Independent Prognostic Impact Research Articles

Epidemiology and treatment outcome of nasopharyngeal carcinoma in a low-incidence population - a DAHANCA analysis in Denmark 2000-2018.

Nasopharyngeal carcinoma (NPC) is a rare disease and most studies have therefore been conducted in endemic areas. The aim of this study was to describe epidemiology and treatment outcomes of NPC in a population-based, non-endemic setting. Patients with NPC diagnosed in Denmark from 2000 to 2018 were identified in the Danish Head and Neck Cancer Study Group (DAHANCA) database. Clinical records were reviewed to obtain missing data and confirm outcome, histological subtypes, Epstein-Barr virus (EBV)-status, prognostic factors, and treatment. NPC was identified in 394 patients corresponding to age-standardized incidence rates of 0.5 and 0.2 per 100,000 in men and women, respectively. The 5-year overall (OS) and disease-specific survival (DSS) were 56 and 66%. In multivariate analysis, stage, smoking, and histology affected both OS and DSS, as patients with undifferentiated carcinomas had superior outcomes. Tumor EBV-status was determined in 221 patients, of whom 160 (72%) tested positive. EBV-positivity was associated with an improved OS in univariate analysis, but not after adjustment for relevant clinical factors. NPC is a rare malignancy in Denmark, and three in four patients have EBV-associated tumors. Tumor histology, smoking status, and stage, but not EBV-status, had independent prognostic impact on survival.

Prognostic implications of guideline-directed medical therapy in functional mitral regurgitation: a meta-analysis

Abstract Background Randomized evidence of the role of heart failure medical therapy for patients with functional mitral regurgitation (FMR) is lacking. Purpose The present meta-analysis sought to investigate the independent long-term prognostic impact of the different medical categories recommended in heart failure, for subjects with FMR. Methods A systematic literature review was conducted in electronic databases to identify studies reporting the association of renin angiotensin system inhibitors (RASi), beta-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs) with outcomes in FMR. A random-effects meta-analysis was conducted to quantify the unadjusted and adjusted hazard ratios [(a)HRs] for all-cause death and the composite outcome in each medical category. Results The final sample comprised 12 studies with 6,715 FMR patients (Picture 1). The use of RASi and BBs was associated with a significantly lower risk for all-cause mortality (HR 0.52 [0.39-0.68]; p <0.00001, I2 =62 % and HR 0.62 [0.49-0.77]; p <0.0001, I2 =44 % respectively) and for the composite outcome (HR 0.54 [0.44-0.67]; p <0.00001, I2 =33 % and HR 0.62 [0.52-0.75], p <0.00001, I2 =35% respectively) in unadjusted models (Picture 2). Both RASi (aHR 0.73 [0.56-0.95], p =0.02, I2 =52%) and BBs (aHR 0.60 [0.41-0.88], p = 0.009, I2 =55%) retained their association with the composite outcome in pooled adjusted models (Picture 2). The prognostic benefit of using RASi or BBs was retained in subgroup analysis including only patients with moderate of severe FMR. MRAs did not demonstrate a significant association with improved outcomes in FMR. Conclusions RASi and BBs appear to have a favorable prognostic impact in patients with FMR, regardless of regurgitation severity.Study flow chart for study selectionPharmacotherapy and prognosis in FMR

Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: Extended follow-up of a multicenter, retrospective real-world experience with 321 cases outside of controlled clinical trials.

The ELOQUENT-3 trial demonstrated the superiority of the combination of elotuzumab, pomalidomide, and dexamethasone (EloPd) in terms of efficacy and safety, compared to Pd in relapsed/refractory multiple myeloma (RRMM), who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor. The present study is an 18-month follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloPd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 17.7months, 213 patients (66.4%) experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 7.5 and 19.2months, respectively. The updated multivariate analysis showed a significant reduction of PFS benefit magnitude both in advanced International Staging System (ISS) (II and III) stages and previous exposure to daratumumab cases. Instead, advanced ISS (II and III) stages and more than 2 previous lines of therapy maintained an independent prognostic impact on OS. Major adverse events included grade three-fourths neutropenia (24.9%), anemia (13.4%), lymphocytopenia (15.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 19.3% and 8.7%, respectively. A slight increase in the incidence of neutropenia and lymphocytopenia was registered with longer follow-up. In conclusion, our real-world study still confirms that EloPd is a safe and possible therapeutic choice for RRMM. Nevertheless, novel strategies are desirable for those patients exposed to daratumumab.

Even a low comorbidity burden predicts poor outcome in chronic heart failure.

Patients with heart failure (HF) often have multiple cardiovascular risk factors (CVRF) and comorbidities (CMB). We evaluated the impact of additive CMB and CVRF in HF prognosis. We retrospectively analyzed ambulatory patients with systolic dysfunction between January 2012 and May 2018. Follow-up: until January 2021. Endpoint: all-cause death. CVRF analyzed: Arterial hypertension, Diabetes mellitus and smoking. CMB evaluated: coronary artery disease, non-coronary atherosclerotic disease, respiratory disease, dementia, anemia, chronic kidney disease, inflammatory/autoimmune disease, active cancer and atrial fibrillation. Classification according to the number of CVRF and/or CMB: < 2 and ≥ 2. The independent prognostic impact of CVRF/CMB burden was assessed with multivariate Cox-regression. Most patients had ≥ 2 CMB (67.9%). Regarding CVRF, 14.9% presented none, 40.2% had one and 32.1% had two. During a median 49-month follow-up, 419 (49.1%) patients died. Mortality was higher among patients with ≥2 CVRF (56.1 vs 43.4% in those with <2) and in those with ≥2 CMB (57.7 vs 31.0%). While patients with one CMB had similar mortality than those with none. Patients with ≥2 CMB had higher long-term mortality risk: HR=2.47 (95% CI: 1.95-3.14). In patients with ≥2CVRF: HR of dying = 1.39 (1.14- 1.70). When taken together there was a clear survival disadvantage for patients with ≥ 2 CVRF/CMB - adjusted HR: 2.20 (1.45-3.34). The presence of only 2 CVRF/CMB more than doubles the patients´ risk of dying. CVRF and CMB should be assessed as part of routine patient management.

Discovery and Validation of a 15-Gene Prognostic Signature for Clear Cell Renal Cell Carcinoma.

Develop and validate gene expression-based biomarker associated with recurrent disease to facilitate risk stratification of clear cell renal cell carcinoma (ccRCC). We retrospectively identified 110 patients who underwent radical nephrectomy for ccRCC (discovery cohort). Patients who recurred were matched on the basis of grade/stage to patients without recurrence. Capture whole-transcriptome sequencing was performed on RNA isolated from archival tissue using the Illumina platform. We developed a gene-expression signature to predict recurrence-free survival/disease-free survival (DFS) using a 15-fold lasso and elastic-net regularized linear Cox model. We derived the 31-gene cell cycle progression (mxCCP) score using RNA-seq data for each patient. Kaplan-Meier (KM) curves and multivariable Cox proportional hazard testing were used to validate the independent prognostic impact of the gene-expression signature on DFS, disease-specific survival (DSS), and overall survival (OS) in two validation data sets (combined n = 761). After quality control, the discovery cohort comprised 50 patients with recurrence and 41 patients without, with a median follow-up of 26 and 36 months, respectively. We developed a 15-gene (15G) signature, which was independently associated with worse DFS and DSS (DFS: hazard ratio [HR], 11.08 [95% CI, 4.9 to 25.1]; DSS: HR, 9.67 [95% CI, 3.4 to 27.7]) in a multivariable model adjusting for clinicopathologic parameters (including stage, size, grade, and necrosis [SSIGN] score and Memorial Sloan Kettering Cancer Center nomogram) and mxCCP score. The 15G signature was also independently associated with worse DFS and DSS in both validation data sets (Validation A [n = 382], DFS: HR, 2.6 [95% CI, 1.6 to 4.3]; DSS: HR, 3 [95% CI, 1.4 to 6.1] and Validation B (n = 379), DFS: HR, 2.1 [95% CI, 1.2 to 3.6]; OS: HR, 3 [95% CI, 1.6 to 5.7]) adjusting for clinicopathologic variables and mxCCP score. We developed and validated a novel 15G prognostic signature to improve risk stratification of patients with ccRCC. Pending further validation, this signature has the potential to facilitate optimal treatment allocation.

Influence of Tumor Stroma on the Aggressiveness of Poorly Cohesive Gastric Carcinoma.

Tumor-stroma crosstalk promotes the adaptation of cancer cells to the local microenvironment and sustains their growth. We assessed the quantitative and qualitative impact of intralesional stroma on clinic-pathological features and the prognosis of poorly cohesive gastric cancer (PCGC) variants. Tissue microarrays including 75 PCGC specimens were immunostained for cytokeratin 8/18 and α-smooth muscle actin to assess the relative proportion of neoplastic cells versus stromal components and the cases were subsequently divided into stroma-rich (SR) and stroma-poor (SP) tumors. Stromal status is significantly associated with the depth of tumor invasion. Patient survival rate was found to be higher in the SP compared to the SR tumor group and, hence, abundant stroma was identified as a significant risk factor in univariable analysis but had no independent prognostic impact. We also investigated the mRNA levels of KRT8 and the associated transcriptional signatures using the molecular data of 82 PCGC cases divided into KRT8-high and KRT8-low groups. KRT8-high tumors were enriched in proteins localized in the extracellular compartment and their expression levels correlated with longer survival in the KRT8-high group and shorter overall survival in the KRT8-low group. Comprehensively, we find that relative intralesional stromal content is a marker of aggressiveness in PCGC tumors and that extracellular proteins characterize functionally and clinically different PCGC subgroups.

Neoadjuvant chemotherapy for breast cancer: Pathologic response rates but not tumor size, has an independent prognostic impact on survival.

We investigated the pathologic complete response rates (pCR) and survival outcomes of early breast cancer patients who underwent neoadjuvant chemotherapy (NAC) over 14 years at a French comprehensive cancer center and reported pCR and survival outcomes by tumor subtypes and size. From January 2005 to December 2018, 1150 patients receiving NAC were identified. Correlations between cT stage, breast tumor response, axillary lymph node response, pCR, surgery, and outcomes were assessed. pCR was defined as (ypT0/ypTis) and (ypN0/pN0sn). A pCR was reached in 31.7% (365/1150) of patients and was strongly associated with tumor subtypes, but not with tumor size (pretreatment cT category). Luminal-B Her2-negative and triple-negative (TN) subtypes, cN1 status, older age, and no-pCR had an independent negative prognostic value. Overall survival (OS), relapse-free survival (RFS), and metastasis-free survival (MFS) were not significantly different for cT0-1 compared to cT2 stages. In Cox-model adjusted on in-breast pCR and pN status, ypN1 had a strong negative impact (OS, RFS, and MFS: HR = 3.153, 4.677, and 6.133, respectively), higher than no in-breast pCR (HR = 2.369, 2.252, and 2.323). A negative impact of no pCR on OS was observed for cN0 patients and TN tumors (HR = 4.972) or HER2-positive tumors (HR = 11.706), as well as in Luminal-B Her2-negative tumors on MFS (HR = 2.223) and for Luminal-A on RFS (HR = 4.465) and MFS (HR = 4.185). Achievement of pCR, but not tumor size (pretreatment cT category), has an independent prognostic impact on survival. These results suggest potential NAC benefits in patients with small tumors (<2 cm), even in absence of clinically suspicious lymph nodes. Residual lymph node disease after NAC is the most powerful adverse prognostic factor.

Surgical and oncological results after rectal resections with or without previous treatment for prostate cancer.

Previous treatment for prostate cancer (PC) may potentially affect the surgical and oncological outcomes of subsequent rectal cancer surgery, but there are only a few studies regarding this particular group. In this study, we present the 3-year surgical and oncological results of rectal cancer patients who had received previous treatment for PC at a single Finnish tertiary referral centre. Data regarding all male patients diagnosed with rectal cancer and treated at Tampere University Hospital (TAUH) between 1997 and 2016 were gathered from medical records. In total, this study included 553 rectal cancer patients who underwent curative surgery, and 54 of them (9.8%) had a prior history of treatment for prostate cancer. Patients in the PC group were older and had more comorbidities compared with those in the non-PC group. The PC patients had a significantly higher risk of permanent stoma compared with the non-PC patients (61.5% vs. 45.2%, respectively, p = 0.025). The PC patients seemed to have lower tumours than the non-PC patients (87% vs. 75%, respectively, p = 0.05). Overall, the 3-year overall survival (OS) for the PC and non-PC patients was 74.1% and 80.6%, respectively. No significant differences were observed between the study groups even in the age-adjusted comparison [hazard ratio (HR): 1.07, confidence interval (CI) 95%: 0.60-1.89]. In the univariable analysis, radically operated patients without a history of PC exhibited an improved overall survival, (HR: 2.46, 95% CI: 1.34-4.53, p = 0.004). However, only a higher age-adjusted Charlson comorbidity index (CCI) and a low tumour location (<10 cm) were found to have an independent prognostic impact on worse OS in the multivariable analysis (HR: 1.57, 95% CI: 1.36-1.82, p < 0.001 and HR: 2.74, 95% CI: 1.32-5.70, p = 0.007, respectively). No significant differences were observed between the groups in terms of disease-free or local recurrence-free survival. Rectal cancer is more frequently found in the middle or lower part of the rectum in patients who have previously received treatment for prostate cancer. These patients also have a higher likelihood of requiring a permanent stoma. In radically operated rectal cancer, the PC group had a worse OS rate, according to the univariable analysis. However, the only independent prognostic factors for a worse OS that were highlighted in the multivariable analysis included a higher CCI and a low tumour location.

Elevated Risk of Adverse Prognosis in Patients with T2-3 Stage Breast Cancer Exhibiting Non-Pathological Complete Response Following Neoadjuvant Chemotherapy: Significance of Regenerating Islet-Derived Family Member 4.

In this study, we aimed to establish the role of regenerating islet-derived family member 4 (Reg IV) as an independent risk factor and prognostic predictor in patients with T2-3 stage breast cancer who exhibit a non-pathological complete response (non-pCR) following neoadjuvant chemotherapy (NACT). Additionally, we examined the potential correlation and interaction between Reg IV and epidermal growth factor receptor (EGFR). A total of 67 patients with T2-3 stage breast cancer exhibiting non-pCR after NACT between September 2019 and December 2021 were included in this study. The analysis involved Kaplan-Meier survival comparisons, pooled hazard ratios for risk quantification, Cox regression analysis to isolate the impact of Reg IV on prognosis, Riskplots for visualizing risk profiles, and SHAP analysis to assess the importance of variables in predicting outcomes. The findings indicate that patients positive for Reg IV had a significantly poorer prognosis (HR: 2.62, 95% CI: 1.06-6.47). Co-expression of Reg IV and EGFR was associated with the worst outcomes compared to patients negative for both markers. Cox regression analysis confirmed the independent prognostic impact of Reg IV (HR: 2.63, 95% CI: 1.66-3.59). Riskplot analysis showed that patients positive for both Reg IV and EGFR predominantly experienced disease progression. SHAP analysis further reinforced the significant effect of Reg IV on the disease course, without substantial interaction with EGFR. Reg IV may serve as an independent risk factor and predictive marker for adverse outcomes in patients with T2-3 stage breast cancer who do not achieve non-pCR following NACT.

Pediatric pulmonary multisystem langerhans cell histiocytosis: does lung lesion severity affect the outcome?

BackgroundThe pediatric pulmonary multisystem Langerhans cell histiocytosis (PPM LCH) is associated with either low risk or high risk organ(s). The nodulo-cystic lung lesions although pathognomonic, yet are very variable in severity and remain a source of controversy in certifying pulmonary LCH diagnosis. The study aimed to examine the prognostic value of clinical respiratory manifestations and radiological lung lesions severity. This is through associating a CT chest triad of bilateral, extensive and diffuse lesions. It is a retrospective study of 350 LCH patients who received systemic treatment at Children’s Cancer Hospital Egypt during the period from 2007 to 2020.ResultsSixty-seven patients (67/350–19.1%) had PPM LCH at presentation. Severe lung lesions were present in 24 of them. The median follow-up period was 61 months (IQR: 3.4–8.3). The 5-year overall survival (OS) and event free survival (EFS) was 89% and 56.6% respectively. The EFS, for severe radiological lesions triad was 38% ± 20.7 versus 66% ± 16.2 for non-severe lesions triad p 0.002, while for presence of chest X-ray changes 27% ± 22.344 versus absence of chest X ray changes 66% ± 14.7 p 0.001, for clinical respiratory manifestations 13% ± 13.9 versus none 62% ± 22.9 p < 0.001, for RO− with severe lung lesions 47% ± 30.4 versus RO− without severe lung lesions 69% ± 5.9 p 0.04. There was a tendency for the independent prognostic impact of severe lung involvement; aHR = 1.7 (95% CI 0.92–3.13, p = 0.09).ConclusionAlthough the lung is a low -risk organ per se in LCH, our study demonstrates a non negligeable prognostic impact of severe lung involvement in the risk stratification of pediatric LCH. This warrants further study and external validation.

Prognostic impact of abnormal sodium burden in heart failure patients with preserved ejection fraction.

Sodium abnormality is common in patients with heart failure (HF) and is associated with adverse clinical outcomes. The aim of this study is to determine the impact of abnormal sodium burden on long-term mortality and hospitalization in HF with preserved ejection fraction (HFpEF). We analysed participants from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial with available baseline and follow-up data (n = 1717). Abnormal sodium burden was defined as the proportion of days with abnormal sodium plasma levels (either <135 mmol/L or > 145 mmol/L). To determine the independent prognostic impact of abnormal sodium burden on the long-term clinical adverse outcomes (The primary outcome was any cause death, the secondary outcomes include cardiovascular disease death, HF hospitalization, any cause hospitalization and the primary endpoint of the original study), a multivariable Cox proportional hazard model and time-updated Cox regression model were performed. Abnormal sodium burden occurred in 717 patients (41.76%). A high abnormal sodium burden was associated with 1.47 (95% CI, 1.15-1.89) higher risk with any cause mortality, 1.51 (95% CI, 1.08-2.09) higher risk with CVD death and 1.31 (95% CI, 1.02-1.69) higher risk with HF hospitalization when compared with no burden group. When sodium level changes over time were accounted for in time-updated models, abnormal sodium level was still associated with poor clinical outcomes. Diuretic and spironolactone usage did not show a statistical interaction effect on the prognostic significance. In HFpEF patients, abnormal sodium burden was an independent predictor long-term any-cause mortality and HF hospitalization.

Toll-like receptors 1, 2, 4, 5, and 6 in gastric cancer.

Toll-like receptors (TLRs) are expressed on both immune cells and tumor cells, triggering both anti-tumor and pro-tumor responses. Therefore, TLRs have potential as prognostic biomarkers and immunotherapeutic targets. The aim of this study was to investigate TLR1, TLR2, TLR4, TLR5, and TLR6 expression and association with clinicopathological variables and survival in gastric cancer. Immunohistochemical study on cancer specimens from 564 resected gastric cancer patients was performed using tissue microarrays. The association between patient survival and TLR expression was calculated with Cox regression adjusted for confounding factors. Patients with high cytoplasmic TLR2 expression had significantly poorer 5-year survival than the low cytoplasmic TLR2 expression group in multivariate analysis (adjusted HR 1.38, 95% CI 1.11-1.71), and this estimate was similar in intestinal type (adjusted HR 1.33, 95% CI 0.98-1.80) and diffuse type (adjusted HR 1.48, 95% CI 1.06-2.05) histology subgroups. Patients with high cytoplasmic TLR6 expression group had significantly better 5-year survival compared with low cytoplasmic TLR6 expression group in multivariate analysis (adjusted HR 0.74, 95% CI 0.60-0.91). In the subgroup analysis of diffuse type of histology, the 5-year survival was better in high cytoplasmic TLR6 expression group in multivariable analysis (HR 0.62, 95% CI 0.46-0.83). In the intestinal type of histology subgroup, no significant differences between the groups were present. TLR1, TLR4, and TLR5 expression were not associated with 5-year survival. In conclusion, cytoplasmic TLR2 and TLR6 expression seem to have independent prognostic impact in gastric cancer, while TLR1, TLR4, and TLR5 do not.

Prognostic and Pharmacotypic Heterogeneity of Hyperdiploidy in Childhood ALL.

High hyperdiploidy, the largest and favorable subtype of childhood ALL, exhibits significant biological and prognostic heterogeneity. However, factors contributing to the varied treatment response and the optimal definition of hyperdiploidy remain uncertain. We analyzed outcomes of patients treated on two consecutive frontline ALL protocols, using six different definitions of hyperdiploidy: chromosome number 51-67 (Chr51-67); DNA index (DI; DI1.16-1.6); United Kingdom ALL study group low-risk hyperdiploid, either trisomy of chromosomes 17 and 18 or +17 or +18 in the absence of +5 and +20; single trisomy of chromosome 18; double trisomy of chromosomes 4 and 10; and triple trisomy (TT) of chromosomes 4, 10, and 17. Additionally, we characterized ALL ex vivo pharmacotypes across eight main cytotoxic drugs. Among 1,096 patients analyzed, 915 had B-ALL and 634 had pharmacotyping performed. In univariate analysis, TT emerged as the most favorable criterion for event-free survival (EFS; 10-year EFS, 97.3% v 86.8%; P = .0003) and cumulative incidence of relapse (CIR; 10-year CIR, 1.4% v 8.8%; P = .002) compared with the remaining B-ALL. In multivariable analysis, accounting for patient numbers using the akaike information criterion (AIC), DI1.16-1.6 was the most favorable criterion, exhibiting the best AIC for both EFS (hazard ratio [HR], 0.45; 95% CI, 0.23 to 0.88) and CIR (HR, 0.45; 95% CI, 0.21 to 0.99). Hyperdiploidy and subgroups with favorable prognoses exhibited notable sensitivities to asparaginase and mercaptopurine. Specifically, asparaginase sensitivity was associated with trisomy of chromosomes 16 and 17, whereas mercaptopurine sensitivity was linked to gains of chromosomes 14 and 17. Among different definitions of hyperdiploid ALL, DI is optimal based on independent prognostic impact and also the large proportion of low-risk patients identified. Hyperdiploid ALL exhibited particular sensitivities to asparaginase and mercaptopurine, with chromosome-specific associations.

Predictors and Prognostic Impact of Hematoma Expansion in Infratentorial Cerebral Hemorrhage.

Hematoma expansion (HE) is common and predicts poor outcome in patients with supratentorial intracerebral hemorrhage (ICH). We investigated the predictors and prognostic impact of HE in infratentorial ICH. We conducted a retrospective analysis of patients with brainstem and cerebellar ICH admitted at seven sites. Noncontrast computed tomography images were analyzed for the presence of hypodensities according to validated criteria, defined as any hypodense region strictly encapsulated within the hemorrhage with any shape, size, and density. Occurrence of HE (defined as > 33% and/or > 6-mL growth) and mortality at 90days were the outcomes of interest. Their predictors were investigated using logistic regression with backward elimination at p < 0.1. Logistic regression models for HE were adjusted for baseline ICH volume, antiplatelet and anticoagulant treatment, onset to computed tomography time, and presence of hypodensities. The logistic regression model for mortality accounted for the ICH score and HE. A total of 175 patients were included (median age 75years, 40.0% male), of whom 38 (21.7%) had HE and 43 (24.6%) died within 90days. Study participants with HE had a higher frequency of hypodensities (44.7 vs. 24.1%, p = 0.013), presentation within 3h from onset (39.5 vs. 24.8%, p = 0.029), and 90-day mortality (44.7 vs. 19.0%, p = 0.001). Hypodensities remained independently associated with HE after adjustment for confounders (odds ratio 2.44, 95% confidence interval 1.13-5.25, p = 0.023). The association between HE and mortality remained significant in logistic regression (odds ratio 3.68, 95% confidence interval 1.65-8.23, p = 0.001). Early presentation and presence of noncontrast computed tomography hypodensities were independent predictors of HE in infratentorial ICH, and the occurrence of HE had an independent prognostic impact in this population.

Venetoclax abrogates the prognostic impact of splicing factor gene mutations in newly diagnosed acute myeloid leukemia

AbstractMutations in splicing factor (SF) genes SRSF2, U2AF1, SF3B1, and ZRSR2 are now considered adverse risk in the European LeukemiaNet 2022 acute myeloid leukemia (AML) risk stratification. The prognostic impact of SF mutations in AML has been predominantly derived from younger patients treated with intensive (INT) therapy. We evaluated 994 patients with newly diagnosed AML, including 266 (27%) with a SFmut. Median age was 67 years overall, with patients with SFmut being older at 72 years. SRSF2 (n = 140, 53%) was the most common SFmut. In patients treated with INT, median relapse-free survival (RFS) (9.6 vs 21.4 months, P = .04) and overall survival (OS) (15.9 vs 26.7 months, P = .06) were shorter for patients with SFmut than without SFwt, however this significance abrogated when evaluating patients who received venetoclax with INT therapy (RFS 15.4 vs 20.3 months, P = .36; OS 19.6 vs 30.7 months, P = .98). In patients treated with LI, median RFS (9.3 vs 7.7 months, P = .35) and OS (12.3 vs 8.5 months, P = .14) were similar for patients with and without SFmut , and outcomes improved in all groups with venetoclax. On multivariate analysis, SFmut did not affect hazards of relapse and death for INT arm but reduced both these hazards in LI arm. In a large AML data set with >60% of patients receiving venetoclax with LI/INT therapy, SFmut had no independent negative prognostic impact. Newer prognostic models that consider LI therapy and use of venetoclax among other factors are warranted.

A Prognostic Model Based on Residual Cancer Burden and Tumor-Infiltrating Lymphocytes on Residual Disease after Neoadjuvant Therapy in HER2+ Breast Cancer.

We aim to evaluate the prognostic significance of tumor-infiltrating lymphocyte on residual disease (RD-TIL) in HER2+ patients with breast cancer who failed to achieve pathologic complete response (pCR) after anti-HER2+ chemotherapy (CT)-based neoadjuvant treatment (NAT). We assessed the feasibility of combining the prognostic information provided by residual cancer burden (RCB) and RD-TILs into a composite score (RCB+TIL). HER2+ patients with breast cancer treated with CT+anti-HER2-based NAT at three institutions were retrospectively included. RCB and TIL levels were evaluated on hematoxylin and eosin-stained slides from surgical samples according to available recommendations. Overall survival (OS) was used as an outcome measure. A total of 295 patients were included, of whom 195 had RD. RCB was significantly associated with OS. Higher RD-TILs were significantly associated with poorer OS as compared with lower RD-TILs (15% cutoff). In multivariate analysis, both RCB and RD-TIL maintained their independent prognostic value. A combined score, RCB+TIL, was calculated from the estimated coefficient of RD-TILs and the RCB index in a bivariate logistic model for OS. The RCB+TIL score was significantly associated with OS. The C-index for OS of the RCB+TIL score was numerically higher than that of RCB and significantly higher than that of RD-TILs. We have reported an independent prognostic impact of RD-TILs after anti-HER2+CT NAT, which might underlie an imbalance of the RD microenvironment towards immunosuppressive features. We provided a new composite prognostic score based on RCB+TIL, which was significantly associated with OS and proved to be more informative than the isolated evaluation of RCB and RD-TILs.

IRF4 rearrangement may predict favorable prognosis in children and young adults with primary head and neck large B‐cell lymphoma

Large B-cell lymphoma with IRF4 rearrangement (LBCL, IRF4+) has been recently recognized as a specific entity that is frequently associated with young age and favorable prognosis. However, whether the good outcome of the disease is due to IRF4+ or other factors remains obscure. We thus analyzed 100 young patients with primary head and neck LBCL to see the clinicopathologic correlates of IRF4+. The histopathology, immunophenotype, IRF4 status of the tumors, and clinical data were reviewed. Twenty-one tumors were diagnosed as LBCL, IRF4+, which were more frequently associated with a follicular growth pattern, medium-sized blastoid cytology, germinal center B-cell-like, and CD5+ phenotype, compared with IRF4- ones. While most of the patients received chemotherapy with or without radiation, eight IRF4+ patients received mere surgical resection of the tumor and exhibited excellent outcome. IRF4+ cases featured a significantly higher complete remission rate, and better survivals compared with IRF4- ones. Multivariate analysis confirmed IRF4+ correlates with a better survival. Our work confirmed the unique clinicopathologic features of LBCL, IRF4+, and disclosed for the first time the independent favorable prognostic impact of IRF4+. These findings may further unravel the heterogeneity of LBCL occurring in youth, and aid in risk stratification and tailoring the therapeutic strategy.

Impact of mitral regurgitation in patients with acute heart failure: insights from the RELAX-AHF-2 trial.

The impact of mitral regurgitation (MR) in patients hospitalized for acute heart failure (AHF) is not well established. We assessed the role of MR in patients enrolled in the Relaxin in Acute Heart Failure 2 (RELAX-AHF-2) trial. Patients enrolled in RELAX-AHF-2 with available data regarding MR status were included in this analysis. Baseline characteristics, in-hospital data, and clinical outcomes through 180-day follow-up were evaluated. The impact of moderate/severe MR was assessed. Among 6420 AHF patients with known MR status, 1810 patients (28.2%) had moderate/severe MR. Compared to patients with no/mild MR, those with moderate/severe MR were more likely to have history of heart failure (HF), prior HF hospitalization, more comorbidities, symptoms/signs of HF, lower left ventricular ejection fraction and higher N-terminal pro-B-type natriuretic peptide levels. Moderate/severe MR was associated with longer length of hospital stay, higher rates of residual dyspnoea, increased jugular venous pressure through the index hospitalization and a higher unadjusted risk of the composite of cardiovascular (CV) death or rehospitalization for HF/renal failure (RF) through 180 days (crude hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.03-1.27, p=0.01). The association between moderate/severe MR and poorer outcomes was not maintained in a multivariable model including several covariates of interest (adjusted HR 1.03, 95% CI 0.91-1.17, p=0.65). Similar findings were observed for HF/RF rehospitalization alone. In patients with AHF, moderate/severe MR was associated with a worse clinical profile but did not have an independent prognostic impact on clinical outcomes.

Prognostic value of 12-month response to therapy in pediatric patients with differentiated thyroid cancer

PurposeIn pediatric patients with differentiated thyroid cancer (DTC) we assessed the prognostic value of the 12-month response to therapy after initial treatment with surgery and radioactive iodine (RAI).MethodsWe retrospectively evaluated 94 pediatric patients with DTC, treated with surgery and RAI who were initially classified as low, intermediate or high risk of relapse of disease according to the American Thyroid Association (ATA) guidelines. Twelve months after RAI administration the response to therapy was assessed by serum thyroglobulin (Tg) measurement and neck ultrasound and patients were classified as having excellent response (ER) or no-ER.ResultsAt the 12 months evaluation, 62 (66%) patients had ER and 32 (34%) no-ER. During a mean follow-up time of 86 months (range 9–517), 19 events occurred (20% cumulative event rate). Events occurred more frequently in younger patients (p < 0.05), in those at ATA intermediate/high risk (p < 0.01) and with a pre-RAI therapy Tg level > 10 ng/mL (p < 0.001), and in those with no-ER (p < 0.001). At multivariate analysis, the evidence of no-ER was the only independent predictor of events.ConclusionIn pediatric patients with DTC, the response to therapy evaluated 12 months after initial treatment has an independent prognostic impact and is able to predict mid-term outcome. Patients with no-ER at 12 months after RAI therapy should be closely followed-up.

Cuproptosis-Related LncRNA-Based Prediction of the Prognosis and Immunotherapy Response in Papillary Renal Cell Carcinoma.

Cuproptosis, a new cell death pattern, is promising as an intervention target to treat tumors. Abnormal long non-coding RNA (lncRNA) expression is closely associated with the occurrence and development of papillary renal cell carcinoma (pRCC). However, cuproptosis-related lncRNAs (CRLs) remain largely unknown as prognostic markers for pRCC. We aimed to forecast the prognosis of pRCC patients by constructing models according to CRLs and to examine the correlation between the signatures and the inflammatory microenvironment. From the Cancer Genome Atlas (TCGA), RNA sequencing, genomic mutations and clinical data of TCGA-KIRP (Kidney renal papillary cell carcinoma) were analyzed. Randomly selected pRCC patients were allotted to the training and testing sets. To determine the independent prognostic impact of the training characteristic, the least absolute shrinkage and selection operator (LASSO) algorithm was utilized, together with univariate and multivariate Cox regression models. Further validation was performed in the testing and whole cohorts. External datasets were utilized to verify the prognostic value of CRLs as well. The CRLs prognostic features in pRCC were established based on the five CRLs (AC244033.2, LINC00886, AP000866.1, MRPS9-AS1 and CKMT2-AS1). The utility of CRLs was evaluated and validated in training, testing and all sets on the basis of the Kaplan-Meier (KM) survival analysis. The risk score could be a robust prognostic factor to forecast clinical outcomes for pRCC patients by the LASSO algorithm and univariate and multivariate Cox regression. Analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) data demonstrated that differentially expressed genes (DEGs) are primarily important for immune responses and the PI3K-Akt pathway. Arachidonic acid metabolism was enriched in the high-risk set by Gene Set Enrichment Analysis (GSEA). In addition, Tumor Immune Dysfunction and Exclusion (TIDE) analysis suggested that there was a high risk of immune escape in the high-risk cohort. The immune functions of the low- and high-risk sets differed significantly based on immune microenvironment analysis. Finally, four drugs were screened with a higher sensitivity to the high-risk set. Taken together, a novel model according to five CRLs was set up to forecast the prognosis of pRCC patients, which provides a potential strategy to treat pRCC by a combination of cuproptosis and immunotherapy.