Adverse Prognostic Factor For Survival Research Articles

Synergistic effect of concurrent high molecular risk mutations and lower JAK2 mutant variant allele frequencies on prognosis in patients with myelofibrosis-insights from a multicenter study.

In addition to high-molecular risk (HMR) mutations (ASXL1, EZH2, SRSF2, IDH, and U2AF1Q157), lower JAK2V617F variant allele frequencies (VAF) have been demonstrated to be associated with poor prognosis of myelofibrosis (MF) patients. Nevertheless, the relationship between JAK2V617F VAF and HMR mutations remains inconclusive. To address this, we analyzed the mutation status of 54 myeloid neoplasm-relevant genes using targeted next-generation sequencing in 124 MF patients. Three cohorts from multiple international centers were analyzed for external validation. Among JAK2-mutated patients, the presence of HMR mutations drove poor prognosis in patients with lower JAK2V617F VAF but not in those with higher JAK2V617F VAF. Survival analyses showed consistent results across validation cohorts. In multivariable analysis, concurrent HMR and a lower JAK2V617F VAF was identified as an independent adverse prognostic factor for survival, irrespective of age, MIPSS70, MIPSS70 + v2, and GIPSS risk groups. Mutation co-occurrence tests revealed no shared mutational pattern over different cohorts, excluding potential confounding effect from other concurrent mutations. Importantly, the integration of HMR/JAK2V617F VAF (≤50%) status significantly enhanced existing prognostic models, as evidenced by higher c-indexes and time-dependent ROC analyses. Single-cell studies with sequential follow-ups are warranted to decipher the clonal evolution of MF and how it relates to JAK2V617F VAF dynamics.

Prognosis Influence of Additional Chromosome Abnormalities in Newly Diagnosed Acute Promyelocytic Leukemia with t(15;17)(q22;q21)

The therapeutic advancements over the last decade have dramatically improved the prognosis and decreased the mortality of acute promyelocytic leukemia (APL). Some patients still recur repeatedly, and the poor curative effect of some patients has become a challenging issue. Survival may be impacted by additional concurrent mechanisms linked to additional chromosome abnormalities (ACA) as a potential pathogenic factor. Therefore, to confirm the role of ACA, we retrospectively analyzed the characteristics and prognostic impact of ACA in a series of newly diagnosed APL patients with t(15;17)(q22;q21). First, we assessed the characteristics of chromosomal abnormalities. Of these 268 patients, 208 (77.6%) had the t(15;17) as the only abnormality and 60 (22.4%) had the t(15;17) with ACA. Based on the number of ACA, the evaluable cohort of APL patients with t(15;17) was further divided into four groups: no ACA, one ACA, two ACA, and three or more ACA, with respective frequencies of 77.24%, 13.81%, 5.22%, and 3.73%. Trisomy 8 was the most frequently observed ACA, alone or combined with other anomalies in 23 cases (39.0%). Second, there was no significant difference presented in main clinical characteristics and response to therapy between the groups t(15;17) with alone and t(15;17) with ACA ( p＞0.05). Similarly, no significant impact was observed in clinical features and response to therapy, such as median white blood cells, platelets, hemoglobin, and the rate of hematologic complete remission between patients with trisomy 8 and patients with other ACA ( p＞0.05). Third, the influence of ACA on prognosis in APL patients with a median follow-up time of 47 months (range 1-89 months) was analyzed. There was still no significant difference in APL patients between the group t(15;17) alone and the group t(15;17) with ACA for the incidence of 5-year overall survival(OS) (90.8% vs. 86.8%, p=0.531) and 5-year disease-free survival (DFS) (89.7% vs. 85.8%, p=0.301). Interestingly, patients in APL with trisomy 8 had a poorer 5-year OS than those with other ACA (91.8% vs. 69.6%, p=0.033) and unaffected 5-year DFS (88.9% vs. 88.2%, p=0.919). The OS and DFS were similar between patients with 0 to 2 ACA and patients with 3 or more ACA ( p=0.294, p=0.283, respectively). Otherwise, no statistical difference was demonstrated for the incidence of OS ( p=0.515) and DFS (p=0.383) among the groups based on the number of ACA besides t(15;17). Finally, the old patients with age ≥60 years were shown to have lower 5-year OS compared with young patients(67.9% vs. 94.0%, p ＜0.001) and unaffected 5-year DFS (94.3% vs. 87.8%, p=0.430). The association between age and ACA on the prognosis of APL was observed. Either Cox analysis of age and ACA or combined with age and trisomy 8, it was all indicated that age ≥60 years was only an adverse prognostic factor for survival ( p＜0.001, HR = 4.627, 95% CI: 2.144-9.982; p＜0.001, HR = 4.412, 95% CI: 2.037-9.553, respectively). It should be noted that OS significantly among the following groups of patients: ＜60 years without ACA, ≥60 years without ACA,＜60 years with ACA, and ≥60 years with ACA ( p＜0.001). The 5-year OS rates were 92.9%, 97.9%, 80.6%, and 52.5%. Overall, the group≥60 years with ACA had worse OS compared to the groups ≥60 years without ACA and＜60 years without ACA ( p＜0.001, p＜0.001, respectively ). The group＜60 years with ACA had lower OS compared to the group ≥60 years without ACA ( p＜0.001). Our results suggested that trisomy 8 as the most common ACA seemed to be an adverse but not independent predictive factor in APL with t(15;17), while the ACA besides t(15;17) did not confer poor prognosis in APL. Elderly patients with ACA appeared to have worse OS.

Reduced Early Mortality with Daratumumab-Based Frontline Therapy in Systemic AL Amyloidosis- Experience from the Columbia Amyloidosis Multidisciplinary Program

Introduction: Despite advances in treatmentof systemic light chain (AL) amyloidosis, early mortality (EM) has been substantial up until recently, with a 6-month EM rate of approximately 25% in the era preceding daratumumab (Muchtar et al. Blood. 2017).Daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone (Dara-VCD) is the first FDA-approved therapy for systemic AL amyloidosis based on the ANDROMEDA trial with an unprecedented hematologic complete response (Heme-CR) rate ≈ 50%. However, data on hematologic and cardiac organ response rate and estimated early mortality (EM) in different stages since routine introduction of daratumumab-based frontline therapy are lacking. Methods: We performed a retrospective cohort study of all consecutive patients treated with daratumumab-based combination therapy at Columbia Amyloidosis Multidisciplinary Program (CAMP). Hematologic and cardiac organ response rates are reported on an intention-to-treat (ITT) basis, with patients who died prior to response evaluation or those with missing data classified as non-responders. Time-to-event analyses were performed by the Kaplan-Meier method. Results: Eighty-three consecutive patients treated with daratumumab-based frontline therapy were included in the analysis. The baseline characteristics of our cohort in comparison with Dara-VCD arm of ANDROMEDA is shown in Table 1. The median age at diagnosis was 68 years (range, 40-91), with 65% being males and 13 patients (16%) of Black/African-American race. The median dFLC (involved - uninvolved) was 21.9 mg/dl, with 61% of patients having baseline dFLC>18 mg/dl. Mayo 2004 stage IIIa/IIIb comprised 65% of our cohort compared to 37% of ANDROMEDA trial. Thirty-three patients (44%) had NYHA Class III/IV symptoms. The daratumumab-based frontline regimens used were Dara-VCD (n=78), Dara-VD (n=2), Dara-D (n=2), and Dara-Ixazomib-D (n=1). High-dose melphalan followed by autologous hematopoietic cell transplantation (HDM-AHCT) as a part of frontline therapy was performed in 11 patients (13.4%), with melphalan dose being 140 mg/m 2 in 8, 200 mg/m2 in 2, and 100 mg/m 2 in 1 patient. Hematologic response was evaluable in 78 patients (i.e. dFLC>2 mg/dl at diagnosis). On an ITT basis, Heme-CR was achieved by 39 patients (50%), and very good partial response or better (Heme ≥VGPR) by 57 patients (73.1%). The median time to Heme-CR from treatment initiation was 2.7 months (range, 0.42-13.97). Among patients evaluable for cardiac organ response (i.e. NT-proBNP≥650 pg/ml; n=64), 35 (58.3%) achieved an organ response. The median time to initial cardiac response (>30% reduction in NT pro-BNP with absolute reduction of >300 pg/ml) was 2.95 months (range, 0.43-10.43). Figure 1 demonstrates comparable hematologic and numerically higher cardiac organ response rate in our cohort vs Dara-VCD arm of ANDROMEDA trial. Next, we estimated the EM rate. The estimated EM at 6 months in our cohort was 7.6% (95% CI, 3.4-15.9). 6-month EM in patients with Mayo 2004 stage IIIb was 22.2% (95% CI, 9.5-43.6) vs 1.96% (95% CI, 0.27-12.65) in those with stage I-IIIa ( p<0.001) [Figure 2]. By Mayo 2012 staging, the estimated 6-month EM rate in patients with stage I, II, III, and IV disease was 0% (95% CI, 0-0), 0% (95% CI, 0-0), 9.6% (95% CI, 2.4-31.3), and 12.9% (95% CI, 4.9-29.8) respectively ( p=0.0425). Among patients who underwent upfront HDM-AHCT (n=11), there was no transplant-related mortality at 100 days. On evaluating the prognostic impact of individual factors in Mayo 2012 staging (NT-proBNP, Troponin, and dFLC) on OS, dFLC>18 mg/dl was no longer a significant adverse prognostic factor for survival in both univariate and multivariate analysis. Updated data will be presented at the meeting. Conclusion: Despite a sicker population with more advanced cardiac involvement compared to ANDROMEDA trial, daratumumab-based frontline induction therapy led to similar Heme-CR rate and favorable cardiac organ response rate in our cohort. Additionally, estimated 6-month EM has decreased by approximately 3-fold compared to historical data, with dramatic reduction in Mayo 2004 stage I-IIIa and continued substantial EM in stage IIIb disease. Finally, as clone-directed therapy has significantly improved, light chain burden at baseline may not be a relevant prognostic factor in contemporary era and should be scrutinized in larger datasets to re-design the staging system.

HNRNPA2B1-mediated m6A modification of TLR4 mRNA promotes progression of multiple myeloma

BackgroundMultiple myeloma (MM) is a malignancy of plasma cells that remains incurable. Toll-like receptor 4 (TLR4) acts as a stress-responsive signal, protecting mitochondria during proteasome inhibitor (PI) exposure, maintaining mitochondrial metabolism and increasing drug resistance in MM. However, the mechanism of TLR4 regulation remains elusive.AimsThe purpose of this study was to investigate the methylation pattern of multiple myeloma and its effect on the expression of HNRNPA2B1 and downstream targets.MethodsThe methylation level in MM and normal bone marrow specimens was detected using a colorimetric assay. HNRNPA2B1 gene knockdown was achieved in RPMI 8226 MM cells via adenovirus transfection. CCK8 and flow cytometric assays were used to detect proliferation and apoptosis, respectively. Transcriptome sequencing and m6A methylation MeRIP sequencing were applied, and differentially expressed genes (DEGs) were detected. Three independent NCBI GEO datasets were applied to examine the effects of HNRNPA2B1 and TLR4 expression on MM patient survival.ResultsHNRNPA2B1 promoted MM progression. Clinical data from database revealed that HNRNPA2B1 was adverse prognostic factor for survival among MM patients. Furthermore, transcriptome sequencing and methylation sequencing showed that HNRNPA2B1 recognized and was enriched at the m6A sites of TLR4 and TLR4 was down-regulated of both the m6A level and transcription level in HNRNPA2B1-knockdown MM cells. Moreover, TLR4 was an adverse survival prognostic factor based on database analysis.ConclusionOverall, our study implies that the RNA-binding protein HNRNPA2B1 increases cell proliferation and deregulates cell apoptosis in MM through TLR4 signaling. Our study suggests HNRNPA2B1 as a potential therapeutic target for MM.

Outcome of Third-Line Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia in Chronic Phase: A Propensity Score Analysis

Background: Tyrosine Kinase Inhibitors (TKI) dramatically improve survival in patients with chronic myeloid leukemia in chronic phase (CML-CP). However, patients may develop intolerance of or resistance to TKI therapy over years. Given multiple effective therapies available, the optimal selection of third-line therapy is not clear. The aim of this study is to evaluate the outcomes of third-line TKI therapy in patients with CML-CP. Methods: We retrospectively combined patient-level data of third-line TKI therapy in the clinical trials of PACE and OPTIC studies with patients who received third-line TKI therapy at our institution. Given equivalent outcomes between second-generation TKIs (2G-TKI), we compared the outcomes of patients between 2G-TKI and ponatinib as third-line TKI therapy. Patients with T315I mutations were excluded in our study given the known resistance to all the 2G-TKI therapies. Multiple imputations was performed for missing covariates to reduce bias. Univariate and multivariate Cox regression analysis was performed for survival to identify prognostic factors with a p-value cutoff of 0.05 from univariate to multivariate analysis. One-to-one propensity score matching was performed with a caliper of 0.200, using matching covariates with age at the time of third-line therapy, gender, race, comorbidity, prior TKI therapy, the duration of prior TKI therapy, best prior response during the front-line and second-line TKI therapy, body mass index, white blood cell count, platelet count, percentages of basophils and blasts in peripheral blood, and BCR::ABL1 levels on the international scale. Progression-free survival (PFS) was defined from the start of third-line TKI therapy to the time of loss of major cytogenetic response during the study, progression to accelerated phase or blast phase at any time, death from any cause at any time, or the date of last follow-up; overall survival (OS) was defined as the start of third-line TKI therapy to death from any cause or the date of last follow-up. The Kaplan-Meier method was used for survival with the log-rank test and a significance p-value level of 0.05. Results: We identified 354 patients who received third-line TKI therapy [204 patients (58%) from our institution; 63 patients (18%) from the PACE study; 87 (25%) patients from the OPTIC study] with a median follow-up of 46 months (Table 1). Among them as third-line TKI therapy, 173 patients received 2G-TKI [69 patients (19%), dasatinib; 64 patients (18%), nilotinib; 40 patients (11%), bosutinib], and 181 patients received ponatinib (51%). Overall, the median age at the time of third-line TKI therapy was 54 years (range, 18-87). Prior to third-line TKI therapy, 313 patients (88%) received imatinib; 156 patients (44%), dasatinib; 161 patients (45%), nilotinib; 35 patients (10%), bosutinib. The overall median BCR::ABL1 level was 16.3% on the international scale at the time of third-line TKI therapy. Patients who received ponatinib had higher rates of non-ischemic cardiovascular comorbidity, shorter total duration of prior TKI therapies, higher percentage of basophiles in peripheral blood, and higher levels of BCR::ABL1 on the international scale. Propensity score matching minimized the baseline covariates and identified 96 patients at each group with a median follow-up of 46 months after propensity score matching. There is a tendency of deeper response with ponatinib at baseline BCR::ABL1 levels of >1-10% and >0.1-1% before and after propensity score matching. Using pre-matched data, multivariate Cox regression showed older age at the time of third-line TKI therapy and higher BCR::ABL1 levels as adverse prognostic factors for survival ; the third-line ponatinib therapy was associated with favorable survival [P=0.003; hazard ratio (HR), 0.435; 95% confidence internal (CI), 0.253-0.748]. The 4-year PFS rates were 58% and 75% in the 2G-TKI and ponatinib group, respectively, before matching (P<0.001); the 4-year PFS rates were 78% and 89%, respectively, after matching (P=0.0099). The 4-year OS rates were 57% and 80% in the 2G-TKI and ponatinib group, respectively, before matching; the 4-year OS rates were 78% and 87%, respectively, after matching (Figure 1). Conclusion: Third-line ponatinib therapy is optimal selection for patients with CML-CP who failed prior 2 TKI therapies in the absence of T315I mutation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

More Than Ten Years Follow-up of Frontline Tyrosine Kinase Inhibitor Therapy in Patients with Chronic Myeloid Leukemia

Background: Tyrosine kinase inhibitor (TKI) therapy improved survival in patients (pts) with chronic myeloid leukemia (CML). Treatment-free remission (TFR) can be considered for a minority of pts, particularly in those who achieved sustained deep molecular response (DMR). Given most pts needs TKI therapy over decades, the aim of this study is to evaluate the very long-term outcome of pts (pts) treated with frontline TKI. Methods: We analyzed 557 pts with newly diagnosed CML in chronic phase (CP) and accelerated phase (AP; based solely on the presence of clonal evolution) who were treated with frontline TKI therapy (standard-dose imatinib, 73 pts; higher-dose imatinib, 210 pts; dasatinib, 144 pts; and nilotinib, 130 pts) from July 2000 to September 2014. The presence of comorbidity was assessed by the Adult Comorbidity Evaluation-27. Responses criteria were previously defined (complete cytogenetic response, CCyR; major molecular response, MMR; molecular response with a 4-log reduction, MR4; molecular response with a 4.5-log reduction, MR4.5). Failure-free survival (FFS) was calculated from the start of therapy to the treatment discontinuation for any reason except of TFR; event-free survival (EFS), to the date of any of the events while on study as defined in the IRIS study; transformation-free survival (TFS), to the date of transformation to accelerated or blast phases during study; overall survival (OS), to the date of death from any cause at any time or date of last follow-up. We evaluated prognostic factors with univariate and multivariate Cox proportional hazard models with a p-value cutoff of 0.100 or less by univariate analysis for variable selections; cumulative incidence of response was assessed with a competing risk model. Multiple imputation was performed for missing variables to reduce bias. Time to complete cytogenetic response was analyzed as a time-dependent variable in the Cox regression Results: The median age at the start of TKI therapy was 49 years (range, 15.1-86.4). The overall median follow-up was 178 months (range, 5.3-253.9) (standard-dose imatinib, 231 months; higher-dose imatinib, 212 months; dasatinib 137 months; nilotinib 138 months) (Table 1). Overall, the 10-year cumulative incidence rates of CCyR, MMR, MR4, and MR4.5 were 91%, 87%, 76%, and 72%, respectively; among pts who responded, the median time to CCyR, MMR, MR4, and MR4.5 were 3.1 months, 5.9 months, 9.5 months, and 12.5 months, respectively. The cumulative incidence rates of CCyR, MMR, MR4, and MR4.5 were higher in the higher-dose imatinib, dasatinib, and nilotinib cohorts compared to standard-dose imatinib. The 10-year FFS rates were 48%, 52%, 67%, and 44% in the standard-dose imatinib, higher-dose imatinib, dasatinib, and nilotinib cohorts, respectively (P<0.001); the 10-year TFS rates were 84%, 98%, 98%, and 96%, respectively (P<0.001); the 10-year EFS rates were 67%, 80%, 89%, 86%, respectively (P=0.001); the 10-year OS rates were 67%, 80%, 89%, and 86%, respectively (P=0.206) (Figure 1). Backward multivariate Cox regression analysis identified older age at TKI therapy, the presence of smoking history, higher severity of comorbidity by the Adult Comorbidity Evaluation-27, higher percentage of blasts in peripheral blood, and longer time to achieve CCyR as adverse prognostic factors for survival. With the minimum median follow-up of more than 10 years in all the TKI groups, the 10-year relative survival rate was 91.4%; among pts who achieved CCyR within 1 year of frontline TKI therapy, the 10-year relative survival rate was 94.4%; MMR, 97.0%; MR4, 96.7%; MR4.5, 96.2%. Conclusion: TKI therapy has significantly improved outcomes of pts with CML-CP. Frontline second-generation TKIs achieve higher rates of DMR response than standard-dose imatinib. The assessment of comorbidity is essential assessment for the optimal selection of frontline TKI therapy. The survival of pts with CML-CP is similar to that of general population at 10 years. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Optimal Threshold of Smoking in Pack-Years and its Association with Survival Outcomes Among Patients Treated with Chemoradiation for Head and Neck Cancer

<h3>Purpose/Objective(s)</h3> A secondary analysis of RTOG 0129 established 10 pack-years of smoking as a threshold of risk stratification for survival among patients treated with chemoradiation for oropharyngeal cancer. We performed a single-institution, observational cohort study to evaluate the optimal threshold of pack-years of smoking and validate 10 pack-years as a prognostic factor. <h3>Materials/Methods</h3> A single-institution, retrospective database was queried for patients with non-metastatic head and neck cancer who underwent definitive-intent chemoradiation from January 2005 to April 2021. An optimal threshold of pack-years of smoking was evaluated based on maximizing log-rank test statistic, and heavy smokers were defined as those with above the threshold. Cox multivariable analysis (MVA) and Kaplan-Meier method were performed to analyze overall survival (OS) and progression-free survival (PFS). Multivariable Fine-Gray competing risk analysis was performed for locoregional (LRF) and distant failure (DF) outcomes with death as a competing event. Propensity score matching was performed to construct matched pairs based on nearest neighbor method in a 1:1 ratio with no replacement. Multivariable analyses were repeated using 10 pack-years of smoking as a threshold. <h3>Results</h3> A total of 518 patients were identified for analysis. Median follow up was 44.1 months (interquartile range 22.3-72.8). The threshold of smoking in pack-years was determined to be 22. On Cox MVA, heavy smokers were associated with worse OS (adjusted hazards ratio [aHR] 1.64, 95% confidence interval [CI] 1.17-2.30, p=0.004) and PFS (aHR 1.42, 95% CI 1.04-1.93, p=0.03). On multivariable Fine-Gray competing risk model, heavy smokers were associated with worse DF (aHR 1.70, 95% CI 1.03-2.83, p=0.04), but not LRF (aHR 1.03, 95% CI 0.59-1.78, p=0.92). Similar findings were noted among 141 matched pairs (OS: HR 1.93, 95% CI 1.29-2.88, p=0.001; PFS: HR 1.50, 95% CI 1.04-2.16, p=0.03; LRF: HR 0.92, 95% CI 0.49-1.71, p=0.78; DF: HR 1.94, 95% CI 1.02-3.68, p=0.04). However, heavy smokers defined using 10 pack-years of smoking as a threshold were not associated with OS (aHR 1.41, 95% CI 0.97-2.06, p=0.07), PFS (aHR 1.21, 95% CI 0.87-1.70, p=0.26), LRF (aHR 1.19, 95% CI 0.66-2.16, p=0.56), or DF (aHR 1.51, 95% CI 0.88-2.58, p=0.13). <h3>Conclusion</h3> In our study, heavy smoking based on 22 pack-years of smoking as a threshold was an independent adverse prognostic factor for survival and distant metastasis. However, using 10 pack-year of smoking as a threshold was not associated with such outcomes. Further studies are warranted to optimize the role of smoking in pack-years for risk stratification.

A comprehensive preoperative predictive score for post-hepatectomy liver failure after hepatocellular carcinoma resection based on patient comorbidities, tumor burden, and liver function: the CTF score

BackgroundPost-hepatectomy liver failure (PHLF) is a dreaded complication following liver resection for hepatocellular carcinoma (HCC) with a high mortality rate. We sought to develop a score based on preoperative factors to predict PHLF. MethodsPatients who underwent resection for HCC between 2000 and 2020 were identified from an international multi-institutional database. Factors associated with PHLF were identified and used to develop a preoperative comorbidity-tumor burden-liver function (CTF) predictive score. ResultsAmong 1785 patients, 106 (5.9%) experienced PHLF. On multivariate analysis, several factors were associated with PHLF including high Charlson comorbidity index (CCI ≥ 5) (OR 2.80, 95%CI, 1.08–7.26), albumin–bilirubin (ALBI) (OR 1.99, 95%CI, 1.10–3.56), and tumor burden score (TBS) (OR 1.06, 95%CI, 1.02–1.11) (all p < 0.05). Using the beta-coefficients of these variables, a weighted predictive score was developed and made available online (https://alaimolaura.shinyapps.io/PHLFriskCalculator/). The CTF score (c-index = 0.67) performed better than Child–Pugh score (CPS) (c-index = 0.53) or Barcelona clinic liver cancer system (BCLC) (c-index = 0.57) to predict PHLF. A high CTF score was also an independent adverse prognostic factor for survival (HR 1.61, 95%CI, 1.12–2.30) and recurrence (HR 1.36, 95%CI, 1.08–1.71) (both p = 0.01). ConclusionRoughly 1 in 20 patients experienced PHLF following resection of HCC. Patient (i.e., CCI), tumor (i.e., TBS), and liver function (i.e., ALBI) factors were associated with risk of PHLF. These preoperative factors were incorporated into a novel CTF tool that was made available online, which outperformed other previously proposed tools.

Generalised autonomic failure as a prognostic factor in systemic light-chain (AL) amyloidosis

Background In the present study, it was investigated whether autonomic dysfunction could predict prognosis in light-chain (AL) amyloidosis patients. Patients and methods Seventy-two patients with biopsy-proven AL amyloidosis were included and underwent an autonomic function test (AFT) between January 2016 and June 2019. Autonomic failure was evaluated using the Composite Autonomic Severity Score (CASS). Survival curves and the three-year overall survival (OS) rate were estimated using the Kaplan–Meier curve, and the Cox proportional hazards regression method was used to evaluate the variables that influenced survival. Results Autonomic dysfunction was observed in 69 (96%) patients with AL amyloidosis, and the three-year OS rate was 67%. Generalised autonomic failure (GAF) was observed in 31 (43%) patients. In the Kaplan–Meier curve, the three-year OS rates in patients with sudomotor dysfunction or GAF were lower than that in control patients (35 vs. 84%, and 33 vs. 81%, respectively). In Cox proportional hazards regression model, female, bone marrow plasma cell percentage, left ventricular systolic dysfunction, and GAF were significant independent variables associated with survival. Conclusion The results of this study indicate that GAF on the AFT is an independent adverse prognostic factor for survival in AL amyloidosis patients.

Association of progesterone receptor status with 21-gene recurrence score and survival among patients with estrogen receptor-positive breast cancer.

529 Background: Among patients with estrogen receptor (ER)-positive breast cancer, progesterone receptor (PR)-negative tumors were shown to have worse prognosis than PR-positive tumors. However, PR-negative tumors were underrepresented in trials such as TAILORx and RxPONDER, and the role of PR status in the setting of 21-gene recurrence score (RS) remains unclear. We performed an observational cohort study to evaluate the association of PR status with RS and the magnitude of chemotherapy benefits on survival. Methods: The National Cancer Database (NCDB) was queried for women diagnosed between 2010 and 2017 with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative, pT1-3N0-1a breast cancer who underwent surgery and endocrine therapy. Logistic and Cox multivariable analyses (MVA) were used to identify variables associated with high RS (&gt; 25) and overall survival (OS), respectively. Interaction test was performed among PR status, chemotherapy, and nodal staging. Propensity score matching was performed to reduce selection bias. Sensitivity analysis was performed after excluding those with postdiagnosis survival of less than 6 months to reduce immortal time bias. Results: A total of 143,828 patients met our criteria (n = 110,421 for PR-positive/pN0, n = 11,897 for PR-negative/pN0, n = 19,928 for PR-positive/pN1a, n = 1,582 for PR-negative/pN1a). Median follow up was 51.5 months (interquartile range 34.8-71.9). On logistic MVA, PR-negative tumors were more likely to have high RS (adjusted odds ratio [aOR] 6.68, 95% confidence interval [CI] 6.40-6.97, p &lt; 0.001). On Cox MVA, PR-negative tumors were associated with worse OS (adjusted hazards ratio [aHR] 1.20, 95% CI 1.10-1.31, p &lt; 0.001). Interaction among PR status, chemotherapy, and nodal staging was statistically significant (interaction p = 0.049). On subgroup analyses, the magnitude of chemotherapy benefit for OS was comparable among pN0 tumors (PR-positive: aHR 0.74, 95% CI 0.66-0.82; PR-negative: aHR 0.63, 95% CI 0.51-0.77) and was greater for PR-negative status among pN1a tumors (PR-positive: aHR 0.57, 95% CI 0.47-0.67; PR-negative: aHR 0.31, 95% CI 0.20-0.47). Similar findings were noted in 9,979, 1,822, 4,196, and 354 matched pairs for PR-positive/pN0 (HR 0.43, 95% CI 0.37-0.50), PR-negative/pN0 (HR 0.53, 95% CI 0.41-0.69), PR-positive/pN1a (HR 0.55, 95% CI 0.45-0.67), and PR-negative/pN1a (HR 0.25, 95% CI 0.14-0.45) tumors, respectively. On sensitivity analysis, our findings were consistent in Cox MVA using interaction and subgroup analyses. Conclusions: To our knowledge, this is the largest study using a nationwide oncology database suggesting that PR-negative status is an independent, adverse prognostic factor for survival associated with high RS, with greater chemotherapy benefits compared to PR-positive status among pN1a tumors even after adjusting for RS.

Factors Predicting Oncological Outcomes of Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma in Taiwan.

BackgroundTaiwan is one of the endemic regions where upper tract urothelial carcinoma (UTUC) accounts for approximately a third of all urothelial tumors. Owing to its high prevalence, extensive experience has been accumulated in minimally invasive radical nephroureterectomy (RNU). Although a variety of predictive factors have been explored in numerous studies, most of them were on a single-center or limited institutional basis and data from a domestic cohort are lacking.ObjectiveThis study aims to identify significant predicting factors of oncological outcomes, including overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and intravesical recurrence-free survival (IVRFS), following RNU for UTUC in Taiwan.MethodsA multicenter registry database, Taiwan UTUC Collaboration Group, was utilized to analyze oncological outcomes of 3,333 patients undergoing RNU from 1988 to 2021 among various hospitals in Taiwan. Clinicopathological parameters were recorded according to the principles established by consensus meetings. The Kaplan-Meier estimator was utilized to estimate the survival rates, and the curves were compared using the stratified log-rank test. Univariate and multivariate analyses were performed with the Cox proportional hazard model to explore potential predicting factors.ResultsWith a median follow-up of 41.8 months in 1,808 patients with complete information, the 5-year IVRFS, DFS, CSS, and OS probabilities were 66%, 72%, 81%, and 70%, respectively. In total, 482 patients experienced intravesical recurrence, 307 died of UTUC, and 583 died of any cause. Gender predominance was female (57%). A total of 1,531 patients (84.7%) had high-grade tumors; preoperative hydronephrosis presented in 1,094 patients (60.5%). Synchronous bladder UC was identified in 292 patients (16.2%). Minimally invasive procedures accounted for 78.8% of all surgeries, including 768 hand-assisted laparoscopic (42.5%) and 494 laparoscopic (27.3%) approaches. Synchronous bladder UC was the dominant adverse predicting factor for all survival outcomes. Other independent predicting factors for OS, CSS, and DFS included age ≧70, presence of preoperative hydronephrosis, positive surgical margin, LVI, pathological T and N staging, and laparoscopic RNU.ConclusionSynchronous UC of the urinary bladder is an independent adverse prognostic factor for survival in UTUC. The presence of preoperative hydronephrosis was also corroborated as a disadvantageous prognostic factor. Our multivariate analysis suggested that laparoscopic RNU might provide better oncological control.

Impact of intratumoural CD73 expression on prognosis and therapeutic response in patients with gastric cancer

AimCD73 overexpression has been reported in several malignancies and is considered to be a novel immune checkpoint. However, the role and significance of CD73 in gastric cancer (GC) still remain obscure. We aim to investigate the role of CD73 expression in predicting prognosis, shaping immune contexture and guiding therapeutic strategy in GC. MethodsThe study enrolled four independent cohorts with a total of 902 patients with GC. CD73 expression and immune contexture were examined by immunohistochemistry, single-sample gene set enrichment analysis and flow cytometry. Clinical outcomes of patient subgroups were evaluated using the Kaplan–Meier curves and Cox proportional hazard analysis. All statistical tests were two-sided. ResultsCD73 was identified as an independent adverse prognostic factor for survival in GC. CD73high tumours showed a specific microenvironment with more CD8+ T cell infiltration, but these CD8+ T cells displayed a dysfunctional phenotype. Furthermore, the CD73 (NT5E) mRNA level was associated with the Cancer Genome Atlas molecular subtypes, and NT5E high tumours showed significant fibroblast growth factor receptor 2 activation and vascular endothelial growth factor and receptor enrichment. In addition, CD73high tumours indicated better chemotherapeutic responsiveness to fluorouracil yet a worse objective response rate to pembrolizumab in GC. ConclusionsHigh CD73 expression indicated an immunoevasive contexture with CD8+ T cell dysfunction and represented an independent predictor for adverse clinical outcomes. As a potential immunotherapeutic target, CD73 could potentially be a novel biomarker for adjuvant chemotherapy, targeted therapies and immunotherapy. The crucial role of CD73 in the therapeutic landscape of GC needs further validation retrospectively and prospectively.

CTSE Overexpression Is an Adverse Prognostic Factor for Survival among Rectal Cancer Patients Receiving CCRT.

The introduction of preoperative concurrent chemoradiotherapy (CCRT) increases the rate of anal preservation and allows tumor downstaging for clinical stage T3/T4 or node-positive rectal cancer patients. However, there is no precise predictive tool to verify the presence of residual tumor apart from surgical resection. The gastrointestinal (GI) tract not only digests nutrients but also coordinates immune responses. As the outermost layer of the GI tract, mucus plays a key role in mediating the interaction between the digestive and immune systems, and aberrant mucus mesh formation may cause chemoresistance by impeding drug delivery. However, the correlations among digestion-related genes, mucin synthesis, and chemoresistance remain poorly understood. In the present study, we evaluated genes related to digestion (GO: 0007586) and identified cathepsin E (CTSE), which is involved in immune regulation, as the most significantly upregulated gene associated with CCRT resistance in rectal cancer in a public transcriptome dataset (GSE35452). We recovered 172 records of rectal cancer patients receiving CCRT followed by surgical resection from our biobank and evaluated the expression level of CTSE using immunohistochemistry. The results revealed that tumors with CTSE overexpression were significantly correlated with pre-CCRT and post-CCRT positive nodal status (both p < 0.001), advanced pre-CCRT and post-CCRT tumor status (p < 0.001 and p = 0.002), perineural invasion (p = 0.023), vascular invasion (p < 0.001), and a lesser degree of tumor regression (p = 0.003). At the univariate level, CTSE overexpression was an adverse prognostic factor for all three endpoints: disease-specific survival (DSS), metastasis-free survival (MeFS) (both p < 0.0001), and local recurrence-free survival (LRFS) (p = 0.0001). At the multivariate level, CTSE overexpression remained an independent prognostic factor for poor DSS, MeFS (both p = 0.005), and LRFS (p = 0.019). Through bioinformatics analysis, we speculated that CTSE overexpression may confer CCRT resistance by forming a defensive mucous barrier. Taken together, these results suggest that CTSE overexpression is related to CCRT resistance and inferior survival in rectal cancer patients, highlighting the potential predictive and prognostic value of CTSE expression.

Prognostic value of radiologic extranodal extension in patients with hypopharyngeal cancer treated with primary chemoradiation

Background and purposeWe aimed to evaluate the prognostic value of radiologic extranodal extension (rENE) in patients with hypopharyngeal cancer (HPC) treated with primary chemoradiation. Materials and methodsCancer registry data were reviewed from 2005 to 2014. Inclusion criteria included HPC, clinical N1–3 disease (AJCC staging system, 7th edition), and receiving radiotherapy. Patients with M1 diseaseor with synchronous/metachronous cancer were excluded. Staging images were reviewed by two radiologists. rENE was defined as infiltration of adjacent fat/muscles, irregular nodal surface, or irregular capsular enhancement. Clinical stage, rENE status, and clinical outcome were analyzed. ResultsOverall, 355 patients were included. Patients with rENE had lower 3-year overall survival (OS) and recurrence-free survival (RFS) rates. Univariate analysis showed that clinical T4 or N3 stage, overall stage IV, and rENE correlated with OS and RFS. In multivariate analysis, clinical T4 or N3 stage correlated with poor OS, while clinical T4 or N3 stage and rENE were independent predictors of poor RFS. N1/2 without rENE was designated as Group 1, N1/2 with rENE as Group 2, and N3 with/without rENE as Group 3. The 3-year RFS rates in Groups 1, 2, and 3 were 55.8%, 41.0%, and 29.3%, respectively. The 3-year RFS rate in Group 1 was significantly higher than that in the other two groups. ConclusionsrENE is an adverse prognostic factor for survival in patients with HPC treated with primary chemoradiation. It correlated with inferior RFS regardless of N stage. rENE may be used as a criterion for clinical ENE in future staging systems.

Prognostic factors in Waldenström macroglobulinemia: a report on 232 patients with the description of a new scoring system and its validation on 253 other patients

AbstractUsing Cox models, we established a new prognostic system based on simple clinical parameters in a training series of 232 patients whose diagnoses were made before 1989. Adverse prognostic factors for survival (P < .01) were age 65 years or older, male gender, albumin level lower than 40 g/L, hemoglobin level lower than 12 g/dL, platelet count less than 150 × 109/L, white blood cell count less than 4 × 109/L, high number of cytopenias, and hepatomegaly. Taking age (age 65 years or older, 1 point; younger than 65 years, 0 points), albumin (less than 40 g/L, 1 point; 40 g/L or more, 0 points), and total number of cytopenias (no cytopenia, 0 points; 1 cytopenia, 1 point; 2 or 3 cytopenias, 2 points) into account, we separated the 232 patients into 3 groups with low (score 0 or 1), intermediate (score 2), or high (score 3 or 4) risk, associated with 5-year survival rates at 87%, 62%, and 25%, respectively (P < .0001). Only the presence of 2 or 3 cytopenias was an independent prognostic factor among patients younger than 65 years (P < .0001). Albumin level lower than 40 g/L and the presence of 1 or more cytopenia defined a prognostic system for patients 65 years and older. Patients at low risk, intermediate risk, and high risk had 5-year survival rates at 92%, 63%, and 27%, respectively (P < .0001). The 3 prognostic systems separated the 167 patients of a test series in groups with significantly different survival rates. The overall scoring system retained a significant prognostic value in 86 additional patients treated between 1990 and 1996. We conclude that the combination of age, albumin level, and blood cell counts might help to select patients with Waldenström macroglobulinemia for treatment and to evaluate therapeutic results.

Outcomes of Patients with Chronic Myeloid Leukemia Treated with Third-Line Tyrosine Kinase Inhibitors

Outcomes of Patients with Chronic Myeloid Leukemia Treated with Third-Line Tyrosine Kinase Inhibitors

A Prognostic Model for Survival in Patients with Relapsed/Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia on the Combination of Low-Intensity Chemotherapy Plus Inotuzumab Ozogamicin with or without Blinatumomab

A Prognostic Model for Survival in Patients with Relapsed/Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia on the Combination of Low-Intensity Chemotherapy Plus Inotuzumab Ozogamicin with or without Blinatumomab

Severe renal impairment as an adverse prognostic factor for survival in newly diagnosed multiple myeloma patients.

BackgroundRenal impairment (RI) is associated with poor survival in newly diagnosed multiple myeloma (MM) patients. Renal function recovery has been one of the main therapeutic goals in those patients.MethodsThe records from 393 newly diagnosed MM patients in our hospital between January 2012 and December 2016 were retrospectively analyzed. RI was defined as an eGFR < 40 mL/min according to the novel IMWG criteria. RI patients were categorized based on their renal function at diagnosis: severe RI: eGFR < 30 mL/min, and mild RI: 30 mL/min ≤ eGFR <40 mL/min. We explored whether RI, and particularly severe RI, was an adverse prognostic factor for survival, and investigated the impact of renal function recovery on survival.ResultsSevere RI, hemoglobin <100 g/L, LDH ≥ 245 U/L, hyperuricemia, 1q21 amplification, and lack of novel agent treatment were associated with decreased overall survival (OS). Severe RI patients with renal response had a median OS of 27 months compared with 18 months for those patients without renal response (P = .030), but their median OS was still significantly lower than that for patients without severe RI, which was 51 months. In severe RI patients, the overall renal response rate in bortezomib‐based regimens was significantly higher than that in nonbortezomib‐based regimens.ConclusionOur results suggest that severe RI is an adverse prognostic factor for survival in newly diagnosed MM patients, restoration of renal function may improve survival, and bortezomib‐based regimens may be the preferred treatment in patients with severe RI.

Prognostic significance of positive surgical margins for scalp angiosarcoma

Scalp angiosarcomas (AS) are aggressive soft tissue sarcomas that present with outcomes different from other AS of the head and neck region. Due to the rarity of the disease, limited data on the clinical outcome of scalp AS are available. In particular, the prognostic significance of surgical margins remains controversial and the impact of margin status on survival has not been documented. We retrospectively reviewed 41 scalp AS patients, including 30 patients with localized disease and 11 patients with initial distant metastasis, treated in our institution between 1997 and 2017. Survival was determined by Kaplan-Meier analysis. In the 30 patients without distant metastasis (localized disease), univariate and multivariate analysis using the Cox proportional hazards model were used to determine clinicopathologic characteristics associated with recurrence free survival (RFS), locoregional control (LRC), and overall survival (OS). Totally 41 patients diagnosed with scalp AS were identified, including 30 patients with localized disease and 11 patients with initial distant metastasis on diagnosis. Overall, the median follow-up period was 19.3 (range 0.3-128.5) months. The median survival time was 16.6 (range 0.3-144.3) months and the 5-year OS (95% Confidence Interval (CI)) rate was 22% (12%-42%). In the 30 patients with localized disease, univariate analysis showed that positive margins, either lateral-side or deep-side, were significant prognostic factors for RFS, LRC, and OS (p<0.05). On multivariate analysis, positive margins emerged as adverse prognostic factors for RFS (Hazard Ratio (HR) 4.29, 95% CI, 1.71-10.75, p=0.002), LRC (HR 6.35, 95% CI, 2.19-18.37, p=0.001), and OS (HR 4.73, 95% CI, 1.71-13.07, p=0.003). Scalp AS is associated with high local recurrence rates and poor survival outcomes. Positive surgical margins are adverse prognostic factors for survival.

Prognosis, biological characteristics and importance of treatment's delay of breast cancer diagnosed during pregnancy.

e12545 Background: Breast cancer in pregnancy is that diagnosed during pregnancy or in the first year after birth (1), is the most frequent malignant neoplasms during pregnancy, (2,3); however, only 0.2% to 2.9% of all breast cancers occur during pregnancy(4), the incidence of breast cancer during pregnancy (BCDP) has increased the last few decades probably because of the delayed childbearing and the rise of maternal age (5,6). Because of the rarity of cases and the impracticability of conducting randomized controlled studies in this setting, several studies are retrospective, whilst some studies suggest outcomes for women are similar to non-pregnant patients with breast cancer(8–11), others (12–17) have demonstrated that pregnancy in itself is an adverse prognostic factor for survival. To contribute with the existing literature, we aimed to perform a cohort to analyze if there is a difference prognosis of patients with BCDP who started treatment during pregnancy or waited for delivery. Methods: We analyzed the baseline characteristics distribution in the BCP using the chi-square test and the Fisher’s exact test for categorical variables. We considered a statistically significant association when p value was &lt; 0.05. DFS and OS analyses were conducted using the Kaplan–Meier method, and the log-rank test was used to determine if there were any differences in the survival curves by the variables of interest. We performed the statistical analysis using the SPSS 25.0 software for Windows (SPSS Inc., Chicago, IL, USA). Results: Among 8037 breast cancer patients enrolled in the database at Instituto Nacional de Cancerología, Mexico (INCan), within the social security program named “Seguro Popular”, between January 2007 and June 2018, we identified and included 61 women, median maternal age at diagnosis in our BCP group was 35 years (range 21-47), triple negative and her2 comprised 50.8% and 49.2% of BCP is comprised by luminal tumors. Conclusions: We strongly believe that the treatment of breast cancer during pregnancy should be started as soon as possible, since we have seen that its delay in childbirth translates into worse disease-free and overall survival. [Table: see text][Table: see text]