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Variations in the hepatitis C virus (HCV) core gene are related to the progression of liver fibrosis and therapy response. However, the influence of individual amino acid (aa) substitutions at different positions of HCV Core protein on the response to combined pegylated interferon/ribavirin (PEG-IFN/RBV) therapy and disease progression is not yet fully understood. The HCV Core protein can inactivate various genes in the host genome by affecting the methylation of their promoters, leading to liver damage and carcinogenesis. Two genes whose methylation status is affected by the HCV Core protein are the tumor suppressor genes RASSF1A and p16. We have previously shown that the methylation status of these two genes, together with the single nucleotide polymorphism (SNP) rs12979860 near the interleukin-28 beta subunit (IL-28B) gene, influences the response to combined therapy. Herein, we investigated a possible association between detected aa substitutions in HCV Core protein and response to combined therapy, liver disease progression, IL28B genotype, and the methylation status of the RASSF1A and p16 genes. In 29 examined patients we found no association between individual aa substitutions and therapy response. However, we observed that patients with HCV Core aa substitutions at position 75 and CT/TT IL28B genotypes were non-responders (NR) (p=0.023), which was associated with the presence of unmethylated RASSF1A gene. In contrast, even 75% of patients with aa substitutions at position 91 and CC IL28B genotype achieved a sustained virologic response (SVR) (p=0.030), and 70% of them had methylated RASSF1A gene. There was no significant association between the methylation status of the p16 gene and aa variations in the HCV core region. Our results suggest that combined analysis of aa substitutions in HCV Core protein, IL28B genotype, and methylation status of the RASSF1A gene may help predict response to PEG-IFN/RBV therapy in patients with chronic hepatitis C genotype 1b.xx. [ABSTRACT FROM AUTHOR]

To evaluate the kinetics of inflammatory biomarkers in septic patients in order to identify the most reliable predictor of unfavorable outcome.

Background. Monoclonal antibodies are modern drugs for the treatment of chronic lymphocytic leukemia.The objective is a comparative study of the monoclonal antibody rituximab efficacy when added to cyclophosphamide + fludarabine (RFC versus FC regimen) in the treatment of chronic lymphocytic leukemia.Materials and methods. A retrospective study was conducted in Clinical Medical Unit No. 1 of Perm. In total, the response to treatment was analyzed in 22patients (11 patients in each group (FC and RFC therapy)).Results. Adding rituximab to the FC treatment regimen reduced the number of lymphocytes below 4 х 10 9/L after the 1st course, while maintaining the neutrophil level above 1.5 х 109/L, the absence of anemia (hemoglobin level >130 g/L) and thrombocytopenia (platelet count > 100 х 109/L). An additional assessment of creatinine and uric acid levels showed the absence of tumor lysis syndrome during RFC therapy.Conclusion. The addition of rituximab (RFC therapy) to cyclophosphamide + fludarabine (FC therapy) provides a more rapid therapy response without adverse toxic effects such as impact on bone marrow functional activity and tumor lysis syndrome.

Abstract Introduction Immune complexes are of importance in systemic lupus erythematosus pathogenesis, and autoantibodies are believed to participate in immune complex formation. Quantification of autoantibody levels in circulating IC might be of prognostic value. Methods A C1q-binding-eluting technique was applied to purify immune complexes from 55 belimumab-treated systemic lupus erythematosus patients during a 24-month follow-up. Autoantibodies in serum and in solubilized immune complexes were quantified using addressable laser bead immunoassay. We investigated whether levels of autoantibodies in immune complexes associate with disease activity and response to belimumab treatment. Results High baseline anti-double-stranded DNA and anti-histone levels in immune complexes associated with attainment of zero scores in clinical systemic lupus erythematosus disease activity index 2000 during the 24-month follow-up (p = 0.003 and p = 0.048, respectively). Low complement levels associated with high serum anti-double-stranded DNA and anti-ribosomal P levels (p = 0.003 and p = 0.008, respectively) and high anti-double-stranded DNA (p = 0.002) but not anti-ribosomal P levels in immune complexes. Anti-SSA/SSB serum levels were lower in patients attaining lupus low disease activity state at month 6; these associations were stronger for corresponding immune complex levels. Serum levels of most autoantibodies had declined at month 3, whereas autoantibody levels in immune complexes, except for anti-double-stranded DNA, showed a more gradual decline over 1–2 years. Serum anti-double-stranded DNA levels decreased in all patients irrespective of systemic lupus erythematosus disease activity index 2000=0 attainment, whereas immune complex levels decreased only in achievers. Conclusion Immune complex levels of autoantibodies against double-stranded DNA and the SSA/SSB complex show more specific associations with treatment outcome compared with serum levels in belimumab-treated systemic lupus erythematosus patients. Characterization of autoantibody content in circulating immune complexes could prove useful in treatment evaluation in systemic lupus erythematosus and other immune complex-associated diseases.

Abstract Circulating tumor cells (CTCs) are important clinical indicators of metastatic progression and treatment efficacy. However, because of their low number and heterogeneity, reliable patient‐derived CTC models are not readily available. We report here the isolation and characterization of the invasive population of CTCs, iCTCs, from blood of 10 patients with epithelial ovarian cancer (EOC) and one pancreatic cancer patient based on the avidity of tumor cells toward an artificial collagen‐based adhesion matrix (CAM), in comparison with tumor progenitor (TP) cells isolated from tumor cell lines, tumors and ascites from EOC patients. CAM‐avid cells identified to be iCTCs were indistinguishable with TP cells using either functional CAM uptake or surface markers (seprase and CD44). In addition, iCTCs were characterized using peritoneal and spontaneous metastasis models in vivo to evaluate their metastatic propensity and therapeutic response. TP cells and iCTCs had a doubling time of about 34‐42 hours. TP cells were rare (

Abstract Background To improve cure rates for neuroblastoma (NB), it is important and necessary to evaluate therapy response. Our investigation focuses on using plasma cell free DNA (cfDNA) as a biomarker to determine tumor burden and minimal residual disease (MRD) of NB patients during chemotherapy. Methods Total 58 NB patients were recruited from July 2016 to December 2017. Therapy regime and risk classification were based on COG standard and BCH‐NB‐2007 protocol. RECIST study was used to judge response to therapy at the end of fourth cycle of chemotherapy (CC4) and maintenance stage (MS) respectively. Serial quantifications of cfDNA, NSE, and LDH were examined at four stages, including newly diagnosed, second and CC4, and maintenance. Results During early chemotherapy, 65.5% of NB kids responded well. Consistently, cfDNA, NSE, and LDH levels were down‐regulated in NB patients with partial remission (PR) compared to those with stable disease (SD). In both training and predicting sets, the levels of cfDNA were significantly comparable between PR and SD only at CC4 stage. To predict the insufficient response to early chemotherapy, the optimal AUC value of cfDNA was 0.732 and 0.747 in training and predicting sets respectively, with a sensitivity of 63.2% and 80% specificity at 11.59 ng/ml and a sensitivity of 68.4% and 90% specificity at 10.35 ng/ml. At MS, responded NB patients were slightly increased up to 70%. This evaluation was confirmed by further decrease in cfDNA and NSE levels during intermediate chemotherapy in comparison with early stage. Conclusion The dynamic change of cfDNA was considered as a surrogate biomarker to evaluate tumor burden and MRD of NB during early and intermediate therapy periods.

Assessment of treatment response to targeted therapies such as everolimus is difficult, especially in slow-growing tumors such as NETs. In this retrospective study, 17 patients with pancreatic neuroendocrine tumors (pNETs) and hepatic metastases (NELMs) (42 target lesions) who received everolimus were analyzed. Intralesional signal intensities (SI) of non-contrast T1w, T2w and DCE imaging, and apparent diffusion coefficients (ADCmean and ADCmin) of DWI, were measured on baseline and first follow-up MRI after everolimus initiation. Response assessment was categorized according to progression-free survival (PFS), with responders (R) showing a PFS of ≥11 months. ADCmin of NELMs decreased in Rs whereas it increased in non-responders (NR). Percentual changes of ADCmin and ADCmean differed significantly between response groups (p < 0.03). By contrast, ADC of the pNETs tended to increase in Rs, while there was no change in NRs. Tumor-to-liver (T/L) ratio of T1 SI of NELMs increased in Rs and decreased in NRs, and percentual changes differed significantly between response groups (p < 0.02). T1 SI of the pNETs tended to decrease in Rs and increase in Ns. The quotient of pretherapeutic and posttherapeutic ADCmin values (DADCmin) and length of everolimus treatment showed significant association with PFS in univariable Cox analysis. In conclusion, quantitative MRI, especially DWI, seems to allow treatment assessment of pNETs with NELMs under everolimus. Interestingly, the responding NELMs showed decreasing ADC values, and there might be an opposite effect on ADC and T1 SI between NELMs and pNETs.

Immune checkpoint blockade (ICB) shows remarkable clinical effects in patients with metastatic microsatellite-unstable (MSI) cancer. However, markers identifying potential non-responders are missing. We examined the prevalence of Beta-2-microglobulin (B2M) mutations, a common immune evasion mechanism, in stage IV MSI gastrointestinal cancer and its influence on metastatic pattern and patients’ survival under ICB. Twenty-five patients with metastatic, MSI gastrointestinal adenocarcinoma were included. Eighteen patients received ICB with pembrolizumab and one patient with nivolumab/ipilimumab. Sequencing was performed to determine B2M mutation status. B2M mutations and loss of B2M expression were detected in 6 out of 25 stage IV MSI cancers. B2M mutations were strongly associated with exclusively peritoneal/peritoneal and lymph node metastases (p=0.0055). However, no significant differences in therapy response (25% vs. 46.6%, p>0.99) and survival (median PFS: 19.5 vs 33.0 months, p=0.74; median OS 39 months vs. not reached, p>0.99) were observed between B2M-mutant and B2M-wild type tumor patients. Among metastatic MSI GI cancers, B2M-mutant tumors represent a biologically distinct disease with distinct metastatic patterns. To assess ICB response in B2M-mutant MSI cancer patients, future studies need to account for the fact that baseline survival of patients with B2M-mutant MSI cancer may be longer than of patients with B2M-wild type MSI cancer.

Immune checkpoint blockade (ICB) shows remarkable clinical effects in patients with metastatic microsatellite-unstable (MSI) cancer. However, markers identifying potential non-responders are missing. We examined the prevalence of Beta-2-microglobulin (B2M) mutations, a common immune evasion mechanism, in stage IV MSI gastrointestinal cancer and its influence on metastatic pattern and patients' survival under ICB. Twenty-five patients with metastatic, MSI gastrointestinal adenocarcinoma were included. Eighteen patients received ICB with pembrolizumab and one patient with nivolumab/ipilimumab. Sequencing was performed to determine B2M mutation status. B2M mutations and loss of B2M expression were detected in 6 out of 25 stage IV MSI cancers. B2M mutations were strongly associated with exclusively peritoneal/peritoneal and lymph node metastases (p=0.0055). However, no significant differences in therapy response (25% vs. 46.6%, p>0.99) and survival (median PFS: 19.5 vs 33.0 months, p=0.74; median OS 39 months vs. not reached, p>0.99) were observed between B2M -mutant and B2M -wild type tumor patients. Among metastatic MSI GI cancers, B2M -mutant tumors represent a biologically distinct disease with distinct metastatic patterns. To assess ICB response in B2M -mutant MSI cancer patients, future studies need to account for the fact that baseline survival of patients with B2M -mutant MSI cancer may be longer than of patients with B2M -wild type MSI cancer. [ABSTRACT FROM AUTHOR]

AimNanoKnife(®) (Angiodynamics, Inc., NY, USA) or irreversible electroporation (IRE) is a newly available ablation technique to induce the formation of nanoscale pores within the cell membrane in targeted tissues. The purpose of this study was to elucidate morphological alterations following 30 min of IRE ablation in a mouse model of pancreatic cancer.Materials & methodsImmunohistochemistry markers were compared with diffusion-weighted MRI apparent diffusion coefficient measurements before and after IRE ablation.ResultsImmunohistochemistry apoptosis index measurements were significantly higher in IRE-treated tumors than in controls. Rapid tissue alterations after 30 min of IRE ablation procedures (structural and morphological alterations along with significantly elevated apoptosis markers) were consistently observed and well correlated to apparent diffusion coefficient measurements.DiscussionThis imaging assay offers the potential to serve as an in vivo biomarker for noninvasive detection of tumor response following IRE ablation.

Approaches to induce tumor differentiation often result in manageable and therapy‐naïve cellular states in cancer cells. This transformation is achieved by activating pathways that drive tumor cells away from plasticity, a state that commonly correlates with enhanced aggression, metastasis and resistance to therapy. Here, we discuss signaling pathways, epigenetics and non‐coding RNAs as three main regulatory levels with the potential to drive tumor differentiation and hence as potential targets in differentiation therapy approaches. The success of an effective therapeutic regimen in one cancer, however, does not necessarily sustain across cancer types; a phenomenon largely resulting from heterogeneity in the genetic and physiological landscapes of tumor types necessitating an approach designed for each cancer's unique genetic and phenotypic build‐up. [ABSTRACT FROM AUTHOR]

Background: Historical and updated information provided by time-course data collected during an entire treatment period proves to be more useful than information provided by single-point data. Accurate predictions made using time-course data on multiple biomarkers that indicate a patient's response to therapy contribute positively to the decision-making process associated with designing effective treatment programs for various diseases. Therefore, the development of prediction methods incorporating time-course data on multiple markers is necessary. Results: We proposed new methods that may be used for prediction and gene selection via time-course gene expression profiles. Our prediction method consolidated multiple probabilities calculated using gene expression profiles collected over a series of time points to predict therapy response. Using two data sets collected from patients with hepatitis C virus (HCV) infection and multiple sclerosis (MS), we performed numerical experiments that predicted response to therapy and evaluated their accuracies. Our methods were more accurate than conventional methods and successfully selected genes, the functions of which were associated with the pathology of HCV infection and MS. Conclusions: The proposed method accurately predicted response to therapy using data at multiple time points. It showed higher accuracies at early time points compared to those of conventional methods. Furthermore, this method successfully selected genes that were directly associated with diseases. [ABSTRACT FROM AUTHOR]

Assessing cancer response to therapeutic interventions has been realized as an important course to early predict curative efficacy and treatment outcomes due to tumor heterogeneity. Compared to the traditional invasive tissue biopsy method, molecular imaging techniques have fundamentally revolutionized the ability to evaluate cancer response in a spatiotemporal manner. The past few years has witnessed a paradigm shift on the efforts from manufacturing functional molecular imaging probes for seeing a tumor to a vantage stage of interpreting the tumor response during different treatments. This review is to stand by the current development of advanced imaging technologies aiming to predict the treatment response in cancer therapy. Special interest is placed on the systems that are able to provide rapid and noninvasive assessment of pharmacokinetic drug fates (e.g., drug distribution, release, and activation) and tumor microenvironment heterogeneity (e.g., tumor cells, macrophages, dendritic cells (DCs), T cells, and inflammatory cells). The current status, practical significance, and future challenges of the emerging artificial intelligence (AI) technology and machine learning in the applications of medical imaging fields is overviewed. Ultimately, the authors hope that this review is timely to spur research interest in molecular imaging and precision medicine. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors originating from the digestive system. Tertiary lymphoid structures (TLS), non-lymphoid tissues outside of the lymphoid organs, are closely connected to chronic inflammation and tumorigenesis. However, the detailed relationship between TLS and HCC prognosis remained unclear. In this study, we aimed to construct a TLS-related gene signature for predicting the prognosis of HCC patients., Methods: The Cancer Genome Atlas (TCGA) clinical data from 369 HCC tissues and 50 normal liver tissues were utilized to examine the differential expression of TLS-related genes. Based on least absolute shrinkage and selection operator (LASSO) Cox regression analysis, the prognostic model was constructed using the TCGA cohort and validated in the GSE14520 cohort and International Cancer Genome Consortium (ICGC) cohort. The Kaplan-Meier (KM) and receiver operating characteristic (ROC) curves were employed to validate the predictive ability of the prognostic model. Furthermore, Cox regression analysis was applied to identify whether the TLS score could be employed as an independent prognosis factor. A nomogram was developed to predict the survival probability of HCC patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed for TLS-related genes. Genetic mutation analysis, the CIBERSORT algorithm, and single-sample gene set enrichment analysis (ssGSEA) were used to assess the tumor mutation landscape and immune infiltration. Finally, the role of the TLS score in HCC therapy was investigated., Results: Six genes were included in the construction of our prognostic model (CETP, DNASE1L3, PLAC8, SKAP1, C7, and VNN2), and we validated its accuracy. Survival analysis showed that patients in the high-TLS score group had a significantly better overall survival than those in the low-TLS score group. Univariate, multivariate Cox regression analysis and the establishment of a nomogram indicated that the TLS score could independently function as a potential prognostic marker. A significant association between TLS score and immunity was revealed by an analysis of gene alterations and immune cell infiltration. In addition, two subtypes of the TLS score could accurately predict the effectiveness of sorafenib, transcatheter arterial chemoembolization (TACE), and immunotherapy in HCC patients., Conclusion: In this research, we conducted and validated a prognostic model associated with TLS that may be helpful for predicting clinical outcomes and treatment responsiveness for HCC patients., Competing Interests: The authors declare that they have no conflict of interest., (Copyright 2024, Liu et al.)

Liquid biopsy, which generally refers to the analysis of biological components such as circulating nuclear acids and circulating tumor cells in body fluids, particularly in peripheral blood, has shown good capacity to overcome several limitations faced by conventional tissue biopsies. Emerging evidence in recent decades has confirmed the promising role of liquid biopsy in the clinical management of various cancers, including colorectal cancer, which is one of the most prevalent cancers and the second leading cause of cancer-related deaths worldwide. Despite the challenges and poor clinical outcomes, patients with metastatic colorectal cancer can expect potential clinical benefits with liquid biopsy. Therefore, in this review, we focus on the clinical prospects of liquid biopsy in metastatic colorectal cancer, specifically with regard to the recently discovered various biomarkers identified on liquid biopsy. These biomarkers have been shown to be potentially useful in multiple aspects of metastatic colorectal cancer, such as auxiliary diagnosis of metastasis, prognosis prediction, and monitoring of therapy response.

Ethylmalonic encephalopathy (EE) is a rare metabolic disorder caused by dysfunction of ETHE1 protein, a mitochondrial dioxygenase involved in hydrogen sulfide (H2S) detoxification. EE is usually a fatal disease with a severe clinical course mainly associated with developmental delay and regression, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhoea. Treatment includes antioxidants, antibiotics that lower H2S levels and antispastic medications, which are not curative. The mutations causing absence of the ETHE1 protein, as is the case for the described patient, usually entail a severe fatal phenotype. Although there are rare reported cases with mild clinical findings, the mechanism leading to these milder cases is also unclear. Here, we describe an 11-year-old boy with an ETHE1 gene mutation who has no neurocognitive impairment but chronic diarrhoea, which is controlled by oral medical treatment, and progressive spastic paraparesis that responded to Achilles tendon lengthening.

Head and Neck Cancers (HNCs) have highly immunosuppressive properties. Small extracellular vesicles (sEVs), including exosomes, nanosized mediators of intercellular communication in the blood, carry immunosuppressive proteins and effectively inhibit anti-tumor immune responses in HNCs. This study evaluates immunosuppressive markers on sEVs from 40 HNC patients at different disease stages and 3- and 6-month follow-up after surgery and/or chemoradiotherapy. As controls, sEVs from normal donors (NDs) are examined. Immunoregulatory surface markers on sEVs were detected as relative fluorescence intensity (RFI) using on-bead flow cytometry, and their expression levels were monitored in the early and late stages of HNC and during follow-up. In parallel, the sEV-mediated apoptosis of CD8+ Jurkat cells was assessed. Together with TGF-β1 and PD-L1 abundance, total sEV proteins are elevated with disease progression. In contrast, total sEV protein, including TGF-β1, PD-1 and PD-L1, decrease upon therapy response during follow-up. Overall survival analysis implies that high sEV PD-1/PD-L1 content is an unfavorable prognostic marker in HNC. Consistently, the sEV-mediated induction of apoptosis in CD8+ T cells correlates with the disease activity and therapy response. These findings indicate that a combination of immunoregulatory marker profiles should be preferred over a single marker to monitor disease progression and therapy response in HNC.

Breast cancer is one of the leading causes of death in women worldwide. One subtype of breast cancer is the triple-negative, which accounts for 15% of total breast cancer cases and is known for its poor prognosis. The main cause of death is due to metastasis. Circulating tumor cells (CTCs) play a key role in the metastatic process. CTCs arise either by detaching from the primary tumor or from cancer stem cells undergoing an epithelial-to-mesenchymal transition (EMT). This review aims to present up-to-date data concerning the role of CTC numbers in relation to the prognostic and treatment response in metastatic triple-negative breast cancer (mTNBC) patients, and also to discuss the methods used for CTCs’ identification. A search in the MEDLINE database was performed. A total of 234 articles were identified. The results of the 24 eligible studies showed that positive CTC status is associated with shorter overall survival (OS) and progression-free survival (PFS) in mTNBC patients. Furthermore, a decrease in number of CTCs during therapy seems to be a favorable prognostic factor, making CTCs’ detection an important prognostic tool before and during therapy in mTNBC patients. The methods used for CTC detection are still developing and need further improvement.

Targeted therapy for patients with HER2‐positive (HER2+) breast cancer has improved overall survival, but many patients still suffer relapse and death from the disease. Intratumor heterogeneity of both estrogen receptor (ER) and HER2 expression has been proposed to play a key role in treatment failure, but little work has been done to comprehensively study this heterogeneity at the single‐cell level. In this study, we explored the clinical impact of intratumor heterogeneity of ER protein expression, HER2 protein expression, and HER2 gene copy number alterations. Using combined immunofluorescence and in situ hybridization on tissue sections followed by a validated computational approach, we analyzed more than 13 000 single tumor cells across 37 HER2+ breast tumors. The samples were taken both before and after neoadjuvant chemotherapy plus HER2‐targeted treatment, enabling us to study tumor evolution as well. We found that intratumor heterogeneity for HER2 copy number varied substantially between patient samples. Highly heterogeneous tumors were associated with significantly shorter disease‐free survival and fewer long‐term survivors. Patients for which HER2 characteristics did not change during treatment had a significantly worse outcome. This work shows the impact of intratumor heterogeneity in molecular diagnostics for treatment selection in HER2+ breast cancer patients and the power of computational scoring methods to evaluate in situ molecular markers in tissue biopsies.

Abstract Background Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths worldwide and is primarily treated with radiation, surgery, and platinum-based drugs like cisplatin and carboplatin. The major challenge in the treatment of NSCLC patients is intrinsic or acquired resistance to chemotherapy. Molecular markers predicting the outcome of the patients are urgently needed. Methods Here, we employed patient-derived xenografts (PDXs) to detect predictive methylation biomarkers for platin-based therapies. We used MeDIP-Seq to generate genome-wide DNA methylation profiles of 22 PDXs, their parental primary NSCLC, and their corresponding normal tissues and complemented the data with gene expression analyses of the same tissues. Candidate biomarkers were validated with quantitative methylation-specific PCRs (qMSP) in an independent cohort. Results Comprehensive analyses revealed that differential methylation patterns are highly similar, enriched in PDXs and lung tumor-specific when comparing differences in methylation between PDXs versus primary NSCLC. We identified a set of 40 candidate regions with methylation correlated to carboplatin response and corresponding inverse gene expression pattern even before therapy. This analysis led to the identification of a promoter CpG island methylation of LDL receptor-related protein 12 (LRP12) associated with increased resistance to carboplatin. Validation in an independent patient cohort (n = 35) confirmed that LRP12 methylation status is predictive for therapeutic response of NSCLC patients to platin therapy with a sensitivity of 80% and a specificity of 84% (p

EEG studies have shown that adult ADHD patients have less stable brain arousal regulation than age and gender matched controls. Psychostimulants have brain arousal stabilising properties evident in EEG patterns. The aim of this study was to investigate whether the stability of brain arousal regulation has prognostic value in predicting response to methylphenidate therapy in adult ADHD patients. In an open-label, single-arm, multi-centre, confirmatory trial, 121 adult ADHD patients were recruited and 112 qualified for the full analysis set. All participants received an initial dose of 20 mg extended release methylphenidate at baseline. After a titration phase of up to 4 weeks, patients remained on a weight-based target dose of extended release methylphenidate for 4 weeks. Using the Vigilance Algorithm Leipzig (VIGALL 2.1), we assessed brain arousal regulation before the treatment with methylphenidate, based on a 15-min EEG at quiet rest recorded at baseline. Using automatic stage-classification of 1 s segments, we computed the mean EEG-vigilance (indexing arousal level) and an arousal stability score (indexing arousal regulation). The primary endpoint was the association between successful therapy, defined by a 30% reduction in CAARS, and stable/unstable brain arousal. 52 patients (46%) showed an unstable brain arousal regulation of which 23% had therapy success. In the stable group, 35% had therapy success, implying an absolute difference of 12 percentage points (95% CI −5 to 29, p = 0.17) in the direction opposite to the hypothesized one. There were no new findings regarding the tolerability and safety of extended release methylphenidate therapy. [ABSTRACT FROM AUTHOR]

Liquid biopsy, which generally refers to the analysis of biological components such as circulating nuclear acids and circulating tumor cells in body fluids, particularly in peripheral blood, has shown good capacity to overcome several limitations faced by conventional tissue biopsies. Emerging evidence in recent decades has confirmed the promising role of liquid biopsy in the clinical management of various cancers, including colorectal cancer, which is one of the most prevalent cancers and the second leading cause of cancer-related deaths worldwide. Despite the challenges and poor clinical outcomes, patients with metastatic colorectal cancer can expect potential clinical benefits with liquid biopsy. Therefore, in this review, we focus on the clinical prospects of liquid biopsy in metastatic colorectal cancer, specifically with regard to the recently discovered various biomarkers identified on liquid biopsy. These biomarkers have been shown to be potentially useful in multiple aspects of metastatic colorectal cancer, such as auxiliary diagnosis of metastasis, prognosis prediction, and monitoring of therapy response. [ABSTRACT FROM AUTHOR]

Prostate cancer is one of the most common causes of death in males. Even if treatment is often of curative intent in early stages of the disease, up to 50% of patients relapse after primary therapy. Moreover, 10% to 15% of patients present in a primary metastatic stage of disease. In the past years the treatment landscape of metastatic castration-resistant prostate cancer expanded due to the development of second-generation antiandrogens (abiraterone acetate, enzalutamide), chemotherapeutic agents and radium-223. With the availability of several therapeutic lines, we are now confronted with the problem of choosing the most suitable therapy in each state of disease. As often observed in clinical routine, prostate specific antigen is not sufficient for early prediction of a therapy response. Furthermore, biomarkers for prediction of the optimal first-line therapy are badly needed in order to avoid primary resistance. Therefore, the present short review article gives an overview of currently available clinical and preclinical biomarkers for treatment response to metastatic castration-resistant prostate cancer therapeutic agents with the aim of providing support for a personalized decision-making process in everyday use. [ABSTRACT FROM AUTHOR]

Organ development is precisely guided by spatiotemporal cross-talks between a variety of signaling pathways regulating cell differentiation, proliferation, growth arrest and physiological cell death. Aberrant signaling inputs invariably lead to tissue dysfunction and to certain conditions, even malignant transformation. In this review, we focus on the functional interplay between the Hippo signaling pathway and autophagy in normal tissue homeostasis and in malignant tumor progression. Mounting experimental evidence for the regulation of cancer cell malignancy and therapy resistance by the functional cross-talk between Hippo signaling and autophagy highlights this signaling axis as a suitable therapeutic target to combat cancer. [ABSTRACT FROM AUTHOR]

Background: Neutrophil-Lymphocyte Ratio (NLR) is known to be associated with anti-tumor response and tumor development through the process of angiogenesis and immunosuppression conditions. This study aims to analyze the strength of the association between NLR and therapy response of DLBCL-type non-Hodgkin's lymphoma (NHL) patients after undergoing 8 cycles of R-CHOP chemotherapy. Methods: This study used a retrospective cohort design with a total sampling of medical records of DLBCLtype NHL patients who received 8-cycle R-CHOP chemotherapy. Pre-chemotherapy NLR was calculated, and therapy response was assessed by clinical criteria. Results: Eighty-three samples were included, consisting of 57 male and 26 female subjects with an average age of 49 years and 16 patients in stage I, 24 patients in stage II and 43 people in stage III. Therapy response showed 48.2% complete response, 21.7% partial response, 7.2% stable disease and 22.9% progressive disease. Mean NLR in cycle 1 was 3.96 with the mean value of NLR in CR group 3.60, PR 4.287, SD 4.255 and PD 4.298. There was a negative association with moderate strength between NLR and post-chemotherapy therapy response (r=-0.498; p=0.000). Conclusion: There was a moderate negative association between NLR and therapy response of DLBCL-type NLH patients after 8 cycles of R-CHOP chemotherapy. [ABSTRACT FROM AUTHOR]

Ha habido pocos estudios que investiguen el papel de los ligandos de PSMA en la evaluación de la respuesta al tratamiento de los casos de cáncer de próstata (CP) resistente a la castración metastatizado (CRPCm). En el presente estudio nos proponemos evaluar la capacidad del antígeno de membrana específico de la próstata (PSMA) 68Ga-tomografía por emisión de positrones/tomografía computarizada (PET/TC) en la evaluación de la respuesta terapéutica en pacientes bajo terapia de docetaxel para el CP. Se analizaron retrospectivamente las historias clínicas de todos los pacientes de CRPCm tratados con docetaxel y referidos a nuestro departamento para imagenología TEP/TC 68Ga-PSMA I&T. Se incluyó en el estudio 16 a pacientes (edad media 69 años, rango 52-82 años) con CP resistente a la castración que recibían tratamiento paliativo con docetaxel y que se habían sometido a una PET/TC 68Ga-PSMA. Se realizaron imágenes 68Ga-PSMA I&T PET/TC y se midieron los niveles de antígeno específico de próstata (PSA) al inicio del estudio antes de la administración del docetaxel (PET1) y después de al menos 3 ciclos (rango 4-12) de quimioterapia (PET2). Se realizó una comparación basada en el paciente y en la lesión de los hallazgos del PET2 con los hallazgos del PET1. Se encontró que el cambio (disminución) observado en los valores SUVmáx de los ganglios linfáticos y la glándula prostática/lecho prostático después del tratamiento en comparación con el pretratamiento fue estadísticamente significativo (p = 0,033). Tres de 16 pacientes (19%) se clasificaron como enfermedad progresiva (ED), 4/16 (25%) como enfermedad estable (EE), 9/16 (56%) como remisión parcial (RP) radiológicamente. Se observó una tendencia creciente del PSA (TC) en 4 pacientes (25%) y una tendencia decreciente del PSA (DT) en 3 pacientes (18%). Nueve pacientes mostraron una respuesta del PSA del 2% (56%). De los 4 pacientes que mostraron EE, 3 tenían IT, 3 tenían BR. De los 9 pacientes que mostraron RP en los estudios de TEP, 8 pacientes mostraron BR y un paciente mostró DT. Las imágenes con 68Ga-PSMA PET/TC mostraron una gran concordancia con la evaluación de la BR en cuanto a los niveles de PSA, especialmente en los pacientes que mostraron una buena respuesta a la terapia. 68Ga-PSMA PET/TC también fue exitoso en la identificación de la enfermedad progresiva en pacientes que mostraron una paradójica disminución de los niveles de PSA. There have been only few studies investigating the role of PSMA ligands in the therapy response assessment of metastasized castration resistant prostate cancer (mCRPC) cases. In this study we aimed at evaluating the capability of 68Ga- prostate-specific membrane antigen (PSMA) I&T positron emission tomography/computerized tomography (PET/CT) in the assessment of therapeutic response in patients under docetaxel therapy for prostate cancer (PCa). The clinical records of all mCRPC patients treated with docetaxel and referred to our department for 68Ga-PSMA I&T PET/CT imaging were retrospectively analysed. Sixteen patients (mean age 69 years, range 52–82 years) with castration-resistant prostate cancer patients receiving palliative docetaxel therapy and had undergone 68Ga-PSMA I&T PET/CT scan were included in the study. 68Ga-PSMA I&T PET/CT imaging was done and prostate specific antigen (PSA) levels were measured at baseline before administration of docetaxel (PET1) and after at least 3 cycles (range 4–12) of chemotherapy (PET2). Patient-based as well as lesion-based comparison of PET2 findings with PET1 findings were done. The change (decrease) observed in lymph node and prostate gland/prostatic bed SUVmax values after treatment compared to pretreatment was found to be statistically significant (P =.033). 3/16 patients (19%) were classified as progressive disease (PD), 4/16 (25%) as stable disease (SD), 9/16 (56%) as partial remission (PR) radiologically. An increasing PSA trend (IT) was observed in 4 patients (25%) and a decreasing PSA trend (DT) in 3 patients (18%). Nine patients showed a PSA response of ≥ 50% (56%). Of the 4 patients showing SD, 3 had IT, 3 had BR. Of the 9 patients who showed PR on PET studies, 8 patients showed BR and 1 patient showed DT. Imaging with 68Ga-PSMA PET/CT showed great concordance with biochemical response evaluation in terms of PSA levels, especially in patients showing good response to therapy. 68Ga-PSMA PET/CT was also successful in identifying progressive disease in patients showing paradoxical decline in PSA levels. [ABSTRACT FROM AUTHOR]

Background: Despite the outstanding results of direct-acting antiviral therapies (DAAs) of Hepatitis C infection (HCV), non-responders had to be more defined. Aim: assess the outcome of DAAs in linkage with Interferon lambda 3 (IFNL3) in HCV patients. Methods: This case-control-study was conducted on 495 chronic-HCV (genotype-4a), previously treated Egyptians by either DAAs (responders 195, 120 relapsers) or interferon/ribavirin (IFN/RBV) (140 responders, 60 relapsers), and 98 healthy controls. IFNL3 distribution, clinical and laboratory data were assessed. Results: CT was the most predominant genotype in Egyptians (51%). All genotypes were sensitive to DAAs mainly CT genotype (60%), even TT genotype (resistant to IFN/RBV 40%) had 29.2% sensitivity. CT genotype was predominant in sofosbuvir/Daclatasvir responders (67.6%) (OR = 0.66), while non-CT prevailed in relapsers (56.7%). TT genotype may respond to SOF/Ledi better than other regimens (66.7%). In IFN/RBV relapsers; CT genotype was commoner (50%) than others, while CC genotype predominated in responders (54.3%). The c allele was the commonest in responders to IFN/RBV (71.4%), while the T allele was resistant to treatment (65% in relapsers). Addition of RBV to SOF/DCV reported higher resistance with CT genotype (42.2%-50%) and TT genotype (17.8%-27.8%). Conclusion: This study recommended IFNL3 genotyping to be a prerequisite before stratifying treatment for HCV-4a Egyptians. [ABSTRACT FROM AUTHOR]

Background: Bone metastasis is the most frequent complication in prostate cancer patients and associated outcome remains fatal. Radium223 (Rad223), a bone targeting radioisotope improves overall survival in patients (3.6 months vs. placebo). However, clinical response is often followed by relapse and disease progression, and associated mechanisms of efficacy and resistance are poorly understood. Research efforts to overcome this gap require a substantial investment of time and resources. Computational models, integrated with experimental data, can overcome this limitation and drive research in a more effective fashion.Methods: Accordingly, we developed a predictive agent-based model of prostate cancer bone metastasis progression and response to Rad223 as an agile platform to maximize its efficacy. The driving coefficients were calibrated on ad hoc experimental observations retrieved from intravital microscopy and the outcome further validated, in vivo.Results: In this work we offered a detailed description of our data-integrated computational infrastructure, tested its accuracy and robustness, quantified the uncertainty of its driving coefficients, and showed the role of tumor size and distance from bone on Rad223 efficacy. In silico tumor growth, which is strongly driven by its mitotic character as identified by sensitivity analysis, matched in vivo trend with 98.3% confidence. Tumor size determined efficacy of Rad223, with larger lesions insensitive to therapy, while medium- and micro-sized tumors displayed up to 5.02 and 152.28-fold size decrease compared to control-treated tumors, respectively. Eradication events occurred in 65 ± 2% of cases in micro-tumors only. In addition, Rad223 lost any therapeutic effect, also on micro-tumors, for distances bigger than 400 μm from the bone interface.Conclusions: This model has the potential to be further developed to test additional bone targeting agents such as other radiopharmaceuticals or bisphosphonates. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of chronic spontaneous urticaria (CSU) and the mechanism of action of omalizumab in CSU remain unclear. Objective: In this study, we assessed the responsiveness and FcεRI expression of various subsets of leucocytes in patients with CSU treated with omalizumab. Methods: In this prospective cohort study, 30 patients were treated with 6 administrations of 300 mg omalizumab every 4 weeks, followed by a follow‐up period of 12 weeks. FcεRI expression and the percentage of basophils, monocytes, and dendritic cell subsets were analysed before and during treatment, and after follow‐up. In addition, anti‐IgE– and C5a‐induced basophil degranulation was measured. The results were correlated with disease activity and response to omalizumab. Results: In addition to a rapid and significant reduction in FcεRI on basophils, we demonstrated a reduction in FcεRI on plasmacytoid dendritic cells during omalizumab treatment, which persisted until 3 months after discontinuation. FcεRI expression on basophils and its reduction did not correlate with the treatment response. Omalizumab led to an increased percentage of basophils in blood but not of the other FcεRI‐bearing leucocytes. Basophil responsiveness was differentially affected; anti‐IgE–, but not C5a‐induced basophil degranulation increased during the treatment. Apart from clinical non‐responders showing a stronger increase in anti‐IgE–induced basophil degranulation over a period time, no differences were found in omalizumab responders vs non‐responders. Conclusions/Clinical Relevance: FcεRI expression on basophils decreased rapidly, while anti‐IgE–induced degranulation significantly increased due to omalizumab treatment in patients with CSU, persisting at least for 3 months after stopping the treatment. None of the markers were able to predict the effectiveness of treatment. Whether basophils play a role in omalizumab responsiveness in CSU remains unclear. [ABSTRACT FROM AUTHOR]

Estrogen receptor-positive (ER+) breast cancer is the most frequent breast cancer subtype. Agents targeting the ER signaling pathway have been successful in reducing mortality from breast cancer for decades. However, mechanisms of resistance to these treatments arise, especially in the metastatic setting. Recently, it has been recognized that epigenetic dysregulation is a common feature that facilitates the acquisition of cancer hallmarks across cancer types, including ER+ breast cancer. Alterations in epigenetic regulators and transcription factors (TF) coupled with changes to the chromatin landscape have been found to orchestrate breast oncogenesis, metastasis, and the development of a resistant phenotype. Here, we review recent advances in our understanding of how the epigenome dictates breast cancer tumorigenesis and resistance to targeted therapies and discuss novel therapeutic interventions for overcoming resistance. [ABSTRACT FROM AUTHOR]

Abstract Background This study evaluates the consistency of PET evaluation response criteria in solid tumours (PERCIST) and European Organisation for Research and Treatment of Cancer (EORTC) classification across different reconstruction algorithms and whether aligning standardized uptake values (SUVs) to the European Association of Nuclear Medicine acquisition (EANM)/EARL standards provides more consistent response classification. Materials and methods Baseline (PET1) and response assessment (PET2) scans in 61 patients with non-small cell lung cancer were acquired in protocols compliant with the EANM guidelines and were reconstructed with point-spread function (PSF) or PSF + time-of-flight (TOF) reconstruction for optimal tumour detection and with a standardized ordered subset expectation maximization (OSEM) reconstruction known to fulfil EANM harmonizing standards. Patients were recruited in three centres. Following reconstruction, EQ.PET, a proprietary software solution was applied to the PSF ± TOF data (PSF ± TOF.EQ) to harmonize SUVs to the EANM standards. The impact of differing reconstructions on PERCIST and EORTC classification was evaluated using standardized uptake values corrected for lean body mass (SUL). Results Using OSEMPET1/OSEMPET2 (standard scenario), responders displayed a reduction of −57.5% ± 23.4 and −63.9% ± 22.4 for SULmax and SULpeak, respectively, while progressing tumours had an increase of +63.4% ± 26.5 and +60.7% ± 19.6 for SULmax and SULpeak respectively. The use of PSF ± TOF reconstruction impacted the classification of tumour response. For example, taking the OSEMPET1/PSF ± TOFPET2 scenario reduced the apparent reduction in SUL in responding tumours (−39.7% ± 31.3 and −55.5% ± 26.3 for SULmax and SULpeak, respectively) but increased the apparent increase in SUL in progressing tumours (+130.0% ± 50.7 and +91.1% ± 39.6 for SULmax and SULpeak, respectively). Consequently, variation in reconstruction methodology (PSF ± TOFPET1/OSEMPET2 or OSEM PET1/PSF ± TOFPET2) led, respectively, to 11/61 (18.0%) and 10/61 (16.4%) PERCIST classification discordances and to 17/61 (28.9%) and 19/61 (31.1%) EORTC classification discordances. An agreement was better for these scenarios with application of the propriety filter, with kappa values of 1.00 and 0.95 compared to 0.75 and 0.77 for PERCIST and kappa values of 0.93 and 0.95 compared to 0.61 and 0.55 for EORTC, respectively. Conclusion PERCIST classification is less sensitive to reconstruction algorithm-dependent variability than EORTC classification but harmonizing SULs within the EARL program is equally effective with either.

Abstract Background Multiple myeloma (MM) is a type of hematological malignancy with significant heterogeneity in clinical features and prognosis. Cytogenetic abnormalities are the major factors affecting patient outcomes. Studies have shown that immunohistochemistry (IHC)-based detection of cancer-related genes expression could be alternative indicators for the prognosis of MM. Methods Nuclear expression of c-maf protein in the bone marrow plasma cells of 128 multiple myeloma patients were examined by IHC, and its association with the clinicopathological features of MM patients was analyzed as well. Results Among the 128 patients, the positive rate of c-maf protein expression was up to 30.5%, which had no correlation with patient age, M protein type, Durie-Salmon staging system, the International Staging System, abnormal plasma cell ratio in the bone marrow, or the level of peripheral blood hemoglobin, serum calcium or lactate dehydrogenase. However, the c-maf-positive patients had a significantly higher rate of hypoproteinemia (p = 0.026) and higher serum β2-microglobulin levels (>2500 μg/L) (p = 0.007). Patients with negative c-maf expression had higher remission rates upon the treatment of non-bortezomib-based regimens although no effect of c-maf expression on progression-free survival or overall survival was observed. Conclusion Patients with negative c-maf expression had higher remission rates upon the treatment of non-bortezomib-based regimens although no effect of c-maf expression on survival was observed. A further large-scale prospective study is required to verify these findings.

Objectives: The aim of this study is to compare degree of left ventricular dyssynchrony as assessed with phase analysis from Gated myocardial perfusion SPECT (GMPS) to that assessed with Echocardiographic Tissue Doppler Imaging (TDI) in patients with left ventricular EF 120 ms. Patients & methodology: 30 patients were included, all scheduled for CRT. TDI was measured as standard deviation of time to peak systolic velocity in 6 basal segments. Gated SPECT TC-99m sestamibi acquisition was performed, software phase analysis parameters is histogram bandwidth which include 95% of the element of the phase distribution. Study population was divided into two groups: responders and non-responders according to increase of at least 15% of LVEF after 3 months. Results: ROC analysis was done to reveal that Phase analysis parameter acted in better way to predict CRT response with histogram bandwidth 55.5° Area Under Curve (AUC) 68.9% sensitivity 87% specificity 42.9% positive predictive value (PPV) 83.3% negative predictive value (NPV) 50% compared to TDI sensitivity 52.25%, specificity 71.4% PPV 85.7% NPV 31.3% When applying histogram bandwidth cutoff 55.5° dyssynchrony was illustrated in 20 (87%) patients in comparison to 14 (60%) patients with Echo TDI, there was significant difference in sensitivity of histogram bandwidth compared to TDI with p value 0.043. Conclusion: Histogram bandwidth of GMPS Tc99m sestamibi may be more predictive of significant response to CRT as compared to TDI.

Human cancers exhibit phenotypic diversity that medical imaging can precisely and non-invasively detect. Multiple factors underlying innovations and progresses in the medical imaging field exert diagnostic and therapeutic impacts. The emerging field of radiomics has shown unprecedented ability to use imaging information in guiding clinical decisions. To achieve clinical assessment that exploits radiomic knowledge sources, integration between diverse data types is required. A current gap is the accuracy with which radiomics aligns with clinical endpoints. We propose a novel methodological approach that synergizes data volumes (images), tissue-contextualized information breadth, and network-driven resolution depth. Following the Precision Medicine paradigm, disease monitoring and prognostic assessment are tackled at the individual level by examining medical images acquired from two patients affected by intracranial ependymoma (with and without relapse). The challenge of spatially characterizing intratumor heterogeneity is tackled by a network approach that presents two main advantages: (a) Increased detection in the image domain power from high spatial resolution, (b) Superior accuracy in generating hypotheses underlying clinical decisions.

Objective: Antigen-presenting dendritic cells (DCs) and monocytes play an essential role in rheumatoid arthritis (RA) pathogenesis, however, their tolerogenic potential remains unclear. Herein, the tolerogenic profiles of DCs are characterized in treatment-naïve RA patients to determine their role to inflammatory arthritis management., Methods: Thirty-six treatment-naïve RA patients were enrolled, of which 62% were non-responders to methotrexate (MTX) monotherapy based on disease activity score (DAS) after 6-months of therapy. DC and monocyte subset frequencies, activation (CD40, CD86, CD209 expression), and tolerogenic profile (intracellular indoleamine-2,3-dioxygenase [IDO1] and cytotoxic T lymphocyte antigen 4 [CTLA-4] expression) were examined in the baseline peripheral blood by multicolor flow-cytometry. Soluble CTLA-4 (sCTLA-4) levels in plasma were measured., Results: DC subsets were decreased in RA compared to healthy controls (HC), and the frequency of conventional DCs (cDC) inversely correlated with inflammatory markers and improvement in disease activity. CD141 + cDC1s were the major IDO1-expressing cells. IDO1 + cDC1s were reduced in RA patients compared to HC. The baseline frequency of IDO1 + cDC1s inversely correlated with improvement in disease activity. CTLA-4 expression in CD1c + cDC2s and monocytes was lower in RA patients compared to HC. Moreover, MTX-responders had a significantly lower frequency of IDO1 + cDC1 cells and higher level of sCTLA-4 in the plasma compared to MTX non-responders. There was a strong predictive association of low IDO1 + cDC1 cells, low sCTLA-4 and non-response to MTX., Conclusions: Our findings reveal altered DC and monocytes immunophenotypes that are associated with RA pathology and treatment response. The frequencies of tolerogenic IDO1 + cDC1s and the low level of sCTLA-4 are strongly associated with MTX non-responsiveness and therapeutic outcome. These results suggest that investigation of the association IDO1 + cDC1 and sCTLA-4 with response to treatment may be more generalizable to other autoimmune diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Malik, Slauenwhite, McAlpine, Hanly, Marshall and Issekutz.)

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 ( t 0 ), after ECT ( t 1 ) and 2 years later ( t 2 ). 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 ( p FWE < 0.001) resulting from significant volume increases from t 0 to t 1 and decreases from t 1 to t 2 in the ECT group, e.g., in limbic areas. There are no effects of time in both control groups. Volume increases from t 0 to t 1 correlate with immediate and delayed symptom increase, while volume decreases from t 1 to t 2 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.

Purpose: To evaluate if a machine learning prediction model based on clinical and easily assessable imaging features derived from baseline breast [ 18 F]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 [ 18 F]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., (© 2023. The Author(s).)

Objective: The BRAF V600E mutation is the universal genetic mutation in papillary thyroid microcarcinoma (PTMC). The present study is to estimate the role of the BRAF V600E mutation in the clinical outcome of PTMC with intermediate to high recurrence risk after radioactive iodine (RAI) therapy, which is considered to be an indolent tumor., Methods: We conducted a single-center retrospective study. Between May 2016 and March 2019, PTMC patients with known BRAF V600E status who received RAI therapy were reviewed at the Second Hospital of Shandong University. Treatment and follow-up were defined according to criteria used in the 2015 ATA guidelines. The association between the BRAF V600E mutation and clinicopathological characteristics, response to RAI therapy, and recurrence after a period of follow-up were analyzed. Propensity score matching (PSM) and logistic regression were used to control confounding variables., Results: Of the 322 patients with intermediate to high recurrence risk in PTMC, the mean age of the patients were 43.7 ± 12.2 years, and 72.1% were women. BRAF V600E mutation was found in 64.9% (209/322). After PSM, 112 pairs of patients were matched, and except for multifocality (P = 0.001), extrathyroidal invasion (P = 0.003) and tumor size (P = 0.03), there was no significant difference in all baseline characteristics between the two groups. An excellent response (ER) to RAI therapy was observed in 273 patients (84.7%). At the end of the study, 17(5.2%) and 6(1.8%) patients showed structural incomplete response (SIR) and biochemical incomplete response (BIR) status. The proportion of patients who achieved ER status in the BRAF V600E mutation positive and negative groups was 86.6% and 81.4%, respectively. Kaplan-Meier analyses showed that the BRAF V600E mutation was not related to lower ER reached time. The median follow-up was 51 months., Conclusions: We found the BRAF V600E mutation was associated with multifocality, extrathyroidal invasion, and tumor size in papillary thyroid microcarcinoma. However, the BRAF V600E mutation had no significant association with clinical outcomes in patients with intermediate to high recurrence risk after RAI therapy. Furthermore, the extra-thyroid uptake results and distant metastasis had been proven to be independent factor predicting the clinical response., Registration Number: ChiCTR2200062911., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The past 25 years have seen significant growth in the role of positron emission tomography/computed tomography (PET/CT) in musculoskeletal oncology. Substantiative advances in technical capability and image quality have been paralleled by increasingly widespread clinical adoption and implementation. It is now recognized that PET/CT is useful in diagnosis, staging, prognostication, response assessment, and surveillance of bone and soft tissue sarcomas, often providing critical information in addition to conventional imaging assessment. As individualized, precision medicine continues to evolve for patients with sarcoma, PET/CT is uniquely positioned to offer additional insight into the biology and management of these tumors., Competing Interests: Disclosure The authors have no relevant financial disclosures or conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Virtual reality (VR) therapy is increasingly used and has shown encouraging effects. Yet, it is unknown which patients respond best to VR-based balance therapy as part of neurorehabilitation., Methods: Data from 30 persons with stroke and 51 persons with multiple sclerosis who performed three to four weeks of VR-based balance therapy during in-patient rehabilitation were analysed. Participants were divided into responders and nonresponders based on achievement of the minimal clinically important difference in functional balance post intervention. Measures of balance, trunk function, mobility, gait, motivation, and exergame parameters were compared between groups., Results: Post intervention, all clinical measurements significantly improved ( p < 0.05; effect size: 0.45-0.59). Participants that achieved the minimal clinically important difference in functional balance (n = 49; 60%) had significantly lower preintervention functional and dynamic balance (median(IQR): 39(27-46) versus 45(37-50); p = 0.02 and 11(6-15) versus 16(11-18); p = 0.03). They spent less time on higher difficulty exercises (11(8-17) versus 14.5(10-12); p = 0.03) and demonstrated increased motivation over time compared with nonresponders (1(-1-5) versus -2(-7-3); p = 0.03)., Conclusion: Lower baseline balance ability, spending more time on adequately challenging exercises, and increased motivation potentially influence response to therapy. These factors can support the personalisation of VR-based balance therapy.

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., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

The immune-modulating protein CD52 attenuates lymphocyte function and is associated with autoimmune disorders, for example, multiple sclerosis (MS). CD52 represents a therapeutic target in MS and chronic lymphocytic leukemia (CLL). Its expression has prognostic and predictive value in CLL and is prognostic in breast cancer. Its significance in melanoma is unclear. We analyzed CD52 mRNA expression data from tumor bulk tissues of N = 445 untreated melanoma patients from The Cancer Genome Atlas (TCGA) Research Network and of N = 121 melanoma patients undergoing anti-PD-1 immune checkpoint blockade (ICB) with regard to outcome (overall survival [OS], disease control [DC], and progression-free survival [PFS]), single-cell RNA-Seq data of N = 4645 cells from N = 19 melanoma tissues, and N = 15,457 cells from normal skin provided by N = 5 donors. Higher CD52 mRNA expression was associated with favorable OS (hazard ratio (HR) = 0.820, [95% CI 0.734-0.916], p < .001) in non-ICB-treated melanoma and with PFS (HR = 0.875, [95% CI 0.775-0.989], p = .033) and DC (p = .005) in ICB-treated melanoma. CD52 expression correlated significantly with distinct immune cell subsets and correlated negatively with immune checkpoint expression in T cells. Moreover, our results suggest CD52 expression by a certain type of tissue-resident macrophages. CD52 mRNA was expressed in a small subgroup (8%) of immune checkpoint coexpressing melanoma cells. CD52 expression is associated with features of ICB response in melanoma. Concomitant ICB and anti-CD52 treatment requires critical review., (© 2023 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)