The CLL comorbidity index in a population-based cohort: a tool for clinical care and research

The chronic lymphocytic leukemia comorbidity index (CLL-CI) is an efficient, CLL-specific tool derived from the Cumulative Illness Rating Scale. The CLL-CI is based on the assessment of the organ systems found to be most strongly associated with event-free survival in CLL: vascular, upper gastrointestinal, and endocrine, at the time of initiation of CLL therapy. The CLL-CI categorizes patients into low, intermediate, and high risk groups. In the present study, we have employed the CLL-CI in a population-based cohort comprising 4 975 patients with CLL. We demonstrate that CLL-CI retains prognostic significance in this large cohort and is associated with overall survival and event-free survival from time of first therapy. Furthermore, CLL-CI associates with overall survival, event-free survival, and time to first treatment from diagnosis independently of the CLL International Prognostic Index. These findings support the use of the CLL-CI both in research and in clinical practice.

The insertion and dysregulation of transposable elements in osteosarcoma and their association with patient event-free survival

The dysregulation of transposable elements (TEs) has been explored in a variety of cancers. However, TE activities in osteosarcoma (OS) have not been extensively studied yet. By integrative analysis of RNA-seq, whole-genome sequencing (WGS), and methylation data, we showed aberrant TE activities associated with dysregulations of TEs in OS tumors. Specifically, expression levels of LINE-1 and Alu of different evolutionary ages, as well as subfamilies of SVA and HERV-K, were significantly up-regulated in OS tumors, accompanied by enhanced DNA repair responses. We verified the characteristics of LINE-1 mediated TE insertions, including target site duplication (TSD) length (centered around 15 bp) and preferential insertions into intergenic and AT-rich regions as well as intronic regions of longer genes. By filtering polymorphic TE insertions reported in 1000 genome project (1KGP), besides 148 tumor-specific somatic TE insertions, we found most OS patient-specific TE insertions (3175 out of 3326) are germline insertions, which are associated with genes involved in neuronal processes or with transcription factors important for cancer development. In addition to 68 TE-affected cancer genes, we found recurrent germline TE insertions in 72 non-cancer genes with high frequencies among patients. We also found that +/− 500 bps flanking regions of transcription start sites (TSS) of LINE-1 (young) and Alu showed lower methylation levels in OS tumor samples than controls. Interestingly, by incorporating patient clinical data and focusing on TE activities in OS tumors, our data analysis suggested that higher TE insertions in OS tumors are associated with a longer event-free survival time.

Usefulness of quantitative 99mTc-pyrophosphate SPECT/CT for predicting the prognosis of patients with wild-type transthyretin cardiac amyloidosis

Purpose Wild-type transthyretin-related amyloidosis cardiomyopathy (ATTRwt-CM) is an increasingly recognized cause of heart failure especially in elderly patients. The purpose of the present study was to determine retrospectively whether the quantitative indices of 99mTc-pyrophosphate (PYP) SPECT/CT help to predict the prognosis of ATTRwt-CM patients when compared with other clinical parameters. Materials and methods Sixty-eight patients with biopsy-proven ATTRwt-CM who underwent PYP SPECT/CT were enrolled. Baseline clinical characteristics, echocardiographic parameters, and qualitative and/or quantitative indices of planar and SPECT/CT imaging in PYP scintigraphy for each patient were included. For quantitative analysis of SPECT/CT, the accumulation ratio of PYP in the septum, posterior, anterior, lateral, and apex walls to the cavity pool was calculated as the septal wall-to-cavity ratio (Se/C), lateral wall-to-cavity ratio (La/C), anterior wall-to-cavity ratio (An/C), inferior wall-to-cavity ratio (In/C), and apical wall-to-cavity ratio (Ap/C), respectively. Endpoints for prognostic accuracy evaluation were cardiac death or hospitalization due to heart failure. Event-free survival rate was evaluated through Cox proportional hazards regression analysis, providing estimated hazard ratios (HRs) with 95% confidence intervals (CIs) and Kaplan–Meier curves. Results High-sensitivity cardiac troponin T (hs-cTnT), La/C, age, interventricular septal thickness in diastole, and E/e′ ratio in the septal wall were significantly associated with event-free survival (P < 0.05). For a multivariable Cox proportional hazards analysis, hs-cTnT (HR 1.153; 95% CI 1.034–1.286; P < 0.01), La/C (HR 2.091; 95% CI 1.012–4.322; P = 0.046), and age (HR 1.116; 95% CI 1.007–1.238; P = 0.037) were significant independent prognostic factors. Conclusion This study indicated that the quantitative indices of PYP SPECT/CT can help to predict the prognosis of ATTRwt-CM patients.

Outcomes of Pediatric Patients with metastatic Ewing sarcoma treated with interval compression

Background: Interval compression (IC), defined as 2 week-long cycles of alternating vincristine/doxorubicin/cyclophosphamide and ifosfamide/etoposide, improves survival for localized Ewing sarcoma. The outcomes of patients with metastatic disease treated with IC are uncertain. Methods: We retrospectively reviewed the charts of pediatric patients with metastatic Ewing sarcoma treated with IC at our center between January-2013 and March-2020. We calculated event-free survival and overall survival and used log rank tests for univariate comparisons. Results: We identified 34 patients aged 2.7–17.1 years (median,11.6 years). Twenty-six patients (76%) had pulmonary metastases, and 14 (41%) had extra-pulmonary metastases in the bone (n = 11), lymph nodes (n = 2), and intraspinal tissue (n = 1). All patients received local control therapy: surgery only (n = 7, 21%), radiotherapy only (n = 18, 53%), or both (n = 9, 26%). The estimated 3-year OS and EFS were 62%±9% and 39%±9%, respectively. Patients with pulmonary only metastasis had a 3-year OS of 88%±8% in comparison to those with extra-pulmonary metastasis of 27%±13% (P=0.0074). Survival did not differ according to age group (> vs < 12 years), metastasis site, or primary tumor site, but 3-year event-free survival significantly differed according to local control therapy (surgery only, 83% ± 15%; combined surgery and radiation, 30% ± 18%; radiation only, 15% ± 10%; P = .048). Conclusion: IC yielded similar outcomes for patients with metastatic Ewing sarcoma to that reported in the literature using other regimens. We suggest including this approach to other blocks of therapy

Comparison of Clinical Outcomes between Salvage and Elective Thoracic Endovascular Aortic Repair in Patients with Advanced Esophageal Cancer with Aortic Invasion: A Retrospective Cohort Study

Aortoesophageal fistula (AEF) caused by esophageal cancer (EC) is a rare but life-threatening complication. However, the optimal management strategy remains undetermined. Previous cases have demonstrated that thoracic endovascular aortic repair (TEVAR) is effective for prophylactic management. In our study, we evaluated the management of AEF with elective TEVAR over salvage TEVAR. In our single-center retrospective cohort study, forty-seven patients with cT4M0 EC were included in this study, and we divided them into salvage (Group S) and elective (Group E) groups based on whether TEVAR was performed before the hemorrhagic AEF occurred. Our study outcomes included survival and complication rate after TEVAR. Group E showed better overall 90-day survival and aortic-event-free survival in 90-day and 180-day over Group S. More patients in Group E could receive subsequent chemoradiotherapy or esophagectomy. Significantly fewer AEF-related complications, including recurrent hemorrhagic events after TEVAR, hypoperfusion-related organ injury, and bloodstream infection, were noted in Group E. In patients with advanced EC-invading aorta, elective TEVAR offered an early overall and aortic-event-free survival benefit compared to salvage TEVAR. By reducing the AEF-related complications, elective TEVAR could provide more patients receiving subsequent curative-intent treatment.

Response Rate, Event-Free Survival, and Overall Survival in Newly Diagnosed Acute Myeloid Leukemia: US Food and Drug Administration Trial-Level and Patient-Level Analyses

PURPOSE To explore trial-level and patient-level associations between response (complete remission [CR] and CR + CR with incomplete hematologic [CRi] or platelet [CRp] recovery), event-free survival (EFS), and overall survival (OS) in newly diagnosed acute myeloid leukemia (AML) trials of intensive chemotherapy. METHODS We identified data from eight randomized, active-controlled trials of intensive chemotherapy submitted to the US Food and Drug Administration for treatment of newly diagnosed AML (N = 4,482). Associations between trial-level odds ratios (ORs) for CR and CR + CRi or CRp, and hazard ratios (HRs) for EFS and OS were analyzed using weighted linear regression models. We performed patient-level responder analyses to compare OS by response using pooled data from all studies. RESULTS In trial-level analyses, association between HR for OS and OR for CR was moderate (R2 = 0.49; 95% CI, 0.05 to 0.86), as was the association with OR for CR + CRi or CRp (R2 = 0.48; 95% CI, 0.05 to 0.99). For OS versus EFS, a strong association was observed (R2 = 0.87; 95% CI, 0.47 to 0.98) when EFS definitions were harmonized across trials using raw data. In the patient-level responder analyses, patients who achieved CR had better OS compared with CRi or CRp responders (0.73; 95% CI, 0.64 to 0.84) and nonresponders (HR, 0.33; 95% CI, 0.31 to 0.37). CONCLUSION On a trial level, there is a moderate association between OS and CR rate. A strong association between EFS and OS was observed. However, CIs were wide, and results became moderate using alternative definitions for EFS. Patient-level analyses showed CR responders have better OS compared with CRi or CRp responders and nonresponders. A therapy in newly diagnosed AML with benefit in EFS or substantial benefit in CR rate would be likely to have an OS effect.

CD123 Expression Is Associated With High-Risk Disease Characteristics in Childhood Acute Myeloid Leukemia: A Report From the Children's Oncology Group

PURPOSE Increased CD123 surface expression has been associated with high-risk disease characteristics in adult acute myeloid leukemia (AML), but has not been well-characterized in childhood AML. In this study, we defined CD123 expression and associated clinical characteristics in a uniformly treated cohort of pediatric patients with newly diagnosed AML enrolled on the Children's Oncology Group AAML1031 phase III trial ( NCT01371981 ). MATERIALS AND METHODS AML blasts within diagnostic bone marrow specimens (n = 1,040) were prospectively analyzed for CD123 protein expression by multidimensional flow cytometry immunophenotyping at a central clinical laboratory. Patients were stratified as low-risk or high-risk on the basis of (1) leukemia-associated cytogenetic and molecular alterations and (2) end-of-induction measurable residual disease levels. RESULTS The study population was divided into CD123 expression–based quartiles (n = 260 each) for analysis. Those with highest CD123 expression (quartile 4 [Q4]) had higher prevalence of high-risk KMT2A rearrangements and FLT3-ITD mutations ( P < .001 for both) and lower prevalence of low-risk t(8;21), inv(16), and CEBPA mutations ( P < .001 for all). Patients in lower CD123 expression quartiles (Q1-3) had similar relapse risk, event-free survival, and overall survival. Conversely, Q4 patients had a significantly higher relapse risk (53% v 39%, P < .001), lower event-free survival (49% v 69%, P < .001), and lower overall survival (32% v 50%, P < .001) in comparison with Q1-3 patients. CD123 maintained independent significance for outcomes when all known contemporary high-risk cytogenetic and molecular markers were incorporated into multivariable Cox regression analysis. CONCLUSION CD123 is strongly associated with disease-relevant cytogenetic and molecular alterations in childhood AML. CD123 is a critical biomarker and promising immunotherapeutic target for children with relapsed or refractory AML, given its prevalent expression and enrichment in patients with high-risk genetic alterations and inferior clinical outcomes with conventional therapy.

Event-Free Survival after 68Ga-PSMA-11 PET/CT in recurrent Hormone-Sensitive Prostate Cancer (HSPC) patients eligible for Salvage Therapy.

Background/AimProstate-Specific-Membrane-Antigen/Positron Emission Tomography (PSMA-PET) detects with high accuracy disease-recurrence, leading to changes in the management of biochemically-recurrent (BCR) prostate cancer (PCa). However, data regarding the oncological outcomes of patients who performed PSMA-PET are needed. The aim of this study was to evaluate the incidence of clinically-relevant events during follow-up in patients who performed PSMA-PET for BCR after radical treatment. Materials and Methodsthis analysis included consecutive, hormone-sensitive, hormone-free, recurrent PCa patients (HSPC) enrolled through a prospective study. All patients were eligible for salvage therapy, having at least 24 months of follow-up after PSMA-PET. The primary endpoint was the Event-Free Survival (EFS), defined as the time between the PSMA-PET and the date of event/last follow-up. The Kaplan-Meier method was used to estimate the EFS curves. EFS was also investigated by Cox proportional hazards regression. Events were defined as: death, radiological progression or PSA recurrence after therapy. ResultsOne-hundred and seventy-six (n=176) patients were analyzed (median PSA 0.62 [IQR:0.43–1.00] ng/mL; median follow-up of 35.4 [IQR:26.5-40.3] months). The EFS was 78.8% at one year, 65.2% (2-years), and 52.2% (3-years). Patients with clinically relevant events had a significantly higher median PSA (0.81 [IQR:0.53-1.28] vs 0.51 [IQR:0.36-0.80] ng/mL) and a lower PSAdt (5.4 [IQR:3.7-11.6] vs 12.7 [IQR:6.6-24.3] months) (p<0,001) compared to event-free patients. The Kaplan-Meier curves showed that PSA>0.5 ng/mL, PSAdt≤6 months and a positive PSMA-PET result were associated with a higher event rate (p<0.01). No significant differences of event rates were observed in patients who received changes in therapy management after PSMA-PET vs. patients who did not receive therapy changes. Finally, PSA> 0.5 ng/mL and PSAdt≤ 6months were statistically significant event-predictors in multi-variate model (p<0.001). ConclusionIn this cohort of HSPC patients prospectively enrolled, low PSA and long PSAdt were significant predictors of event. Furthermore, a lower incidence of events was observed also in patients having negative PSMA-PET, since longer EFS was significantly more probable in case of a negative scan.