Markers Of Treatment Response Research Articles

Review of adjuvant Intravenous immunoglobulins in patients with refractory pyoderma gangrenosum: a single-centre experience.

This retrospective review assessed adjuvant IVIG treatment in six patients with refractory Pyoderma Gangrenosum. All patients reported decreased ulcer size or depth, with one achieving complete healing. Most had a reduction in pain, and an increase in pain coincided with disease flares. IVIG was well-tolerated, though two patients required hospitalisation for infection management. Results suggest IVIG is a safe and effective option for refractory PG, with pain reduction potentially serving as a marker for treatment response, though recurrence remains a concern.

Average steps per day as marker of treatment response with anti-CGRP mAbs in adults with chronic migraine: a pilot study

Physical activity can worsen migraine, leading to reduced activity levels in adults with chronic migraine. This study investigated the change in average steps per day, as a surrogate marker of physical activity, in adults with chronic migraine successfully treated with monoclonal antibodies against calcitonin gene-related peptide or its receptor. Data were obtained from adults with chronic migraine, who were classified as responders to preventive treatment with monoclonal antibodies. The primary endpoint was the difference in a mean number of steps per day between the 3 months prior to treatment initiation and the first 3 months after treatment initiation. The secondary endpoint was the correlation between the change in steps per day and the change in monthly migraine days. Twenty-two (20 females) participants with a median age of 48.5 years were enrolled. The median number of steps per day increased from 4421 at baseline to 5241 after treatment (P = 0.039). We found a positive correlation between the increase in steps per day and the treatment response (P = 0.013). In conclusion, an increase in physical activity, based on steps per day, positively correlated with treatment response to monoclonal antibodies. Automatically registered daily step count data might be used to monitor physical activity as a response to preventive treatment in adults with chronic migraine.

Diffusion tensor imaging shows increased physis organization after growth hormone initiation in hypophosphatasia.

Hypophosphatasia is a rare heritable disorder of bone mineralization, with a spectrum of severity based on age of initial presentation. We describe the case of a 14-year-old boy with gene-confirmed inherited hypophosphatasia and growth hormone deficiency, who presented with short stature, unremarkable radiographs, and only minor physeal and metaphyseal changes on magnetic resonance (MR) imaging. Diffusion tensor imaging (DTI) before growth hormone initiation revealed abundant, non-parallel tracts in the physes and metaphyses with loss of the typical columnar organization. After 8months of growth hormone treatment, DTI scans revealed realigned, nearly parallel, longer physeal tracts; duplication of tract volume; and decreased and more typical fractional anisotropy values. DTI can thus visualize physeal tract changes over time, could be a more sensitive diagnostic technique in milder physeal abnormality cases, and may be a potential marker of growth hormone treatment response.

Pretreatment plasma osteopontin level as a marker of response to curative radiotherapy and hormonal treatment for prostate cancer

Background and purposeOsteopontin is a known marker for tumour hypoxia with relevance for the outcome of radiotherapy. We analysed the plasma concentration of OPN in prostate cancer patients receiving RT with or without ADT to evaluate OPN as a potential marker of treatment response. Materials and methodsBetween 2012 and 2014, 274 patients with prostate cancer qualifying for RT were enrolled to the study. SCADT received 34.3 % of patients, LCADT 46.3 %. The median OPN concentration was 83.9 ng/mL. We analysed the groups by OPN level: group A with OPN below and group B with OPN above the median. ResultsThere was a significant difference in OPN between the Gleason score (p = 0.005), the D’Amico risk (p = 0.002), the ADT (p < 0.001) and the RT (p = 0.019) groups. We found a positive correlation between OPN and clinical stage (p = 0.042).There were no significant effect of OPN on bRFS, RFS and MFS. The 10-year OS rate for group A was 81 % and for group B 60 % (p < 0.001). Cox analysis showed that low OPN level (p < 0.001), low age (p = 0.002) and low Gleason score (p = 0.038) were associated with higher OS. The prognostic influence of OPN on survival decreased with duration of ADT with the strongest effect of OPN (HR=3.93) observed when RT alone was used, weakest effect (HR=2.48) for SCADT and the smallest effect (HR=2.09) for LCADT. ConclusionsBased on the obtained results, we assume that the level of OPN measured before the start of radiotherapy may be an independent predictor of OS of patients with prostate cancer treated with radiotherapy with and without ADT.

Accumulation of alkyl-lysophosphatidylcholines in Niemann-Pick disease type C1

Lysosomal function is impaired in Niemann-Pick disease type C1 (NPC1), a rare and inherited neurodegenerative disorder, resulting in late endosomal/lysosomal accumulation of unesterified cholesterol. The precise pathogenic mechanism of NPC1 remains incompletely understood. In this study, we employed metabolomics to uncover secondary accumulated substances in NPC1. Our findings unveiled a substantial elevation in the levels of three alkyl-lysophosphatidylcholine [alkyl-LPC, also known as lyso-platelet activating factor (PAF)] species in NPC1 compared to controls across various tissues, including brain tissue from individuals with NPC1, liver, spleen, cerebrum, cerebellum, and brain stem from NPC1 mice, as well as in both brain and liver tissue from NPC1 cats. The three elevated alkyl-LPC species were as follows: LPC O-16:0, LPC O-18:1, and LPC O-18:0. However, the levels of PAF 16:0, PAF 18:1, and PAF 18:0 were not altered in NPC1. In the NPC1 feline model, the brain and liver alkyl-LPC levels were reduced following 2-hydroxypropyl-β-cyclodextrin (HPβCD) treatment, suggesting that alkyl-LPCs are secondary storage metabolites in NPC1 disease. Unexpectedly, cerebrospinal fluid (CSF) levels of LPC O-16:0 and LPC O-18:1 were decreased in individuals with NPC1 compared to age-appropriate comparison samples, and their levels were increased in 80% of participants 2 years after intrathecal HPβCD treatment. The fold increases in CSF LPC O-16:0 and LPC O-18:1 levels were more pronounced in responders compared to nonresponders. This study identified alkyl-LPC species as secondary storage metabolites in NPC1 and indicates that LPC O-16:0 and LPC O-18:1, in particular, could serve as potential biomarkers for tracking treatment response in NPC1 patients.

Response-adapted consolidation therapy strategy for patients with metastatic high-risk neuroblastoma: Results of the SMC NB-2014 study.

Tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) and incorporation of 131I-metaiodobenzylguanidine (131I-MIBG) treatment have shown positive outcomes in high-risk neuroblastoma. However, more optimized treatment strategies are still needed. The NB-2014 study was a nonrandomized, prospective trial that examined survival outcomes in metastatic high-risk neuroblastoma patients using response-adapted consolidation therapy. We used post-induction residual 123I-MIBG status at metastatic sites as a treatment response marker. Patients achieving complete resolution of MIBG uptake at metastatic sites underwent a reduced first HDCT/auto-SCT with a 20% dose reduction in HDCT. After the first HDCT/auto-SCT, patients with remaining MIBG uptake received dose-escalated (18mCi/kg) 131I-MIBG treatment. In contrast, those with complete resolution of MIBG at metastatic sites received a standard dose (12mCi/kg) of 131I-MIBG. We compared survival and toxicity outcomes with a historical control group from the NB-2009. Of 65 patients treated, 63% achieved complete resolution of MIBG uptake at metastatic sites following induction chemotherapy, while 29% of patients still had MIBG uptake at metastatic sites after the first HDCT/auto-SCT. The 3-year event-free survival (EFS) and overall survival (OS) rates were 68.2%±6.0% and 86.5%±4.5%, respectively. Compared to NB-2009, EFS was similar (p=.855); however, NB-2014 had a higher OS (p=.031), a lower cumulative incidence of treatment-related mortality (p=.036), and fewer acute and late toxicities. Our results suggest that response-adaptive consolidation therapy based on chemotherapy response at metastatic sites facilitates better treatment tailoring, and appears promising for patients with metastatic high-risk neuroblastoma.

Changes in the Cutaneous Nerve Fiber Staining and Distribution of PGP9.5 in Clinically Uninvolved Skin in Leprosy Patients after Completion of Multidrug Therapy and Assessing PGP9.5 as a Marker of Treatment Response.

Subclinical involvement of nerves may sometimes be present much before the overt clinical manifestations become apparent. Protein gene product (PGP) 9.5, a ubiquitin-C-terminal hydrolase, has been widely used as a marker to study the involvement of peripheral nerve fibers in many diseases. To evaluate the change in cutaneous nerve fiber staining and distribution from pre-treatment and post completion of multidrug therapy through the expression of PGP9.5 and to assess PGP9.5 as a marker of treatment response. In this prospective single-center observational study, skin biopsy was taken in patients with leprosy, having areas of nerve function impairment (NFI), based on findings of nerve conduction studies (NCSs), but not having lesions or impaired tactile or thermal impairment clinically. The thin nerve fiber density in the clinically normal skin in areas supplied by nerve showing changes of sensory neuropathy was evaluated to study the density of the fibers. A second biopsy was taken at the end of treatment from a site near the previous site to assess the changes in intra-epidermal nerve fiber staining and distribution. Thirty-three patients were recruited in the present study (24 males and 9 females). Pre-treatment, 27 patients had abnormal NCSs, while six patients did not have any evidence of neuropathy on NCSs. Staining for nerve fibers using PGP9.5; in the epidermis was positive in five patients pre-treatment and 11 patients post treatment (P = 0.181). Staining in the dermis revealed positivity in 14 pre-treatment, which increased to 18 post treatment (P = 0.342). Adnexae showed positivity in five patients pre-treatment and increased to 17 post treatment (P = 0.005). A reduced PGP9.5 staining in the epidermal, dermal, and adnexal regions was seen in leprosy patients, which improved post treatment. Thus, PGP9.5 may serve as a marker of NFI and treatment response.

Multiparametric MRI in hepatocellular carcinoma, part2 : Diffusion-weighted imaging in the primary diagnostics and treatment monitoring

In addition to morphology and tissue perfusion, diffusion-weighted imaging (DWI) is the third pillar of multiparametric diagnostics in oncology. Due to the strong correlation between the apparent diffusion coefficient (ADC) and cell count in hepatocellular carcinoma (HCC), it can be used as asurrogate marker for tumor cell quantity. Therefore, ADC effectively reflects the effects of cytoreductive treatment, such as transarterial chemoembolization (TACE) and systemic chemotherapy and becomes an important clinical marker for treatment response. The DWI should remain an integral part of a magnetic resonance imaging (MRI) protocol in primary HCC diagnostics and treatment monitoring but is of secondary clinical importance compared to contrast-enhanced MRI perfusion sequences and the use of liver-specific contrast agents. For the future, standardization of DWI sequences for better comparability of various study protocols would be desirable.

Automated digital oncologic data review for breast cancer research: AI-enabled mCODE and field-of-interest extraction framework.

e12647 Background: Enhancing outcomes in cancer care and research can be optimally achieved by accelerating data extraction from unstructured electronic health resources. Understanding the association between treatment response markers and long-term outcomes is crucial for refining cancer therapeutic approaches and improving patient prognosis. In this study, we explore the association of oncologic outcomes with pathologic complete response (pCR) in high-risk early-stage breast cancer treated with neoadjuvant chemotherapy (NACT) using automated oncologic data extraction framework. Methods: Patients with primary stage I-III breast cancer who received NACT followed by mastectomy, with or without immediate breast reconstruction from January 2010 to August 2023 were retrospectively analyzed. We extracted pCR results and data on clinical and pathological stage, tumor subtype, grade, and treatment regimens and factors affecting postoperative complications from electronic medical records based on the AI enabled-mCODE (Minimal Common Oncology Data Elements) and fields of interest extraction framework. Employing mixed-effects Cox models, we explored the association between pCR and event-free survival (EFS), distant recurrence free Survival (DRFS) and overall survival (OS). Survival curves of patients were estimated using Kaplan-Meier method. Multivariate analysis was performed to evaluate the predictive factors for pCR. Results: Overall, 2725 patients were analyzed. The median age was 50.6 years. The median follow-up was 67 months. pCR was achieved in 31.0%. Hazard ratio for pCR vs. non-pCR were 0.34 for EFS (95% CI, 0.25-0.45), 0.32 for DRFS (95% CI, 0.23-0.43), 0.21 for OS (95% CI, 0.13-0.34), varying from 0.13 to 0.56 for EFS, 0.12 to 0.48 for DRFS and 0.07 to 0.40 for OS. The presence of pCR remained prognostic for event-free survival in multivariate models adjusted for age, tumor size, and nodal status at baseline. Conclusions: This study confirms that patients achieving pCR after NACT have better long-term survival outcomes that patients who do not. Oncologic data extraction from unstructured electronic medical records using AI-enabled extraction framework can be expected to enhance robust cancer research and generate valuable insights from real-world practice settings for tailored therapeutic decision-making. [Table: see text]

Efficacy and safety of CalliSpheres drug-eluting beads for bronchial arterial chemoembolization combined with intravenous chemotherapy for extensive-stage small cell lung cancer.

e20137 Background: We aim to explore the efficacy and tolerability of Drug-Eluting Bead Bronchial Arterial Chemotherapy Embolization (DEB-BACE) combined with intravenous chemotherapy in the treatment of patients with initially diagnosed extensive-stage small cell lung cancer (SCLC). Methods: We collected data from 24 patients with extensive-stage small cell lung cancer who received DEB-BACE combined with intravenous chemotherapy (DEB-BACE-V) and initially diagnosed at our hospital between 2013 and 2022. Among them, nine patients received BACE combined with intravenous chemotherapy from the first-line (first-line DEB-BACE-V), ten patients from the third-line (third -line DEB-BACE-V), and five patients from the second-line (second -line DEB-BACE-V). Then, the treatment response (objective response rate and rate of cancer regression) and tumor marker levels were evaluated at the first month and third month after treatment. The quality of life was assessed using the EORTC QLQ-C30 scale. Overall survival (OS) was also evaluated. First, compare the first-line DEB-BACE-V group with the second-line DEB-BACE-V group. Then, compare the first-line DEB-BACE-V group with third-line DEB-BACE-V group. Lastly, compare the second-line DEB-BACE-V group with the third-line DEB-BACE-V group. Results: In initially diagnosed extensive-stage SCLC patients treated with DEB-BACE combined with intravenous chemotherapy, first and third month post treatment, the objective response rates were 58.33% and 79.17%, respectively; and the rates of cancer regression were 75% and 91.67%, respectively. In addition, the neuron-specific enolase (NSE) and progastrin-releasing peptide levels were reduced at the third and sixth month. Quality of life assessed by EORTC QLQ-C30 scale, which included subscales of general health status, functional domains, symptom domains, and single domains except for financial difficulty, was markedly improved in first and third month of post treatment. Adverse reactions were mild and manageable, the most common being chest pain and low fever. Median values of OS in first-line DEB-BACE-V, second -line DEB-BACE-V and third -line DEB-BACE-V were 15.7 (95% CI: 9.1595-20.759) months, 29.63 (95% CI: 20.5684-36.268) months 16.92 (95% CI: 10.4044-21.871) months, and respectively. Conclusions: Due to its favorable therapeutic response, quality of life, survival benefits, and safety profile, DEB-BACE combined with intravenous chemotherapy may become a treatment option for patients with extensive-stage SCLC, particularly as second-line therapy.

Pluvicto in the real world setting and timing to PSA50 as a predictive marker of treatment response.

e17026 Background: Prostate cancer, the leading cause of cancer mortality in men, has seen notable advances with PSMA-targeted therapies like 177Lu-PSMA-617 (Pluvicto), particularly in the metastatic castrate resistant setting. While prostate specific antigen (PSA) serves as a useful biomarker in newly diagnosed patients or those on androgen deprivation therapy, its efficacy in monitoring patients under PSMA-directed therapy remains unclear. This underscores a critical gap: the absence of established biomarkers for tracking response to these emerging treatments. Such biomarkers are vital for enhancing patient outcomes and evaluating therapeutic efficacy in early-stage trials. Methods: In this real-world, cohort study, we retrospectively followed adult patients with metastatic, castrate-resistant prostate cancer who are treated with Pluvicto at our institution beginning January 1, 2022 through November 2023. We assessed several potential biomarkers of response temporally throughout the treatment duration of Pluvicto, including serial blood counts, chemistry profiles, PSA levels, BMI, as well as their historical treatment patterns and demographics. All patients were heavily pre-treated prior to receiving Pluvicto. By using logistic regression, we identify factors associated with treatment response. Results: In our study, 21 patients qualified for enrolment. These patients received a median of 6 treatments prior to Pluvicto. Among them, 8 (38.1%) demonstrated at least PSA50 and showed response post-treatment. Of these, 6 (75%) completed all six Pluvicto treatments, while 2 (25%) are currently undergoing treatment. Remarkably, 7 of the 8 responders (87.5%) achieved a PSA50 response after two Pluvicto doses, with all 8 (100%) reaching this marker by the third dose. Furthermore, 6 of these 8 patients (75%) exhibited a PSA90 response after the fourth dose, though 2 patients (25%) did not attain PSA90. Conclusions: Our real-world study at Scripps Clinic provides valuable insights into the efficacy of Pluvicto in treating metastatic, castrate-resistant prostate cancer. Out of 21 patients treated with Pluvicto, 38.1% exhibited a significant PSA decrease during the treatment course. Notably, 87.5% of responders achieved PSA50 before their third dose, and all responders reached this benchmark prior to their fourth dose. These findings are crucial, especially as clinical trials are exploring Pluvicto's application in earlier treatment stages. Additionally, the use of PSA50 as a biomarker could guide clinicians in timely decision-making, allowing for quicker intervention and therapy adjustments, thus potentially mitigating disease progression. Updated data to be presented.

PKMYT1 Is a Marker of Treatment Response and a Therapeutic Target for CDK4/6 Inhibitor-Resistance in ER+ Breast Cancer.

Endocrine therapies (ET) with cyclin-dependent kinase 4/6 (CDK4/6) inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of patient-derived xenografts (PDXs) from patients with 22 ER+ breast cancer demonstrated that protein kinase, membrane-associated tyrosine/threonine one (PKMYT1), a WEE1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast cancer cells without functional p53. In vitro the combination increased DNA damage and apoptosis. In palbociclib-resistant, TP53 mutant PDX-derived organoids and PDXs, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer.

Esophageal Baseline Impedance is Associated with Laryngopharyngeal Reflux and Treatment Response.

To evaluate the efficacy of distal esophageal mean nocturnal baseline impedance (MNBI), a general marker of esophageal mucosal barrier integrity, in predicting laryngopharyngeal reflux (LPR) and symptomatic response to acid reflux therapy. This retrospective study analyzed 173 patients who presented with symptoms of laryngopharyngeal reflux and underwent 24-h multichannel intraluminal impedance-pH (MII-pH) testing. Mean nocturnal baseline impedance values were calculated and assessed for their association and ability to predict LPR symptoms, MII-pH results, treatment response, and other markers of LPR. Notably, 153 of the 173 patients were tested off acid suppression medication and included in statistical analysis. Based on the MII-pH probe data, 108 (71%) patients had LPR, 8 (5%) had gastroesophageal reflux disease (GERD), and 37 (24%) were without pathologic reflux. Distal esophageal MNBI of LPR patients was significantly lower in LPR patients than patients with negative studies (1332 ± 94.8 vs. 2158 ± 173.5, p = 0.001). Among 118 patients who trialed antireflux therapy, a distal esophageal MNBI cutoff value of <1580 Ω was an independent predictor of treatment response (OR = 4.148 [1.877-9.189]). This value better predicted improvement with antireflux therapy for LPR than other objective MII-pH probe data, which were not independent predictors of treatment response. Distal esophageal MNBI values may have value in the diagnosis of LPR and potentially predict medication responsiveness in LPR patients. 3 Laryngoscope, 134:4071-4077, 2024.

Phosphorylated neurofilament heavy chain in cerebrospinal fluid and plasma as a Nusinersen treatment response marker in childhood-onset SMA individuals from Serbia.

Biomarkers capable of reflecting disease onset and short- and long-term therapeutic effects in individuals with spinal muscular atrophy (SMA) are still an unmet need and phosphorylated neurofilament heavy chain (pNF-H) holds significant promise. We conducted a longitudinal prospective study to evaluate pNF-H levels in the cerebrospinal fluid (CSF) and plasma of 29 individuals with childhood-onset SMA treated with Nuinersen (SMA type 1: n = 6, 2: n = 17, 3: n = 6). pNF-H levels before and during treatment were compared with the levels of controls (n = 22), patients with Duchenne muscular dystrophy (n = 17), myotonic dystrophy type 1 (n = 11), untreated SMA individuals with chronic type 3 disease (n = 8), and children with presymptomatic SMA (n = 3). SMA type 1 showed the highest mean CSF pNF-H levels before treatment initiation. All Nusinersen-treated individuals (types 1, 2, and 3) showed significantly elevated mean baseline CSF pNF-H compared to controls, which inversely correlated with age at disease onset, age at first dose, disease duration and the initial CHOP INTEND result (SMA type 1 and 2). During 22 months of treatment, CSF pNF-H levels declined during loading doses, stabilizing at reduced levels from the initial maintenance dose in all individuals. Baseline plasma pNF-H levels in type 1 and 2 SMA were significantly increased compared to other cohorts and decreased notably in type 1 after 2 months of treatment and type 2 after 14 months. Conversely, SMA type 3, characterized by lower baseline pNF-H levels, did not show significant fluctuations in plasma pNF-H levels after 14 months of treatment. Our findings suggest that CSF pNF-H levels in untreated SMA individuals are significantly higher than in controls and that monitoring of CSF pNF-H levels may serve as an indicator of rapid short-term treatment response in childhood-onset SMA individuals, irrespective of the subtype of the disease, while also suggesting its potential for assessing long-term suppression of neurodegeneration. Plasma pNF-H may serve as an appropriate outcome measure for disease progression and/or response to treatment in types 1 and 2 but not in type 3. Presymptomatic infants with SMA may show elevated pNF-H levels, confirming early neuronal degeneration.

Advanced neuroimaging techniques to explore the effects of motor and cognitive rehabilitation in multiple sclerosis.

Progress in magnetic resonance imaging (MRI) technology and analyses is improving our comprehension of multiple sclerosis (MS) pathophysiology. These advancements, which enable the evaluation of atrophy, microstructural tissue abnormalities, and functional plasticity, are broadening our insights into the effectiveness and working mechanisms of motor and cognitive rehabilitative treatments. This narrative review with selected studies discusses findings derived from the application of advanced MRI techniques to evaluate structural and functional neuroplasticity modifications underlying the effects of motor and cognitive rehabilitative treatments in people with MS (PwMS). Current applications as outcome measure in longitudinal trials and observational studies, their interpretation and possible pitfalls and limitations in their use are covered. Finally, we examine how the use of these techniques could evolve in the future to improve monitoring of motor and cognitive rehabilitative treatments. Despite substantial variability in study design and participant characteristics in rehabilitative studies for PwMS, improvements in motor and cognitive functions accompanied by structural and functional brain modifications induced by rehabilitation can be observed. However, significant enhancements to refine rehabilitation strategies are needed. Future studies in this field should strive to implement standardized methodologies regarding MRI acquisition and processing, possibly integrating multimodal measures. This will help identifying relevant markers of treatment response in PwMS, thus improving the use of rehabilitative interventions at individual level. The combination of motor and cognitive strategies, longer periods of treatment, as well as adequate follow-up assessments will contribute to enhance the quality of evidence in support of their routine use.

Developing and Validating Marker of Treatment Response for Subcallosal Cingulate Deep Brain Stimulation

Developing and Validating Marker of Treatment Response for Subcallosal Cingulate Deep Brain Stimulation

Altered Serotonin 1B Receptor Binding After Escitalopram for Depression Is Correlated With Treatment Effect.

Major depressive disorder (MDD) is commonly treated with selective serotonin reuptake inhibitors (SSRIs). SSRIs inhibit the serotonin transporter (5-HTT), but the downstream antidepressant mechanism of action of these drugs is poorly understood. The serotonin 1B (5-HT1B) receptor is functionally linked to 5-HTT and 5-HT1B receptor binding and 5-HT1B receptor mRNA is reduced in the raphe nuclei after SSRI administration in primates and rodents, respectively. The effect of SSRI treatment on 5-HT1B receptor binding in patients with MDD has not been examined previously. This positron emission tomography (PET) study aimed to quantify brain 5-HT1B receptor binding changes in vivo after SSRI treatment for MDD in relation to treatment effect. Eight unmedicated patients with moderate to severe MDD underwent PET with the 5-HT1B receptor radioligand [11C]AZ10419369 before and after 3 to 4 weeks of treatment with the SSRI escitalopram 10mg daily. Depression severity was assessed at time of PET and after 6 to 7 weeks of treatment with the Montgomery-Åsberg Depression Rating Scale. We observed a significant reduction in [11C]AZ10419369 binding in a dorsal brainstem (DBS) region containing the median and dorsal raphe nuclei after escitalopram treatment (P = .036). Change in DBS [11C]AZ10419369 binding correlated with Montgomery-Åsberg Depression Rating Scale reduction after 3-4 (r = 0.78, P = .021) and 6-7 (r = 0.94, P < .001) weeks' treatment. Our findings align with the previously reported reduction of 5-HT1B receptor binding in the raphe nuclei after SSRI administration and support future studies testing change in DBS 5-HT1B receptor binding as an SSRI treatment response marker.

Prior psychiatric morbidity and differential psychopharmacological treatment patterns: Exploring the heterogeneity of bipolar disorder in a nationwide study of 9594 patients.

Individuals with bipolar disorders (BD) have heterogenic pre-onset illness courses and responses to treatment. The pattern of illness preceding the diagnosis of BD may be a marker of future treatment response. Here, we examined associations between psychiatric morbidity preceding the diagnosis of BD and pharmacological treatment patterns in the 2 years following diagnosis. In this register-based study, we included all patients with a diagnosis of BD attending Danish Psychiatric Services between January 1, 2012 and December 31, 2016. We examined the association between a diagnosis of substance use disorder, psychosis (other than schizophrenia or schizoaffective disorder), unipolar depression, anxiety/OCD, PTSD, personality disorder, or ADHD preceding BD and pharmacological treatment patterns following the diagnosis of BD (lithium, valproate, lamotrigine, antidepressants, olanzapine, risperidone, and quetiapine) via multivariable Cox proportional hazards regression adjusted for age, sex, and year of BD diagnosis. We included 9594 patients with a median age of 39 years, 58% of whom were female. Antidepressants, quetiapine, and lamotrigine were the most commonly used medications in BD and were all linked to prior depressive illness and female sex. Lithium was used among patients with less diagnostic heterogeneity preceding BD, while valproate was more likely to be used for patients with prior substance use disorder or ADHD. The pharmacological treatment of BD is linked to psychiatric morbidity preceding its diagnosis. Assuming that these associations reflect well-informed clinical decisions, this knowledge may inform future clinical trials by taking participants' prior morbidity into account in treatment allocation.

Clinical Utility of Circulating Tumor DNA in Patients With Advanced KRASG12C-Mutated NSCLC Treated With Sotorasib

IntroductionFor patients with KRASG12C-mutated NSCLC who are treated with sotorasib, there is a lack of biomarkers to guide treatment decisions. We therefore investigated the clinical utility of pretreatment and on-treatment circulating tumor DNA (ctDNA) and treatment-emergent alterations on disease progression. MethodsPatients with KRASG12C-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker study (NCT05221372). Plasma samples were collected before sotorasib treatment, at first-response evaluation and at disease progression. The TruSight Oncology 500 panel was used for ctDNA and variant allele frequency analysis. Tumor response and progression-free survival were assessed per Response Evaluation Criteria in Solid Tumors version 1.1. ResultsPretreatment KRASG12C ctDNA was detected in 50 of 66 patients (76%). Patients with detectable KRASG12C had inferior progression-free survival (hazard ratio [HR] 2.13 [95% confidence interval [CI]: 1.06–4.30], p = 0.031) and overall survival (HR 2.61 [95% CI: 1.16–5.91], p = 0.017). At first-response evaluation (n = 40), 29 patients (73%) had a molecular response. Molecular nonresponders had inferior overall survival (HR 3.58 [95% CI: 1.65–7.74], p = 0.00059). The disease control rate was significantly higher in those with a molecular response (97% versus 64%, p = 0.015). KRAS amplifications were identified as recurrent treatment-emergent alterations. ConclusionsOur data suggest detectable pretreatment KRASG12C ctDNA as a marker for poor prognosis and on-treatment ctDNA clearance as a marker for treatment response. We identified KRAS amplifications as a potential recurring resistance mechanism to sotorasib. Identifying patients with superior prognosis could aid in optimizing time of treatment initiation, and identifying patients at risk of early progression could allow for earlier treatment decisions.

One size does not fit all: notable individual variation in brain activity correlates of antidepressant treatment response.

To date, no robust electroencephalography (EEG) markers of antidepressant treatment response have been identified. Variable findings may arise from the use of group analyses, which neglect individual variation. Using a combination of group and single-participant analyses, we explored individual variability in EEG characteristics of treatment response. Resting-state EEG data and Montgomery-Åsberg Depression Rating Scale (MADRS) symptom scores were collected from 43 patients with depression before, at 1 and 12 weeks of pharmacotherapy. Partial least squares (PLS) was used to: 1) identify group differences in EEG connectivity (weighted phase lag index) and complexity (multiscale entropy) between eventual medication responders and non-responders, and 2) determine whether group patterns could be identified in individual patients. Responders showed decreased alpha and increased beta connectivity, and early, widespread decreases in complexity over treatment. Non-responders showed an opposite connectivity pattern, and later, spatially confined decreases in complexity. Thus, as in previous studies, our group analyses identified significant differences between groups of patients with different treatment outcomes. These group-level EEG characteristics were only identified in ~40-60% of individual patients, as assessed quantitatively by correlating the spatiotemporal brain patterns between groups and individual results, and by independent raters through visualization. Our single-participant analyses suggest that substantial individual variation exists, and needs to be considered when investigating characteristics of antidepressant treatment response for potential clinical applicability. https://clinicaltrials.gov, identifier NCT00519428.