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PURPOSE: Given the high heterogeneity in survival for patients with multiple myeloma, it would be clinically useful to quantitatively predict the individual survival instead of attributing patients to two to four risk groups as in current models, for example, revised International Staging System (R-ISS), R2-ISS, or Mayo-2022-score. PATIENTS AND METHODS: Our aim was to develop a quantitative prediction tool for individual patient's 3-/5-year overall survival (OS) probability. We integrated established clinical and molecular risk factors into a comprehensive prognostic model and evaluated and validated its risk discrimination capabilities versus R-ISS, R2-ISS, and Mayo-2022-score. RESULTS: A nomogram for estimating OS probabilities was built on the basis of a Cox regression model. It allows one to translate the individual risk profile of a patient into 3-/5-year OS probabilities by attributing points to each prognostic factor and summing up all points. The nomogram was externally validated regarding discrimination and calibration. There was no obvious bias or overfitting of the prognostic index on the validation cohort. Resampling-based and external evaluation showed good calibration. The c-index of the model was similar on the training (0.76) and validation cohort (0.75) and significantly higher than for the R-ISS (P < .001) or R2-ISS (P < .01). CONCLUSION: In summary, we developed and validated individual quantitative nomogram-based OS prediction. Continuous risk assessment integrating molecular prognostic factors is superior to R-ISS, R2-ISS, or Mayo-2022-score alone.
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Bortezomib , Mieloma Múltiplo , Nomogramas , Transplante Autólogo , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Mieloma Múltiplo/tratamento farmacológico , Humanos , Bortezomib/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Prognóstico , Transplante de Células-Tronco Hematopoéticas , Antineoplásicos/uso terapêutico , Quimioterapia de Indução , Adulto , Taxa de SobrevidaRESUMO
Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; n = 395) randomizing VAD induction (vincristin/adriamycin/dexamthasone)/tandem-transplantation/thalidomide-maintenance vs. PAD induction (bortezomib/adriamycin/dexamethasone)/tandem transplantation/bortezomib maintenance, we discern how chromosomal aberrations determine long-term prognosis by different patterns of association with proliferation and treatment-dependent response, whether responses achieved by different regimens are equal regarding prognosis, and whether subpopulations of patients could be defined as treatable without upfront "novel agents" in cases of limited resources, e.g., in low- or middle-income countries. Serum parameters and risk factors were assessed in 395 patients. CD138-purified plasma cells were subjected to fluorescence in situ hybridization (n = 354) and gene expression profiling (n = 204). We found chromosomal aberrations to be associated in four patterns with survival, proliferation, and response: deletion (del) del17p13, del8p21, del13q14, (gain) 1q21+, and translocation t(4;14) (all adverse) associate with higher proliferation. Of these, del17p is associated with an adverse response (pattern 1), and 1q21+, t(4;14), and del13q14 with a treatment-dependent better response (pattern 2). Hyperdiploidy associates with lower proliferation without impacting response or survival (pattern 3). Translocation t(11;14) has no association with survival but a treatment-dependent adverse response (pattern 4). Significantly fewer patients reach a near-complete response or better with "conventional" (VAD) vs. bortezomib-based treatment after induction or high-dose melphalan. These patients, however, show significantly better median progression-free and overall survival. Molecularly, patients responding to the two regimens differ in gene expression, indicating distinct biological properties of the responding myeloma cells. Patients with normal renal function (89.4%), low cytogenetic risk (72.5%), or low proliferation rate (37.9%) neither benefit in progression-free nor overall survival from bortezomib-based upfront treatment. We conclude that response level, the treatment by which it is achieved, and molecular background determine long-term prognosis. Chromosomal aberrations are associated in four patterns with proliferation and treatment-dependent responses. Associations with faster and deeper responses can be deceptive in the case of prognostically adverse aberrations 1q21+ and t(4;14). Far from advocating a return to "outdated" treatments, if resources do not permit state-of-the-art-treatment, normal renal function and/or molecular profiling identifies patient subpopulations doing well without upfront "novel agents".
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Aberrações Cromossômicas , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Prognóstico , Adulto , Países em Desenvolvimento , Dexametasona/uso terapêutico , Dexametasona/farmacologia , Bortezomib/uso terapêutico , Bortezomib/farmacologia , Talidomida/uso terapêuticoRESUMO
Multiple myeloma involves early dissemination of malignant plasma cells across the bone marrow; however, the initial steps of dissemination remain unclear. Human bone marrow-derived mesenchymal stromal cells (hMSC) stimulate myeloma cell expansion (e.g., IL6) and simultaneously retain myeloma cells via chemokines (e.g., CXCL12) and adhesion factors. Hence, we hypothesized that the imbalance between cell division and retention drives dissemination. We present an in vitro model using primary hMSCs cocultured with INA-6 myeloma cells. Time-lapse microscopy revealed proliferation and attachment/detachment dynamics. Separation techniques (V-well adhesion assay and well plate sandwich centrifugation) were established to isolate MSC-interacting myeloma subpopulations that were characterized by RNA sequencing, cell viability, and apoptosis. Results were correlated with gene expression data (n = 837) and survival of patients with myeloma (n = 536). On dispersed hMSCs, INA-6 saturate hMSC surface before proliferating into large homotypic aggregates, from which single cells detached completely. On confluent hMSCs, aggregates were replaced by strong heterotypic hMSC-INA-6 interactions, which modulated apoptosis time dependently. Only INA-6 daughter cells (nMA-INA6) detached from hMSCs by cell division but sustained adherence to hMSC-adhering mother cells (MA-INA6). Isolated nMA-INA6 indicated hMSC autonomy through superior viability after IL6 withdrawal and upregulation of proliferation-related genes. MA-INA6 upregulated adhesion and retention factors (CXCL12), that, intriguingly, were highly expressed in myeloma samples from patients with longer overall and progression-free survival, but their expression decreased in relapsed myeloma samples. Altogether, in vitro dissemination of INA-6 is driven by detaching daughter cells after a cycle of hMSC-(re)attachment and proliferation, involving adhesion factors that represent a bone marrow-retentive phenotype with potential clinical relevance. SIGNIFICANCE: Novel methods describe in vitro dissemination of myeloma cells as detachment of daughter cells after cell division. Myeloma adhesion genes were identified that counteract in vitro detachment with potential clinical relevance.
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Adesão Celular , Proliferação de Células , Células-Tronco Mesenquimais , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/patologia , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Apoptose , Técnicas de Cocultura , Linhagem Celular Tumoral , Agregação Celular , Sobrevivência CelularRESUMO
This study analyzed whether extended molecular profiling can predict the development of epidermal growth factor receptor (EGFR) gene T790M mutation, which is the most frequent resistance alteration in non-small cell lung cancer (NSCLC) after treatment with the first-/second-generation (1G/2G) EGFR inhibitors (tyrosine kinase inhibitors [TKIs]), but only weakly associated with clinical characteristics. Whole exome sequencing (WES) was performed on pretreatment tumor tissue with matched normal samples from NSCLC patients with (n = 25, detected in tissue or blood rebiopsies) or without (n = 14, negative tissue rebiopsies only) subsequent EGFR p.T790M mutation after treatment with 1G/2G EGFR TKI. Several complex genetic biomarkers were assessed using bioinformatic methods. After treatment with first-line afatinib (44%) or erlotinib/gefitinib (56%), median progression-free survival and overall survival were 12.1 and 33.7 months, respectively. Clinical and tumor genetic characteristics, including age (median, 66 years), sex (74% female), smoking (69% never/light smokers), EGFR mutation type (72% exon 19 deletions), and TP53 mutations (41%) were not significantly associated with T790M mutation (p > 0.05). By contrast, complex biomarkers including tumor mutational burden, the clock-like mutation signature SBS1 + 5, tumor ploidy, and markers of subclonality including mutant-allele tumor heterogeneity, subclonal copy number changes, and median tumor-adjusted variant allele frequency were significantly higher at baseline in tumors with subsequent T790M mutation (all p < 0.05). Each marker alone could predict subsequent development of T790M with an area under the curve (AUC) of 0.72-0.77, but the small number of cases did not allow confirmation of better performance for biomarker combinations in leave-one-out cross-validated logistic regression (AUC 0.69, 95% confidence interval: 0.50-0.87). Extended molecular profiling with WES at initial diagnosis reveals several complex biomarkers associated with subsequent development of T790M resistance mutation in NSCLC patients receiving first-/second-generation TKIs as the first-line therapy. Larger prospective studies will be necessary to define a forecasting model.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Feminino , Idoso , Masculino , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Estudos Prospectivos , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Genômica , BiomarcadoresRESUMO
Background: Immunotherapeutic targets in multiple myeloma (MM) have variable expression height and are partly expressed in subfractions of patients only. With increasing numbers of available compounds, strategies for appropriate choice of targets (combinations) are warranted. Simultaneously, risk assessment is advisable as patient's life expectancy varies between months and decades. Methods: We first assess feasibility of RNA-sequencing in a multicenter trial (GMMG-MM5, n=604 patients). Next, we use a clinical routine cohort of untreated symptomatic myeloma patients undergoing autologous stem cell transplantation (n=535, median follow-up (FU) 64 months) to perform RNA-sequencing, gene expression profiling (GEP), and iFISH by ten-probe panel on CD138-purified malignant plasma cells. We subsequently compare target expression to plasma cell precursors, MGUS (n=59), asymptomatic (n=142) and relapsed (n=69) myeloma patients, myeloma cell lines (n=26), and between longitudinal samples (MM vs. relapsed MM). Data are validated using the independent MMRF CoMMpass-cohort (n=767, FU 31 months). Results: RNA-sequencing is feasible in 90.8% of patients (GMMG-MM5). Actionable immune-oncological targets (n=19) can be divided in those expressed in all normal and >99% of MM-patients (CD38, SLAMF7, BCMA, GPRC5D, FCRH5, TACI, CD74, CD44, CD37, CD79B), those with expression loss in subfractions of MM-patients (BAFF-R [81.3%], CD19 [57.9%], CD20 [82.8%], CD22 [28.4%]), aberrantly expressed in MM (NY-ESO1/2 [12%], MUC1 [12.7%], CD30 [4.9%], mutated BRAF V600E/K [2.1%]), and resistance-conveying target-mutations e.g., against part but not all BCMA-directed treatments. Risk is assessable regarding proliferation, translated GEP- (UAMS70-, SKY92-, RS-score) and de novo (LfM-HRS) defined risk scores. LfM-HRS delineates three groups of 40%, 38%, and 22% of patients with 5-year and 12-year survival rates of 84% (49%), 67% (18%), and 32% (0%). R-ISS and RNA-sequencing identify partially overlapping patient populations, with R-ISS missing, e.g., 30% (22/72) of highly proliferative myeloma. Conclusion: RNA-sequencing based assessment of risk and targets for first choice treatment is possible in clinical routine.
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Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Mieloma Múltiplo/tratamento farmacológico , RNA , Antígeno de Maturação de Linfócitos B , Transplante AutólogoRESUMO
The skin is a barrier organ and thus exposed to environmental factors from birth, which essentially determine skin aging. In order to describe and understand this complex process exactly, we applied the concept of the "exposome" to the environmentally induced skin aging process. In this review, we summarize current knowledge on the skin aging exposome. In this context, we characterize the most important exposomal factors, address their relative importance for skin aging and also the relevance of their mutual interactions. Finally, we discuss the clinical consequences resulting from this concept for an effective prevention of skin aging.
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Expossoma , Envelhecimento da Pele , Gravidez , Feminino , Humanos , Conhecimento , Parto , RegistrosRESUMO
Homologous recombination deficiency (HRD) is a predictive marker for response to poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian carcinoma. HRD scores have entered routine diagnostics, but the influence of algorithms, parameters and confounders has not been analyzed comprehensively. A series of 100 poorly differentiated ovarian carcinoma samples was analyzed using whole exome sequencing (WES) and genotyping. Tumor purity was determined using conventional pathology, digital pathology, and two bioinformatic methods. HRD scores were calculated from copy number profiles determined by Sequenza and by Sclust either with or without fixed tumor purity. Tumor purity determination by digital pathology combined with a tumory purity informed variant of Sequenza served as reference method for HRD scoring. Seven tumors had deleterious mutations in BRCA1/2, 12 tumors had deleterious mutations in other homologous recombination repair (HRR) genes, 18 tumors had variants of unknown significance (VUS) in BRCA1/2 or other HRR genes, while the remaining 63 tumors had no relevant alterations. Using the reference method for HRD scoring, 68 tumors were HRD-positive. HRDsum determined by WES correlated strongly with HRDsum determined by single nucleotide polymorphism (SNP) arrays (R = 0.85). Conventional pathology systematically overestimated tumor purity by 8% compared to digital pathology. All investigated methods agreed on classifying the deleterious BRCA1/2-mutated tumors as HRD-positive, but discrepancies were observed for some of the remaining tumors. Discordant HRD classification of 11% of the tumors was observed comparing the tumor purity uninformed default of Sequenza and the reference method. In conclusion, tumor purity is a critical factor for the determination of HRD scores. Assistance by digital pathology helps to improve accuracy and imprecision of its estimation.
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BACKGROUND: Diabetic retinopathy (DR) remains one of the most common complications of diabetes despite great efforts to uncover its underlying mechanisms. The pathogenesis of DR is characterized by the deterioration of the neurovascular unit (NVU), showing damage of vascular cells, activation of glial cells and dysfunction of neurons. Activation of the hexosamine biosynthesis pathway (HBP) and increased protein O-GlcNAcylation have been evident in the initiation of DR in patients and animal models. SCOPE OF REVIEW: The impairment of the NVU, in particular, damage of vascular pericytes and endothelial cells arises in hyperglycemia-independent conditions as well. Surprisingly, despite the lack of hyperglycemia, the breakdown of the NVU is similar to the pathology in DR, showing activated HBP, altered O-GlcNAc and subsequent cellular and molecular dysregulation. MAJOR CONCLUSIONS: This review summarizes recent research evidence highlighting the significance of the HBP in the breakdown of the NVU in hyperglycemia-dependent and -independent manners, and thus identifies joint avenues leading to vascular damage as seen in DR and thus identifying novel potential targets in such retinal diseases.
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Retinopatia Diabética , Hiperglicemia , Animais , Células Endoteliais/metabolismo , Vias Biossintéticas , Hexosaminas/metabolismo , Hiperglicemia/metabolismo , Retinopatia Diabética/metabolismoRESUMO
TP53 is the most frequently mutated gene in human cancer. While no TP53-targeting drugs have been approved in the USA or Europe so far, preclinical and clinical studies are underway to investigate targeting of specific or all TP53 mutations, for example, by restoration of the functionality of mutated TP53 (TP53mut) or protecting wildtype TP53 (TP53wt) from negative regulation. We performed a comprehensive mRNA expression analysis in 24 cancer types of TCGA to extract (i) a consensus expression signature shared across TP53 mutation types and cancer types, (ii) differential gene expression patterns between tumors harboring different TP53 mutation types such as loss of function, gain of function or dominant-negative mutations, and (iii) cancer-type-specific patterns of gene expression and immune infiltration. Analysis of mutational hotspots revealed both similarities across cancer types and cancer type-specific hotspots. Underlying ubiquitous and cancer type-specific mutational processes with the associated mutational signatures contributed to explaining this observation. Virtually no genes were differentially expressed between tumors harboring different TP53 mutation types, while hundreds of genes were over- and underexpressed in TP53mut compared to TP53wt tumors. A consensus list included 178 genes that were overexpressed and 32 genes that were underexpressed in the TP53mut tumors of at least 16 of the investigated 24 cancer types. In an association analysis of immune infiltration with TP53 mutations in 32 cancer subtypes, decreased immune infiltration was observed in six subtypes, increased infiltration in two subtypes, a mixed pattern of decreased and increased immune cell populations in four subtypes, while immune infiltration was not associated with TP53 status in 20 subtypes. The analysis of a large cohort of human tumors complements results from experimental studies and supports the view that TP53 mutations should be further evaluated as predictive markers for immunotherapy and targeted therapies.
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BACKGROUND: The prognostic significance of tumour budding (TB) and minimal cell nest size (MCNS) was shown in human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCC). However, the optimisation of cutpoints, the prognostic impact in HPV-positive HNSCC, and the comparison with other histopathological grading systems are insufficiently investigated. METHODS: TB and MCNS were analysed digitally in 1 and 10 high-power fields (HPF) of 331 HPV-positive and HPV-negative cases from TCGA. Optimising the cutpoints a new cellular dissociation grading (CDG) system was defined and compared to the WHO grading and the Brandwein-Gensler (BG) risk model. RESULTS: The two-tiered CDG system based solely on TB yielded optimal prognostic stratification with shortened overall survival for CDG-high cases. Optimal cut-offs were two buds (1 HPF) and six buds (10 HPF), respectively. Analysing MCNS did not add prognostic significance to quantifying TB. CDG was a significant prognostic marker in HPV-negative and HPV-positive tumours and prognostically superior to the WHO and BG systems. High CDG was associated with clinically occult lymph-node metastases. CONCLUSIONS: The most comprehensive study of TB in HNSCC so far confirmed its prognostic impact in HPV-negative tumours and for the first time in HPV-positive tumours. Further studies are warranted to evaluate its applicability for therapy guidance in HNSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Carcinoma de Células Escamosas/patologia , Prognóstico , Infecções por Papillomavirus/complicações , Papillomaviridae , BiomarcadoresRESUMO
The ability of the ancient Egyptians to preserve the human body through embalming has not only fascinated people since antiquity, but also has always raised the question of how this outstanding chemical and ritual process was practically achieved. Here we integrate archaeological, philological and organic residue analyses, shedding new light on the practice and economy of embalming in ancient Egypt. We analysed the organic contents of 31 ceramic vessels recovered from a 26th Dynasty embalming workshop at Saqqara1,2. These vessels were labelled according to their content and/or use, enabling us to correlate organic substances with their Egyptian names and specific embalming practices. We identified specific mixtures of fragrant or antiseptic oils, tars and resins that were used to embalm the head and treat the wrappings using gas chromatography-mass spectrometry analyses. Our study of the Saqqara workshop extends interpretations from a micro-level analysis highlighting the socio-economic status of a tomb owner3-7 to macro-level interpretations of the society. The identification of non-local organic substances enables the reconstruction of trade networks that provided ancient Egyptian embalmers with the substances required for mummification. This extensive demand for foreign products promoted trade both within the Mediterranean8-10 (for example, Pistacia and conifer by-products) and with tropical forest regions (for example, dammar and elemi). Additionally, we show that at Saqqara, antiu and sefet-well known from ancient texts and usually translated as 'myrrh' or 'incense'11-13 and 'a sacred oil'13,14-refer to a coniferous oils-or-tars-based mixture and an unguent with plant additives, respectively.
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Embalsamamento , Múmias , Humanos , Antigo Egito , Embalsamamento/economia , Embalsamamento/história , Embalsamamento/métodos , Cromatografia Gasosa-Espectrometria de Massas , História Antiga , Múmias/história , Resinas Vegetais/análise , Resinas Vegetais/história , Cerâmica/química , Cerâmica/história , Alcatrões/análise , Alcatrões/história , Óleos de Plantas/análise , Óleos de Plantas/história , Região do Mediterrâneo , Clima Tropical , Florestas , Traqueófitas/química , Comércio/históriaRESUMO
Background and Aims: Female pattern hair loss affects females of all ages with a trend to increase after menopause. This disorder may have significant psychological impact and lead to anxiety and depression. Objective: In a single center, double blind, randomized, placebo-controlled study, the effects of oral Pycnogenol® intake (3 × 50 mg/day for a total of 6 months) on hair density, scalp microcirculation, and a variety of skin physiological parameters was studied in Han Chinese menopausal women (N = 76) in Shanghai, China. Methods: Measurements were taken at the beginning and after 2 and 6 months, respectively. Hair density was determined by digital photographs and further evaluated by Trichoscan software. Transepidermal water loss was measured by a humidity sensor in a closed chamber on the skin surface. Changes in microcirculation were detected as resting flux on the scalp by reflection photoplethysmography. Results: Pycnogenol® intake significantly increased hair density by 30% and 23% after 2 and 6 months of treatment, respectively, as detected by Trichoscan® evaluation of digital photographs. Interestingly, photoplethysmography revealed that this beneficial effect was associated with a decrease in resting flux of the scalp skin, which might indicate an improvement of microcirculation. None of these effects were observed in the placebo taking group. In addition, a significant transient decrease of transepidermal water loss was observed in scalp skin under Pycnogenol,® but not placebo treatment. Conclusion: Oral intake of Pycnogenol® might have the potential to reduce hair loss in postmenopausal women.
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Glioblastomas are incurable primary brain tumors harboring a heterogeneous landscape of genetic and metabolic alterations. Longitudinal imaging by MRI and [18F]FET-PET measurements enable us to visualize the features of evolving tumors in a dynamic manner. Yet, close-meshed longitudinal imaging time points for characterizing temporal and spatial metabolic alterations during tumor evolution in patients is not feasible because patients usually present with already established tumors. The replication-competent avian sarcoma-leukosis virus (RCAS)/tumor virus receptor-A (tva) system is a powerful preclinical glioma model offering a high grade of spatial and temporal control of somatic gene delivery in vivo. Consequently, here, we aimed at using MRI and [18F]FET-PET to identify typical neuroimaging characteristics of the platelet-derived growth factor B (PDGFB)-driven glioma model using the RCAS-tva system. Our study showed that this preclinical glioma model displays MRI and [18F]FET-PET features that highly resemble the corresponding established human disease, emphasizing the high translational relevance of this experimental model. Furthermore, our investigations unravel exponential growth dynamics and a model-specific tumor microenvironment, as assessed by histology and immunochemistry. Taken together, our study provides further insights into this preclinical model and advocates for the imaging-stratified design of preclinical therapeutic interventions.
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BACKGROUND: Cholangiocarcinoma (CCA) is a primary malignancy of the biliary tract with a dismal prognosis. Recently, several actionable genetic aberrations were identified with significant enrichment in intrahepatic CCA, including FGFR2 gene fusions with a prevalence of 10-15%. Recent clinical data demonstrate that these fusions are druggable in a second-line setting in advanced/metastatic disease and the efficacy in earlier lines of therapy is being evaluated in ongoing clinical trials. This scenario warrants standardised molecular profiling of these tumours. METHODS: A detailed analysis of the original genetic data from the FIGHT-202 trial, on which the approval of Pemigatinib was based, was conducted. RESULTS: Comparing different detection approaches and displaying representative cases, we described the genetic landscape and architecture of FGFR2 fusions in iCCA and show biological and technical aspects to be considered for their detection. We elaborated parameters, including a suggestion for annotation, that should be stated in a molecular diagnostic FGFR2 report to allow a complete understanding of the analysis performed and the information provided. CONCLUSION: This study provides a detailed presentation and dissection of the technical and biological aspects regarding FGFR2 fusion detection, which aims to support molecular pathologists, pathologists and clinicians in diagnostics, reporting of the results and decision-making.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/tratamento farmacológico , Genômica , Humanos , Técnicas de Diagnóstico Molecular , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
Homologous recombination deficiency (HRD) leads to DNA double-strand breaks and can be exploited by the use of poly (ADP-ribose) polymerase (PARP) inhibitors to induce synthetic lethality. Extending the original therapeutic concept, the role of HRD is currently being investigated in clinical trials testing immune checkpoint blockers alone or in combination with PARP inhibitors, but the relationship between HRD and immune cell context in cancer is incompletely understood. We analyzed the association between immune cell composition, gene expression, and HRD in 9,041 tumors of 32 solid cancer types from The Cancer Genome Atlas (TCGA). The numbers of genomic scars were quantified by the HRD sum score (HRDsum) including loss of heterozygosity, large-scale state transitions, and telomeric allelic imbalance. The T-cell inflamed gene expression profile correlated weakly, but significantly positively, with HRDsum across cancer types (ρ = 0.17). Within individual cancer types, a significantly positive correlation was observed only in breast cancer, ovarian cancer, and four other cancer types, but not in the remaining 26 cancer types. HRDsum and tumor mutational burden (TMB) correlated significantly positively across cancer types (ρ = 0.42) and within 18 cancer types. HRDsum and a proliferation metagene correlated significantly positively across cancer types (ρ = 0.52) and within 20 cancer types. Mismatch repair deficiency and HRD as well as proofreading deficiency showed a high level of exclusivity. High HRD scores were associated with an immunologically activated tumor microenvironment only in a minority of cancer types. Our data favor the combination of genetic markers, complex genomic markers (including HRDsum and TMB), and other molecular markers (including proliferation scores) for a precise and comprehensive read-out of the tumor biology and an individually tailored treatment.
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Instabilidade de Microssatélites , Neoplasias Ovarianas , Biomarcadores Tumorais/genética , Carcinoma Epitelial do Ovário , Feminino , Recombinação Homóloga , Humanos , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: While pain in the severe sacroiliac joint (SIJ) is a common cause of lower back pain, SIJ disease is often overlooked as a diagnosis. OBJECTIVE: This study examines the extent of sufficient long-term pain relief and functional improvement in patients with SIJ syndrome that are treated with thermocoagulation. Some patients treated with thermocoagulation noted initial improvement, but the functionality and pain relief had limited duration and efficacy. Patients with insufficient improvement were recommended to undergo fusion surgery as an option for better and longer lasting results. METHOD: Patients with a long history of back or pelvic problems were selected for the study. Endoscopic thermal coagulation of the SIJ was carried out. The follow-up examinations took place after 1, 3, 6, 12 months. In patients with insufficient pain relief and functionality after thermocoagulation, a fusion surgery was performed. The results of the fusion surgery were documented over a 12-month follow-up period. To carry out the statistical evaluation visual analog scale (VAS), Oswestry-Disability-Index (ODI) and the consumption of opioids were recorded. RESULTS: Forty-eight patients were included. The mean VAS values 12 months after thermocoagulation were 68.9. The ODI after 12 months was very near or somewhat higher than their baseline prior to the thermocoagulation. Thus, a fusion surgery was recommended. Thirty-three patients agreed to the fusion operation. The VAS values 12 months after fusion surgery decreased to 53.1. Analogous to the VAS values, the Oswestry index (ODI) showed a significant improvement after the fusion operation. CONCLUSION: The success of surgical intervention in 88% of the SIJ syndrome patients with inadequate results 12 months after thermocoagulation proves the superiority of SIJ fusion surgery. This study showed long-lasting pain relief by an average of 65% and a median improvement in functional impairments of 60%. In view of these results, fusion surgery should be considered for patients without sufficient success of thermocoagulation.
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Dor Lombar , Fusão Vertebral , Analgésicos Opioides , Eletrocoagulação , Humanos , Dor Lombar/cirurgia , Articulação Sacroilíaca/cirurgia , Fusão Vertebral/métodosRESUMO
BACKGROUND: Skin aging is a process regulated by chronological aging and amplified by exposome factors including chronic UV exposure and pollution, which both induce reactive oxygen species. Topical antioxidants have the potential to counteract this process and to improve skin aging signs, including wrinkles and hyperpigmentation. OBJECTIVE: To evaluate the efficacy of a topical antioxidant serum containing 15% L-ascorbic acid, neohesperidin, Pinus pinaster bark, tocopherol, and hyaluronic acid (HA) ex vivo on air pollution-induced pigmentation and gene expression, as well as in vivo on skin aging signs in Brazilian volunteers, after 90 days of use. METHODS: Ex vivo human skin samples were repetitively exposed to Diesel Exhaust Particles (DEP) and subsequently analyzed for changes in pigmentation and gene expression. Clinical efficacy was evaluated in 40 healthy adult females with phototype II to IV and visible photoaging signs, including facial hyperpigmentation, through dermatological evaluation and instrumental analysis including Reflectance Confocal Microscopy. RESULTS: Ex vivo, the topical antioxidant serum significantly reduced DEP-induced skin pigmentation and expression of proinflammatory genes. A significant improvement of skin aging signs was observed after 90 days. Local tolerance was good. CONCLUSION: The tested serum is effective in protecting human skin ex vivo against air pollution-induced skin pigmentation/aging and reduced in vivo skin aging signs, with a good safety profile after 90 days of daily use.