associated with CHIKV infection, and better inform therapeutic guidelines.

Gut microbiome and serum short-chain fatty acids are associated with responses to chemo- or targeted therapies in Chinese patients with lung cancer.

The association between gut microbes and short-chain fatty acids (SCFAs) and therapeutic responses of patients with lung cancer (LC) receiving therapy remains unknown. Fecal and serum samples were prospectively collected from patients with LC, classified as responders, if they presented durable clinical benefits, and non-responders, if not. The composition of gut microbes was analyzed using 16S ribosomal DNA sequencing. Serum SCFA concentrations were detected using gas chromatography. Cell proliferation, migration, invasion, cell cycle, and apoptosis assays were performed on isobutyric acid-treated A549 cells. Reverse transcription-quantitative PCR, Western blotting, immunocytochemistry, and immunofluorescence staining experiments have been performed to investigate the expression of associated genes or proteins. Non-responders harbored higher microbiome α-diversity but lower β-diversity compared with responders. Compared to the patients with low α-diversity, those with high α-diversity showed significantly shorter progression-free survival. Additionally, β-diversity has also been observed between these two groups. Specifically, Parasutterella, Clostridiaceae, and Prevotella_7 were more abundant among responders, whereas Bacteroides_stercoris and Christensenellaceae_R-7_group were more abundant in non-responders. The serum SCFA (especially acetate and isobutyrate) levels tended to be higher in responders. Isobutyric acid inhibited the proliferation, migration, and invasion of A549 cells by inducing apoptosis and G1/S arrest while upregulating the expression of GPR41, GPR43, and GPR5C and downregulating that of PAR1, and increasing the activity of histone acetyltransferases. We revealed the influence of gut microbiota and SCFAs on the therapeutic responses in patients with LC and the anti-tumor effect of isobutyric acid, indicating their potential use as therapeutic targets.

Relationship between Plasma IP-10/CXCL10 Levels and the Initial Therapeutic Response in Patients Treated with Atezolizumab plus Bevacizumab for Unresectable Hepatocellular Carcinoma

Introduction: Atezolizumab plus bevacizumab combination therapy (AB) was the first-line treatment for unresectable hepatocellular carcinoma (u-HCC). IFN-γ-induced protein 10 (IP-10/CXCL10) is a chemokine to inhibit HCC proliferation by promoting the migration of cytotoxic T cells. We focused on the relationship between plasma IP-10/CXCL10 levels and the initial therapeutic response in patients receiving AB therapy. Methods: Forty-six patients receiving AB therapy were enrolled. Plasma IP-10/CXCL10 levels were measured at baseline, 3–7 days, 3 weeks, 6 weeks, and 8–12 weeks after the start of AB therapy. The initial therapeutic response was evaluated at 8–12 weeks. Results: The baseline IP-10/CXCL10 levels of partial response (PR) group was higher than that of stable disease (SD) or progressive disease (PD) group. Patients with the baseline IP-10/CXCL10 of 84 pg/mL or higher were likely to present PR than patients below (71 vs. 35%, p = 0.031), but prediction of PD using the baseline IP-10/CXCL10 levels was difficult. In contrast, IP-10/CXCL10 ratio of the PR group was lower than that of the SD/PD group at 3, 6, and 8–12 weeks. Patients with the 3, 6, and 8–12 weeks IP-10/CXCL10 ratio of 1.3, 0.4, and 0.4 or lower were likely to present PR than patients with ≥1.3, 0.4, and 0.4 (88, 35, 35 vs. 30, 3.8, 0%, p < 0.001, 0.011, 0.002). In other hand, the 3, 6, and 8–12 weeks IP-10/CXCL10 ratio for PD group was higher than that for non-PD group. Patients with the 3, 6, and 8–12 weeks IP-10/CXCL10 ratio of 1.3, 1.7, and 1.9 or higher were likely to present PD than patients below (85, 62, 57 vs. 32, 23, 14%, p = 0.002, 0.034, 0.009). Conclusion: High baseline IP-10/CXCL10 levels may be associated with better outcome, and high IP-10/CXCL10 ratio after 3–12 weeks may be associated with worse outcome in u-HCC patients receiving AB therapy.