Improved outcomes in metastatic germ cell cancer: results from a large cohort study

PURPOSE Treatment of metastatic germ cell cancer (GCC) is based on the International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic classification published in 1997. 5-year survival rates were reported to be 91%, 79%, and 48% for patients with good, intermediate and poor prognosis, respectively. However, treatment results may have improved over time due to cumulative experience, improved supportive care and modern-type chemotherapy. METHODS Patients with metastatic GCC who received cisplatin-based chemotherapy at two institutions in Munich between 2000 and 2013 were retrospectively studied. Clinical characteristics, treatment and outcomes were analyzed with respect to the IGCCG prognostic classification. RESULTS Of 225 patients (median age 35~years), 72 (32%) had seminoma (S) and 153 (68%) nonseminoma. 175 (78%), 30 (13%) and 20 patients (9%) had good, intermediate and poor prognosis according to the IGCCCG classification. The 2-year-progression free survival of patients with good, intermediate and poor prognosis was 91%, 83% and 37%, and the 5-year-overall survival (OS) was 98%, 96%, and 66%, respectively. There was no significant difference in the OS between patients in the good and intermediate prognosis group. CONCLUSION Compared to data from the original IGCCCG classification system, the outcome of patients with metastatic GCC has considerably improved over time. While the prognosis of intermediate-risk patients is excellent, treatment in the poor-prognosis group remains to be improved

Large-scale benchmark study of survival prediction methods using multi-omics data

Multi-omics data, that is, datasets containing different types of high-dimensional molecular variables, are increasingly often generated for the investigation of various diseases. Nevertheless, questions remain regarding the usefulness of multi-omics data for the prediction of disease outcomes such as survival time. It is also unclear which methods are most appropriate to derive such prediction models. We aim to give some answers to these questions through a large-scale benchmark study using real data. Different prediction methods from machine learning and statistics were applied on 18 multi-omics cancer datasets (35 to 1000 observations, up to 100 000 variables) from the database 'The Cancer Genome Atlas' (TCGA). The considered outcome was the (censored) survival time. Eleven methods based on boosting, penalized regression and random forest were compared, comprising both methods that do and that do not take the group structure of the omics variables into account. The Kaplan-Meier estimate and a Cox model using only clinical variables were used as reference methods. The methods were compared using several repetitions of 5-fold cross-validation. Uno's C-index and the integrated Brier score served as performance metrics. The results indicate that methods taking into account the multi-omics structure have a slightly better prediction performance. Taking this structure into account can protect the predictive information in low-dimensional groups-especially clinical variables-from not being exploited during prediction. Moreover, only the block forest method outperformed the Cox model on average, and only slightly. This indicates, as a by-product of our study, that in the considered TCGA studies the utility of multi-omics data for prediction purposes was limited

Inferior Outcomes of EU Versus US Patients Treated With CD19 CAR-T for Relapsed/Refractory Large B-cell Lymphoma: Association With Differences in Tumor Burden, Systemic Inflammation, Bridging Therapy Utilization, and CAR-T Product Use

B-cell lymphoma; Tumor burden; Systemic inflammationLinfoma de células B; Carga tumoral; Inflamación sistémicaLimfoma de cèl·lules B; Càrrega tumoral; Inflamació sistèmicaReal-world evidence suggests a trend toward inferior survival of patients receiving CD19 chimeric antigen receptor (CAR) T-cell therapy in Europe (EU) and with tisagenlecleucel. The underlying logistic, patient- and disease-related reasons for these discrepancies remain poorly understood. In this multicenter retrospective observational study, we studied the patient-individual journey from CAR-T indication to infusion, baseline features, and survival outcomes in 374 patients treated with tisagenlecleucel (tisa-cel) or axicabtagene-ciloleucel (axi-cel) in EU and the United States (US). Compared with US patients, EU patients had prolonged indication-to-infusion intervals (66 versus 50 d; P < 0.001) and more commonly received intermediary therapies (holding and/or bridging therapy, 94% in EU versus 74% in US; P < 0.001). Baseline lactate dehydrogenase (LDH) (median 321 versus 271 U/L; P = 0.02) and ferritin levels (675 versus 425 ng/mL; P = 0.004) were significantly elevated in the EU cohort. Overall, we observed inferior survival in EU patients (median progression-free survival [PFS] 3.1 versus 9.2 months in US; P < 0.001) and with tisa-cel (3.2 versus 9.2 months with axi-cel; P < 0.001). On multivariate Lasso modeling, nonresponse to bridging, elevated ferritin, and increased C-reactive protein represented independent risks for treatment failure. Weighing these variables into a patient-individual risk balancer (high risk [HR] balancer), we found higher levels in EU versus US and tisa-cel versus axi-cel cohorts. Notably, superior PFS with axi-cel was exclusively evident in patients at low risk for progression (according to the HR balancer), but not in high-risk patients. These data demonstrate that inferior survival outcomes in EU patients are associated with longer time-to-infusion intervals, higher tumor burden/LDH levels, increased systemic inflammatory markers, and CAR-T product use.This work was supported by a Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) research grant provided within the Sonderforschungbereich SFB-TRR 388/1 2021 – 452881907, and DFG research grant 451580403 (to MS). The work was further supported by the Bavarian Elite Graduate Training Network (to MS), the Wilhelm-Sander Stiftung (to MS, project no. 2018.087.1), the Else-Kröner-Fresenius Stiftung (to MS), the Bavarian Center for Cancer Research (BZKF), and NCI Cancer Center Support Grant P30 CA076292. VLB, KR, and VB were funded by the Else-Kröner Forschungskolleg (EKFK) within the Munich Clinician Scientist Program (MCSP)

Comprehensive analysis of beta-catenin target genes in colorectal carcinoma cell lines with deregulated Wnt/beta-catenin signaling

Background: Deregulation of Wnt/beta-catenin signaling is a hallmark of the majority of sporadic forms of colorectal cancer and results in increased stability of the protein beta-catenin. beta-catenin is then shuttled into the nucleus where it activates the transcription of its target genes, including the proto-oncogenes MYC and CCND1 as well as the genes encoding the basic helix-loop-helix (bHLH) proteins ASCL2 and ITF-2B. To identify genes commonly regulated by beta-catenin in colorectal cancer cell lines, we analyzed beta-catenin target gene expression in two non-isogenic cell lines, DLD1 and SW480, using DNA microarrays and compared these genes to beta-catenin target genes published in the PubMed database and DNA microarray data presented in the Gene Expression Omnibus (GEO) database. Results: Treatment of DLD1 and SW480 cells with beta-catenin siRNA resulted in differential expression of 1501 and 2389 genes, respectively. 335 of these genes were regulated in the same direction in both cell lines. Comparison of these data with published beta-catenin target genes for the colon carcinoma cell line LS174T revealed 193 genes that are regulated similarly in all three cell lines. The overlapping gene set includes confirmed beta-catenin target genes like AXIN2, MYC, and ASCL2. We also identified 11 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that are regulated similarly in DLD1 and SW480 cells and one pathway - the steroid biosynthesis pathway - was regulated in all three cell lines. Conclusions: Based on the large number of potential beta-catenin target genes found to be similarly regulated in DLD1, SW480 and LS174T cells as well as the large overlap with confirmed beta-catenin target genes, we conclude that DLD1 and SW480 colon carcinoma cell lines are suitable model systems to study Wnt/beta-catenin signaling and associated colorectal carcinogenesis. Furthermore, the confirmed and the newly identified potential beta-catenin target genes are useful starting points for further studies

Priority-Lasso: a simple hierarchical approach to the prediction of clinical outcome using multi-omics data

BACKGROUND The inclusion of high-dimensional omics data in prediction models has become a well-studied topic in the last decades. Although most of these methods do not account for possibly different types of variables in the set of covariates available in the same dataset, there are many such scenarios where the variables can be structured in blocks of different types, e.g., clinical, transcriptomic, and methylation data. To date, there exist a few computationally intensive approaches that make use of block structures of this kind. RESULTS In this paper we present priority-Lasso, an intuitive and practical analysis strategy for building prediction models based on Lasso that takes such block structures into account. It requires the definition of a priority order of blocks of data. Lasso models are calculated successively for every block and the fitted values of every step are included as an offset in the fit of the next step. We apply priority-Lasso in different settings on an acute myeloid leukemia (AML) dataset consisting of clinical variables, cytogenetics, gene mutations and expression variables, and compare its performance on an independent validation dataset to the performance of standard Lasso models. CONCLUSION The results show that priority-Lasso is able to keep pace with Lasso in terms of prediction accuracy. Variables of blocks with higher priorities are favored over variables of blocks with lower priority, which results in easily usable and transportable models for clinical practice

Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19

Background: Coronavirus disease 2019 (COVID-19) can manifest as a viral-induced hyperinflammation with multiorgan involvement. Such patients often experience rapid deterioration and need for mechanical ventilation. Currently, no prospectively validated biomarker of impending respiratory failure is available.Objective: We aimed to identify and prospectively validate biomarkers that allow the identification of patients in need of impending mechanical ventilation.Methods: Patients with COVID-19 who were hospitalized from February 29 to April 9, 2020, were analyzed for baseline clinical and laboratory findings at admission and during the disease. Data from 89 evaluable patients were available for the purpose of analysis comprising an initial evaluation cohort (n = 40) followed by a temporally separated validation cohort (n = 49).Results: We identified markers of inflammation, lactate dehydrogenase, and creatinine as the variables most predictive of respiratory failure in the evaluation cohort. Maximal IL-6 level before intubation showed the strongest association with the need for mechanical ventilation, followed by maximal CRP level. The respective AUC values for IL-6 and CRP levels in the evaluation cohort were 0.97 and 0.86, and they were similar in the validation cohort (0.90 and 0.83, respectively). The calculated optimal cutoff values during the course of disease from the evaluation cohort (IL-6 level &gt; 80 pg/mL and CRP level &gt; 97 mg/L) both correctly classified 80% of patients in the validation cohort regarding their risk of respiratory failure.Conclusion: The maximal level of IL-6, followed by CRP level, was highly predictive of the need for mechanical ventilation. This suggests the possibility of using IL-6 or CRP level to guide escalation of treatment in patients with COVID-19-related hyperinflammatory syndrome

Adverse stem cell clones within a single patient’s tumor predict clinical outcome in AML patients

Acute myeloid leukemia (AML) patients suffer dismal prognosis upon treatment resistance. To study functional heterogeneity of resistance, we generated serially transplantable patient-derived xenograft (PDX) models from one patient with AML and twelve clones thereof, each derived from a single stem cell, as proven by genetic barcoding. Transcriptome and exome sequencing segregated clones according to their origin from relapse one or two. Undetectable for sequencing, multiplex fluorochrome-guided competitive in vivo treatment trials identified a subset of relapse two clones as uniquely resistant to cytarabine treatment. Transcriptional and proteomic profiles obtained from resistant PDX clones and refractory AML patients defined a 16-gene score that was predictive of clinical outcome in a large independent patient cohort. Thus, we identified novel genes related to cytarabine resistance and provide proof of concept that intra-tumor heterogeneity reflects inter-tumor heterogeneity in AML

Outcomes of men with HIV and germ cell cancer : Results from an international collaborative study

Background: Previous studies have shown that men with HIV and germ cell cancer (HIV-GCC) have inferior overall survival (OS) in comparison with their HIV-negative counterparts. However, little information is available on treatments and outcomes of HIV-GCC in the era of combination antiretroviral therapy (cART). Methods: This study examined men living with HIV who were 18 years old or older and had a diagnosis of histologically proven germ cell cancer (GCC). The primary outcomes were OS and progression-free survival (PFS). Results: Data for 89 men with a total of 92 HIV-GCCs (2 synchronous GCCs and 1 metachronous bilateral GCC) were analyzed; among them were 64 seminomas (70%) and 28 nonseminomas (30%). The median age was 36 years, the median CD4 T-cell count at GCC diagnosis was 420 cells/µL, and 77% of the patients on cART had an HIV RNA load < 500 copies/mL. Stage I disease was found in 44 of 79 gonadal GCCs (56%). Among 45 cases with primary disseminated GCC, 78%, 18%, and 4% were assigned to the good-, intermediate-, and poor-prognosis groups, respectively, of the International Germ Cell Cancer Collaborative Group. Relapses occurred in 14 patients. Overall, 12 of 89 patients (13%) died. The causes of death were refractory GCC (n = 5), an AIDS-defining illness (n = 3), and other causes (n = 4). After a median follow-up of 6.5 years, the 5- and 10-year PFS rates were 81% and 73%, respectively, and the 5- and 10-year OS rates were 91% and 85%, respectively. Conclusions: The 5- and 10-year PFS and OS rates of men with HIV-GCC were similar to those reported for men with HIV-negative GCC. Patients with HIV-GCC should be managed identically to HIV-negative patients. Lay Summary: Men living with HIV are at increased risk for germ cell cancer (GCC). Previous studies have shown that the survival of men with HIV-associated germ cell cancer (HIV-GCC) is poorer than the survival of their HIV-negative counterparts. This study examined the characteristics, treatments, and outcomes of 89 men with HIV-GCC in the era of effective combination antiretroviral therapies. The long-term outcomes of men with HIV-GCC were similar to those reported for men with HIV-negative GCC. Patients with HIV-GCC should be managed identically to HIV-negative patients