Pharmacometabolomics Identifies Candidate Predictor Metabolites of an L-carnitine Treatment Mortality Benefit in Septic Shock

AbstractBackgroundSepsis-induced metabolic dysfunction contributes to organ failure and death. L-carnitine has shown promise for septic shock, but a recent study demonstrated a non-significant reduction in mortality.MethodsA pharmacometabolomics study of patients (n=250) in a Phase II trial of L-carnitine to identify metabolic profiles predictive of a 90-day mortality benefit from L-carnitine. The independent predictive value of each pre-treatment metabolite concentration, adjusted for L-carnitine dose, on 90-day mortality was determined by logistic regression. A grid-search analysis maximizing the Z-statistic from a binomial proportion test identified specific metabolite threshold levels that discriminated L-carnitine responsive patients. Threshold concentrations were further assessed by hazard-ratio and Kaplan-Meier estimate.FindingsAccounting for L-carnitine treatment and dose, 11 1H-NMR metabolites and 12 acylcarnitines were independent predictors of 90-day mortality. Based on the grid-search analysis numerous acylcarnitines and valine were identified as candidate metabolites of drug response. Acetylcarnitine emerged as highly viable for the prediction of an L-carnitine mortality benefit due to its abundance and biological relevance. Using its most statistically significant threshold concentration, patients with acetylcarnitine ≥35µM were less likely to die at 90 days if treated with L-carnitine (18 g) versus placebo (p=0.01 by log rank test).InterpretationMetabolomics identified independent predictors of 90-day sepsis mortality. Our proof-of-concept approach shows how pharmacometabolomics may be useful for tackling the heterogeneity of sepsis and informing clinical trial design. Also, metabolomics can help understand mechanisms of sepsis heterogeneity and variable drug response, since sepsis induces alterations in numerous metabolite concentrations.

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Pharmacometabolomics identifies candidate predictor metabolites of an L‐carnitine treatment mortality benefit in septic shock

Clinical and Translational Science ◽

10.1111/cts.13088 ◽

2021 ◽

Author(s):

Michael A. Puskarich ◽

Theodore S. Jennaro ◽

Christopher E. Gillies ◽

Charles R. Evans ◽

Alla Karnovsky ◽

...

Keyword(s):

Septic Shock ◽

Mortality Benefit ◽

Candidate Predictor ◽

Treatment Mortality

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Comparison of effects of medicinal cannabis or standard palliative care on quality of life of patients with cholangiocarcinoma in Northeast Thailand

F1000Research ◽

10.12688/f1000research.75060.1 ◽

2022 ◽

Vol 11 ◽

pp. 20

Author(s):

Narisara Phansila ◽

Chaiyasit Sittiwet ◽

Ranee Wongkongdech

Keyword(s):

Quality Of Life ◽

Palliative Care ◽

Rank Test ◽

Northeast Thailand ◽

Care Clinic ◽

Early Access ◽

Signed Rank Test ◽

Medicinal Cannabis ◽

Pre Treatment

Background: Cholangiocarcinoma (CCA) has a poor prognosis and is a major cause of mortality and suffering in Thailand’s Northeastern (Isaan) Region. Methods: This prospective cohort study aimed to compare the health-related quality of life (HRQoL) among 72 newly diagnosed CCA patients; 42 patients who received cannabis treatment (CT) and 30 patients who received a standard palliative care treatment (ST). The study was carried out between 1st September 2019 to 31st October 2020. Data were collected from patients from oncology clinics of six hospitals in five provinces of northeast Thailand. The HRQoL was measured at baseline, and at 2 and 4 months after diagnosis by the European Organisation for Research and Treatment of Cancer (EORTC) Core Quality of Life questionnaires QLQ-C30, and QLQ-BIL21. The Mann-Whitney U-test was performed to compare quality of life scores between the two patient groups and Wilcoxon signed rank test was performed to compare within groups QoL scores at pre-treatment, and 2 and 4 month follow-ups. Results: Global health status and functional scales, for both groups were high at pre-treatment. At 2 and 4 month follow-up, CT group patients had consistent statistically significantly better Palliative Performance Scale (PPS), and QoL scores, and many symptom scores than the ST group. Conclusions: Medicinal cannabis may increase QoL for advanced CCA patients. Our findings support the importance of early access to palliative cannabis care clinic before the terminal and acceleration phase close to death.

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A Network Analysis of Multiple Myeloma Related Gene Signatures

Cancers ◽

10.3390/cancers11101452 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1452 ◽

Cited By ~ 4

Author(s):

Yu Liu ◽

Haocheng Yu ◽

Seungyeul Yoo ◽

Eunjee Lee ◽

Alessandro Laganà ◽

...

Keyword(s):

Multiple Myeloma ◽

Drug Response ◽

Molecular Mechanisms ◽

Proteasome Inhibitors ◽

Risk Groups ◽

Rank Test ◽

P Value ◽

Causal Network ◽

Gene Signatures ◽

Network Analyses

Multiple myeloma (MM) is the second most prevalent hematological cancer. MM is a complex and heterogeneous disease, and thus, it is essential to leverage omics data from large MM cohorts to understand the molecular mechanisms underlying MM tumorigenesis, progression, and drug responses, which may aid in the development of better treatments. In this study, we analyzed gene expression, copy number variation, and clinical data from the Multiple Myeloma Research Consortium (MMRC) dataset and constructed a multiple myeloma molecular causal network (M3CN). The M3CN was used to unify eight prognostic gene signatures in the literature that shared very few genes between them, resulting in a prognostic subnetwork of the M3CN, consisting of 178 genes that were enriched for genes involved in cell cycle (fold enrichment = 8.4, p value = 6.1 × 10−26). The M3CN was further used to characterize immunomodulators and proteasome inhibitors for MM, demonstrating the pleiotropic effects of these drugs, with drug-response signature genes enriched across multiple M3CN subnetworks. Network analyses indicated potential links between these drug-response subnetworks and the prognostic subnetwork. To elucidate the structure of these important MM subnetworks, we identified putative key regulators predicted to modulate the state of these subnetworks. Finally, to assess the predictive power of our network-based models, we stratified MM patients in an independent cohort, the MMRF-CoMMpass study, based on the prognostic subnetwork, and compared the performance of this subnetwork against other signatures in the literature. We show that the M3CN-derived prognostic subnetwork achieved the best separation between different risk groups in terms of log-rank test p-values and hazard ratios. In summary, this work demonstrates the power of a probabilistic causal network approach to understanding molecular mechanisms underlying the different MM signatures.

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Neutrophilia and mortality in women with uterine carcinosarcoma

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2019-000440 ◽

2019 ◽

Vol 29 (8) ◽

pp. 1258-1263 ◽

Cited By ~ 1

Author(s):

Rebecca Arend ◽

Anne Van Arsdale ◽

Anar Gojayev ◽

Brandon Michael Roane ◽

David Doo ◽

...

Keyword(s):

Absolute Neutrophil Count ◽

Neutrophil Count ◽

Progression Free Survival ◽

Rank Test ◽

Uterine Carcinosarcoma ◽

Poor Prognostic Factor ◽

Log Rank Test ◽

Pre Treatment ◽

Relationship Of ◽

The Relationship

ObjectiveThe objective of this study was to investigate the relationship between pre-treatment absolute neutrophil count and clinical outcomes in patients with uterine carcinosarcoma.MethodsIn an Institutional Review Board approved, retrospective cohort study of 103 patients with uterine carcinosarcoma, the pre-treatment absolute neutrophil count data were obtained from the medical records, along with clinical, pathologic, treatment, and outcome data. Kaplan–Meier survival estimates were calculated and compared by the log rank test. Univariable and multivariable Cox proportional hazard regression models were used to examine the relationship of pre-treatment absolute neutrophil count with progression-free survival and overall survival.ResultsUterine carcinosarcoma patients in the highest quartile of pre-treatment absolute neutrophil count had significantly reduced progression-free survival (p<0.001, log rank test), and overall survival (p<0.001, log rank test), compared with patients in the lower absolute neutrophil count quartiles. On multivariable analysis, high absolute neutrophil count was an independent poor prognostic factor for disease recurrence, HR 2.97 (95% CI 1.35 to 6.53, p=0.007) for highest versus lowest quartile absolute neutrophil count, and for mortality, HR 4.43 (95% CI 1.64 to 12.00, p= 0.003).ConclusionsHigh pre-treatment absolute neutrophil count is an independent poor prognostic factor in patients with uterine carcinosarcoma and may be useful as a potential biomarker in clinical trials. The mechanistic relationship of neutrophilia and uterine carcinosarcoma progression merits further investigation.

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The predictive role of CA 19–9 kinetics for time-to-progression (TTP) and overall survival (OS) in patients receiving palliative first-line chemotherapy for advanced pancreatic cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15637 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15637-e15637

Author(s):

M. Haas ◽

S. Boeck ◽

P. Stieber ◽

R. P. Laubender ◽

H. Buchner ◽

...

Keyword(s):

Pancreatic Cancer ◽

Statistical Significance ◽

Univariate Analysis ◽

Advanced Pancreatic Cancer ◽

Rank Test ◽

First Line ◽

Predictive Role ◽

Pre Treatment ◽

Line Chemotherapy

e15637 Background: Previous studies showed contradictory results for a predictive role of CA 19–9 kinetics during chemotherapy in patients (pts) with pancreatic cancer (PC). Methods: We performed a retrospective, multicenter study in order to evaluate the role of CA 19–9 as a biomarker for TTP and OS in PC. Main inclusion criteria: histological confirmed diagnosis of PC, treatment with first-line chemotherapy for advanced disease, pre-treatment CA 19–9 level of > 5.2 U/ml. As CA 19–9 measurements were conducted in different laboratories using different commercial assays, we defined a subgroup of pts where CA 19–9 was assessed exclusively by the Elecsys assay (Roche Diagnostics). For the analysis of CA 19–9 kinetics, at least one follow-up measurement between day 20 and 64 during first-line chemotherapy had to be available. Pts were divided into two subgroups of CA 19–9 responders and non-responders by cut-offs of a 25% and 50% decline, respectively. OS and TTP were estimated with the Kaplan-Meier-Method, differences between the subgroups were analyzed by using the log-rank test. Results: One hundred and eighty-six pts were included, 83 of them were tested with the Elecsys method. Median age was 63 years, 90 % of the pts were treated within prospective clinical trials. Median pre-treatment CA 19–9 was 1076 U/ml (range 5.7–100,000 U/ml), the median bilirubin was 0.6 mg/dl. Median OS and TTP were 9.8 months (mo) and 5.4 mo, respectively. In univariate analysis, pts with a CA 19–9 decline of at least 25% during chemotherapy lived significantly longer (11.9 mo vs. 8.2 mo, p=0.003) and had a significantly prolonged TTP (5.8 mo vs. 4.4 mo, p=0.018) than those with a lower decline or even CA 19–9 increase. Data for the Elecsys-measurements were comparable (OS: 13.4 mo vs. 8.6 mo, p=0.004; TTP: 7.0 mo vs. 2.6 mo, p=0.003). None of the analyses demanding a CA 19–9 drop of at least 50% reached the level of statistical significance. Conclusion: An early CA 19–9 decline of 25% during first-line chemotherapy may predict OS and TTP in pts with advanced PC. Innovative statistical methods are required to improve our understanding of the utility of CA 19–9 as a predictive biomarker in PC. [Table: see text]

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Senescence, a new concept in pathologic response evaluation of rectal carcinomas (RC) after neoadjuvant treatment.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e21021 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e21021-e21021

Author(s):

Claudia María Valverde ◽

Miren Aizpurua ◽

Jaume Capdevila ◽

Rafael Morales ◽

Isaac Nuñez ◽

...

Keyword(s):

Cox Regression ◽

Neoadjuvant Treatment ◽

Disease Free Survival ◽

Inverse Correlation ◽

Pathologic Response ◽

Rank Test ◽

Response Evaluation ◽

Neoadjuvant Radiotherapy ◽

P53 Expression ◽

Pre Treatment

e21021 Background: Available protocols of response evaluation after therapy are based on the presence of viable cells, fibrosis and necrosis. Senescence is an irreversible cell cycle arrest that can be activated by different kinds of stress like DNA damage and cytotoxic drugs. Senescent cells are histologically very similar to viable neoplasic cells and usually evaluated alike. Our hypothesis is that neoadjuvant treatment can induce senescence as part of the therapeutic response and its presence may impact the prognosis. Methods: Tumor samples of 45 consecutive patients (pts) with RC treated between sept/02 and feb/2007 with fluorouracil-based chemotherapy and neoadjuvant radiotherapy, and of 33 non-treated colon cancer pts (controls), were selected. p53 and P16-ki67 double immunostaining were retrospectively evaluated in endoscopic-pretreatment biopsies, post-therapy specimens, and controls. P16+/ki67- malignant glands were considered as senescent-like glands. SPSS v20.0 (Kruskal-Wallis, Cox regression and log-rank test) was employed for analysis. Results: After a median follow up of 60 months 13 pts had relapsed. Significant differences in the percentage of senescent-like glands were observed between treated carcinomas and their pre-treatment samples (p=0.0001) and also with the colonic-non-treated carcinomas (p=0.0001). A tendency toward a better disease free survival (DFS) (p=0.236) in those patients with more than 30% of senescent glands after treatment was observed. No differences in p53 were found between the 3 groups. However, low levels of p53 expression in pretreatment-rectal biopsies correlate with a better pathologic response (GR) (p=0.029), and better DFS (p=0.0958). Conclusions: The number of senescent-like glands increases after neoadjuvant therapy. There was a tendency for a better DFS in the pts with treatment-induced senescence. Moreover, an inverse correlation between p53 expression in pretreated endoscopic-samples and pathologic response and DFS was observed. Further and larger studies should be performed to confirm the prognostic implications of evaluating senescence markers in treated rectal carcinomas.

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Whole blood FOLH1 mRNA expression and treatment response in metastatic castration-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.188 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 188-188

Author(s):

Edmond Michael Kwan ◽

Sarah Q To ◽

Heidi C Fettke ◽

Maria M Docanto ◽

Patricia Bukczynska ◽

...

Keyword(s):

Prostate Cancer ◽

Whole Blood ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

Response Rates ◽

Predictive Biomarker ◽

Rank Test ◽

Castration Resistant Prostate Cancer ◽

Psa Response ◽

Pre Treatment

188 Background: Identifying predictive biomarkers for mCRPC patients receiving androgen receptor signalling inhibitors (ARSI) or chemotherapy remains an unmet clinical need. FOLH1 encodes for Prostate-Specific Membrane Antigen (PSMA), a type II glycoprotein highly expressed on prostate cancer cells. We designed a whole blood assay to detect FOLH1 mRNA, and correlated expression with clinical outcomes in patients commencing ARSI (abiraterone or enzalutamide) or chemotherapy (docetaxel or cabazitaxel). Methods: mCRPC patients commencing ARSI or chemotherapy were prospectively recruited at three Australian centres from June 2016 to July 2018. A quantitative reverse transcription polymerase chain reaction assay was used to detect FOLH1 transcript from whole blood samples collected in PAXgene® RNA tubes. Pre-treatment FOLH1 expression was correlated with PSA response rate (Fisher’s exact test) and PSA progression-free survival (PSA-PFS) (log-rank test). Results: Median follow-up was 13.6 months (IQR 9.7–19.3). In total, 88 pre-treatment samples were analysed, of which 75 (85%) were FOLH1-positive. In patients receiving ARSI, outcomes favoured FOLH1-positive patients compared to FOLH1-negative patients, with higher PSA response rates (39/60, 65% vs. 2/7, 29%; p = 0.1) and longer PSA-PFS (median 9.0 months [95% CI, 7.2-10.8] vs. 2.8 months [95% CI, 2.3-3.3]; p = 0.03). Conversely, in chemotherapy-treated patients, inferior outcomes were observed in FOLH1-positive patients compared to FOLH1-negative patients, with lower PSA response rates (4/15, 27% vs. 5/6, 83%, p = 0.05) and shorter PSA-PFS (median 2.9 months [95% CI, 2.8-3.0] vs. 4.1 months [95% CI, 3.7-4.5]; p = 0.32). Conclusions: Pre-treatment FOLH1 expression may differentiate between outcomes on ARSI vs. chemotherapy in mCRPC patients. The utility of FOLH1 as a predictive biomarker in mCRPC warrants further evaluation in larger, independent cohorts. [Table: see text]

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