PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells.

Aberrant cell proliferation is a hallmark of cancer, including glioblastoma (GBM). Here we report that protein arginine methyltransferase (PRMT) 6 activity is required for the proliferation, stem-like properties, and tumorigenicity of glioblastoma stem cells (GSCs), a subpopulation in GBM critical for malignancy. We identified a casein kinase 2 (CK2)-PRMT6-regulator of chromatin condensation 1 (RCC1) signaling axis whose activity is an important contributor to the stem-like properties and tumor biology of GSCs. CK2 phosphorylates and stabilizes PRMT6 through deubiquitylation, which promotes PRMT6 methylation of RCC1, which in turn is required for RCC1 association with chromatin and activation of RAN. Disruption of this pathway results in defects in mitosis. EPZ020411, a specific small-molecule inhibitor for PRMT6, suppresses RCC1 arginine methylation and improves the cytotoxic activity of radiotherapy against GSC brain tumor xenografts. This study identifies a CK2α-PRMT6-RCC1 signaling axis that can be therapeutically targeted in the treatment of GBM.

Multimodal profiling of peripheral blood identifies proliferating circulating effector CD4+ T cells as predictors for response to integrin α4ß7-blocking therapy in inflammatory bowel disease.

BACKGROUND AND AIMS: Despite the success of biological therapies in treating inflammatory bowel disease (IBD), managing patients remains challenging due to the absence of reliable predictors of therapy response. METHODS: In this study, we prospectively sampled two cohorts of IBD patients receiving the anti-integrin α4ß7 antibody vedolizumab. Samples were subjected to mass cytometry, single-cell RNA sequencing, single-cell V(D)J sequencing, serum proteomics, and multidimensional flow cytometry to comprehensively assess vedolizumab-induced immunological changes in the peripheral blood and their potential associations with treatment response. RESULTS: Vedolizumab treatment led to substantial alterations in the abundance of circulating immune cell lineages and modified the T cell receptor diversity of gut-homing CD4+ memory T cells. Through integration of multimodal parameters and machine learning, we identified a significant increase in proliferating CD4+ memory T cells among non-responders prior to treatment compared with responders. This predictive T cell signature demonstrated an activated Th1/Th17 phenotype and exhibited elevated levels of integrin α4ß1, potentially making these cells less susceptible to direct targeting by vedolizumab. CONCLUSION: These findings provide a reliable predictive classifier with significant implications for personalized IBD management.

Image-based multiplex immune profiling of cancer tissues: translational implications. A report of the International Immuno-oncology Biomarker Working Group on Breast Cancer.

Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Blood-based molecular and cellular biomarkers of early response to neoadjuvant PD-1 blockade in patients with non-small cell lung cancer.

BACKGROUND: Despite the improved survival observed in PD-1/PD-L1 blockade therapy, a substantial proportion of cancer patients, including those with non-small cell lung cancer (NSCLC), still lack a response. METHODS: Transcriptomic profiling was conducted on a discovery cohort comprising 100 whole blood samples, as collected multiple times from 48 healthy controls (including 43 published data) and 31 NSCLC patients that under treatment with a combination of anti-PD-1 Tislelizumab and chemotherapy. Differentially expressed genes (DEGs), simulated immune cell subsets, and germline DNA mutational markers were identified from patients achieved a pathological complete response during the early treatment cycles. The predictive values of mutational markers were further validated in an independent immunotherapy cohort of 1661 subjects, and then confirmed in genetically matched lung cancer cell lines by a co-culturing model. RESULTS: The gene expression of hundreds of DEGs (FDR p < 0.05, fold change < -2 or > 2) distinguished responders from healthy controls, indicating the potential to stratify patients utilizing early on-treatment features from blood. PD-1-mediated cell abundance changes in memory CD4 + and regulatory T cell subset were more significant or exclusively observed in responders. A panel of top-ranked genetic alterations showed significant associations with improved survival (p < 0.05) and heightened responsiveness to anti-PD-1 treatment in patient cohort and co-cultured cell lines. CONCLUSION: This study discovered and validated peripheral blood-based biomarkers with evident predictive efficacy for early therapy response and patient stratification before treatment for neoadjuvant PD-1 blockade in NSCLC patients.

Prediction of therapy response of breast cancer patients with machine learning based on clinical data and imaging data derived from breast [18F]FDG-PET/MRI.

PURPOSE: To evaluate if a machine learning prediction model based on clinical and easily assessable imaging features derived from baseline breast [18F]FDG-PET/MRI staging can predict pathologic complete response (pCR) in patients with newly diagnosed breast cancer prior to neoadjuvant system therapy (NAST). METHODS: Altogether 143 women with newly diagnosed breast cancer (54 ± 12 years) were retrospectively enrolled. All women underwent a breast [18F]FDG-PET/MRI, a histopathological workup of their breast cancer lesions and evaluation of clinical data. Fifty-six features derived from positron emission tomography (PET), magnetic resonance imaging (MRI), sociodemographic / anthropometric, histopathologic as well as clinical data were generated and used as input for an extreme Gradient Boosting model (XGBoost) to predict pCR. The model was evaluated in a five-fold nested-cross-validation incorporating independent hyper-parameter tuning within the inner loops to reduce the risk of overoptimistic estimations. Diagnostic model-performance was assessed by determining the area under the curve of the receiver operating characteristics curve (ROC-AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. Furthermore, feature importances of the XGBoost model were evaluated to assess which features contributed most to distinguish between pCR and non-pCR. RESULTS: Nested-cross-validation yielded a mean ROC-AUC of 80.4 ± 6.0% for prediction of pCR. Mean sensitivity, specificity, PPV, and NPV of 54.5 ± 21.3%, 83.6 ± 4.2%, 63.6 ± 8.5%, and 77.6 ± 8.1% could be achieved. Histopathological data were the most important features for classification of the XGBoost model followed by PET, MRI, and sociodemographic/anthropometric features. CONCLUSION: The evaluated multi-source XGBoost model shows promising results for reliably predicting pathological complete response in breast cancer patients prior to NAST. However, yielded performance is yet insufficient to be implemented in the clinical decision-making process.

End of induction [18F]FDG PET is prognostic for progression-free survival and overall survival in follicular lymphoma patients enrolled in the FOLL12 trial.

PURPOSE: To evaluate the reliability of the Deauville score (DS) in therapy response assessment and to define the prognostic value of the metabolic response of end of induction (EOI) [18F]FDG PET (PET) in follicular lymphoma patients. METHODS: Adult patients with untreated grade 1-3a FL/ stage II-IV enrolled in the multicentre, prospective, phase III FOLL12 trial (NCT02063685) were randomized to receive standard immunochemotherapy followed by rituximab maintenance (standard arm) versus standard immunochemotherapy followed by response-adapted post-induction management (experimental arm). Baseline and EOI PET were mandatory for the study. All PET scans were centralized on the WIDEN® platform and classified according to DS in a blind independent central review. DS1-3 was considered negative (CMR), whereas DS4-5 was considered positive (not CMR). The primary endpoint was PFS. The main secondary endpoint was overall survival (OS). RESULTS: Overall, 807 follicular lymphoma patients-52% women, 89% stage III-IV disease, 40% with a high-risk FLIPI-2 score (3-5)-were enrolled in the study; 729 (90.4%) baseline and EOI PET were available for the analysis. EOI PET was positive (DS4-5) in 88/729 (12.1%) cases. Overall inter-reviewer agreement on PET pos/neg result was 0.92, while agreement on positive and negative cases was 0.77 and 0.94, respectively. The median follow-up was 69 months; 247 events were registered in the 5-yr follow-up, with a 5-yr PFS of 67% (95%CI: 63%-70%). The 5-yr PFS rate for PET neg (DS1-3) and PET pos (DS4-5) patients was 71% (95%CI: 67%-75%) and 36% (95%CI: 25%-46%), respectively, with HR 3.49 (95%CI: 2.57-4.72). Five-year PFS was worse as DS increased, with 74% (70%-78%), 58% (48%-67%; HR 1.71; p = 0.001)] and 36% (25%-46%; HR 3.88; p < 0.001) in DS1-2, DS3 and DS4-5, respectively. EOI PET maintained its prognostic value in both the standard and experimental arms. In the whole population, 5-yr OS was 94% (95%CI: 92%-96%), with 96% (95%CI: 94-97) and 82% (95%CI: 72%-89%) in EOI PET negative (DS1-3) and positive (DS4-5), respectively (HR 4.48; p < 0.001). When DS was associated with FLIPI-2, patients with DS3 or DS1-2 with high FLIPI-2 (3-5) experienced worse OS than patients with DS1-2 and low FLIPI-2 (1-2) (p = 0.003). CONCLUSION: This study shows that DS is a reliable prognostic tool to evaluate EOI PET in follicular lymphoma patients, with prognostic value maintained both in the standard and experimental arms, making metabolic imaging a robust tool to assess response in FL. Moreover, although preliminary, this study provides further information on DS3 patients, who are considered as CMR but show a less favourable PFS than DS1-2 patients.

Evaluating trophinin associated protein as a biomarker of prognosis and therapy response in renal cell carcinoma.

BACKGROUND: Trophinin Associated Protein (TROAP) has been implicated in some tumors, yet its role in renal cell carcinoma (RCC) remains underexplored. This study aims to elucidate the prognostic and therapeutic implications of TROAP in RCC, encompassing different subtypes. METHODS: Firstly, we identified the expression patterns of TROAP across various tumors within the TCGA pan-cancer cohort. Subsequently, the prognostic significance of TROAP was validated in three TCGA RCC cohorts and a local cohort. Finally, we conducted functional enrichment analysis, somatic mutations and copy number variations, assessed therapeutic response cohorts, and performed in vitro experiments to explore the biological characteristics of TROAP. RESULTS: TROAP serves as an unfavorable factor in both the TCGA RCC datasets and our local cohort. Functional enrichment analysis and in vitro experiments have demonstrated its oncogene effect in promoting tumor progression. Additionally, the relationship between TROAP expression and gene mutations in RCC appears to be limited. Furthermore, elevated TROAP expression is associated with reduced efficacy of RCC therapies, including nivolumab and everolimus. CONCLUSIONS: Our findings illustrate TROAP as a pivotal biomarker for prognosis and therapeutic response in RCC. Elevated TROAP expression is indicative of aggressive tumor behavior and resistance to conventional therapies, making it a valuable target for personalized treatment strategies in RCC management.

Long-term effects of electroconvulsive therapy on brain structure in major depression.

BACKGROUND: Magnetic resonance imaging (MRI) studies on major depressive disorder (MDD) have predominantly found short-term electroconvulsive therapy (ECT)-related gray matter volume (GMV) increases, but research on the long-term stability of such changes is missing. Our aim was to investigate long-term GMV changes over a 2-year period after ECT administration and their associations with clinical outcome. METHODS: In this nonrandomized longitudinal study, patients with MDD undergoing ECT (n = 17) are assessed three times by structural MRI: Before ECT (t0), after ECT (t1) and 2 years later (t2). A healthy (n = 21) and MDD non-ECT (n = 33) control group are also measured three times within an equivalent time interval. A 3(group) × 3(time) ANOVA on whole-brain level and correlation analyses with clinical outcome variables is performed. RESULTS: Analyses yield a significant group × time interaction (pFWE < 0.001) resulting from significant volume increases from t0 to t1 and decreases from t1 to t2 in the ECT group, e.g., in limbic areas. There are no effects of time in both control groups. Volume increases from t0 to t1 correlate with immediate and delayed symptom increase, while volume decreases from t1 to t2 correlate with long-term depressive outcome (all p ⩽ 0.049). CONCLUSIONS: Volume increases induced by ECT appear to be a transient phenomenon as volume strongly decreased 2 years after ECT. Short-term volume increases are associated with less symptom improvement suggesting that the antidepressant effect of ECT is not due to volume changes. Larger volume decreases are associated with poorer long-term outcome highlighting the interplay between disease progression and structural changes.

A convenient and practical index for predicting the induction response in adult patients with hemophagocytic lymphohistiocytosis: ferritin/platelet ratio.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome with high mortality rate. The response to induction therapy is an important factor affecting survival. The purpose is to investigate laboratory predictors for induction response in adult patients with HLH, which are convenient, practical, and timeliness. Clinical data from January 2017 to December 2020 was retrospectively analyzed, and 269 patients were included. Patients were divided into remission and non-remission groups according to their induction response, 177 in the remission group, and 92 in the non-remission group. We reviewed general characteristics and analyzed the predictive value of serum ferritin, triglycerides, alanine aminotransferase (ALT), and blood cells before and 1-4 weeks after induction therapy for induction response by univariate analysis, ROC curves, etc. There was a correlation between serum ferritin, ALT, leukocytes, neutrophils, hemoglobin, platelets, and induction response (P < 0.05). Serum ferritin and platelets 1-4 weeks after induction therapy, respectively, might be a good predictor for induction response in adults with HLH, with AUC values close to or greater than 0.7. We established a new clinical model of the ferritin/platelet ratio. The results showed that the ferritin/platelet ratio at 1-4 weeks after induction therapy might be a practical index for predicting induction response, which significantly improved the area under the ROC curve (AUC > 0.75). Patients with a ferritin/platelet ratio > 16.08 at 2 weeks after induction therapy may have a relatively poor induction response. Ferritin/platelet ratio after induction therapy can be a good predictor for induction response in adult patients with HLH.

Performance of amide proton transfer imaging to differentiate true progression from therapy-related changes in gliomas and metastases.

OBJECTIVES: Differentiating true progression or recurrence (TP/TR) from therapy-related changes (TRC) is complex in brain tumours. Amide proton transfer-weighted (APT) imaging is a chemical exchange saturation transfer (CEST) MRI technique that may improve diagnostic accuracy during radiological follow-up. This systematic review and meta-analysis elucidated the level of evidence and details of state-of-the-art imaging for APT-CEST in glioma and brain metastasis surveillance. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library were systematically searched for original articles about glioma and metastasis patients who received APT-CEST imaging for suspected TP/TR within 2 years after (chemo)radiotherapy completion. Modified Quality Assessment of Diagnostic Accuracy Studies-2 criteria were applied. A meta-analysis was performed to pool results and to compare subgroups. RESULTS: Fifteen studies were included for a narrative synthesis, twelve of which (500 patients) were deemed sufficiently homogeneous for a meta-analysis. Magnetisation transfer ratio asymmetry performed well in gliomas (sensitivity 0.88 [0.82-0.92], specificity 0.84 [0.72-0.91]) but not in metastases (sensitivity 0.64 [0.38-0.84], specificity 0.56 [0.33-0.77]). APT-CEST combined with conventional/advanced MRI rendered 0.92 [0.86-0.96] and 0.88 [0.72-0.95] in gliomas. Tumour type, TR prevalence, sex, and acquisition protocol were sources of significant inter-study heterogeneity in sensitivity (I2 = 62.25%; p < 0.01) and specificity (I2 = 66.31%; p < 0.001). CONCLUSION: A growing body of literature suggests that APT-CEST is a promising technique for improving the discrimination of TP/TR from TRC in gliomas, with limited data on metastases. CLINICAL RELEVANCE STATEMENT: This meta-analysis identified a utility for APT-CEST imaging regarding the non-invasive discrimination of brain tumour progression from therapy-related changes, providing a critical evaluation of sequence parameters and cut-off values, which can be used to improve response assessment and patient outcome. KEY POINTS: Therapy-related changes mimicking progression complicate brain tumour treatment. Amide proton imaging improves the non-invasive discrimination of glioma progression from therapy-related changes. Magnetisation transfer ratio asymmetry measurement seems not to have added value in brain metastases.

Assessment and prediction of glioblastoma therapy response: challenges and opportunities.

Glioblastoma is the most aggressive type of primary adult brain tumour. The median survival of patients with glioblastoma remains approximately 15 months, and the 5-year survival rate is <10%. Current treatment options are limited, and the standard of care has remained relatively constant since 2011. Over the last decade, a range of different treatment regimens have been investigated with very limited success. Tumour recurrence is almost inevitable with the current treatment strategies, as glioblastoma tumours are highly heterogeneous and invasive. Additionally, another challenging issue facing patients with glioblastoma is how to distinguish between tumour progression and treatment effects, especially when relying on routine diagnostic imaging techniques in the clinic. The specificity of routine imaging for identifying tumour progression early or in a timely manner is poor due to the appearance similarity of post-treatment effects. Here, we concisely describe the current status and challenges in the assessment and early prediction of therapy response and the early detection of tumour progression or recurrence. We also summarize and discuss studies of advanced approaches such as quantitative imaging, liquid biomarker discovery and machine intelligence that hold exceptional potential to aid in the therapy monitoring of this malignancy and early prediction of therapy response, which may decisively transform the conventional detection methods in the era of precision medicine.

Study protocol TransTAM: Transdiagnostic research into emotional disorders and cognitive-behavioral therapy of the adaptive mind.

BACKGROUND: Emotional disorders such as depression and anxiety disorders share substantial similarities in their etiology and treatment. In recent decades, these commonalities have been increasingly recognized in classification systems and treatment programs crossing diagnostic boundaries. METHODS: To examine the prospective effects of different transdiagnostic markers on relevant treatment outcomes, we plan to track a minimum of N = 200 patients with emotional disorders during their routine course of cognitive behavioral therapy at two German outpatient clinics. We will collect a wide range of transdiagnostic markers, ranging from basic perceptual processes and self-report measures to complex behavioral and neurobiological indicators, before entering therapy. Symptoms and psychopathological processes will be recorded before entering therapy, between the 20th and 24th therapy session, and at the end of therapy. DISCUSSION: Our results could help to identify transdiagnostic markers with high predictive power, but also provide deeper insights into which patient groups with which symptom clusters are less likely to benefit from therapy, and for what reasons. TRIAL REGISTRATION: The trial was preregistered at the German Clinical Trial Register (DRKS-ID: DRKS00031206; 2023-05-09).

Diffusion-weighted MRI (DWI) for assessment of response to high-dose-rate CT-guided brachytherapy (HDR-BT) of hepatocellular carcinoma.

BACKGROUND: High-dose-rate computed tomography (CT)-guided brachytherapy (HDR-BT) has shown promising results in patients with hepatocellular carcinoma (HCC). While growing evidence shows clear limitations of mRECIST, diffusion-weighted imaging (DWI) has relevant potential in improving the response assessment. PURPOSE: To assess whether DWI allows evaluation of short- and long-term tumor response in patients with HCC after HDR-BT. MATERIAL AND METHODS: A total of 22 patients with 11 non-responding HCCs (NR-HCC; local tumor recurrence within two years) and 24 responding HCCs (R-HCC; follow-up at least two years) were included in this retrospective bi-center study. HCCs were treated with HDR-BT and patients underwent pre- and post-interventional magnetic resonance imaging (MRI). Analyses of DWI were evaluated and compared between pre-interventional MRI, 1.follow-up after 3 months and 2.follow-up at the time of the local tumor recurrence (in NR-HCC) or after 12 months (in R-HCC). RESULTS: ADCmean of R-HCC increased significantly after HDR-BT on the first and second follow-up (ADCmean: 0.87 ± 0.18 × 10-3 mm2/s [pre-interventional]: 1.14 ± 0.23 × 10-3 mm2/s [1. post-interventional]; 1.42 ± 0.32 × 10-3 mm2/s [2. post-interventional]; P < 0.001). ADCmean of NR-HCC did not show a significant increase from pre-intervention to 1. post-interventional MRI (ADCmean: 0.85 ± 0.24 × 10-3 mm2/s and 1.00 ± 0.30 × 10-3 mm2/s, respectively; P = 0.131). ADCmean increase was significant between pre-intervention and 2. follow-up (ADCmean: 1.03 ± 0.19 × 10-3 mm2/s; P = 0.018). There was no significant increase of ADCmean between the first and second follow-up. There was, however, a significant increase of ADCmin after 12 months (ADCmin: 0.87 ± 0.29 × 10-3 mm2/s) compared to pre-interventional MRI and first follow-up (P < 0.005) only in R-HCC. CONCLUSION: The tumor response after CT-guided HDR-BT was associated with a significantly higher increase in ADCmean and ADCmin in short- and long-term follow-up.

Prediction of prognostic and immune therapy response in lung adenocarcinoma based on MHC-I-related genes.

OBJECTIVES: The study investigated the prognostic and immune predictive potential of major histocompatibility complex class I (MHC-I) in lung adenocarcinoma (LUAD). MATERIALS AND METHODS: With The Cancer Genome Atlas (TCGA)-LUAD and Gene Expression Omnibus datasets (GSE26939, GSE72094) as the training and validation sets, respectively, we used Cox regression analysis to construct a prognostic model, and verified independence of riskscore. The predictive capacity of the model was assessed in both sets using the receiver operating characteristic curve and Kaplan-Meier survival curves. Immune analysis was performed by using ssGSEA. Additionally, immune checkpoint blockade therapy was assessed by using immunophenoscore, Tumor Immune Dysfunction and Exclusion score. Based on the cMAP database, effective small molecule compounds were predicted. RESULTS: A prognostic model was established based on 8 MHC-I-related genes, and the predictive capacity of the model was accurate. Immune analysis results revealed that patients classified as high-risk had lower levels of immune cell infiltration and impaired immune function. The low-risk group possessed a better response to immune checkpoint blockade therapy. Theobromine and pravastatin were identified as having great potential in improving the prognosis of LUAD. CONCLUSION: Overall, the study revealed MHC-I-related molecular prognostic biomarkers as robust indicators for LUAD prognosis and immune therapy response.

Trauma history and course of therapy in a naturalistic cognitive behavior therapy outpatient sample: An archive data study.

OBJECTIVE: Cognitive Behavior Therapy (CBT) is an effective treatment for anxiety and depression disorders. Nonetheless, nearly 50% of all patients do not respond. Besides other factors, nonresponse may be linked to traumatic life events. This study aims to assess the relationship between trauma history, applied therapy interventions, and therapy outcomes. METHODS: We analyzed data from 340 CBT outpatients diagnosed with a depression or anxiety disorder and possibly a trauma history treated under naturalistic conditions. Based on their therapy files, we collected information on trauma history, diagnoses, applied interventions, and severity of depression and anxiety symptoms at the start and end of therapy. The relationship between trauma, diagnoses, and intervention use and the development of depression and anxiety symptoms was analyzed using Linear Mixed Models. RESULTS: Patients with a trauma history reported higher pre- and posttreatment symptom severity than those without trauma. No differences in applied interventions or decrease in symptom severity were found between patients with and without a trauma history. Specialized interventions were seldom applied. CONCLUSION: Although no differences between patients with and without a trauma history were found in therapy response, patients with a trauma history maintained higher levels of symptom severity. These results indicate a need for more personalized interventions and evidence-based guidelines to personalize CBT for patients with a trauma history and high symptom severity.

A prognostic model based on tumor microenvironment-related lncRNAs predicts therapy response in pancreatic cancer.

Pancreatic cancer is an aggressive malignant tumor with high mortality and a low survival rate. The immune and stromal cells that infiltrate in the tumor microenvironment (TME) significantly impact immunotherapy and drug responses. Therefore, we identify the TME-related lncRNAs to develop a prognostic model for predicting the therapy efficacy in pancreatic cancer patients. Firstly, we identified differentially expressed genes (DEGs) for weighted gene co-expression network analysis (WGCNA) to identify the TME-related module eigengenes. According to the module eigengenes, the TME-related prognostic lncRNAs were screened through the univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox analyses to construct a prognostic risk score (RS) model. Next, the predictive power of this model was evaluated by the time-dependent receiver operating characteristic (ROC) curve and Kaplan-Meier analyses. In addition, functional enrichment, immune cell infiltration, and somatic mutation analyses were performed. Finally, tumor immune dysfunction and exclusion (TIDE) score and drug sensitivity analyses were applied to predict therapy response. In this study, 11 TME-related prognostic lncRNAs were identified to develop the prognostic RS model. According to the RS, the low-risk patients had a better prognosis, lower rates of somatic mutation, lower TIDE scores, and higher sensitivity to gemcitabine and paclitaxel compared to high-risk patients. The findings above suggested that low-risk patients may benefit more from immunotherapy, and high-risk patients may benefit more from chemotherapy. Within this study, we established a prognostic RS model based on 11 TME-related lncRNAs, which may help improve clinical decision-making.

225Ac-PSMA-617 radioligand therapy of de novo metastatic hormone-sensitive prostate carcinoma (mHSPC): preliminary clinical findings.

PURPOSE: 225Ac-PSMA-617 has demonstrated good anti-tumor effect as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) patients. No study has previously assessed treatment outcome and survival following 225Ac-PSMA-617 treatment of de novo metastatic hormone-sensitive prostate carcinoma (mHSPC) patients. Based on the potential side effects that are known and explained to the patients by the oncologist, some of the patients refused the standard treatment and are seeking alternative therapies. Thus, we report our preliminary findings in a retrospective series of 21 mHSPC patients that refused standard treatment options and were treated with 225Ac-PSMA-617. METHODS: We retrospectively reviewed patients with histologically confirmed de novo treatment-naïve bone ± visceral mHSPC that were treated with 225Ac-PSMA-617 radioligand therapy (RLT). Inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, treatment-naive bone ± visceral mHSPC, and patients refusal for ADT ± docetaxel, abiraterone acetate, or enzalutamide. We evaluated the response to treatment using prostate-specific antigen (PSA) response and the progression-free survival (PFS) and overall survival (OS) as well as the toxicities. RESULTS: Twenty-one mHSPC patients were included in this preliminary work. Following treatment, twenty patients (95%) had any decline in PSA and eighteen patients (86%) presented with a PSA decline of ≥ 50% including 4 patients in whom PSA became undetectable. A lower percentage decrease in PSA following treatment was associated with increased mortality and shorter progression-free survival. Overall, administration of 225Ac-PSMA-617 was well tolerated. The commonest toxicity seen was grade I/II dry mouth observed in 94% of patients. CONCLUSIONS: Given these favorable results, randomized prospective multicenter trials assessing the clinical value of 225Ac-PSMA-617 as a therapeutic agent for mHSPC administered either as monotherapy or administered concomitant with ADT are of interest.

Excretion of glucose analogue with SGLT2 affinity predicts response effectiveness to sodium glucose transporter 2 inhibitors in patients with type 2 diabetes mellitus.

PURPOSE: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) regulation, developed as treatment for patients with type 2 diabetes, can be imaged with the glucose analogue alpha-methyl-4-deoxy-4-[18F]fluoro-D-glucopyranoside (Me4FDG), a positron emission tomography (PET) tracer with a high affinity for SGLT1 and SGLT2 proteins. With regard to therapy effectiveness, we aimed to investigate whether clinical parameters or Me4FDG excretion could predict response to SGLT2i in patients with type 2 diabetes. METHODS: In a longitudinal, prospective study, 19 patients with type 2 diabetes underwent Me4FDG combined PET and magnetic resonance imaging (PET/MRI) scans at baseline and 2 weeks after initiation of therapy with SGLT2i, accompanied by the collection of blood and urine samples. Me4FDG-excretion was determined from the Me4FDG uptake in the bladder. Long-term response was determined by HbA1c level after 3 months; a strong response to the therapy was defined as a reduction of HbA1c by at least 10% from baseline. RESULTS: SGLT2i resulted in significantly increased Me4FDG excretion (4.8 vs. 45.0, P < 0.001) and urine glucose (56 vs. 2806 mg/dl, P < 0.001). Baseline urine glucose and baseline Me4FDG excretion correlated both with long-term decline in HbA1c with r = 0.55 (P < 0.05). However, only Me4FDG excretion was a predictor of a strong response to SGLT2i (P = 0.005, OR 1.9). CONCLUSIONS: Using Me4FDG-PET, we demonstrated for the first time renal SGLT2-related excretion before and after short-term SGLT2i treatment. In contrary to other clinical parameters, SGLT2-related excretion before treatment was a robust predictor of long-term HbA1c response in patients with type 2 diabetes, suggesting that therapy effectiveness is only dependent of endogenous SGLT2 processes.

External validation of a clinical prediction model in multiple sclerosis.

BACKGROUND: Timely initiation of disease modifying therapy is crucial for managing multiple sclerosis (MS). OBJECTIVE: We aimed to validate a previously published predictive model of individual treatment response using a non-overlapping cohort from the Middle East. METHODS: We interrogated the MSBase registry for patients who were not included in the initial model development. These patients had relapsing MS or clinically isolated syndrome, a recorded date of disease onset, disability and dates of disease modifying therapy, with sufficient follow-up pre- and post-baseline. Baseline was the visit at which a new disease modifying therapy was initiated, and which served as the start of the predicted period. The original models were used to translate clinical information into three principal components and to predict probability of relapses, disability worsening or improvement, conversion to secondary progressive MS and treatment discontinuation as well as changes in the area under disability-time curve (ΔAUC). Prediction accuracy was assessed using the criteria published previously. RESULTS: The models performed well for predicting the risk of disability worsening and improvement (accuracy: 81%-96%) and performed moderately well for predicting the risk of relapses (accuracy: 73%-91%). The predictions for ΔAUC and risk of treatment discontinuation were suboptimal (accuracy < 44%). Accuracy for predicting the risk of conversion to secondary progressive MS ranged from 50% to 98%. CONCLUSION: The previously published models are generalisable to patients with a broad range of baseline characteristics in different geographic regions.

Expression of MMP-2, MMP-7, MMP-9, and TIMP-1 by Inflamed Mucosa in the Initial Diagnosis of Ulcerative Colitis as a Response Marker for Conventional Medical Treatment.

INTRODUCTION: Experimental and clinical data involve matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs) in the pathogenesis of inflammatory bowel diseases. However, the impact of MMPs/TIMPs expression by inflamed mucosa on medical response therapy has scarcely been investigated. METHODS: The expression of MMP-2, MMP-7, MMP-9, and TIMP-1 was determined by immunohistochemical analysis in inflamed mucosa samples at diagnosis in 82 patients with ulcerative colitis (UC; 22 never-treated with corticosteroids, 28 nonresponders, and 32 responders to corticosteroid therapy) and 15 patients with acute diverticulitis (AD). The global expression (score value) of each factor was analyzed by computer-generated image analysis. RESULTS: UC samples showed higher MMP-2 and MMP-9 expression but lower TIMP-1 expression than the AD samples (p < 0.0001, for all). High MMP-9 and TIMP-1 scores were significantly associated with no need for corticosteroid treatment (p < 0.001 and p = 0.017, respectively); whereas higher score in the MMP-7 expression was significantly associated with nonresponse to corticosteroid therapy (p = 0.037). In addition, in this latter UC subgroup, MMP-7 correlated positively with the younger age of the patients and with the extension of the disease (p = 0.030 and p = 0.010, respectively). CONCLUSION: Our results suggest the relevance of MMPs and TIMPs for predicting treatment response to both 5-aminosalicylates and corticosteroids in UC.