Biomarkers Of Treatment Response Research Articles

Evaluating atezolizumab in patients with urinary tract squamous cell carcinoma (AURORA): study protocol for a single arm, open-label, multicentre, phase II clinical trial

BackgroundBladder and urinary tract cancers account for approximately 21,000 new diagnoses and 5,000 deaths annually in the UK. Approximately 90% are transitional cell carcinomas where advanced disease is treated with platinum based chemotherapy and PD-1/PD-L1 directed immunotherapy. Urinary tract squamous cell carcinoma (UTSCC) accounts for about 5% of urinary tract cancers overall making this a rare disease. We have yet to establish definitive systemic treatment options for advanced UTSCC.Preliminary translational data, from UTSCC patient tumour samples, indicate high PD-L1 expression and tumour infiltrating lymphocytes in a proportion of cases. Both of these features are associated with differential gene expression consistent with a tumour/immune microenvironment predicted to be susceptible to immune checkpoint directed immunotherapy which we will evaluate in the AURORA trial.MethodsAURORA is a single arm, open-label, multicentre,UK phase II clinical trial. 33 patients will be recruited from UK secondary care sites. Patients with UTSCC, suitable for treatment with palliative intent, will receive atezolizumab PD-L1 directed immunotherapy (IV infusion, 1680 mg, every 28 days) for one year if tolerated. Response assessment, by cross sectional imaging will occur every 12 weeks. AURORA uses a Simon’s 2-stage optimal design with best overall objective response rate (ORR, by RECIST v1.1) at a minimum of 12 weeks from commencing treatment as the primary endpoint. Secondary endpoints will include overall survival, progression-free survival, duration of response, magnitude of response using waterfall plots of target lesion measurements, quality of life using the EORTC QLQ-C30 tool, safety and tolerability (CTCAE v5) and evaluation of potential biomarkers of treatment response including PD-L1 expression. Archival tumour samples and blood samples will be collected for translational analyses.DiscussionIf this trial shows atezolizumab to be safe and effective it may lead to a future late phase randomised controlled trial in UTSCC. Ultimately, we hope to provide a new option for treatment for such patients.Trial registrationsEudraCT Number: 2021-001995-32 (issued 8th September 2021); ISRCTN83474167 (registered 11 May 2022); NCT05038657 (issued 9th September 2021).

Differences in diffusion tensor imaging parameters of brain white matter tracts between patients with myotonic dystrophy type 1 and type 2 - a retrospective single-centre study.

The main aim of our study was to compare diffusion tensor imaging (DTI) parameters in patients with myotonic dystrophy types 1 and 2 (DM1 and DM2). To ascertain whether DTI could be used to assess the integrity of white matter tracts in the brain and identify any abnormalities or disruptions in connectivity between different brain regions in patients with DM. By providing a more detailed understanding of the structural changes in the brain associated with DM, could DTI potentially be used to develop more effective treatments for the cognitive and neurological symptoms of the disorder? We retrospectively compared MRI scans of 19 patients with DM1 to those of 23 healthy, matched controls, and of 16 patients with DM2 to those of 20 healthy, matched controls, and finally compared the DM1 and DM2 samples. Fraction anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) values were assessed using Tract Based Spatial Statistics (TBSS). In patients with DM1, a statistically significant decrease in the values of the FA parameter was revealed in 45/48 white matter tracts compared to patients with DM2. There was no statistically significant decrease in the values of the FA parameter in patients with DM2 compared to DM1. The values of MD and RD were significantly higher in 47 tracts in DM1 patients compared to DM2 patients. AD values were significantly higher in all 48 tracts in DM1 patients compared to DM2 patients. There were no tracts with increased MD, AD, or RD values in DM2 patients compared to DM1. Our results indicate diffuse disintegration of white matter pathways in DM patients, especially in the DM1 group. The damage to all types of fibres (association, commissural, and projection) may explain the diversity of clinical symptoms, which were more severe in the DM1 group of patients than in the DM2 group. DTI in patients with DM may help us to understand the neural mechanisms underlying brain involvement during the disease. In future, it may help to identify biomarkers for disease progression and treatment response.

Carriers of HLA-DRB1*04:05 have a better clinical response to abatacept in rheumatoid arthritis

HLA-DRB1 shared epitope risk alleles are the strongest genetic risk factors for rheumatoid arthritis (RA) and potential biomarkers for treatment response to biological disease-modifying antirheumatic drugs (bDMARDs). This study aimed to investigate the association between treatment response and individual HLA-DRB1 alleles in RA patients receiving different bDMARDs. We recruited 106 patients with active RA who had started abatacept, tocilizumab, or TNF inhibitors as a first-line bDMARDs. We examined the relationship between Simplified Disease Activity Index (SDAI) improvement at 3 months and HLA-DRB1 allele carriage. The results revealed that the HLA-DRB1*04:05 allele, a shared-epitope allele, was significantly associated with better SDAI improvement only after abatacept treatment (SDAI improvement 28.5% without the allele vs 59.8% with allele, p = 0.003). However, no significant association was found with other treatments. Both multivariate linear regression and mediation analysis confirmed that the HLA-DRB1*04:05 allele was independently associated with abatacept treatment response, regardless of anti-CCP antibody titers. The study concluded that in patients with RA receiving their first-line bDMARD treatment, carrying the HLA-DRB1*04:05 allele was associated with better SDAI improvement specifically in abatacept-treated patients. These disease-risk HLA alleles have the potential to serve as genomic biomarkers for predicting treatment response with co-stimulation blockage therapy.

Clinical utility of the prognostic nutritional index in patients with metastatic hormone-sensitive prostate cancer: A retrospective, multicenter, cohort study.

The prognostic nutritional index (PNI) based on the serum albumin level and the lymphocyte count has been investigated as a prognostic factor in patients with malignant tumors. However, it has been poorly studied in prostate cancer (PCa), and little is known about its clinical utility. Clinical data of 353 patients with de novo, metastatic, hormone-sensitive PCa (mHSPC) who received androgen deprivation therapy (ADT) were obtained from multiple institutions between 2000 and 2019. The impacts of the pretreatment PNI level on treatment response and survival, together with clinical parameters, were examined. The Mann-Whitney U test, Cox proportional hazards models, and Kaplan-Meier methods were used to evaluate significance. The median age and initial prostate-specific antigen level were 73 and 266.18 ng/mL, respectively. Patients with a low PNI had shorter progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS) (p < 0.0001). On multivariate analysis, low PNI was an independent prognostic factor for OS (p = 0.0027, HR = 1.65), as well as advanced age (p = 0.049, HR = 1.38), the International Society of Urological Pathology (ISUP) grade group (GG) 5 (p = 0.0027, HR = 1.69), and elevated lactate dehydrogenase (LDH) (p < 0.0001, HR = 2.08). A propensity score-matching analysis showed that the PNI level remained a significant prognostic biomarker for PFS (p = 0.0263), CSS (p = 0.0006), and OS (p = 0.0015). Furthermore, a novel risk classification using PNI, LDH, and the ISUP GG was established to stratify patients' prognosis. An increase in the number of risk factors was significantly correlated with poor outcomes. A low pretreatment PNI might be an effective biomarker of poor treatment response and survival in patients with mHSPC undergoing ADT.

P14.06.A GLIOMA ESPIONAGE: UTILIZING CSF PROTEOMICS FOR PHARMACODYNAMIC BIOMARKER DISCOVERY

Abstract BACKGROUND Cerebrospinal fluid (CSF) is emerging as an abundant source of candidate biomarkers, including proteins, for gliomas. Longitudinal CSF access may enable insights into treatment response and resistance. To that end, we have established a growing biobank of CSF samples, many of which have been obtained longitudinally via CSF access devices, such as Ommaya reservoirs, through our ongoing biomarker discovery clinical trials (NCT04692337, 04692324). We have previously presented our initial data demonstrating a conserved proteomic signature of HGG that decreased with resection and increased with recurrence. Since then, samples have been acquired throughout individual patients’ treatments toward our goal of identifying CSF-derived biomarkers of treatment response. MATERIAL AND METHODS CSF samples obtained prior to, during, and throughout treatment underwent global proteomics analysis via the SomaScan® assay by Somalogic, which uses slow off-rate modified aptamers to sensitively detect over 7,000 proteins. Fold-changes for each protein were calculated between different timepoints for each patient and ranked based on the comparison of interest. Comparisons included prior to versus after resection, chemoradiation or adjuvant temozolomide (each with or without pembrolizumab), bevacizumab, and low versus high blood contamination. RESULTS Treatment with pembrolizumab alone resulted in increased IL-23 (5.01x), IL-12 (4.25x), lymphocyte activation gene 3 protein (LAG3) (3.26x), and granzyme A (2.93x). Chemoradiation, with or without pembrolizumab, consistently downregulated NAD kinase, acetyl CoA transferase, and Bcl-2 and upregulated proteins related to neuronal signaling, such as neurexins and cerebellins, in addition to LAG-3, suggesting potential for synergy between chemoradiation and anti-LAG-3 antibodies currently in clinical trials. Interestingly, pembrolizumab and chemoradiation decreased MMP-12 and MMP-9 abundance as compared to chemoradiation alone (0.25x vs. 18.5x; 0.54x vs. 4.99x). Finally, bevacizumab treatment consistently increased VEGF (7.32x), GFAP (3.38x), and MMP-3 (2.99x) abundance, while decreasing the presence of our previously reported plasma-associated protein signature in CSF, suggesting decreased blood-brain barrier disruption. CONCLUSION The global CSF proteome can be longitudinally accessed to evaluate response to standard-of-care and experimental therapies. Further studies are ongoing to identify signatures of therapeutic resistance and to assess the impact of novel immunotherapeutic combinations on the CSF proteome.

Granzyme B Expression in the Tumor Microenvironment as a Prognostic Biomarker for Patients with Triple-Negative Breast Cancer.

Tumor-infiltrating lymphocytes in the tumor microenvironment are important in the treatment of triple-negative breast cancer (TNBC). Cytotoxic T cells produce cytokines and cytotoxic factors, such as perforin and granzyme, which induce apoptosis by damaging target cells. To identify biomarkers of these cells, we investigated granzyme B (GZMB) in the tumor microenvironment as a biomarker of treatment response and prognosis in 230 patients with primary TNBC who underwent surgery without preoperative chemotherapy between January 2004 and December 2014. Programmed cell death ligand 1 (PD-L1) positivity was defined as a composite positive score ≥10 based on the PD-L1 immunostaining of tumor cells and immune cells. GZMB-high was defined as positivity in ≥1% of tumor-infiltrating lymphocytes (TILs). Among the 230 TNBC patients, 117 (50.9%) had CD8-positive infiltrating tumors. In the PD-L1-positive group, a Kaplan-Meier analysis showed that GZMB-high TNBC patients had better recurrence-free survival (RFS) and overall survival (OS) than GZMB-low patients and that OS was significantly longer (RFS: p = 0.0220, OS: p = 0.0254). A multivariate analysis also showed significantly better OS in PD-L1- and GZMB-high patients (hazard ratio: 0.25 (95% IC: 0.07-0.88), p = 0.03). Our findings indicate that GZMB is a useful prognostic biomarker in PD-L1-positive TNBC patients.

Reproductive Hormones and Female Mental Wellbeing

Fluctuating hormone levels during the menstrual cycle and major reproductive cycle stages have been linked to mood changes, mental health conditions, and an increased likelihood of psychotic episodes. This knowledge could potentially be used for the predictive modeling of exacerbations and mood deterioration through the collection and analysis of data from wearables and apps. A literature search for a narrative review has been conducted using selected keywords in Pubmed, Embase and Google Scholar. Based on published data, it can be seen that hormonal changes affect the severity of symptoms in several mental health conditions, including depression, PMDD, PTSD, bipolar disorder and schizophrenia. The influence of FSH, LH, testosterone, and other hormone precursors has also been investigated, but there is less information available regarding their impact. E2 levels have been measured as a treatment–response biomarker and have demonstrated significant predictive ability for treatment responder groups. On the other hand, FSH has been demonstrated to be helpful in predicting treatment non-responder groups in schizophrenia. Monitoring reproductive hormones in combination with wearables or digital solutions has the potential to predict mood changes more effectively. Precise and frequent hormone measurements might prove to be more effective than relying on absolute threshold levels. Further research is needed to validate the utility and precision of hormone use in the field of mental health.

Frequency and prognostic influence of ASXL1 mutations and its potential association with BCR-ABL1 transcript type and smoke in chronic myeloid leukemia patients

BackgroundHeterogeneous response to tyrosine kinase inhibitors (TKIs) and progress to advance phases, still is a significant clinical problem. These are attributed to additional mutations in mutated non-ABL1 genes. we aimed to determine prognostic effects of ASXL1 mutations as a biomarker for diverse treatment response and disease progression to aid clinical management. MethodsWe performed ASXL1 gene mutational screening in 80 Ph+CML patients at different phases and 10 healthy control by direct sequencing method. Multiplex and qRT-PCR, standard chromosome banding analysis were used to determine BCR-ABL1 transcript type, molecular and cytogenetic responses respectively. Resultsoverall, four type mutations were identified in 11.25% of the patients. There was significant difference regarding mutation frequency between chronic and advance phases (P = 0.0002), sokal risk score (P = 0.0001), smoking (P = 0.02) and mean of during time of imatinib treatment (P = 0.009) between patients with and without ASXL1 mutations. ASXL1 mutations frequency had a bias toward younger than older and women than men, but no significant (P > 0.05). ASXL1 mutations were found more recurrently in patients carrying ABL1 KD mutations (P = 0.003). The risk of increasing resistance and disease progression in patients with ASXL1 mutations was 32 and 63 fold higher than those without mutations respectively (P = 0.01; P = 0.0002). The risk of ASXL1 mutations presence in patients with b2a2 transcript type was much higher than b3a2 type (P = 0.02, OR = 10). ConclusionOur findings suggest that ASXL1 mutations may be favorable predictive biomarkers to determine the best TKI for each patient, and to prevent CML progression.

PARP Inhibitors Effectively Reduce MAPK Inhibitor Resistant Melanoma Cell Growth and Synergize with MAPK Inhibitors through a Synthetic Lethal Interaction In Vitro and In Vivo.

We show that MAPK inhibitor resistant melanoma cells exhibit low ATM expression increasing their sensitivity toward PARP inhibitors and that a combination of MAPK/PARP inhibitors act synthetically lethal in melanoma cells. Our study shows that PARP inhibitor treatment is a valuable therapy option for patients with melanoma, either as a single treatment or as a combination with MAPK inhibitors depending on ATM expression, which could serve as a novel biomarker for treatment response.

Utility of Smartphone-Based Digital Phenotyping Biomarkers in Assessing Treatment Response to Transcranial Magnetic Stimulation in Depression: Proof-of-Concept Study.

Identifying biomarkers of response to transcranial magnetic stimulation (TMS) in treatment-resistant depression is a priority for personalizing care. Clinical and neurobiological determinants of treatment response to TMS, while promising, have limited scalability. Therefore, evaluating novel, technologically driven, and potentially scalable biomarkers, such as digital phenotyping, is necessary. This study aimed to examine the potential of smartphone-based digital phenotyping and its feasibility as a predictive biomarker of treatment response to TMS in depression. We assessed the feasibility of digital phenotyping by examining the adherence and retention rates. We used smartphone data from passive sensors as well as active symptom surveys to determine treatment response in a naturalistic course of TMS treatment for treatment-resistant depression. We applied a scikit-learn logistic regression model (l1 ratio=0.5; 2-fold cross-validation) using both active and passive data. We analyzed related variance metrics throughout the entire treatment duration and on a weekly basis to predict responders and nonresponders to TMS, defined as ≥50% reduction in clinician-rated symptom severity from baseline. The adherence rate was 89.47%, and the retention rate was 73%. The area under the curve for correct classification of TMS response ranged from 0.59 (passive data alone) to 0.911 (both passive and active data) for data collected throughout the treatment course. Importantly, a model using the average of all features (passive and active) for the first week had an area under the curve of 0.7375 in predicting responder status at the end of the treatment. The results of our study suggest that it is feasible to use digital phenotyping data to assess response to TMS in depression. Early changes in digital phenotyping biomarkers, such as predicting response from the first week of data, as shown in our results, may also help guide the treatment course.

Induction therapy with ipilimumab and nivolumab followed by consolidative chemoradiation as organ-sparing treatment in urothelial bladder cancer: study protocol of the INDIBLADE trial.

Studies that assessed the efficacy of pre-operative immune checkpoint blockade (ICB) in locally advanced urothelial cancer of the bladder showed encouraging pathological complete response rates, suggesting that a bladder-sparing approach may be a viable option in a subset of patients. Chemoradiation is an alternative for radical cystectomy with similar oncological outcomes, but is still mainly used in selected patients with organ-confined tumors or patients ineligible to undergo radical cystectomy. We propose to sequentially administer ICB and chemoradiation to patients with (locally advanced) muscle-invasive bladder cancer. The INDIBLADE trial is an investigator-initiated, single-arm, multicenter phase 2 trial. Fifty patients with cT2-4aN0-2M0 urothelial bladder cancer will be treated with ipilimumab 3 mg/kg on day 1, ipilimumab 3 mg/kg plus nivolumab 1 mg/kg on day 22, and nivolumab 3 mg/kg on day 43 followed by chemoradiation. The primary endpoint is the bladder-intact event-free survival (BI-EFS). Events include: local or distant recurrence, salvage cystectomy, death and switch to platinum-based chemotherapy. We will also evaluate the potential of multiparametric magnetic resonance imaging of the bladder to identify non-responders, and we will assess the clearance of circulating tumor DNA as a biomarker for ICB treatment response. This is the first trial in which the efficacy of induction combination ICB followed by chemoradiation is being evaluated to provide bladder-preservation in patients with (locally advanced) urothelial bladder cancer. The INDIBLADE trial was registered on clinicaltrials.gov on January 21, 2022 (NCT05200988).

Bioinformatics in urology - molecular characterization of pathophysiology and response to treatment.

The application of bioinformatics has revolutionized the practice of medicine in the past 20 years. From early studies that uncovered subtypes of cancer to broad efforts spearheaded by the Cancer Genome Atlas initiative, the use of bioinformatics strategies to analyse high-dimensional data has provided unprecedented insights into the molecular basis of disease. In addition to the identification of disease subtypes - which enables risk stratification - informatics analysis has facilitated the identification of novel risk factors and drivers of disease, biomarkers of progression and treatment response, as well as possibilities for drug repurposing or repositioning; moreover, bioinformatics has guided research towards precision and personalized medicine. Implementation of specific computational approaches such as artificial intelligence, machine learning and molecular subtyping has yet to become widespread in urology clinical practice for reasons of cost, disruption of clinical workflow and need for prospective validation of informatics approaches in independent patient cohorts. Solving these challenges might accelerate routine integration of bioinformatics into clinical settings.

Associations between frontal lobe activity and depressive symptoms in patients with major depressive disorder receiving rTMS treatment: a near-infrared spectroscopy study.

The effects of repetitive transcranial magnetic stimulation (rTMS) on the left dorsolateral prefrontal cortex (DLPFC) in patients with major depressive disorder (MDD) have been proved to have antidepressant effects. However, the absence of biomarkers to assess treatment response remains a challenge. This research aims to explore the relationship between frontal lobe activity, measured using near infrared spectroscopy (NIRS), and changes in symptoms among MDD patients following rTMS treatment. A total of 26 MDD patients underwent 20 sessions of 10 Hz rTMS targeting the left DLPFC. NIRS was used to measure frontal lobe activity during a verbal fluency test at baseline, after 10 rTMS sessions, and after 20 rTMS sessions. Responders were defined as individuals with more than a 50% reduction in symptoms based on the 21-item Hamilton Depression Rating Scale after 20 rTMS sessions. Among the 14 responders, an increase in frontal lobe activity was significantly correlated with improvements in depressive symptoms following 10 (p = 0.0001) and 20 rTMS sessions (p = 0.007). Additionally, frontal lobe activity after 10 rTMS sessions was significantly associated with symptom improvement after 20 sessions (p = 0.001). These associations were not observed among non-responders. The findings from this study indicate distinct patterns of frontal lobe activity between responders and non-responders to rTMS treatment, suggesting that NIRS has the potential to serve as a biomarker for monitoring treatment response in MDD patients undergoing rTMS.

Can Serum Biomarkers for Prurigo Nodularis Expose Pathophysiology or Just Treatment Response?

Can Serum Biomarkers for Prurigo Nodularis Expose Pathophysiology or Just Treatment Response?

Treatment response and neurofilament light chain levels with long-term patisiran in hereditary transthyretin-mediated amyloidosis with polyneuropathy: 24-month results of an open-label extension study

Background Longitudinal changes in neurofilament light chain (NfL) levels were evaluated alongside prespecified clinical assessments 24 months into the patisiran Global open-label extension (OLE) study in patients with ATTRv amyloidosis with polyneuropathy. Methods All patients enrolled in the Global OLE, from phase III APOLLO and phase II OLE parent studies, received patisiran. Assessments included measures of polyneuropathy (modified Neuropathy Impairment Score+7 (mNIS+7)), quality of life (QOL; Norfolk QOL-Diabetic Neuropathy questionnaire (Norfolk QOL-DN)), and plasma NfL. Results Patients receiving patisiran in the parent study (APOLLO-patisiran, n = 137; phase II OLE-patisiran, n = 25) demonstrated sustained improvements in mNIS+7 (mean change from parent study baseline (95% confidence interval): APOLLO-patisiran −4.8 (−8.9, −0.6); phase II OLE-patisiran −5.8 (−10.5, −1.2)) and Norfolk QOL-DN (APOLLO-patisiran −2.4 (−7.2, 2.3)), and maintained reduced NfL levels at Global OLE 24 months. After initiating patisiran in the Global OLE, APOLLO-placebo patients (n = 49) demonstrated stabilized mNIS+7, improved Norfolk QOL-DN, and significantly reduced NfL levels. Patisiran continued to demonstrate an acceptable safety profile. Earlier patisiran initiation was associated with a lower exposure-adjusted mortality rate. Conclusions Long-term patisiran treatment led to sustained improvements in neuropathy and QOL, with NfL demonstrating potential as a biomarker for disease progression and treatment response in ATTRv amyloidosis with polyneuropathy.

Metabolic fingerprinting of systemic sclerosis: a systematic review.

Introduction: Systemic sclerosis (SSc) is a chronic autoimmune disease, marked by an unpredictable course, high morbidity, and increased mortality risk that occurs especially in the diffuse and rapidly progressive forms of the disease, characterized by fibrosis of the skin and internal organs and endothelial dysfunction. Recent studies suggest that the identification of altered metabolic pathways may play a key role in understanding the pathophysiology of the disease. Therefore, metabolomics might be pivotal in a better understanding of these pathogenic mechanisms. Methods: Through a systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA), searches were done in the PubMed, EMBASE, Web of Science, and Scopus databases from 2000 to September 2022. Three researchers independently reviewed the literature and extracted the data based on predefined inclusion and exclusion criteria. Results: Of the screened studies, 26 fulfilled the inclusion criteria. A total of 151 metabolites were differentially distributed between SSc patients and healthy controls (HC). The main deregulated metabolites were those derived from amino acids, specifically homocysteine (Hcy), proline, alpha-N-phenylacetyl-L-glutamine, glutamine, asymmetric dimethylarginine (ADMA), citrulline and ornithine, kynurenine (Kyn), and tryptophan (Trp), as well as acylcarnitines associated with long-chain fatty acids and tricarboxylic acids such as citrate and succinate. Additionally, differences in metabolic profiling between SSc subtypes were identified. The diffuse cutaneous systemic sclerosis (dcSSc) subtype showed upregulated amino acid-related pathways involved in fibrosis, endothelial dysfunction, and gut dysbiosis. Lastly, potential biomarkers were evaluated for the diagnosis of SSc, the identification of the dcSSc subtype, pulmonary arterial hypertension, and interstitial lung disease. These potential biomarkers are within amino acids, nucleotides, carboxylic acids, and carbohydrate metabolism. Discussion: The altered metabolite mechanisms identified in this study mostly point to perturbations in amino acid-related pathways, fatty acid beta-oxidation, and in the tricarboxylic acid cycle, possibly associated with inflammation, vascular damage, fibrosis, and gut dysbiosis. Further studies in targeted metabolomics are required to evaluate potential biomarkers for diagnosis, prognosis, and treatment response.

TIPS-21 PHASE I/II STUDY OF STEREOTACTIC RADIOSURGERY WITH CONCURRENT OLAPARIB FOLLOWED BY ADJUVANT DURVALUMAB AND PHYSICIAN’S CHOICE SYSTEMIC THERAPY IN SUBJECTS WITH BREAST CANCER BRAIN METASTASES (SOLARA)

Abstract BACKGROUND Despite progress in the treatment of brain metastasis (BrM) for HER2+ breast cancer (BC), outcomes for patients with HER2-negative BC BrM remain poor. Current standard of care consists of surgery and/or radiotherapy followed by systemic therapy. Preclinical studies show inhibitors of poly(ADP-ribose) polymerase (PARP) are effective together with radiotherapy as DNA damage response inhibitors. Triple-negative BC (TNBC) has higher rates of homologous recombination deficiency compared to other BC subtypes, and together with HER2-negative, BRCA-mutated BC would be particularly sensitive to PARP inhibition. PARP inhibition with immunotherapy has demonstrated promising efficacy in patients with germline BRCA-mutant and metastatic TNBC in clinical trials (MEDIOLA, TOPACIO). In addition, immunotherapy with stereotactic radiosurgery (SRS) is associated with favorable outcomes in patients with BrM. We hypothesize that this biologically-driven combination will enhance local control of SRS-treated BrM through synergy with PARP inhibition, while controlling micrometastatic disease in the brain and extracranial sites by potentiating the immune response. METHODS We are conducting a multi-institution, Phase I/II trial of SRS plus olaparib, followed by durvalumab (with physician’s choice systemic therapy), for patients with TNBC (any BRCA status) or HER2-negative with BRCA-mutated (germline or somatic) BC BrM [NCT04711824]. The primary objectives are to evaluate safety and tolerability (Phase I) and intracranial disease control at 6 months (Phase II). Secondary objectives include assessing intracranial and global progression-free survival, overall survival, and intracranial/extracranial response rate. Exploratory objectives will assess potential biomarkers of treatment response, including changes in circulating tumor cells/DNA in blood and cerebrospinal fluid, germline and tumor mutations in DNA repair pathway genes, and PD-L1 expression, as well as quality of life and patient-reported outcomes. A surgical sub-study (n=5) will evaluate olaparib concentration/distribution in resected BrM. As of January 2023, cohort 1 of phase I has been completed without dose-limiting toxicity.

Evaluation of the neurofilament light chain as a biomarker in children with spinal muscular atrophy treated with nusinersen

BackgroundThis study aimed to evaluate the neurofilament light chain (NfL) as a biomarker for treatment responses in children with a broad spectrum of spinal muscular atrophy (SMA) under nusinersen treatment. MethodWe measured NfL levels in serum (sNfL) and cerebrospinal fluid (cNfL) in nusinersen-treated patients with SMA and children without neurologic disorders. Correlations between cNfL and sNfL levels and motor function scores were analyzed. ResultssNfL and cNfL levels were measured in eight patients with SMA (SMA type 1, n = 3; SMA type 2, n = 5). sNfL levels were strongly correlated with cNfL levels regardless of the SMA subtype (r = 0.97, P < 0.001). Patients with SMA type 1 had higher baseline cNfL and sNfL levels before treatment initiation than those with SMA type 2 and neurologically healthy children. In patients with acute stage of SMA type 1 and 2, the NfL level rapidly decreased during the nusinersen treatment loading phase followed by stabilization at a lower plateau level. In contrast, in a patient with a chronic stage of SMA type 2, the NfL level remained within the normal range with no apparent downward trend. Motor function scores showed a tendency toward an inverse correlation with NfL levels in patients with acute stage although not in patients with chronic stage. ConclusionscNfL and sNfL levels can be promising biomarkers for monitoring treatment response in patients within their acute stage, particularly in SMA type 1, although not in patients with a chronic stage of SMA type 2.

Blood and saliva-derived ctDNA is a marker of residual disease after treatment and correlates with recurrence in human papillomavirus-associated head and neck cancer.

There is an alarming increase in human papillomavirus-associated head and neck cancer (HNC), reaching epidemic levels. While patient prognosis is generally good, off-target treatment effects are associated with decreased quality of life. Thus, non-invasive strategies to predict treatment response and risk of recurrence could help de-escalate treatment. In this study, we tested circulating tumor (ct)DNA in liquid biopsies (blood/saliva) of HPV-positive HNC patients to assess treatment response and disease progression. A total of 235 blood and saliva samples were collected from 60 HPV-positive and 17 HPV-negative HNC patients (control group) before and/or after treatment. Samples were analyzed using ddPCR for HPV16/18/31/33/35/45 and correlated with imaging and pathological examination. HPV-ctDNA detection was significantly higher prior to treatment (91%) than after treatment (8.0%) (χ2 p < 0.00001), with high concordance between saliva and blood (93%). In matched samples, all patients positive for ctDNA before treatment showed significant reductions in ctDNA levels post treatment (p < 0.0001). All but one patient with persistent ctDNA after treatment showed residual tumor and subsequent recurrence. Finally, fragmentomic analysis revealed shifts in cell-free DNA fragment size after treatment, suggesting a complementary biomarker for treatment response. Blood and saliva were found to be good sources of HPV-ctDNA. The presence of ctDNA strongly correlated with treatment response, demonstrating clinical utility as a non-invasive biomarker to monitor tumor progression in HPV-positive HNC. Liquid biopsy based ctDNA testing could be an effective approach to predict recurrence and stratify patients for de-escalation of treatment, thereby improving quality of life.

Functional connectivity analysis on electroencephalography signals reveals potential biomarkers for treatment response in major depression

BackgroundThe treatment efficacy varies across individual patients with major depressive disorder (MDD). It lacks robust electroencephalography (EEG) markers for an antidepressant-responsive phenotype.MethodThis is an observational study enrolling 28 patients with MDD and 33 healthy controls (mean age of 40.7 years, and 71.4% were women). Patients underwent EEG exams at baseline (week0) and week1, while controls’ EEG recordings were acquired only at week0. A resting eye-closing EEG segment was analyzed for functional connectivity (FC). Four parameters were used in FC analysis: (1) node strength (NS), (2) global efficiency (GE), (3) clustering coefficient (CC), and (4) betweenness centrality (BC).ResultsWe found that controls had higher values in delta wave in the indices of NS, GE, BC, and CC than MDD patients at baseline. After treatment with antidepressants, patients’ FC indices improved significantly, including GE, mean CC, and mean NS in the delta wave. The FC in the alpha and beta bands of the responders were higher than those of the non-responders.ConclusionsThe FC of the MDD patients at baseline without treatment was worse than that of controls. After treatment, the FC improved and was close to the values of controls. Responders showed better FC in the high-frequency bands than non-responders, and this feature exists in both pre-treatment and post-treatment EEG.