Real-world survival improvements in patients with newly diagnosed metastatic prostate cancer treated in the United States.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 48-48
Author(s):  
Carlo Cattrini ◽  
Elisa Zanardi ◽  
Alessandra Rubagotti ◽  
Linda Zinoli ◽  
Matteo Capaia ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Cox Regression ◽  
De Novo ◽  
The United States ◽  
New Drugs ◽  
Rank Test ◽  
Cancer Specific Survival ◽  
Risk Of Death ◽  
T1 And T2

48 Background: New drugs have become available for the treatment of metastatic prostate cancer (mPCa) during the last two decades. Here, we explored the clinical outcomes of de novo mPCa in 3 large cohorts of patients diagnosed in 3 treatment eras: pre-docetaxel 2000-2003 (T1), docetaxel 2004-2010 (T2) and new androgen-receptor signalling inhibitors (ARSi) + cabazitaxel 2011-2016 (T3). Methods: The USA Surveillance Epidemiology and End Results (SEER) Incidence Data were investigated using the SEER*Stat software. We used the Kaplan – Meier method, log-rank test, Cox regression, hazard ratio (HR) and confidence intervals (CI) to analyse overall survival (OS) and cancer-specific survival (CSS). The maximum follow-up time point was 5 years. Results: A total 34.034 patients with de novo mPCa were analysed for OS, of these 6.621 T1, 12.711 T2 and 14.702 T3. Median OS was 29 months (mo) [95% CI: 28.5-29.5], 28 mo [27.0-28.9], 28 mo [27.3-28.7] and 31 mo [30.2-31.8] in whole, T1, T2 and T3 cohorts, respectively. In the multivariable model, adjusted for age and race, T3 patients showed better OS compared to T1 and T2 patients (HR: 0,92 [95% CI: 0,88-0,95] and 0,92 [0,89 to 0,95], respectively, p<0.001). A total of 33.641 patients were analysed for CSS, of these 6.514 T1, 12.540 T2 and 14.587 T3. Median CSS was 36 mo [35.3-36.7], 34 mo [32.6-35.3], 34 mo [33.0-35.0] and 38 mo [36.9-39.1] in whole, T1, T2, T3 cohorts, respectively. T3 patients had better CSS compared to T1 and T2 patients (HR: 0,93 [0,89-0,97] and 0,92 [0,89 to 0,96], respectively, p<0.001). No difference in OS or CSS was found between T1 and T2 cohorts. Conclusions: The prognosis of patients with de novo mPCa remains poor, with a median CSS of 3 years and a 5-year CSS of 35%. Approximately 8% decrease in the risk of death was found in the era of ARSi and cabazitaxel. The recent intensification of therapy in metastatic hormone-sensitive setting might lead to better outcomes in the next years.[Table: see text]

scholarly journals Epidemiological Characteristics and Survival in Patients with de novo Metastatic Prostate Cancer.

2020 ◽  
Author(s):  
Carlo Cattrini ◽  
Davide Soldato ◽  
Alessandra Rubagotti ◽  
Linda Zinoli ◽  
Elisa Zanardi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Cox Regression ◽  
De Novo ◽  
Cancer Specific Survival ◽  
Risk Of Death ◽  
The Usa ◽  
Epidemiological Characteristics ◽  
Risk Of Cancer ◽  
Reduced Risk

The real-world outcomes of patients with metastatic prostate cancer (mPCa) are largely unexplored. We investigated the improvements in overall survival (OS) and cancer-specific survival (CSS) in patients with de novo mPCa in latest years. The USA SEER Research Data (2000-2017) were analyzed using the SEER*Stat software. The Kaplan-Meier method and Cox regression were used. Patients with de novo mPCa were allocated to 3 cohorts based on year of diagnosis: A (2000-2003), B (2004-2010), C (2011-2014). Maximum follow-up was fixed to 5 years. Overall, 26434 patients were included. Age, race and metastatic stage significantly affected OS and CSS. After adjustment for age and race, patients in cohort C showed 9% reduced risk of death (HR:0.91 [95% CI, 0.87-0.95], p&amp;lt;0.001) and 8% reduced risk of cancer-specific death (HR:0.91 [95% CI, 0.87-0.95], p&amp;lt;0.001) compared to those in cohort A. After adjustment for age, race and metastatic stage, patients in cohort C showed an improvement in OS and CSS compared to cohort B (HR:0.94 [95% CI, 0.91-0.97], p=0.001 and HR:0.89 [95% CI, 0.85-0.92], p&amp;lt;0.001). Patients with M1c disease had a more pronounced improvement in OS and CSS compared with the other stages. No differences were found between cohort B and C. In conclusion, the prognosis of de novo mPCa remains poor with a median OS of 30 months and a median CSS of 35 months. Limited OS and CSS improvements were observed in latest years.

scholarly journals Epidemiological Characteristics and Survival in Patients with De Novo Metastatic Prostate Cancer

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2855 ◽  
Author(s):  
Carlo Cattrini ◽  
Davide Soldato ◽  
Alessandra Rubagotti ◽  
Linda Zinoli ◽  
Elisa Zanardi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Real World ◽  
Metastatic Prostate Cancer ◽  
Cox Regression ◽  
De Novo ◽  
The Real ◽  
Risk Of Death ◽  
Epidemiological Characteristics ◽  
Risk Of Cancer ◽  
Reduced Risk

The real-world outcomes of patients with metastatic prostate cancer (mPCa) are largely unexplored. We investigated the trends in overall survival (OS) and cancer-specific survival (CSS) in patients with de novo mPCa according to distinct time periods. The U.S. Surveillance, Epidemiology, and End Results (SEER) Research Data (2000–2017) were analyzed using the SEER*Stat software. The Kaplan–Meier method and Cox regression were used. Patients with de novo mPCa were allocated to three cohorts based on the year of diagnosis: A (2000–2003), B (2004–2010), and C (2011–2014). The maximum follow-up was fixed to 5 years. Overall, 26,434 patients were included. Age, race, and metastatic stage (M1) significantly affected OS and CSS. After adjustment for age and race, patients in Cohort C showed a 9% reduced risk of death (hazard ratio (HR): 0.91 (95% confidence interval [CI] 0.87–0.95), p < 0.001) and an 8% reduced risk of cancer-specific death (HR: 0.92 (95% CI 0.88–0.96), p < 0.001) compared with those in Cohort A. After adjustment for age, race, and metastatic stage, patients in Cohort C showed an improvement in OS and CSS compared with Cohort B (HR: 0.94 (95% CI 0.91–0.97), p = 0.001; HR: 0.89 (95% CI 0.85–0.92), p < 0.001). Patients with M1c disease had a more pronounced improvement in OS and CSS compared with the other stages. No differences were found between Cohorts B and C. In conclusion, the real-world survival of de novo mPCa remains poor, with a median OS and CSS improvement of only 4 months in the latest years.

Oncological outcomes of surgery in very high risk pT3b prostate cancer

2011 ◽  
Vol 18 (3) ◽  
pp. 113-119
Author(s):  
Daimantas MILONAS ◽  
Giedrė SMAILYTĖ ◽  
Darius TRUMBECKAS ◽  
Mindaugas JIEVALTAS
Keyword(s):  
Prostate Cancer ◽  
Radical Prostatectomy ◽  
Gleason Score ◽  
Cox Regression ◽  
Locally Advanced ◽  
Specific Antigen ◽  
Oncologic Outcomes ◽  
Cancer Specific Survival ◽  
Risk Of Death ◽  
Surgery Outcome

Background. The aim of the study was to present the oncologic outcomes and to determine the prognostic factors of overall (OS) and cancer-specific survival (CSS) as well as disease-progression-free survival (DPFS) after surgery for pT3b prostate cancer. Materials and methods. In 2002–2007, a pT3b stage after radical prostatectomy was detected in 56 patients. Patients were divided into groups according to the prostate-specific antigen (PSA) level (20 ng/ml), lymph nodes status (N0 vs. Nx vs. N1) and the Gleason score (6–7 vs. 8–10). The Kaplan–Meier analysis was used to calculate OS, CSS and DPFS. The Cox regression was used to identify the predictive factors of survival. Results. Five-year OS, CSS and DPFS rates were 75.1%, 79.6% and 79.3%, respectively. The survival was significantly different when comparing the Gleason 6–7 and 8–10 groups. The 5-year OS, CSS and DPFS were 91.2% vs. 48.6%, 97.1% vs. 51.1% and 93.8 vs. 51.1%, respectively. There was no difference in survival among the groups with a different PSA level. The OS and CSS but not DPFS were significantly different when comparing the N0 and N1 groups. The 5-year OS and CSS was 84.4% vs. 37.5% and 87.3% vs. 47.6%, respectively. The specimen Gleason score was a significant predictor of OS and CSS. The risk of death increased up to 4-fold when a Gleason score 8–10 was present at the final pathology. Conclusions. Radical prostatectomy may offer acceptable CSS, DPFS and OS rates in pT3b PCa. However, outcomes in patients with N1 and specimen Gleason ≥8 were significantly worse, suggesting the need of multimodality treatment in such cases. Keywords: prostate cancer, locally advanced, surgery, outcome

scholarly journals Prognostic Impact of Different Gleason Patterns on Biopsy Within Grade Group 4 Prostate Cancer

2021 ◽  
Author(s):  
Keiichiro Mori ◽  
Vidit Sharma ◽  
Eva M. Comperat ◽  
Shun Sato ◽  
Ekaterina Laukhtina ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cox Regression ◽  
Multivariable Analysis ◽  
Rank Test ◽  
Prognostic Impact ◽  
Grade Group ◽  
Cancer Specific Survival ◽  
Kaplan Meier ◽  
Pathologic Features ◽  
Increased Risk

Abstract Background Grade group (GG) 4 prostate cancer (PC) is considered a single entity; however, there are questions regarding prognostic heterogeneity. This study assessed the prognostic differences among various Gleason scores (GSs) classified as GG 4 PC on biopsy before radical prostatectomy (RP). Methods We conducted a multicenter retrospective study, and a total of 1791 patients (GS 3 + 5: 190; GS 4 + 4: 1557; and GS 5 + 3: 44) with biopsy GG 4 were included for analysis. Biochemical recurrence (BCR)-free survival, cancer-specific survival, and overall survival were analyzed using the Kaplan–Meier method and the log-rank test. Logistic regression analysis was performed to identify factors associated with high-risk surgical pathologic features. Cox regression models were used to analyze time-dependent oncologic endpoints. Results Over a median follow-up of 75 months, 750 patients (41.9%) experienced BCR, 146 (8.2%) died of any causes, and 57 (3.2%) died of PC. Biopsy GS 5 + 3 was associated with significantly higher rates of GS upgrading in RP specimens than GS 3 + 5 and GS 4 + 4. On multivariable analysis adjusted for clinicopathologic features, different GSs within GG 4 were significantly associated with BCR (p = 0.03) but not PC-specific or all-cause mortality. Study limitations include the lack of central pathological specimen evaluation. Conclusions Patients with GG 4 at biopsy exhibited some limited biological and clinical heterogeneity. Specifically, GS 5 + 3 had an increased risk of GS upgrading. This can help individualize patients’ counseling and encourage further study to refine biopsy specimen-based GG classification.

scholarly journals The Impact of Palliative Transurethral Resection of the Prostate on the Prognosis of Patients With Bladder Outlet Obstruction and Metastatic Prostate Cancer: A Population-Matched Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Kun Fang ◽  
Pan Song ◽  
Jiahe Zhang ◽  
Luchen Yang ◽  
Peiwen Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transurethral Resection ◽  
Bladder Outlet Obstruction ◽  
Metastatic Prostate Cancer ◽  
Cox Regression ◽  
Outlet Obstruction ◽  
Survival Curves ◽  
Cancer Specific Survival ◽  
The Impact ◽  
Surgical Group

Objective: This study aimed to evaluate the survival outcomes of patients with bladder outlet obstruction (BOO) and metastatic prostate cancer (mPCa) after having a palliative transurethral resection of the prostate (pTURP) surgery.Methods: We identified patients with mPCa between 2004 and 2016 in the Surveillance, Epidemiology, and End Results (SEER) database. Patients who received pTURP and non-surgical therapy were identified. A propensity-score matching was introduced to balance the covariate. Kaplan–Meier analysis and COX regression were conducted to evaluate the overall survival (OS) and cancer-specific survival (CSS) outcomes.Results: A total of 36,003 patients were identified; 2,823 of them were in the pTURP group and 33,180 were in the non-surgical group. The survival curves of the overall cohort showed that the pTURP group was associated with worse outcomes in both OS (HR: 1.12, 95% CI: 1.07–1.18, p &lt; 0.001) and CSS (HR: 1.08, 95% CI: 1.02–1.15, p = 0.004) compared with the non-surgical group. The mean survival time in the overall cohort of the pTURP group was shorter than the non-surgical group in both OS [35.13 ± 1.53 vs. 40.44 ± 0.59 months] and CSS [48.8 ± 1.27 vs. 55.92 ± 0.43 months]. In the matched cohort, the pTURP group had significantly lower survival curves for both OS (HR: 1.25, 95% CI: 1.16–1.35, p &lt; 0.001) and CSS (HR: 1.23, 95% CI: 1.12–1.35, p &lt; 0.001) than the non-surgical group. pTURP significantly reduced the survival months of the patients (36.49 ± 0.94 vs. 45.52 ± 1.23 months in OS and 50.1 ± 1.49 vs. 61.28 ± 1.74 months in CSS). In the multivariate COX analysis, pTURP increased the risk of overall mortality (HR: 1.19, 95% CI: 1.09–1.31, p &lt; 0.001) and cancer-specific mortality CSS (HR: 1.23, 95% CI: 1.14–1.33, p &lt; 0.001) compared with the non-surgical group.Conclusions: For mPCa patients with BOO, pTURP could reduce OS and CSS while relieving the obstruction.

scholarly journals Oncologic Outcomes of Surgery in T3 Prostate Cancer: Experience of a Single Tertiary Center

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
D. Milonas ◽  
G. Smailyte ◽  
M. Jievaltas
Keyword(s):  
Prostate Cancer ◽  
Radical Prostatectomy ◽  
Gleason Score ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Oncologic Outcomes ◽  
Cancer Specific Survival ◽  
Free Survival ◽  
Risk Of Death ◽  
Tertiary Center

Aim. The aim of this study is to present the oncologic outcomes and to determine the prognostic factors of overall survival (OS), cancer-specific survival (CSS), disease-progression-free survival (DPFS), and biochemical-progression-free survival (BPFS) after surgery for pT3 prostate cancer (PCa).Methods. Between 2002 and 2007, a pT3 stage after radical prostatectomy was detected in 182 patients at our institution. The Kaplan-Meier analysis was used to calculate OS, CSS, DPFS, and BPFS. Cox regression was used to identify predictive factors of survival.Results. pT3a was detected in 126 (69%) and pT3b in 56 (31%) of cases. Five-year OS, CSS, DPFS, and BPFS rates were 90.7%, 94%, 91.8%, and 48.4%, respectively. Survival was significantly different when comparing pT3a to pT3b groups. The 5-year OS, CSS, DPFS, and BPFS were 96% versus 72%, 98% versus 77%, 97.3% versus 79.3%, and 60% versus 24.2%, respectively. Specimen Gleason score was the most significant predictor of OS, CSS, DPFS, and BPFS. The risk of death increased up to 3-fold when a Gleason score 8–10 was present at the final pathology.Conclusions. Radical prostatectomy may offer very good CSS, OS, DPFS, and BPFS rates in pT3a PCa. However, outcomes in patients with pT3b or specimen Gleason ≥8 were significantly worse, suggesting the need for multimodality treatment in those cases.

scholarly journals Outcomes of metastasis-directed therapy of bone oligometastatic prostate cancer

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Paul Rogowski ◽  
Christian Trapp ◽  
Rieke von Bestenbostel ◽  
Nina-Sophie Schmidt-Hegemann ◽  
Run Shi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Local Control ◽  
Cox Regression ◽  
De Novo ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Primary Treatment ◽  
Rank Test ◽  
Bone Lesions ◽  
Oligometastatic Disease

Abstract Background The aim of this work was to investigate the outcome of metastasis-directed radiotherapy (MDT) in prostate cancer patients with bone metastases following current ESTRO/EORTC subclassifications for oligometastatic disease. Methods Clinical data of 80 consecutive oligometastatic patients with 115 bone lesions receiving MDT between 2011 and 2019 were retrospectively evaluated. Hormone-sensitive (77.5%) and castrate-resistant (22.5%) patients were included. MDT was delivered with conventional fractionated or stereotactic body radiotherapy (SBRT) techniques. Kaplan–Meier method, log rank test, as well as Cox regression were used to calculate local control (LC) and biochemical and clinical progression-free survival (bPFS/cPFS). Results At the time of MDT 31% of patients had de-novo synchronous oligometastatic disease, 46% had de-novo metachronous oligorecurrence after primary treatment and 23% had either de-novo oligoprogressive disease, repeat oligometastatic disease or induced oligometastatic disease. The median BED3 was 93.3 Gy (range 75.8–95.3 Gy). Concomitant ADT was administered in 69% of patients. After a median follow-up of 23 months the median bPFS and cPFS were 16.5 and 21.5 months, respectively. The 2-year LC rate was 98.3%. In multivariate analysis, age ≤ 70 (HR = 2.60, 95% CI 1.20–5.62, p = 0.015) and concomitant ADT (HR = 0.26, 95% CI 0.12–0.58, p = 0.001) significantly correlated with cPFS. Category of oligometastatic disease and hormone-sensitivity were predictive for cPFS in univariate analysis. Of 45 patients with biochemical relapse, nineteen patients (42.2%) had repeat oligometastatic disease. Fourteen patients (31%) underwent a second course of MDT. No patients experienced grade ≥ 3 toxicities. Conclusions MDT is safe and offers high local control rates in bone oligometastases of prostate cancer. At 2 years after treatment, more than 2 out of 5 patients are progression-free. Trial registration Retrospectively registered.

scholarly journals Prognostic role of docetaxel-induced suppression of free testosterone serum levels in metastatic prostate cancer patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Paula Kappler ◽  
Michael A. Morgan ◽  
Philipp Ivanyi ◽  
Stefan J. Brunotte ◽  
Arnold Ganser ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Cox Regression ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Serum Levels ◽  
Biologically Active ◽  
Free Form ◽  
Total Testosterone ◽  
The Impact

AbstractTo date, only few data concerning the biologically active, free form of testosterone (FT) are available in metastatic prostate cancer (mPC) and the impact of FT on disease, therapy and outcome is largely unknown. We retrospectively studied the effect of docetaxel on FT and total testosterone (TT) serum levels in 67 mPC patients monitored between April 2008 and November 2020. FT and TT levels were measured before and weekly during therapy. The primary endpoint was overall survival (OS). Secondary endpoints were prostate-specific antigen response and radiographic response (PSAR, RR), progression-free survival (PFS), FT/TT levels and safety. Median FT and TT serum levels were completely suppressed to below the detection limit during docetaxel treatment (FT: from 0.32 to < 0.18 pg/mL and TT: from 0.12 to < 0.05 ng/mL, respectively). Multivariate Cox regression analyses identified requirement of non-narcotics, PSAR, complete FT suppression and FT nadir values < 0.18 pg/mL as independent parameters for PFS. Prior androgen-receptor targeted therapy (ART), soft tissue metastasis and complete FT suppression were independent prognostic factors for OS. FT was not predictive for treatment outcome in mPC patients with a history of ART.

scholarly journals Prognostic Association between Common Laboratory Tests and Overall Survival in Elderly Men with De Novo Metastatic Castration Sensitive Prostate Cancer: A Population-Based Study in Canada

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2844
Author(s):  
Christopher J. D. Wallis ◽  
Bobby Shayegan ◽  
Scott C. Morgan ◽  
Robert J. Hamilton ◽  
Ilias Cagiannos ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Clinical Decision Making ◽  
Cox Regression ◽  
De Novo ◽  
Population Based ◽  
Population Based Study ◽  
Cox Regression Analysis ◽  
Lymphocyte Ratio ◽  
Laboratory Markers

De novo cases of metastatic prostate cancer (mCSPC) are associated with poorer prognosis. To assist in clinical decision-making, we aimed to determine the prognostic utility of commonly available laboratory-based markers with overall survival (OS). In a retrospective population-based study, a cohort of 3556 men aged ≥66 years diagnosed with de novo mCSPC between 2014 and 2019 was identified in Ontario (Canada) administrative database. OS was assessed by using the Kaplan–Meier method. Multivariate Cox regression analysis was performed to evaluate the association between laboratory markers and OS adjusting for patient and disease characteristics. Laboratory markers that were assessed include neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), albumin, hemoglobin, serum testosterone and PSA kinetics. Among the 3556 older men with de novo mCSPC, their median age was 77 years (IQR: 71–83). The median survival was 18 months (IQR: 10–31). In multivariate analysis, a statistically significant association with OS was observed with all the markers (NLR, PLR, albumin, hemoglobin, PSA decrease, reaching PSA nadir and a 50% PSA decline), except for testosterone levels. Our findings support the use of markers of systemic inflammation (NLR, PLR and albumin), hemoglobin and PSA metrics as prognostic indicators for OS in de novo mCSPC.

scholarly journals Elevated Expression of Glycerol-3-Phosphate Phosphatase as a Biomarker of Poor Prognosis and Aggressive Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1273
Author(s):  
Mohamed Amine Lounis ◽  
Veronique Ouellet ◽  
Benjamin Péant ◽  
Christine Caron ◽  
Zhenhong Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Biochemical Recurrence ◽  
Poor Prognosis ◽  
Cox Regression ◽  
Specific Antigen ◽  
Metabolic Stress ◽  
Cancer Specific Survival ◽  
High Risk Prostate Cancer ◽  
Increased Risk

The limitations of the biomarker prostate-specific antigen (PSA) necessitate the pursuit of biomarkers capable of better identifying high-risk prostate cancer (PC) patients in order to improve their therapeutic management and outcomes. Aggressive prostate tumors characteristically exhibit high rates of glycolysis and lipogenesis. Glycerol 3-phosphate phosphatase (G3PP), also known as phosphoglycolate phosphatase (PGP), is a recently identified mammalian enzyme, shown to play a role in the regulation of glucose metabolism, lipogenesis, lipolysis, and cellular nutrient-excess detoxification. We hypothesized that G3PP may relieve metabolic stress in cancer cells and assessed the association of its expression with PC patient prognosis. Using immunohistochemical staining, we assessed the epithelial expression of G3PP in two different radical prostatectomy (RP) cohorts with a total of 1797 patients, for whom information on biochemical recurrence (BCR), metastasis, and mortality was available. The association between biomarker expression, biochemical recurrence (BCR), bone metastasis, and prostate cancer-specific survival was established using log-rank and multivariable Cox regression analyses. High expression of G3PP in PC epithelial cells is associated with an increased risk of BCR, bone metastasis, and PC-specific mortality. Multivariate analysis revealed high G3PP expression in tumors as an independent predictor of BCR and bone metastasis development. High G3PP expression in tumors from patients eligible for prostatectomies is a new and independent prognostic biomarker of poor prognosis and aggressive PC for recurrence, bone metastasis, and mortality.

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