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Modern clinical cancer research increasingly relies on the visual communication of complex response and treatment sequencing data. Graphical representations used in oncology currently fail to provide adequate information on any prior treatment(s) responses, focussing on current treatment effects in isolation. We have developed a new graphical illustration, the ‘iceberg plot,’ to allow improved comparison of prior treatment response with current therapy. To demonstrate the potential clinical utility of this new graphical representation, we have performed an independent reanalysis of a clinical study trialling sequence-directed therapy. In this example, prior therapy responses are contrasted with current treatment response, with further validation using the ‘Von Hoff’ criteria to assess for exceptional response. This example demonstrates the versatility and clinical utility of the ‘iceberg plot,’ showing what was previously hidden and provides improved visualisation of prior and current treatment responses together.

Colorectal cancer (CRC) is one of the most common cancers both in the world and in the Czech Republic. Predispositions for the development of CRC include genetic and epigenetic changes, as well as environmental and microenvironmental factors. These tumours often respond very well to treatment, especially in the early stages, but some patients experience early recurrence of the disease. As the incidence of CRC has not declined in recent years, this is a current problem requiring a new approach aimed at improving diagnosis, survival and quality of life of patients with CRC. For this reason, liquid biopsy, which is a minimally invasive approach to the patient and allows real-time monitoring of changes in the body, is increasingly gaining prominence. One of the biomarkers that can be detected by liquid biopsy are small non-coding RNA molecules - microRNAs (miRNAs). In this thesis, the gene expression of two miRNAs, namely miR-122-5p and miR-142-5p, was analyzed in plasma and tissues of CRC patients and in plasma of a control group of healthy blood donors. In our study, we identified significant changes in the expression levels of both miRNAs in CRC patients compared to healthy cancer- free subjects. Specifically, higher expression levels of both miRNAs were observed in CRC patients compared to the...

Acute myeloblastic leukemia (AML) comprises a heterogeneous group of hematological malignancies that are characterized by the increased proliferation and accumulation of immature myeloid cells. The initiation and progression of malignant neoplasms arises from genomic instability. DNA damage and defects associated with its repair are the main drivers of this instability. Furthermore, altered DNA damage repair (DDR) pathways can also modulate chemotherapy response. Thus, understanding the mechanisms of DNA damage and repair underlying AML is essential to comprehend its progression and response to therapy. As such, the aim of this work was to characterize DNA damage and DNA damage repair in AML through the use of in vitro models, and to evaluate its impact on therapy response. To achieve this goal, seven AML cell lines (LAMA-84, K562, HEL, KG-1, HL-60, THP-1, and NB-4), and a normal lymphocyte cell line (IMC) were used. Chromosome damage levels were evaluated by the cytokinesis-block micronucleus (CBMN) assay. Double-strand breaks (DSBs) were quantified through the fast halo assay and by flow cytometry-based quantification of γH2AX. 8-hydroxy-2' -deoxyguanosine (8-OHdG) levels present in cell culture medium were quantified through the use of a competitive ELISA kit. To evaluate DNA repair kinetics, levels of chromosome damage (CBMN assay) and of DSBs (cytometry-based γH2AX quantification) were assessed immediately after exposure to hydrogen peroxide (H₂O₂), 1h or 4h, and 24h after exposure. Drug sensitivity data of the different neoplastic cell lines was retrieved from the Genomics of Drug Sensitivity in Cancer platform. Results showed that LAMA-84 cells have the highest percentage of chromosome damage (8.84%) while IMC cells have the lowest (2.52%). Additionally, LAMA-84 cells showed a higher frequency of nucleoplasmic bridges, KG-1 and IMC cells showed a higher percentage of micronucleus, and the remaining cell lines presented a higher frequency of nuclear buds. Levels of γH2AX indicated that HEL cells had the highest prevalence of DSBs (MFI = 66), while IMC cells had the lowest (MFI = 19). NB-4 cells had the highest 8-OHdG levels (8.3 ng/mL) and K562 cells the lowest (2.4 ng/mL). After exposure to H₂O₂, cells were able to revert the induced chromosome damage after 24h, with exception of KG-1 and THP-1 cells. Following exposure to this genotoxic agent, cells were also able to repair the induced DSBs, with exception of HEL cells. The combined analysis of the retrieved drug sensitivity data and the previously determined damage parameters showed that baseline DNA damage levels represent accurate biomarkers that distinguish resistance from sensitivity to conventional therapeutic agents and DDR inhibitors. Taken together these results suggest that the evaluation of background DNA damage in AML may allow to predict cell sensitivity to several drugs and could thus represent a possible treatment response biomarker. A leucemia mieloblástica aguda (LMA) compreende um grupo heterogéneo de neoplasias hematológicas que se caracterizam pela rápida proliferação e acumulação de células imaturas da linhagem mieloide. A iniciação e progressão de neoplasias malignas está associada à instabilidade genómica, que por sua vez é impulsionada por lesões no DNA e alterações nos mecanismos de reparação do DNA (DDR). Estas alterações condicionam também a resposta ao tratamento. Assim, entender os mecanismos de lesão e reparação do DNA subjacentes à LMA é essencial para compreender a sua progressão e resposta à terapêutica. Neste contexto, este trabalho pretendeu caracterizar a lesão e reparação do DNA em modelos in vitro de LMA e avaliar o seu impacto na resposta à terapêutica. Para isso, foram utilizadas sete linhas celulares de LMA (HL-60, HEL, KG-1, K562, LAMA-84, THP-1 e NB-4) e uma linha de linfócitos normais (IMC). Os níveis de lesão cromossómica foram avaliados através do ensaio de micronúcleo com bloqueio em citocinese (CBMN). A quantificação das quebras de cadeia dupla (DSBs) foi avaliada pelo ensaio do halo e por citometria de fluxo através da marcação da γH2AX. Os níveis de 8-hidroxi-2'-desoxiguanosina (8-OHdG) presentes no meio de cultura foram quantificados com um kit de ELISA competitivo. Para avaliar a cinética de reparação do DNA, os níveis de lesão cromossómica (ensaio CBMN) e de DSBs (quantificação de γH2AX por citometria) foram determinados imediatamente após a exposição ao peróxido de hidrogénio (H₂O₂), 1h ou 4h e 24h após a exposição. A sensibilidade das diferentes linhas neoplásicas a agentes terapêuticos foi obtida através da plataforma Genomics of Drug Sensitivity in Cancer. Os resultados mostraram que a linha LAMA-84 apresentou a maior percentagem de lesão cromossómica (8.84%) enquanto a linha IMC apresentou a menor (2.52%). A linha LAMA-84 mostrou maior frequência de pontes nucleoplasmáticas, as KG-1 e IMC apresentaram maior percentagem de micronúcleos e as restantes apresentaram maior frequência de protrusões nucleares. Os níveis de γH2AX indicaram que a linha HEL tem a maior prevalência de DSBs (MIF = 66) e a IMC tem a menor (MIF = 19). A linha NB-4 apresentou níveis mais elevados de 8-OHdG (8.27 ng/mL) e a K562 os mais baixos (2.42 ng/mL). Após a exposição ao H₂O₂, as células foram capazes de reverter a lesão cromossómica induzida após 24h, com exceção das KG-1 e THP-1. Posteriormente à exposição a este agente genotóxico, as linhas foram também capazes de reparar as DSBs induzidas após 24h, com exceção das HEL. A análise combinada dos níveis de lesão previamente determinados e dos dados da sensibilidade a fármacos mostraram que os níveis basais de lesão do DNA representam biomarcadores precisos que permitem fazer a distinção entre sensibilidade ou resistência a agentes terapêuticos convencionais e inibidores da DDR. Em suma, estes resultados sugerem que a avaliação da lesão do DNA na LMA poderá predizer a sensibilidade das células a vários fármacos e, pode por isso representar um possível biomarcador de resposta ao tratamento. Mestrado em Biomedicina Molecular

Target therapy with BRAF/MEK inhibitors in metastatic melanoma is characterised by a high response rate; however, acquired resistance to treatment develops in many cases. We aimed to investigate if baseline total metabolic tumour volume (TMTV) and therapy-response assessment by [18F]FDG PET/CT have a prognostic role on progression-free survival (PFS) and overall survival (OS) in patients with metastatic melanoma receiving BRAF ± MEK inhibitors. Fifty-seven patients who performed an [18F]FDG PET/CT at baseline and on treatment were retrospectively evaluated. A Cox proportional-hazard model was used to examine associations between OS and PFS with baseline clinical/PET parameters as well as for PET response. According to EORTC criteria, 34 patients were classified as responders (partial/complete metabolic response [PMR/CMR]) and 23 as non-responders (progressive/stable metabolic disease [PMD/SMD]). Baseline characteristics associated with a shorter PFS were more than two metastatic organ sites and TMTV > 56 cm3; the latter was the only independent feature at multivariate analysis. Patients achieving a CMR were associated with a prolonged PFS compared with those with PMR (median PFS 42.9 vs 8.8 months; p = 0.009). Disease progression occurred in new-onset disease sites in 87.5% of CMR, 7.1% of PMR and 34.8% of PMD/SMD (p < 0.001). High baseline TMTV and lack of treatment response were independent prognostic factors for OS, stratifying patients in three different prognostic classes (median OS 6.7, 18.3 and 102.2 months, respectively). Baseline TMTV and metabolic response may be useful prognostic indicators for PFS and OS in patients with advanced melanoma treated with BRAF/MEK inhibitors. • In a retrospective cohort of 57 metastatic melanoma patients treated with BRAF/MEK inhibitors, a TMTV > 56 cm 3 at baseline [ 18 F]FDG PET/CT was significantly correlated with a shorter PFS and OS. • The combined use of baseline TMTV along with PET response during treatment allowed for the identification of three groups of patients with very different median OS.

Aim: The goal of this meta-analysis was to assess the apparent diffusion coefficient (ADC) as a pre- and posttreatment (ADC value changes [ΔADC]) predictive imaging biomarker of response to transcatheter arterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). Methods: Scopus database, Embase database, and MEDLINE library were scanned for connections between pre- and posttreatment ADC values of HCC and response to TACE. Six studies qualified for inclusion. The following parameters were collected: authors, publication year, study design, number of patients, drugs for TACE, mean ADC value, standard deviation, measure method, b values, and Tesla strength. The Quality Assessment of Diagnostic Studies 2 instrument was employed to check the methodological quality of each study. The meta-analysis was performed by utilizing RevMan 5.3 software. DerSimonian and Laird random-effects models with inverse-variance were used to regard heterogeneity. The mean ADC values and 95% confidence intervals were computed. Results: Six studies (n = 271 patients with 293 HCC nodules) were included. The pretreatment mean ADC in the responder group was 1.20 × 10−3 mm2/s (0.98, 1.42) and 1.14 × 10−3 mm2/s (0.89, 1.39) in the nonresponder group. The analysis of post-TACE ΔADC revealed a threshold of ≥20% to identify treatment responders. No suitable pretreatment ADC threshold to predict therapy response or discriminate between responders and nonresponders before therapy could be discovered. Conclusion: ΔADC can facilitate early objective response evaluation through post-therapeutic ADC alterations ≥20%. Pretreatment ADC cannot predict response to TACE.

Background: Polymerase chain reaction (PCR) is currently considered the method of choice for diagnosing ocular tuberculosis. However, the sensitivity and specificity of PCR using ocular samples remain uncertain. Our meta-analysis aimed to review the diagnostic accuracy of PCR testing in confirming ocular tuberculosis, with responses to antitubercular therapy (ATT) as reference indices. Methods: A systematic literature search of the PubMed, EBSCOHost, Scopus, and Google Scholar databases was performed using the standardized PRISMA guideline. Observational studies reporting both PCR MTb positivity and ATT response were included. Meta-analysis was performed to estimate the pooled positivity rate, sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratios (DOR), and summary receiver operating curves (SROC). Results: The pooled positivity rate for PCR MTb was 0.55 (95% CI 0.44–0.67). The overall sensitivity and specificity were 88% (95% CI 83–92) and 71% (95% CI 60–80), respectively. The pooled DOR was 12.15 (95% CI 5.55–26.62). The area under the SROC was 0.83. Conclusions: The diagnostic accuracy of PCR Mtb is not sufficient for use as a benchmark for ocular TB diagnosis routinely based on ATT response. A negative result may help avoid prescribing unnecessary ATT in dilemmatic cases.

Introduction: Squamous cell carcinoma (SCC) is the most common skin cancer with a high rate of death. Different lymphocyte populations play an important role in modulating the immune response in the tumor microenvironment. The increase in the proportion of cluster of differentiation (CD)4+ CD25+ regulatory T-cell (Treg) lymphocytes is associated, in different studies, with the increase of the cell multiplication rate. Aim: To analyze the Treg lymphocyte subpopulations and to correlate the results with the presence of the CD8+ cytotoxic T-cell (Tc) lymphocyte population. Materials and Methods: Sixty primary skin SCC specimens were incubated with anti-CD8 (clone SP57) rabbit monoclonal antibody and anti-CD25 (clone 4C9) mouse monoclonal antibody. Results: The ratio of the intratumoral/peritumoral CD4+ CD25+ forkhead box protein p3 (Foxp3) lymphocytes was 0.46, emphasizing that at tumor margins, where tumor aggressiveness is higher, these lymphocytes subpopulations facilitate tumor progression. The comparative analysis of the tumor microenvironment profile revealed that in the case of intratumoral immune response, the number of Tc-type lymphocytes (CD8+) was 3.34 times higher compared to Treg lymphocytes (p

Organotypic three-dimensional (3D) cell cultures more accurately mimic the characteristics of solid tumors in vivo in comparison with traditional two-dimensional (2D) monolayer cell models. Currently, studies on the regulation of long non-coding RNAs (lncRNAs) have not been explored in breast cancer cells cultured in 3D microenvironments. In the present research, we studied the expression and potential roles of lncRNAs in estrogen receptor-positive luminal B subtype BT-474 breast cancer cells grown over extracellular matrix proteins-enriched 3D cultures. Global expression profiling using DNA microarrays identifies 290 upregulated and 183 downregulated lncRNAs in 3D cultures relative to 2D condition. Using a co-expression analysis approach of lncRNAs and mRNAs pairs expressed in the same experimental conditions, we identify hundreds of regulatory axes modulating genes involved in cancer hallmarks, such as responses to estrogens, cell proliferation, hypoxia, apical junctions, and resistance to endocrine therapy. In addition, we identified 102 lncRNAs/mRNA correlations in 3D cultures, which were similar to those reported in TCGA datasets obtained from luminal B breast cancer patients. Interestingly, we also found a set of mRNAs transcripts co-expressed with LINC00847 and CTD-2566J3.1 lncRNAs, which were predictors of pathologic complete response and overall survival. Finally, both LINC00847 and CTD -2566J3.1 were co-expressed with essential genes for cancer genetic dependencies, such as FOXA1 y GINS2. Our experimental and predictive findings show that co-expressed lncRNAs/mRNAs pairs exhibit a high degree of similarity with those found in luminal B breast cancer patients, suggesting that they could be adequate pre-clinical tools to identify not only biomarkers related to endocrine therapy response and PCR, but to understand the biological behavior of cancer cells in 3D microenvironments.

Background: TP53 is frequently mutated in solid tumors, but its basic mutation mapping is mixed, particularly in aggressive-stage lung cancer. Experimental Design: We curated a total of 139 advanced non-small cell lung cancer (NSCLC) patients who harbored wild-type TP53 (TP53wt) or mutated TP53 (TP53mut) based on next-generation sequencing (NGS) to analyze multiple-dimensional data types, including tumor mutation burden (TMB), programmed death receptor ligand 1 (PD-L1) expression, co-mutant alterations, hotspot mutations distribution, and therapy response. Results: TP53 was evident in 125 mutations and significantly associated with male sex, adenocarcinoma differentiation, smoking history, PD-L1 tumor proportion score, and TMB level. The most frequent mutations were distributed on exon 8, but there were no distinct hotspot mutations. After outlining the co-mutation genes, it is interesting to note that DNA damage repair (DDR) genes were frequent alterations in the mutated TP53 cohort. Even though there was no significant difference between the TP53wt and TP53mut cohorts on therapy response, patients with nucleotide variation in G>T achieved a relatively higher durable clinical benefit (DCB) rate. Conclusions: This real-world retrospective study suggests that molecular stratification on the basis of TP53 mutations should be deeply explored for NSCLC to optimize and modify clinical therapy choices.

Funder: Universitätsklinikum Schleswig-Holstein - Campus Kiel (6509), BACKGROUND AND AIMS: Treatment with tumor necrosis factor α (TNFα) antagonists in IBD patients suffers from primary non-response rates of up to 40%. Biomarkers for early prediction of therapy success are missing. We investigated the dynamics of gene expression and DNA methylation in blood samples of IBD patients treated with the TNF antagonist infliximab and analyzed the predictive potential regarding therapy outcome. METHODS: We performed a longitudinal, blood-based multi-omics study in two prospective IBD patient cohorts receiving first-time infliximab therapy (discovery: 14 patients, replication: 23 patients). Samples were collected at up to 7 time points (from baseline to 14 weeks after therapy induction). RNA-sequencing and genome-wide DNA methylation data were analyzed and correlated with clinical remission at week 14 as a primary endpoint. RESULTS: We found no consistent ex ante predictive signature across the two cohorts. Longitudinally upregulated transcripts in the non-remitter group comprised TH2- and eosinophil-related genes including ALOX15, FCER1A, and OLIG2. Network construction identified transcript modules that were coherently expressed at baseline and in non-remitting patients but were disrupted at early time points in remitting patients. These modules reflected processes such as interferon signaling, erythropoiesis, and platelet aggregation. DNA methylation analysis identified remission-specific temporal changes, which partially overlapped with transcriptomic signals. Machine learning approaches identified features from differentially expressed genes cis-linked to DNA methylation changes at week 2 as a robust predictor of therapy outcome at week 14, which was validated in a publicly available dataset of 20 infliximab-treated CD patients. CONCLUSIONS: Integrative multi-omics analysis reveals early shifts of gene expression and DNA methylation as predictors for efficient response to anti-TNF treatment. Lack of such signatures might be used to identify patients with IBD unlikely to benefit from TNF antagonists at an early time point.

Programmed cell death ligend-1 (PD-L1) expression by immunohistochemistry (IHC) assays is a predictive marker of anti-PD-1/PD-L1 therapy response. With the popularity of anti-PD-1/PD-L1 inhibitor drugs, quantitative assessment of PD-L1 expression becomes a new labor for pathologists. Manually counting the PD-L1 positive stained tumor cells is an obviously subjective and time-consuming process. In this paper, we developed a new computer aided Automated Tumor Proportion Scoring System (ATPSS) to determine the comparability of image analysis with pathologist scores. A three-stage process was performed using both image processing and deep learning techniques to mimic the actual diagnostic flow of the pathologists. We conducted a multi-reader multi-case study to evaluate the agreement between pathologists and ATPSS. Fifty-one surgically resected lung squamous cell carcinoma were prepared and stained using the Dako PD-L1 (22C3) assay, and six pathologists with different experience levels were involved in this study. The TPS predicted by the proposed model had high and statistically significant correlation with sub-specialty pathologists’ scores with Mean Absolute Error (MAE) of 8.65 (95% confidence interval (CI): 6.42–10.90) and Pearson Correlation Coefficient (PCC) of 0.9436 ($$p < 0.001$$ p < 0.001 ), and the performance on PD-L1 positive cases achieved by our method surpassed that of non-subspecialty and trainee pathologists. Those experimental results indicate that the proposed automated system can be a powerful tool to improve the PD-L1 TPS assessment of pathologists.

Objective: To define the relationship between cystoscopic findings, including novel findings such as the hypervascularization, of bladder pain syndrome/interstitial cystitis (BPS/IC) and the response to intravesical therapy. Material and methods: We retrospectively evaluated cystoscopy findings in patients who had a preliminary diagnosis of BPS/IC. All patients received early intravesical combined therapy (ICT), ie, within 2 hours after hydrodistention. Additionally, ICT was continued according to our protocol. Cystoscopic findings were classified as glomerulations, hypervascularization, and Hunner’s lesion (HL). The therapy responses were evaluated at 1st, 3rd, 6th, and 12th months using the visual analog scale (VAS), O’Leary/Sant interstitial cystitis symptom index (ICSI), and interstitial cystitis problem index (ICPI) scores. Results: Out of 61 patients, HL was diagnosed during cystoscopy in six (9.8%) patients, glomerulations in 35 (57.4%) patients, and hypervascularization in 15 (24.6%) patients. No pathological findings were defined in five (8.2%) patients. In the glomerulation and hypervascularization group, the median VAS, ICSI, and ICPI scores were lower than those in the preoperative period in the follow-up. In patients with HL, the median VAS scores were lower in the entire follow-up compared to the preoperative period, with an increase at 1st year compared to 6th month, and ICSI scores were lower than preoperative period in the entire follow-up, with an increase at 3rd month and 1st year. ICPI scores were also lower during the follow-up, with an increase observed in the 1st year. Conclusion: The presence of hypervascularization should be defined since it might show different characteristics that may affect the ICT response. Patients with glomerulations might be good candidates for early combined intravesical therapy.

Lung cancer has the highest mortality rate of any tumour type. The main driver of lung tumour growth and development is uncontrolled cellular proliferation. Poor patient outcomes are partly the result of the limited range of effective anti-cancer therapies available and partly due to the limited accuracy of biomarkers to report on cell proliferation rates in patients. Accordingly, accurate methods of diagnosing, staging and assessing response to therapy are crucial to improve patient outcomes. One effective way of assessing cell proliferation is to employ non-invasive evaluation using 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) positron emission tomography [18F]FLT-PET. [18F]FLT, unlike the most commonly used PET tracer [18F]fluorodeoxyglucose ([18F]FDG), can specifically report on cell proliferation and does not accumulate in inflammatory cells. Therefore, this radiotracer could exhibit higher specificity in diagnosis and staging, along with more accurate monitoring of therapy response at early stages in the treatment cycle. This review summarises and evaluates published studies on the clinical use of [18F]FLT to diagnose, stage and assess response to therapy in lung cancer.

Multiple sclerosis is a highly heterogeneous disease, and the detection of neuroaxonal damage as well as its quantification is a critical step for patients. Blood-based serum neurofilament light chain (sNfL) is currently under close investigation as an easily accessible biomarker of prognosis and treatment response in patients with multiple sclerosis. There is abundant evidence that sNfL levels reflect ongoing inflammatory-driven neuroaxonal damage (e.g. relapses or MRI disease activity) and that sNfL levels predict disease activity over the next few years. In contrast, the association of sNfL with long-term clinical outcomes or its ability to reflect slow, diffuse neurodegenerative damage in multiple sclerosis is less clear. However, early results from real-world cohorts and clinical trials using sNfL as a marker of treatment response in multiple sclerosis are encouraging. Importantly, clinical algorithms should now be developed that incorporate the routine use of sNfL to guide individualized clinical decision-making in people with multiple sclerosis, together with additional fluid biomarkers and clinical and MRI measures. Here, we propose specific clinical scenarios where implementing sNfL measures may be of utility, including, among others: initial diagnosis, first treatment choice, surveillance of subclinical disease activity and guidance of therapy selection., Bittner et al. discuss the association of emerging biomarker serum neurofilament light chain (sNfL) with clinical activity, disease progression, MRI measures and therapeutic interventions in multiple sclerosis. They propose specific scenarios implementing sNfL for individualized clinical decision-making.

Objectives Patients with acquired aplastic anemia (AA) without HLA-matched sibling donors or aged >40 years receive immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG). We investigated the relationship between plasma rabbit ATG (r-ATG) concentration and IST response. Methods From May 2012 to October 2017, 81 patients with severe AA who required initial IST were included. A 1:1 block randomization was employed for 2.5 and 3.5 mg/kg doses of r-ATG. Results No significant difference in response rates was observed between the 2.5 and 3.5 mg/kg groups (63% vs. 58%, P = .894). Median r-ATG concentrations on days 14 and 28 after IST were 15.2 (0.0-97.7) and 1.8 (0.0-74.9 µg/mL), respectively. According to r-ATG concentration, response rates were significantly higher in the group with higher r-ATG concentration than in those with lower r-ATG concentration (day 14, 88% vs. 52%; P = .006 and day 28, 79% vs. 46%; P = .005). In multivariate analysis, higher r-ATG concentrations at day 28 were independent predictors of favorable response to IST at 6 months (odds ratio, 0.29; 95% confidence interval, 0.09-0.93; P = .037). Conclusions The present data indicate that higher r-ATG concentration at day 28 resulted in improved IST response.

Purpose The aim of this retrospective study was to evaluate the use of [68Ga]Ga-PSMA PET/CT in therapy response assessment (TRA) of mCRPC patients treated with [177Lu]Lu-PSMA-617 and its correlation with overall survival (OS). Methods Thirty-nine patients were included in the study. Patient-/lesion-based early and late response assessment (ERA/LRA) was defined as PET2 (after two therapy cycles) vs. PET1 (before the first cycle) (n = 29) and end of treatment PET vs. PET1 (n = 17), respectively. PET-based response (PET parameters; modified (m) PERCIST/EORTC), biochemical response (ΔPSA; category-based) and category-based clinical response (CRA) was tested for correlation/agreement. PET-based TRA was correlated with OS. Results A significant correlation/agreement was shown between PET parameters and CRA as well as biochemical response in LRA of all lesions and between mPERCIST-based and category-based PSA response assessment in LRA (bone lesion-based, P = 0.045, κ = 0.184). At ERA, OS was significantly higher in CR/PR/SD compared to progressive disease applying mPERCIST/EORTC criteria (P = 0.0024). Conclusion In [177Lu]Lu-PSMA-617-treated mCRPC patients OS of the group of CR/PR/SD was significantly higher compared to the progressive disease group (mPERCIST/EORTC) in ERA. Therefore, [68Ga]Ga-PSMA PET might serve as a complementary diagnostic tool for TRA offering prognostic value regarding OS.

Variants in the epidermal growth factor receptor (EGFR) gene are recognized as predictors of therapy response and are correlated with progression-free and overall survival in non-small cell lung cancer (NSCLC) patients. Molecularly guided therapy needs precise and cost-effective molecular tests. This review focused primarily on screening or target methods for the EGFR variants detection with diagnostic and prognostic potential in the clinical research published papers. Concerning the inclusion and exclusion criteria, the search interval comprised available articles published from 2010 until 2020 in three electronic databases, ISI Web of Science, Pub Med, and Scopus. The analysis of eligible studies started with 5647 and obtained the final 987 full-text articles analyzed as clinical research. The regions comprised were Africa, America, Australia, Asia, Euro-Asia, Europe, or a consortium of different countries. All of the tested methods were applied prevalently in Asia. In clinical research, the polymerase chain reaction (PCR), followed by sequencing methods have been involved mostly over the years. The identified high-through output approaches evolved to improve the survival and quality of the NSCLC patient's life becoming more sensitive, specific, and cost-effective.

Technological innovation and rapid reduction in sequencing costs have enabled the genomic profiling of hundreds of cancer-associated genes as a component of routine cancer care. Tumour genomic profiling can refine cancer subtype classification, identify which patients are most likely to benefit from systemic therapies and screen for germline variants that influence heritable cancer risk. Here, we discuss ongoing efforts to enhance the clinical utility of tumour genomic profiling by integrating tumour and germline analyses, characterizing allelic context and identifying mutational signatures that influence therapy response. We also discuss the potential clinical utility of more comprehensive whole-genome and whole-transcriptome sequencing and ultra-sensitive cell-free DNA profiling platforms, which allow for minimally invasive, serial analyses of tumour-derived DNA in blood.

BackgroundHistorical 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.ResultsWe 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.ConclusionsThe 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.

Defects in DNA repair and the protection of stalled DNA replication forks are thought to underlie the chemosensitivity of tumors deficient in the hereditary breast cancer genes BRCA1 and BRCA2 (BRCA). Challenging this assumption are recent findings that indicate chemotherapies, such as cisplatin used to treat BRCA-deficient tumors, do not initially cause DNA double-strand breaks (DSB). Here, we show that ssDNA replication gaps underlie the hypersensitivity of BRCA-deficient cancer and that defects in homologous recombination (HR) or fork protection (FP) do not. In BRCA-deficient cells, ssDNA gaps developed because replication was not effectively restrained in response to stress. Gap suppression by either restoration of fork restraint or gap filling conferred therapy resistance in tissue culture and BRCA patient tumors. In contrast, restored FP and HR could be uncoupled from therapy resistance when gaps were present. Moreover, DSBs were not detected after therapy when apoptosis was inhibited, supporting a framework in which DSBs are not directly induced by genotoxic agents, but rather are induced from cell death nucleases and are not fundamental to the mechanism of action of genotoxic agents. Together, these data indicate that ssDNA replication gaps underlie the BRCA cancer phenotype, “BRCAness,” and we propose they are fundamental to the mechanism of action of genotoxic chemotherapies. Significance: This study suggests that ssDNA replication gaps are fundamental to the toxicity of genotoxic agents and underlie the BRCA-cancer phenotype “BRCAness,” yielding promising biomarkers, targets, and opportunities to resensitize refractory disease. See related commentary by Canman, p. 1214

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.

Background: This study aimed to evaluate tumor heterogeneity of metastatic breast cancer (MBC) and investigate its impact on the efficacy of pyrotinib in patients with HER2-positive MBC. Methods: MBC patients who underwent 18F-FDG PET/CT before pyrotinib treatment were included. Temporal and spatial tumor heterogeneity was evaluated by the discordance between primary and metastatic immunohistochemistry (IHC) results and baseline 18F-FDG uptake heterogeneity (intertumoral and intratumoral heterogeneity indexes: HI-inter and HI-intra), respectively. Progression-free survival (PFS) was estimated by the Kaplan–Meier method and compared by a log-rank test. Results: A total of 572 patients were screened and 51 patients were included. In 36 patients with matched IHC results, 25% of them had HER2 status conversion. Patients with homogenous HER2 positivity had the longest PFS, followed by patients with gained HER2 positivity, while patients with HER2 negative conversion could not benefit from pyrotinib (16.8 vs. 13.7 vs. 3.6 months, p < 0.0001). In terms of spatial heterogeneity, patients with high HI-intra and HI-inter had significantly worse PFS compared to those with low heterogeneity (10.6 vs. 25.3 months, p = 0.023; 11.2 vs. 25.3 months, p = 0.040). Conclusions: Temporal heterogeneity of HER2 status and spatial heterogeneity of 18F-FDG uptake could predict the treatment outcome of pyrotinib in patients with HER2-positive MBC, which provide practically applicable methods to assess tumor heterogeneity and guidance for treatment decisions.

Trastuzumab, the prototype HER2-directed therapy, has markedly improved survival for women with HER2-positive breast cancers. However, only 40–60% of women with HER2-positive breast cancers achieve a complete pathological response to chemotherapy combined with HER2-directed therapy. The current diagnostic assays have poor positive-predictive accuracy in identifying therapy-responsive breast cancers. Here, we deployed quantitative single molecule localization microscopy to assess the molecular features of HER2 in a therapy-responsive setting. Using fluorescently labeled trastuzumab as a probe, we first compared the molecular features of HER2 in trastuzumab-sensitive (BT-474 and SK-BR-3) and trastuzumab-resistant (BT-474R and JIMT-1) cultured cell lines. Trastuzumab-sensitive cells had significantly higher detected HER2 densities and clustering. We then evaluated HER2 in pre-treatment core biopsies from women with breast cancer undergoing neoadjuvant therapy. A complete pathological response was associated with a high detected HER2 density and significant HER2 clustering. These results established the nano-organization of HER2 as a potential signature of therapy-responsive disease.

Two studies unmask the essentiality of methionine synthase activity in powering the folate cycle to replenish the tetrahydrofolate pool from 5-methyltetrahydrofolate; this generates nucleotides that support tumour growth. Dietary manipulation alters folate availability and holds implications for anti-cancer therapy response.

Even though the treatment options and survival of patients with glioblastoma multiforme (GBM), the most common type of malignant glioma, have improved over the past decade, there is still a high unmet medical need to develop novel therapies. Complexity in pathology and therapy require biomarkers to characterize tumors, to define malignant and active areas, to assess disease prognosis, and to quantify and monitor therapy response. While conventional magnetic resonance imaging (MRI) techniques have improved these assessments, limitations remain. In this review, we evaluate the role of various non-invasive biomarkers based on advanced structural and functional MRI techniques in the context of GBM drug development over the past 5 years.

Up to one-third of patients who undergo cardiac resynchronization therapy do not obtain clinical benefit. A systematic approach can identify treatable causes in many nonresponding patients. We present a case of nonresponse to cardiac resynchronization therapy that resolved by ablation of the atrioventricular node in a patient with complete atrioventricular block. (Level of Difficulty: Advanced.), Graphical abstract

Data-independent acquisition mass spectrometry (DIA-MS) is a next generation proteomic methodology that generates permanent digital proteome maps offering highly reproducible retrospective analysis of cellular and tissue specimens. The adoption of this technology has ushered a new wave of oncology studies across a wide range of applications including its use in molecular classification, oncogenic pathway analysis, drug and biomarker discovery and unravelling mechanisms of therapy response and resistance. In this review, we provide an overview of the experimental workflows commonly used in DIA-MS, including its current strengths and limitations versus conventional data-dependent acquisition mass spectrometry (DDA-MS). We further summarise a number of key studies to illustrate the power of this technology when applied to different facets of oncology. Finally we offer a perspective of the latest innovations in DIA-MS technology and machine learning-based algorithms necessary for driving the development of high-throughput, in-depth and reproducible proteomic assays that are compatible with clinical diagnostic workflows, which will ultimately enable the delivery of precision cancer medicine to achieve optimal patient outcomes.

In the last decade, the use of nanotheranostics as emerging diagnostic and therapeutic tools for various diseases, especially cancer, is held great attention. Up to date, several approaches have been employed in order to develop smart nanotheranostics, which combine bioactive targeting on specific tissues as well as diagnostic properties. The nanotheranostics can deliver therapeutic agents by concomitantly monitor the therapy response in real-time. Consequently, the possibility of over- or under-dosing is decreased. Various non-invasive imaging techniques have been used to quantitatively monitor the drug delivery processes. Radiolabeling of nanomaterials is widely used as powerful diagnostic approach on nuclear medicine imaging. In fact, various radiolabeled nanomaterials have been designed and developed for imaging tumors and other lesions due to their efficient characteristics. Inorganic nanoparticles as gold, silver, silica based nanomaterials or organic nanoparticles as polymers, carbon based nanomaterials, liposomes have been reported as multifunctional nanotheranostics. In this review, the imaging modalities according to their use in various diseases are summarized, providing special details for radiolabeling. In further, the most current nanotheranostics categorized via the used nanomaterials are also summed up. To conclude, this review can be beneficial for medical and pharmaceutical society as well as material scientists who work in the field of nanotheranostics since they can use this research as guide for producing newer and more efficient nanotheranostics., Graphical abstract Image, graphical abstract

This scientific review presents a current data on the effect of genetic polymorphism of CYP2C9 genes and genes encoding components of the renin-angiotensin-aldosterone system (RAAS) on the angiotensin II receptor blockers (ARBs) pharmacokinetics and pharmacodynamics. The data shows that genetic polymorphisms of these genes determine the large interindividual variability of the pharmacological response to ARBs. In this article, we carried out a comprehensive review of recent findings on interpatient variability in antihypertensive therapy response due to genetic factors and individualized treatment approach in ARBs therapy.

Chronic urticaria (CU) is one of the most commonly diagnosed skin conditions. CU is characterised by the presence of recurrent wheals and/or angioedema and intense pruritus persisting for at least 6 weeks. Subtypes of CU include chronic spontaneous urticaria and chronic inducible urticaria. Following diagnosis, adequate trigger identification and appropriate treatment can significantly reduce disease activity and improve the patient’s quality of life and disease outcomes. Current guidelines recommend a stepwise approach in the management of CU, including non-sedating oral antihistamines, administered in up to four times the conventional dose, the monoclonal antibody omalizumab (anti-IgE), and eventually cyclosporine as an add-on therapy for patients with antihistamine-refractory CU. Potential disease-related biomarkers are needed to predict the therapeutic response that would lead to establishment of personalised regimens and treatment plans. This paper reviews the current perspectives and guidelines for classification, diagnosis, and management of CU.

Introduction: VNS is an adjunctive neuromodulation therapy for patients with drug-refractory epilepsy. The antiseizure effect of VNS is thought to be related to a diffuse modulation of functional connectivity but remains to be confirmed. Aim: To investigate electroencephalographic (EEG) metrics of functional connectivity in patients with drug-refractory epilepsy treated by vagus nerve stimulation (VNS), between VNS-stimulated “ON” and nonstimulated “OFF” periods and between responder (R) and nonresponder (NR) patients. Methods: Scalp-EEG was performed for 35 patients treated by VNS, using 21 channels and 2 additional electrodes on the neck to detect the VNS stimulation. Patients were defined as VNS responders if a reduction of seizure frequency of ∼50% was documented. We analyzed the synchronization in EEG time series during “ON” and “OFF” periods of stimulation, using average phase lag index (PLI) in signal space and phase-locking value (PLV) between 10 sources. Based on graph theory, we computed brain network models and analyzed minimum spanning tree (MST) for responder and nonresponder patients. Results: Among 35 patients treated by VNS for a median time of 7 years (range 4 months to 22 years), 20 were R and 15 were NR. For responder patients, PLI during ON periods was significantly lower than that during OFF periods in delta (p = 0.009), theta (p = 0.02), and beta (p = 0.04) frequency bands. For nonresponder patients, there were no significant differences between ON and OFF periods. Moreover, variations of seizure frequency with VNS correlated with the PLI OFF/ON ratio in delta (p = 0.02), theta (p = 0.04), and beta (p = 0.03) frequency bands. Our results were confirmed using PLV in theta band (p

Background: CD10, BCL6, and MUM1 are commonly used immunohistochemical stains for classifying diffuse large B-cell lymphoma (DLBCL), which is useful in predicting outcome. Conflicting reports of the prognostic value of other markers such as BCL2, CD23, and Ki67 proliferation index have been reported. Our objective was to correlate these immunostains and Hans classification with response to therapy and overall survival. Materials and Methods: A retrospective study of patients diagnosed with DLBCL from 2008–2014 at a tertiary-care cancer hospital. The slides with the IHC stains were reviewed by two independent pathologists. The clinical outcomes––assessed independently––were response to therapy and overall survival. The treatment response evaluation was based on the new Lugano classification. Statistical analyses were conducted using the Fisher’s exact test and Kaplan–Meier survival curves. Significance was set at P < 0.05. Results: Forty-one patients were included in the study with a known Hans classification, available clinical data, and at least 5-year follow-up. CD10 immunostain was reported in all patients, whereas CD23 was the least reported in only four patients. No significant association was observed between CD10, BCL6, MUM1, BCL2, and both Response to therapy and overall survival. Owing to few cases reported CD23 immunostain, further analysis of association is not reported. High Ki67 proliferative index of >80% was statistically significantly associated with shorter overall survival and not statistically significant associated with no response to therapy. Hans classification subtypes were not predictive in regard to therapy response. Conclusion: High Ki67 expression (>80%) was associated with shorter overall survival in DLBCL. Hans classification subtypes were not predictive.

This study examined sST2, GDF-15, and galectin-3 as indicators of disease severity and therapy response in chronic thromboembolic pulmonary hypertension (CTEPH).This study included 57 inoperable CTEPH patients who underwent balloon pulmonary angioplasty and 25 controls without cardiovascular disease. Biomarker levels were examined in relation to advanced hemodynamic impairment [tertile with worst right atrial pressure (RAP) and cardiac index], hemodynamic therapy response [normalized hemodynamics (meanPAP ≤25 mmHg, PVR ≤3 WU and RAP ≤6 mmHg) or a reduction of meanPAP ≥25%; PVR ≥ 35%, RAP ≥25%].GDF-15 [820 (556-1315) pg/ml vs. 370 (314-516) pg/ml;GDF-15 and sST2 levels are higher in CTEPH and identified patients with advanced hemodynamic impairment. Further, decreased GDF-15 levels at follow-up were associated with hemodynamic therapy response. The diagnostic strength was not superior to NT-proBNP.

Purpose: To evaluate and compare the clinical utility of simultaneously obtained quantitative 18F-fluorodeoxyglucose positron-emission-tomography (18F-FDG PET) and diffusion-weighted imaging (DWI) datasets for the prediction of histopathological therapy response of soft tissue sarcomas (STS) under neoadjuvant isolated limb perfusion (ILP). Methods: A total of 37 patients with confirmation of a STS of the extremities underwent an 18F-FDG PET/magnetic resonance imaging (MRI) examination before (1st scan) and after (2nd scan) ILP with melphalan and TNF-α. For each patient, the maximum tumor size, metabolic activity (standardized uptake values, SUV) and diffusion-restriction (apparent diffusion restriction values, ADC) were determined in pre- and posttherapeutic examinations and percentage changes during treatment were calculated. A Mann-Whitney U test was used and receiver operating characteristic (ROC) analysis was performed to compare the results of the different quantitative parameters to predict histopathological therapy response. Results from histopathological analysis after subsequent tumor resection served as reference standard and patients were defined as responders/non-responders based on the grading scale by Salzer-Kuntschik. Results: Histopathological analysis categorized 22 (59%) patients as therapy responders (Grade I-III) and 15 (41%) patients as non-responders (Grade IV-VI). Tumors in the responder group showed a mean reduction in size of -9.7% and metabolic activity (SUVpeak: -51.9%; SUVmean: -43.8%) as well as an increase of the ADC values (ADCmin: +29.4% and ADCmean: +32.8%) under treatment. Percentage changes in the non-responder group amounted to: tumor size -6.2%; SUVpeak: -17.3%; SUVmean: -13.9%; ADCmin: +15.3% and ADCmean: +14.6%. Changes of the SUVs and ADCmean values between responders and non-responders were significantly different ( 0.05). The corresponding AUCs were 0.63 (tumor size), 0.87 (SUVpeak), 0.82 (SUVmean), 0.63 (ADCmin), 0.84 (ADCmean) and 0.89 (ratio: ADCmean/SUVpeak), respectively. Conclusion:18F-FDG PET and MR-derived quantitative imaging parameters (SUVs and ADCmean) and their combination reveal a good performance for the prediction of histopathological therapy response of STS under neoadjuvant ILP. Therefore, integrated PET/MRI could serve as a valuable tool for pretherapeutic assessment as well as monitoring of neoadjuvant treatment strategies of STS.

Background Nutrition is a key component of oncologic therapies and treatments. Patients and families are interested in the integration of alternative diets to promote therapy response as well as counteract the cancer. With the expansion of online and social media presence comes the endorsement of nonscientific claims. Objectives The purpose of this article is to review alternative diets and discuss the basis of good nutrition in pediatric patients with cancer. This article will also explore where patients and families are likely to seek their information and assess their level of trust in the information. Methods Five alternative diets and two supplements were assessed through a literature review for their effect on pediatric patients with cancer. Findings Additional research is needed to prove consistent and definitive dietary benefits for pediatric patients with cancer; however, some diets have demonstrated promising results. A general diet for pediatric patients with cancer consists of an appropriate distribution of nutritious carbohydrates, proteins, and fats. However, unregulated sources of information remain a risk.

Cancer is a leading cause of death worldwide. Identifying the best treatment using computational models to personalize drug response prediction holds great promise to improve patient’s chances of successful recovery. Unfortunately, the computational task of predicting drug response is very challenging, partially due to the limitations of the available data and partially due to algorithmic shortcomings. The recent advances in deep learning may open a new chapter in the search for computational drug response prediction models and ultimately result in more accurate tools for therapy response. This review provides an overview of the computational challenges and advances in drug response prediction, and focuses on comparing the machine learning techniques to be of utmost practical use for clinicians and machine learning non-experts. The incorporation of new data modalities such as single-cell profiling, along with techniques that rapidly find effective drug combinations will likely be instrumental in improving cancer care.

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.

Altered expression and function of the transcription factor cyclic AMP response-binding protein (CREB) has been identified to play an important role in cancer and is associated with the overall survival and therapy response of tumor patients. This review focuses on the expression and activation of CREB under physiologic conditions and in tumors of distinct origin as well as the underlying mechanisms of CREB regulation by diverse stimuli and inhibitors. In addition, the clinical relevance of CREB is summarized, including its use as a prognostic and/or predictive marker as well as a therapeutic target. Electronic supplementary material The online version of this article (10.1007/s00018-020-03525-8) contains supplementary material, which is available to authorized users.

Predictive models trained on sequencing profiles often fail to achieve expected performance when externally validated on unseen profiles. While many factors such as batch effects, small data sets, and technical errors contribute to the gap between source and unseen data distributions, it is a challenging problem to generalize the predictive models across studies without any prior knowledge of the unseen data distribution. Here, this study proposes DeepBioGen, a sequencing profile augmentation procedure that characterizes visual patterns of sequencing profiles, generates realistic profiles based on a deep generative model capturing the patterns, and generalizes the subsequent classifiers. DeepBioGen outperforms other methods in terms of enhancing the generalizability of the prediction models on unseen data. The generalized classifiers surpass the state-of-the-art method, evaluated on RNA sequencing tumor expression profiles for anti-PD1 therapy response prediction and WGS human gut microbiome profiles for type 2 diabetes diagnosis. VT's OASF Published version This work is partially supported by VT's OASF support.

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.

One of the most innovative medical trends is personalized therapy, based on simple and reproducible methods that detect unique features of cancer cells. One of the good prognostic and diagnostic markers may be the miRNA family. Our work aimed to evaluate changes in selected miRNA levels in various breast cancer cell lines (MCF7, MDA-MB-231, SK-BR-3) treated with doxorubicin or cisplatin. The selection was based on literature data regarding the most commonly altered miRNAs in breast cancer (21-3p, 21-5p, 106a-5p, 126-3p, 126-5p, 155-3p, 155-5p, 199b-3p, 199b-5p, 335-3p, 335-5p). qPCR assessment revealed significant differences in the basal levels of some miRNAs in respective cell lines, with the most striking difference in miR-106a-5p, miR-335-5p and miR-335-3p—all of them were lowest in MCF7, while miR-153p was not detected in SK-BR-3. Additionally, different alterations of selected miRNAs were observed depending on the cell line and the drug. However, regardless of these variables, 21-3p/-5p, 106a, 126-3p, 155-3p and 199b-3p miRNAs were shown to respond either to doxorubicin or to cisplatin treatment. These miRNAs seem to be good candidates for markers of breast cancer cell response to doxorubicin or cisplatin. Especially since some earlier reports suggested their role in affecting pathways and expression of genes associated with the DNA-damage response. However, it must be emphasized that the preliminary study shows effects that may be highly related to the applied drug itself and its concentration. Thus, further examination, including human samples, is required.

Lung cancer is the most common cause of cancer-related deaths in both men and women, accounting for one-quarter of total cancer-related mortality globally. Lung adenocarcinoma is the major subtype of non-small cell lung cancer (NSCLC) and accounts for around 40% of lung cancer cases. Lung adenocarcinoma is a highly heterogeneous disease and patients often display variable histopathological morphology, genetic alterations, and genomic aberrations. Recent advances in transcriptomic and genetic profiling of lung adenocarcinoma by investigators, including our group, has provided better stratification of this heterogeneous disease, which can facilitate devising better treatment strategies suitable for targeted patient cohorts. In a recent study we have shown gene expression profiling identified novel clustering of early stage LUAD patients and correlated with tumor invasiveness and patient survival. In this study, we focused on copy number alterations in LUAD patients. SNP array data identified amplification at chromosome 12q15 on MDM2 locus and protein overexpression in a subclass of LUAD patients with an invasive subtype of the disease. High copy number amplification and protein expression in this subclass correlated with poor overall survival. We hypothesized that MDM2 copy number and overexpression predict response to MDM2-targeted therapy. In vitro functional data on a panel of LUAD cells showed that MDM2-targeted therapy effectively suppresses cell proliferation, migration, and invasion in cells with MDM2 amplification/overexpression but not in cells without MDM2 amplification, independent of p53 status. To determine the key signaling mechanisms, we used RNA sequencing (RNA seq) to examine the response to therapy in MDM2-amplified/overexpressing p53 mutant and wild-type LUAD cells. RNA seq data shows that in MDM2-amplified/overexpression with p53 wild-type condition, the E2F → PEG10 → MMPs pathway is operative, while in p53 mutant genetic background, MDM2-targeted therapy abrogates tumor progression in LUAD cells by suppressing epithelial to mesenchymal transition (EMT) signaling. Our study provides a potentially clinically relevant strategy of selecting LUAD patients for MDM2-targeted therapy that may provide for increased response rates and, thus, better survival.

Prostate cancer is a leading cause of death worldwide and new estimates revealed prostate cancer as the leading cause of death in men in 2021. Therefore, new strategies are pertinent in the treatment of this malignant disease. Macroautophagy/autophagy is a "self-degradation" mechanism capable of facilitating the turnover of long-lived and toxic macromolecules and organelles. Recently, attention has been drawn towards the role of autophagy in cancer and how its modulation provides effective cancer therapy. In the present review, we provide a mechanistic discussion of autophagy in prostate cancer. Autophagy can promote/inhibit proliferation and survival of prostate cancer cells. Besides, metastasis of prostate cancer cells is affected (via induction and inhibition) by autophagy. Autophagy can affect the response of prostate cancer cells to therapy such as chemotherapy and radiotherapy, given the close association between autophagy and apoptosis. Increasing evidence has demonstrated that upstream mediators such as AMPK, non-coding RNAs, KLF5, MTOR and others regulate autophagy in prostate cancer. Anti-tumor compounds, for instance phytochemicals, dually inhibit or induce autophagy in prostate cancer therapy. For improving prostate cancer therapy, nanotherapeutics such as chitosan nanoparticles have been developed. With respect to the context-dependent role of autophagy in prostate cancer, genetic tools such as siRNA and CRISPR-Cas9 can be utilized for targeting autophagic genes. Finally, these findings can be translated into preclinical and clinical studies to improve survival and prognosis of prostate cancer patients. 35317831

Background and aims Treatment with tumor necrosis factor α (TNFα) antagonists in IBD patients suffers from primary non-response rates of up to 40%. Biomarkers for early prediction of therapy success are missing. We investigated the dynamics of gene expression and DNA methylation in blood samples of IBD patients treated with the TNF antagonist infliximab and analyzed the predictive potential regarding therapy outcome. Methods We performed a longitudinal, blood-based multi-omics study in two prospective IBD patient cohorts receiving first-time infliximab therapy (discovery: 14 patients, replication: 23 patients). Samples were collected at up to 7 time points (from baseline to 14 weeks after therapy induction). RNA-sequencing and genome-wide DNA methylation data were analyzed and correlated with clinical remission at week 14 as a primary endpoint. Results We found no consistent ex ante predictive signature across the two cohorts. Longitudinally upregulated transcripts in the non-remitter group comprised TH2- and eosinophil-related genes including ALOX15, FCER1A, and OLIG2. Network construction identified transcript modules that were coherently expressed at baseline and in non-remitting patients but were disrupted at early time points in remitting patients. These modules reflected processes such as interferon signaling, erythropoiesis, and platelet aggregation. DNA methylation analysis identified remission-specific temporal changes, which partially overlapped with transcriptomic signals. Machine learning approaches identified features from differentially expressed genes cis-linked to DNA methylation changes at week 2 as a robust predictor of therapy outcome at week 14, which was validated in a publicly available dataset of 20 infliximab-treated CD patients. Conclusions Integrative multi-omics analysis reveals early shifts of gene expression and DNA methylation as predictors for efficient response to anti-TNF treatment. Lack of such signatures might be used to identify patients with IBD unlikely to benefit from TNF antagonists at an early time point.

This project aims to investigate the prediction of treatment response in patients with anxiety disorders using machine learning algorithms. Two groups of anxiety disorder patients will be examined: an experimental sample of spider phobia patients (group A) using a well-established research pipeline and a naturalistic sample of patients with social anxiety disorder and panic disorder from routine clinical care (group B). The predictive usefulness of both subjective and neurofunctional data assessed during emotion regulation (ER), a psychological key process of pathogenesis and therapeutic change in anxiety disorders, will be investigated. Short-term and six-month long-term response to CBT will be considered. We thus hope to pave a way for effective a priori prediction and consequently better treatment of patients with anxiety disorders in routine clinical care.

Background Musician’s Dystonia (MD) by impaired or complete loss of fine motor control in extensively trained movements at the instrument. In pianists, it frequently leads to involuntary flexion or extension of one or more fingers. Treatment remains challenging, although local injections with Botulinum toxin, anticholinergic medication and pedagogical retraining seem to be helpful in individual cases. Evaluation of therapies however is frequently hampered by lack of practicability, or validity. This retrospective observational study aims to assess the long-term development of MD and efficacy of therapies in keyboard players by means of a simple video-rating procedure by informed expert raters. Methods Video rating is characterisedwas done by 6 carefully instructed pianists, rating a total of 266 videos from 80 patients, recorded over a period of almost 20 years. These showed the affected hand playing a C-major scale as “regularly” as possible at a moderate tempo on a grand piano. Raters assessed the acoustic irregularity of scale playing and any visible movement impairment on visual analogue scales. Influence of patient-specific factors including applied treatment was estimated in a Bayesian multilevel beta regression. Results For ratings of irregularity and impairment intra-rater reliability was strong and inter-rater concordance was moderate. The average estimated improvement across all therapies was 14% in irregularity and 15% in impairment. Highest improvement rates in ratings of irregularity were found after the combined treatment with Botulinum toxin and Trihexyphenidyl (45%) as well as in retraining (29% improvement) as single therapy. In ratings of impairment the highest improvement was shown for retraining in combination with Trihexyphenidyl (36% improvement) as well as retraining as single therapy (23%). Conclusions This study provides a new perspective on the course of MD in keyboard players in a larger cohort using methods other than self-report. Video rating of scale-playing was shown to be a reliable and useful method to evaluate MD in keyboard players. Average improvement rates were different to previous studies using patient-subjective questionnaires. Treatment options showed different effects in the two rating criteria, with retraining showing the highest improvement rates in single and combined use.

Background: The response to BoNT is not uniform; a broad spectrum of responses and side-effects usually occurs. This study aimed to show special cervical dystonia cases with therapy response very different to normal treatment course which indicate the extreme ends of therapy spectrum. Patients: Clinical data and course of treatment of five long-term treated patients with cervical dystonia out of therapy response norms are presented: a patient who was supersensitive to standard dose and has required dose adjustment to lower dose of BoNT; one patient who worsened under a standard dose, but responded excellently to twice the standard dose; one insensitive patient who responded poorly for years to a dose well above the standard dose, but responded when dose was further increased; and two patients with a totally different response pattern to BoNT/A preparation 1, but the development of a neutralizing antibody induced secondary treatment failure in both cases and a totally different response after switch to BoNT/A preparation 2. Conclusions: These five patients indicate that the response of a patient to a BoNT preparation may be unexpected. Therefore, cautious onset of BoNT therapy is recommended as well as consequent dose adjustment later on and even switch to another BoNT/A preparation when a patient has already developed NABs against BoNT/A.

FDG PET/CT in an 18-year-old man with known familial hemophagocytic lymphohistiocytosis (HLH) type 2 demonstrated abnormally in the brain, liver, and lymph nodes. Pathology showed no sign of lymphoproliferative disease. The patient underwent the chemotherapy of HLH. Six months after chemotherapy, a follow-up FDG PET/CT did not show any abnormal 18F-FDG activity, suggesting a complete response. The present case shows FDG PET/CT might not only be useful in staging the familial HLH but also able to evaluate the therapy response.

Acute promyelocytic leukemia (APL) is a unique and very deeply studied acute myeloid leukemia [...]