Subsequent Treatment Response Research Articles

Allysine-Targeted Molecular MRI Enables Early Prediction of Chemotherapy Response in Pancreatic Cancer.

Neoadjuvant therapy is routinely used in pancreatic ductal adenocarcinoma (PDAC), but not all tumors respond to this treatment. Current clinical imaging techniques are not able to precisely evaluate and predict the response to neoadjuvant therapies over several weeks. A strong fibrotic reaction is a hallmark of a positive response, and during fibrogenesis, allysine residues are formed on collagen proteins by the action of lysyl oxidases. Here, we report the application of an allysine-targeted molecular MRI probe, MnL3, to provide an early, noninvasive assessment of treatment response in PDAC. Allysine increased 2- to 3-fold after one dose of neoadjuvant therapy with FOLFIRINOX in sensitive human PDAC xenografts in mice. Molecular MRI with MnL3 could specifically detect and quantify fibrogenesis in PDAC xenografts. Comparing the MnL3 signal before and 3 days after one dose of FOLFIRINOX predicted subsequent treatment response. The MnL3 tumor signal increased by 70% from day 0 to day 3 in mice that responded to subsequent doses of FOLFIRINOX, whereas no signal increase was observed in FOLFIRINOX-resistant tumors. This study indicates the promise of allysine-targeted molecular MRI as a noninvasive tool to predict chemotherapy outcomes. Significance: Allysine-targeted molecular MRI can quantify fibrogenesis in pancreatic tumors and predict response to chemotherapy, which could guide rapid clinical management decisions by differentiating responders from nonresponders after treatment initiation.

Anterior–temporal hippocampal network mechanisms of left angular gyrus-navigated rTMS for memory improvement in aMCI: A sham-controlled study

IntroductionNeuro-navigated repetitive transcranial magnetic stimulation (rTMS) of the left angular gyrus has been broadly investigated for the treatment of amnestic mild cognitive impairment (aMCI). Although abnormalities in two hippocampal networks, the anterior–temporal (AT) and posterior–medial (PM) networks, are consistent with aMCI and are potential therapeutic targets for rTMS, the underlying mechanisms of the therapeutic effects of rTMS on hippocampal network connections remain unknown. Here, we assessed the impact of left angular gyrus rTMS on activity in these networks and explored whether the treatment response was due to the distance between the clinically applied target (the group average optimal site) and the personalized target in patients with aMCI. MethodsSixty subjects clinically diagnosed with aMCI participated in this study after 20 sessions of sham-controlled rTMS targeting the left angular gyrus. Resting-state functional magnetic resonance imaging and neuropsychological assessments were performed before and after rTMS. Functional connectivity alterations in the PM and AT networks were assessed using seed-based functional connectivity analysis and two-factor repeated measures analysis of variance (ANOVA). We then computed the correlations between the functional connectivity changes and clinical rating scales. Finally, we examined whether the Euclidean distance between the clinically applied and personalized targets predicted the subsequent treatment response. ResultsCompared with the sham group, the active rTMS group showed rTMS-induced deactivation of functional connectivity within the medial temporal lobe-AT network, with a negative correlation with episodic memory score changes. Moreover, the active rTMS lowers the interdependency of changes in the PM and AT networks. Finally, the Euclidean distance between the clinically applied and personalized target distances could predict subsequent network lever responses in the active rTMS group. ConclusionsNeuro-navigated rTMS selectively modulates widespread functional connectivity abnormalities in the PM and AT hippocampal networks in aMCI patients, and the modulation of hippocampal-AT network connectivity can efficiently reverse memory deficits. The results also highlight the necessity of personalized targets for fMRI.

Aberrant connectivity in the hippocampus, bilateral insula and temporal poles precedes treatment resistance in first-episode psychosis: a prospective resting-state functional magnetic resonance imaging study with connectivity concordance mapping.

Functional connectivity resting-state functional magnetic resonance imaging has been proposed to predict antipsychotic treatment response in schizophrenia. However, only a few prospective studies have examined baseline resting-state functional magnetic resonance imaging data in drug-naïve first-episode schizophrenia patients with regard to subsequent treatment response. Data-driven approaches to conceptualize and measure functional connectivity patterns vary broadly, and model-free, voxel-wise, whole-brain analysis techniques are scarce. Here, we apply such a method, called connectivity concordance mapping to resting-state functional magnetic resonance imaging data acquired from an Asian sample (n = 60) with first-episode psychosis, prior to pharmaceutical treatment. Using a longitudinal design, 12 months after the resting-state functional magnetic resonance imaging, we measured and classified patients into two groups based on psychometric testing: treatment responsive and treatment resistant. Next, we compared the two groups' connectivity concordance maps that were derived from the resting-state functional magnetic resonance imaging data at baseline. We have identified consistently higher functional connectivity in the treatment-resistant group in a network including the left hippocampus, bilateral insula and temporal poles. These data-driven novel findings can help researchers to consider new regions of interest and facilitate biomarker development in order to identify treatment-resistant schizophrenia patients early, in advance of treatment and at the time of their first psychotic episode.

The impact of antibiotic resistance on the rampant spread of infectious diseases in Pakistan: Insights from a narrative review.

Antibiotic resistance (ABR) is a global public health emergency which has seen an uptick in low- to middle-income countries in recent times due to a plethora of aggravating factors and has led to a whole host of setting-specific pathogens registering high rates of resistance, causing outbreaks with graver mortality and morbidity. This review analyzes available literature to determine the causes and effects of ABR and recommend solutions to the problem in a Pakistani setting. Sources for this narrative review were identified via electronic databases using keyword search methods. The information was retrieved using databases such as PubMed and Science Direct. Additionally, websites such as CDC and World Health Organizationwere used to attain pertinent information. All the sources were selected as per their relevance and appropriateness towardthe purpose of this review. This review details the causes by dividing them into three primary strata, namely (1) under-regulation, (2) over-prescription and self-medication, and (3) lack of medical stewardship. This is made much graver when the COVID-19 pandemic and the subsequent erratic treatment response is considered, with the pandemic augmenting already high levels of consumption. These factors have led a cascade of effects including, but not limited to, a considerable increase in ABR in pathogens to first-line drugs. ABR is a serious and growing issue which will result in undesirable personal, local, and national consequences if unchecked. Mitigation and reversal of this trend is necessary by developing existing programs and investing in novel therapies and pharmaceutical research and strengthening regulatory policies and mechanisms.

Allogeneic Hematopoietic Cell Transplantation in Advanced Systemic Mastocytosis: A retrospective analysis of the DRST and GREM registries

We identified 71 patients with AdvSM (aggressive SM [ASM], SM with an associated hematologic neoplasm [SM-AHN, e.g., acute myeloid leukemia, SM-AML], mast cell leukemia [MCL]) in two national registries (DRST/GREM) who received an allogeneic hematopoietic cell transplantation (alloHCT) performed in Germany from 1999–2021. Median overall survival (OS) of ASM/SM-AHN (n = 30, 45%), SM-AML (n = 28, 39%) and MCL ± AHN (n = 13, 19%) was 9.0, 3.3 and 0.9 years (P = 0.007). Improved median OS was associated with response of SM (17/41, 41%; HR 0.4 [0.2–0.9], P = 0.035) and/or of AHN (26/43, 60%, HR 0.3 [0.1–0.7], P = 0.004) prior to alloHCT. Adverse predictors for OS included absence of KIT D816V (10/61, 16%, HR 2.9 [1.2–6.5], P < 0.001) and a complex karyotype (9/60, 15%, HR 4.2 [1.8–10.0], P = 0.016). HLA-match, conditioning type or transplantation at centers reporting above-average alloHCTs (≥7) had no impact on OS. Taking into account competing events at years 1, 3 and 5, relapse-related mortality and non-relapse mortality rate were 15%/23%, 20%/30% and 23%/35%, respectively. Irrespective of subtype, subsequent treatment response was achieved in 13/30 (43%) patients and was highest on midostaurin/avapritinib (7/9, 78%). We conclude that outcome of alloHCT in AdvSM is more affected by disease phenotype and treatment response prior to transplant than by transplant characteristics.

Epigenetic profile of the immune system associated with symptom severity and treatment response in schizophrenia.

Environmental modification of genetic information (epigenetics) is often invoked to explain interindividual differences in the phenotype of schizophrenia. In clinical practice, such variability is most prominent in the symptom profile and the treatment response. Epigenetic regulation of immune function is of particular interest, given the therapeutic relevance of this mechanism in schizophrenia. We analyzed the DNA methylation data of immune-relevant genes in patients with schizophrenia whose disease duration was less than 3 years, with previous lifetime antipsychotic treatment of no more than 2 weeks total. A total of 441 patients met the inclusion criteria. Core symptoms were consistently associated with 206 methylation positions, many of which had previously been implicated in inflammatory responses. Of these, 24 methylation positions were located either in regulatory regions or near the CpG islands of 20 genes, including the SRC gene, which is a key player in glutamatergic signalling. These symptom-associated immune genes were enriched in neuronal development functions, such as neuronal migration and glutamatergic synapse. Compared with using only clinical information (including scores on the Positive and Negative Syndrome Scale), integrating methylation data into the model significantly improved the predictive ability (as indicated by area under the curve) for response to 8 weeks of antipsychotic treatment. We focused on a small number of methylation probes (immune-centred search) and lacked nutritional data and direct brain-based measures. Epigenetic modifications of the immune system are associated with symptom severity at onset and subsequent treatment response in schizophrenia.

89Zr]-CD8 ImmunoPET imaging of glioblastoma multiforme response to combination oncolytic viral and checkpoint inhibitor immunotherapy reveals CD8 infiltration differential changes in preclinical models.

Rationale: Novel immune-activating therapeutics for the treatment of glioblastoma multiforme (GBM) have shown potential for tumor regression and increased survival over standard therapies. However, immunotherapy efficacy remains inconsistent with response assessment being complicated by early treatment-induced apparent radiological tumor progression and slow downstream effects. This inability to determine early immunotherapeutic benefit results in a drastically decreased window for alternative, and potentially more effective, treatment options. The objective of this study is to evaluate the effects of combination immunotherapy on early CD8+ cell infiltration and its association with long term response in orthotopic syngeneic glioblastoma models. Methods: Luciferase positive GBM orthotopic mouse models (GSC005-luc) were imaged via [89Zr]-CD8 positron emission tomography (PET) one week following treatment with saline, anti-PD1, M002 oncolytic herpes simplex virus (oHSV) or combination immunotherapy. Subsequently, brains were excised, imaged via [89Zr]-CD8 ImmunoPET and evaluated though autoradiography and histology for H&E and CD8 immunohistochemistry. Longitudinal immunotherapeutic effects were evaluated through [89Zr]-CD8 PET imaging one- and three-weeks following treatment, with changes in tumor volume monitored on a three-day basis via bioluminescence imaging (BLI). Response classification was then performed based on long-term BLI signal changes. Statistical analysis was performed between groups using one-way ANOVA and two-sided unpaired T-test, with p < 0.05 considered significant. Correlations between imaging and biological validation were assessed via Pearson's correlation test. Results: [89Zr]-CD8 PET standardized uptake value (SUV) quantification was correlated with ex vivo SUV quantification (r = 0.61, p < 0.01), autoradiography (r = 0.46, p < 0.01), and IHC tumor CD8+ cell density (r = 0.55, p < 0.01). Classification of therapeutic responders, via bioluminescence signal, revealed a more homogeneous CD8+ immune cell distribution in responders (p < 0.05) one-week following immunotherapy. Conclusions: Assessment of early CD8+ cell infiltration and distribution in the tumor microenvironment provides potential imaging metrics for the characterization of oHSV and checkpoint blockade immunotherapy response in GBM. The combination therapies showed enhanced efficacy compared to single agent immunotherapies. Further development of immune-focused imaging methods can provide clinically relevant metrics associated with immune cell localization that can inform immunotherapeutic efficacy and subsequent treatment response in GBM patients.

Differential response to neoadjuvant endocrine therapy for Black/African American and White women in NCDB

PurposeCompared to White women, there are higher mortality rates in Black/African American (BAA) women with hormone receptor-positive breast cancer (HR + BC) which may be partially due to differences in treatment resistance. We assessed factors associated with response to neoadjuvant endocrine therapy (NET).MethodsThe National Cancer Database (NCDB) was queried for women with clinical stage I–III HR + BC diagnosed 2006–2017 and treated with NET. Univariate and multivariate analyses described associations between the sample, duration of NET, and subsequent treatment response, defined by changes between clinical and pathological staging.ResultsThe analytic sample included 9864 White and 1090 BAA women. Compared to White women, BAA women were younger, had more co-morbidities, were higher stage at presentation, and more likely to have > 24 weeks of NET. After excluding those with unknown pT/N/M, 3521 White and 365 BAA women were evaluated for NET response. On multivariate analyses, controlling for age, stage, histology, HR positivity, and duration of NET, BAA women were more likely to downstage to pT0/Tis (OR 3.0, CI 1.2–7.1) and upstage to Stage IV (OR 2.4, CI 1.002–5.6). None of the women downstaged to pT0/Tis presented with clinical stage III disease; only 2 of the women upstaged to Stage IV disease presented with clinical Stage I disease.ConclusionIndependent of NET duration and clinical stage at presentation, BAA women were more likely to experience both complete tumor response and progression to metastatic disease. These results suggest significant heterogeneity in tumor biology and warrant a more nuanced therapeutic approach to HR + BC.

Early sonographic response to a new medical therapy is associated with future treatment response or failure in patients with inflammatory bowel disease.

Gastrointestinal ultrasound (GIUS) accurately assesses inflammation and is responsive to changes in inflammatory bowel disease. This study aimed to determine the prognostic utility of sonographic response in the first 14 weeks of a newly-instituted therapy with therapeutic response at 46 weeks and to compare its performance with standard clinical assessment tools. Patients with sonographic evidence of inflammation were assessed by GIUS, clinical activity, serum C-reactive protein and faecal calprotectin again 2, 6 and 14 weeks after commencing a new biologic or thiopurine. Treatment failure was defined as undergoing surgery, hospitalisation, escalation of dosage or introduction of new medication over 46-weeks' follow-up. Sonographic response was defined as a decrease in bowel wall thickness and improved vascularity. In 31 patients (median age 49 years, 74% Crohn's disease), sonographic response at 14 weeks [OR 19.3, 95% confidence interval (CI), 3.23-101.10; P = 0.0054] and faecal calprotectin (P = 0.018), but no clinical disease activity or C-reactive protein, were predictive of subsequent treatment response. Sonographic response alone was predictive at week 6 (P = 0.016), but not week 2. 16% reduction in bowel wall thickness at 6 weeks (area-under-the-receiver-operator-curve=0.86; P = 0.002; sensitivity 72%, specificity 90%), with similar performance for 10% at 14 weeks, was associated with treatment response. Sonographic response as early as 6 weeks after initiation of a new therapy may accurately predict treatment outcomes over 46 weeks and is superior to other markers used to monitor disease activity.

Predicting treatment response and clinicopathological findings in lupus nephritis with urine epidermal growth factor, monocyte chemoattractant protein-1 or their ratios.

IntroductionThere is a need for sensitive and specific biomarkers to predict kidney damage and therapeutic response in lupus nephritis (LN). Monocyte chemoattractant protein-1 (MCP-1) and epidermal growth factor (EGF) are cytokines with divergent roles. EGF or EGF/MCP1 ratio have been shown to correlate with prognosis in primary glomerulonephritis, but there is limited information in lupus nephritis (LN). This study evaluated the roles of MCP-1, EGF or their ratio as biomarkers of histopathology and response to treatment in LN.MethodsThis was a cross-sectional and observational study. Baseline urine MCP-1 and EGF levels in systemic lupus erythematosus (SLE) patients and controls (total n = 101) were compared, and levels were correlated with clinicopathological findings and subsequent response to treatment.ResultsMCP-1 was higher in active LN (n = 69) compared to other SLE groups and controls, whereas EGF was not different. MCP-1 correlated with disease activity (proteinuria, renal SLEDAI, classes III/IV/V, and high activity index.) By contrast, EGF correlated with eGFR, but not with proteinuria, activity index, or class III/IV/V. MCP-1 was higher, and EGF was lower in high chronicity index. EGF/MCP-1 decreased with greater clinicopathological severity. In a subgroup with proliferative LN who completed six months of induction therapy (n = 41), EGF at baseline was lower in non-responders compared to responders, whereas MCP-1 was similar. By multivariable analysis, baseline EGF was independently associated with subsequent treatment response. Area under the curve for EGF to predict response was 0.80 (0.66–0.95). EGF ≥ 65.6 ng/ mgCr demonstrated 85% sensitivity and 71% specificity for response. EGF/MCP-1 did not improve the prediction for response compared to EGF alone.ConclusionMCP-1 increased with disease activity, whereas EGF decreased with low GFR and chronic damage. Urine EGF may be a promising biomarker to predict therapeutic response in LN. EGF/MCP-1 did not improve the prediction of response.

Impact of Progressive Site-Directed Therapy in Oligometastatic Castration-Resistant Prostate Cancer on Subsequent Treatment Response.

Simple SummaryLocal treatment for oligometastatic hormone-naive prostate cancer has been shown to be effective in phase II trials. As for the efficacy of targeted therapy for oligometastatic castration-resistant prostate cancer, the results of the phase trial are not yet available, but the number of reports showing efficacy by retrospective analysis is increasing. Progressive site-directed therapy has been shown to delay the next intervention and prolong progression-free survival, but its impact on subsequent treatment efficacy and contribution to overall survival has not been reported. The purpose of this retrospective study is to evaluate the impact of progressive site-directed therapy for oligometastatic castration-resistant prostate cancer on the subsequent treatment outcomes. We found that progressive site-directed therapy was associated with better response to subsequent androgen receptor axis-targeted drugs and better overall survival. Progressive site-directed therapy for oligometastatic castration-resistant prostate cancer may improve subsequent oncological outcomes.The purpose of this study was to evaluate the impact of progressive site-directed therapy (PSDT) for oligometastatic castration-resistant prostate cancer (OM-CRPC) on the efficacy of subsequent androgen receptor axis-targeted (ARAT) drugs, and to demonstrate the possibility of prolonging overall survival (OS). We performed a retrospective analysis of 15 OM-CRPC patients who underwent PSDT and subsequently received first-line ARAT drugs (PSDT group) and 13 OM-CRPC patients who were treated with first-line ARAT drugs without PSDT (non-PSDT group). PSDT was performed with the intention of treating all progressing sites detected by whole-body diffusion-weighted MRI with radiotherapy. Thirteen patients (86.7%) treated with PSDT had a decrease in PSA levels, which was at least 50% in 10 (66.7%) patients. The median PSA progression-free survival (PFS) for PSDT was 7.4 months. The median PSA-PFS for ARAT was 27.2 months in patients in the PSDT group and 11.7 months in the non-PSDT group, with a significant difference between the two groups (hazard ratio [HR], 0.28; p = 0.010). The median OS was not reached in the PSDT group and was significantly longer than 44.5 months in the non-PSDT group (HR, 0.11; p = 0.014). In OM-CRPC, PSDT may improve the efficacy of subsequent ARAT and OS.

The Role of Machine Learning and Radiomics for Treatment Response Prediction in Idiopathic Normal Pressure Hydrocephalus.

IntroductionVentricular shunting remains the standard of care for patients with idiopathic normal pressure hydrocephalus (iNPH); however, not all patients benefit from the shunting. Prediction of response in advance can result in improved patient selection for ventricular shunting. This study aims to develop a machine learning predictive model for treatment response after shunt placement using the clinical and radiomics features.MethodsIn this retrospective pilot study, the medical records of iNPH patients who underwent ventricular shunting were evaluated. In each patient, the “idiopathic normal pressure hydrocephalus grading scale” (iNPHGS) and a “Modified Rankin Scale” were calculated before and after surgery. The subsequent treatment response was calculated as the difference between the iNPHGS scores before and after surgery. iNPHGS score reduction of two or more than two were considered as treatment response. The presurgical MRI scans were evaluated by radiologists, the ventricular systems were segmented on the T2-weighted images, and the radiomics features were extracted from the segmented ventricular system. Using Orange data mining open-source platform, different machine learning models were then developed based on the presurgical clinical features and the selected radiomics features to predict treatment response after shunt placement.ResultsAfter the implementation of the inclusion criteria, 78 patients were included in this study. One hundred twenty radiomics features were extracted, and the 12 best predictive radiomics features were selected. Using only clinical data (iNPHGS and Modified Rankin Scale), the random forest model achieved the best performance in treatment prediction with an area under the curve (AUC) of 0.71. Adding the Radiomics analysis to the clinical data improved the prediction performance, with the support vector machine (SVM) achieving the highest rank in treatment prediction with an AUC of 0.8. Adding age and sex to the analysis did not improve the prediction.ConclusionUsing machine learning models for treatment response prediction in patients with iNPH is feasible with acceptable accuracy. Adding the Radiomics analysis to the clinical features can further improve the predictive performance. SVM is likely the best model for this task.

Modeling and Bioinformatics Identify Responders to G-CSF in Patients With Amyotrophic Lateral Sclerosis.

Objective: Developing an integrative approach to early treatment response classification using survival modeling and bioinformatics with various biomarkers for early assessment of filgrastim (granulocyte colony stimulating factor) treatment effects in amyotrophic lateral sclerosis (ALS) patients. Filgrastim, a hematopoietic growth factor with excellent safety, routinely applied in oncology and stem cell mobilization, had shown preliminary efficacy in ALS.Methods: We conducted individualized long-term filgrastim treatment in 36 ALS patients. The PRO-ACT database, with outcome data from 23 international clinical ALS trials, served as historical control and mathematical reference for survival modeling. Imaging data as well as cytokine and cellular data from stem cell analysis were processed as biomarkers in a non-linear principal component analysis (NLPCA) to identify individual response.Results: Cox proportional hazard and matched-pair analyses revealed a significant survival benefit for filgrastim-treated patients over PRO-ACT comparators. We generated a model for survival estimation based on patients in the PRO-ACT database and then applied the model to filgrastim-treated patients. Model-identified filgrastim responders displayed less functional decline and impressively longer survival than non-responders. Multimodal biomarkers were then analyzed by PCA in the context of model-defined treatment response, allowing identification of subsequent treatment response as early as within 3 months of therapy. Strong treatment response with a median survival of 3.8 years after start of therapy was associated with younger age, increased hematopoietic stem cell mobilization, less aggressive inflammatory cytokine plasma profiles, and preserved pattern of fractional anisotropy as determined by magnetic resonance diffusion tensor imaging (DTI-MRI).Conclusion: Long-term filgrastim is safe, is well-tolerated, and has significant positive effects on disease progression and survival in a small cohort of ALS patients. Developing and applying a model-based biomarker response classification allows use of multimodal biomarker patterns in full potential. This can identify strong individual treatment responders (here: filgrastim) at a very early stage of therapy and may pave the way to an effective individualized treatment option.

New Predictive Biomarkers for Ovarian Cancer.

Ovarian cancer is the eighth-most common cause of death among women worldwide. In the absence of distinctive symptoms in the early stages, the majority of women are diagnosed in advanced stages of the disease. Surgical debulking and systemic adjuvant chemotherapy remain the mainstays of treatment, with the development of chemoresistance in up to 75% of patients with subsequent poor treatment response and reduced survival. Therefore, there is a critical need to revisit existing, and identify potential biomarkers that could lead to the development of novel and more effective predictors for ovarian cancer diagnosis and prognosis. The capacity of these biomarkers to predict the existence, stages, and associated therapeutic efficacy of ovarian cancer would enable improvements in the early diagnosis and survival of ovarian cancer patients. This review not only highlights current evidence-based ovarian-cancer-specific prognostic and diagnostic biomarkers but also provides an update on various technologies and methods currently used to identify novel biomarkers of ovarian cancer.

Assessment of Clinical Benefit of Integrative Genomic Profiling in Advanced Solid Tumors

Use of next-generation sequencing (NGS) to identify clinically actionable genomic targets has been incorporated into routine clinical practice in the management of advanced solid tumors; however, the clinical utility of this testing remains uncertain. To determine which patients derived the greatest degree of clinical benefit from NGS profiling. Patients in this cohort study underwent fresh tumor biopsy and blood sample collection for genomic profiling of paired tumor and normal DNA (whole-exome or targeted-exome capture with analysis of 1700 genes) and tumor transcriptome (RNA) sequencing. Somatic and germline genomic alterations were annotated and classified according to degree of clinical actionability. Results were returned to treating oncologists. Data were collected from May 1, 2011, to February 28, 2018, and analyzed from May 1, 2011, to April 30, 2020. Patients' subsequent therapy and treatment response were extracted from the medical record to determine clinical benefit rate from NGS-directed therapy at 6 months and exceptional responses lasting 12 months or longer. During the study period, NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%) (MET1000 cohort) (538 men [53.0%]; mean [SD] age, 57.7 [13.3] years). Potentially clinically actionable genomic alterations were discovered in 817 patients (80.5%). Of these, 132 patients (16.2%) received sequencing-directed therapy, and 49 had clinical benefit (37.1%). Exceptional responses were observed in 26 patients (19.7% of treated patients). Pathogenic germline variants (PGVs) were identified in 160 patients (15.8% of cohort), including 49 PGVs (4.8% of cohort) with therapeutic relevance. For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), and sequencing-directed therapy in 13 patients resulted in clinical benefit in 7 instances (53.8%), including 5 exceptional responses. The high rate of therapeutically relevant PGVs identified across diverse cancer types supports a recommendation for directed germline testing in all patients with advanced cancer. The high frequency of therapeutically relevant somatic and germline findings in patients with carcinoma of unknown primary origin and other rare cancers supports the use of comprehensive NGS profiling as a component of standard of care for these disease entities.

Structural and Functional Default Mode Network Connectivity and Antipsychotic Treatment Response in Medication-Naïve First Episode Psychosis Patients.

IntroductionOnly a few studies have comprehensively characterized default mode network (DMN) pathology on a structural and functional level, and definite conclusions cannot be drawn due to antipsychotic medication exposure and illness chronicity. The objective of this study was to characterize DMN pathology in medication-naïve first episode psychosis (FEP) patients, and determine if DMN structural and functional connectivity (FC) have potential utility as a predictor for subsequent antipsychotic treatment response. MethodsDiffusion imaging and resting state FC data from 42 controls and 52 FEP were analyzed. Patients then received 16 weeks of antipsychotic treatment. Using region of interest analyses, we quantified FC of the DMN and structural integrity of the white matter tracts supporting DMN function. We then did linear regressions between DMN structural and FC indices and antipsychotic treatment response. ResultsWe detected reduced DMN fractional anisotropy and axial diffusivity in FEP compared to controls. No DMN FC abnormalities nor correlations between DMN structural and FC were found. Finally, DMN fractional anisotropy and radial diffusivity were associated with response to treatment. ConclusionOur study highlights the critical role of the DMN in the pathophysiology suggesting that axonal damage may already be present in FEP patients. We also demonstrated that DMN pathology is clinically relevant, as greater structural DMN alterations were associated with a less favorable clinical response to antipsychotic medications.

Optical coherence tomography angiography measured area of retinal neovascularization is predictive of treatment response and progression of disease in patients with proliferative diabetic retinopathy

BackgroundThe purpose of this study was to evaluate the area of retinal neovascularization in patients with treatment-naïve proliferative diabetic retinopathy (PDR) as measured by optical coherence tomography angiography (OCT-A) as a marker of subsequent treatment response after panretinal photocoagulation (PRP), and to examine if this area correlated with area of retinal neovascularization as measured by fluorescein angiography (FA).MethodsEn face OCT-A scans (4.5 × 4.5 mm) of neovascularizations were obtained at baseline (BL) before PRP and at month (M) 3 and M6 after treatment. Progression of PDR were defined as lesion growth (assessed by ophthalmoscopy and wide-field fundus photo) or increasing leakage by Optos ultra-widefield FA, and patients were divided into two groups; progression or non-progression. Mann–Whitney U test and Wilcoxon signed-rank test were used to analyse differences between groups and between time points. Areas of retinal neovascularizations (OCT-A and FA) were calculated by algorithms developed in Python (version 3.6.8, The Python Software Foundation, USA).ResultsOf 21 eyes included, 14 had progression of disease. Median OCT-A area did not differ between the two groups (progression vs. non-progression) at BL (76.40 ± 162.03 vs. 72.62 ± 94.15, p = 0.43) but were statistically significantly larger in the progression group at M6 (276.69 ± 168.78 vs. 61.30 ± 70.90, p = 0.025). Median FA area did not differ in the progression vs. the non-progression group at BL (111.42 ± 143.08 vs. 60.80 ± 54.83, p = 0.05) or at M6 (200.12 ± 91.81 vs. 123.86 ± 162.16, p = 0.62). Intraclass correlation between area by OCT-A and FA was −5.99 (95% CI: −35.28–0.993), p = 0.71.ConclusionsIn this study of patients with treatment-naïve PDR, we showed that increasing area of retinal neovascularizations measured by OCT-A at M6 indicated progression of disease after PRP treatment. Our results suggest that area by OCT-A reflects disease activity and that it can be used as an indicator to monitor the progression of PDR over time, and to evaluate treatment response six months after PRP.Trial registrationhttps://clinicaltrials.gov (identifier: NCT03113006). Registered April 13, 2017.

CXCR4-Targeted PET Imaging of Central Nervous System B-Cell Lymphoma.

C-X-C chemokine receptor 4 (CXCR4) is a transmembrane chemokine receptor involved in growth, survival, and dissemination of cancer, including aggressive B-cell lymphoma. MRI is the standard imaging technology for central nervous system (CNS) involvement of B-cell lymphoma and provides high sensitivity but moderate specificity. Therefore, novel molecular and functional imaging strategies are urgently required. Methods: In this proof-of-concept study, 11 patients with lymphoma of the CNS (8 primary and 3 secondary involvement) were imaged with the CXCR4-directed PET tracer 68Ga-pentixafor. To evaluate the predictive value of this imaging modality, treatment response, as determined by MRI, was correlated with quantification of CXCR4 expression by 68Ga-pentixafor PET in vivo before initiation of treatment in 7 of 11 patients. Results:68Ga-pentixafor PET showed excellent contrast with the surrounding brain parenchyma in all patients with active disease. Furthermore, initial CXCR4 uptake determined by PET correlated with subsequent treatment response as assessed by MRI. Conclusion:68Ga-pentixafor PET represents a novel diagnostic tool for CNS lymphoma with potential implications for theranostic approaches as well as response and risk assessment.

Early improvements of individual symptoms as a predictor of treatment response to asenapine in patients with schizophrenia.

AimIt is well accepted that early improvement with antipsychotics predicts subsequent response in patients with schizophrenia. However, no study has examined the contribution of individual symptoms rather than overall symptom severity as the predictors. Thus, we aimed to detect individual symptoms whose improvements could predict subsequent response in patients with schizophrenia during treatment with asenapine and examine whether a prediction model with individual symptoms would be superior to a model using overall symptom severity.MethodsThis study analyzed a dataset including 532 patients with schizophrenia enrolled in a 6‐week double‐blind, placebo‐controlled, randomized trial of asenapine. Response to asenapine was defined as a ≥30% decrease in Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 6. Stepwise logistic regression analyses were performed to investigate the associations among response and PANSS total/individual item score improvements at week 1 or week 2.ResultsResponse was associated with early improvement in the following PANSS items: disturbance of volition, active social avoidance, poor impulse control at week 1; and active social avoidance, poor attention, lack of judgment and insight at week 2. Prediction accuracy was almost compatible between the model with individual symptoms and the model with PANSS total score both at weeks 1 and 2 (Nagelkerke R 2: .51, .42 and .55, .54, respectively).ConclusionEarly improvement in negative symptoms, poor attention and impulse control, and lack of insight, in particular predicted subsequent treatment response in patients with schizophrenia during treatment with asenapine as accurately as prediction based on overall symptom severity.

Identifying predictive factors for efficacy in high intensity focused ultrasound (HIFU) ablation of benign thyroid nodules – a retrospective analysis

Objective Since it is unclear whether clinical parameters can independently predict the subsequent treatment response following high intensity focused ultrasound (HIFU) ablation of benign thyroid nodules, we aimed to examine clinical factors that may independently predict 12-month efficacy after HIFU treatment. Methods One hundred and forty patients who had single ablation were categorized into two groups, those with 12-month nodule shrinkage above the median (Group I, n = 70) and with shrinkage below or equal to the median (Group II, n = 70). Baseline characteristics, treatment parameters, percentage change in serum TSH, Free thyroxine (FT4) and thyroglobulin (Tg) from baseline to Day 4 and appearance of microbubbles (hyperechoic marks (HEMs)) during treatment were compared between groups. To determine independent factors, a multivariate analysis was done by logistic regression analysis. Results Baseline characteristics and treatment parameters were comparable between groups. However, on Day-4, group I had significantly lower serum TSH (0.49mIU/L vs. 0.84mIU/L, p = 0.011) and higher FT4 (22.11 pmol/L vs. 18.47 pmol/L, p = 0.008) than group II. The percentage change in TSH, FT4 and Tg were significantly greater in group I (p = 0.002, p = 0.009 and p = 0.001 respectively). The proportion of HEMs observed during treatment was also significantly higher in group I (42.69% vs. 31.72%, p = 0.030). Among the significant factors, the percentage change in FT4 was the only independent factor for 12-month shrinkage (OR = 1.018, 95%CI =1.003–1.032, p = 0.017). Conclusions Percentage change in serum FT4 on post-treatment Day-4 was an independent blood parameter for the subsequent nodule shrinkage at 12 months. This finding could potentially facilitate the decision for earlier retreatment of treated nodules.