Disease-related Survival Research Articles

Comparison of Prognostic Performance of 8th and 7th Edition of AJCC Staging System for Patients With Gallbladder Cancer Undergoing Curative Intent Surgery.

We compared the predictive performance of the 7th and 8th editions of the AJCC staging systems in stratifying disease-related survival outcomes in patients with GBC undergoing curative intent surgery. Patients that underwent curative intent surgery for GBC at our institution (2014 and 2021) were included in the study. Various clinico-pathological data were extracted to perform Kaplan-Meier survival analysis. A total of 240 patients were included in the study. Both, TNM-7, and TNM-8 staging systems can stratify patients into stages with statistically significant differences in disease-free and overall survival. Survival rates drop with stage progression. Using TNM-8, 8/240 (3.33%) patients were upstaged from Stage IIIB (TNM-7) to IVB (TNM-8) and 12/240 (5%) were down-staged from Stage IVB(TNM-7) to IIIB(TNM-8). Survival curves of the re-classified patients matched those of the corresponding TNM-8 stage. Additionally, there was statistically significant difference in their survival (p < 0.001) compared to their corresponding TNM-7 stage. There was no statistically significant difference in survival rates between stages IIA, IIB (TNM-8), and stage II (TNM-7). However, stage IIA had a slightly better survival than stage IIB. Though both TNM-7 and TNM-8 are useful for stratifying patients with GBC, TNM-8 has a better prognostic performance than TNM-7.

Prognostic Significance of Disseminated Tumor Cells in Bone Marrow for Endometrial Carcinoma Patients.

Background: Until now, limited clinical significance had been reported for disseminated tumor cells (DTCs) in gynecologic malignancies. DTCs were previously reported not to be associated with established risk factors, L1CAM immunoreactivity, and outcome in endometrial carcinoma (EC). This study's primary objective was to investigate potential correlations of DTCs in the bone marrow (BM) of EC patients with disease-related survival, and a secondary objective was to evaluate associations between molecular classification of EC and DTCs. Methods: Patients treated for primary EC at Tuebingen University women's hospital between 2003 and 2016 were identified. A total of 402 patients with a complete set of BM cytology, molecular, and clinical data were evaluable. Results: DTC occurrence was distributed equally among all four molecular groups (p = 0.651). DTC positivity was associated with a less favorable disease-free survival (HR: 1.86, 95% CI: 1.03-3.36, p = 0.036) and progression-free survival (HR: 1.86, 95% CI: 1.01-3.44, p = 0.045). Presence of DTCs was associated with a higher frequency of distant disease recurrence (p = 0.017). Conclusions: In line with our previous findings, tumor cell dissemination is not associated with molecular features in our large cohort of primary EC patients. Since DTCs seem to be associated with survival and location of disease recurrence, further studies are needed to decisively define their role in EC survival.

Non-invasive prediction of pulmonary vascular disease-related exercise intolerance and survival in non-group 1 pulmonary hypertension.

The clinical utility of pulmonary hypertension (PH) risk scores in non-group 1 PH with pulmonary vascular disease (PVD) remains unresolved. We utilized the prospective multicenter PVDOMICS cohort with group 2, 3, 4 or 5 PH-related PVD and calculated group 1 PH risk scores (REVEAL 2.0, REVEAL Lite 2, French registry score and COMPERA 2). The c-statistic to predict death was compared separately in (i) pre-capillary PH groups 3/4/5, and (ii) combined post- and pre-capillary PH group 2. Exercise right heart catheterization reserve, ventricular interdependence and right ventricular-pulmonary artery (RV-PA) coupling were compared across risk categories. Among 449 individuals with group 3/4/5 PH, the REVEAL 2.0 risk score had the highest c-statistic for predicting death (0.699, 95% confidence interval [CI] 0.660-0.737, p < 0.0001) with comparable performance using the simpler REVEAL Lite 2 score (0.695, 95% CI 0.656-0.734, p < 0.0001). The French and COMPERA 2 risk scores were also predictive of mortality, but performance of both was statistically inferior to REVEAL 2.0 (c-statistic difference -0.072, 95% CI -0.123 to -0.020, p = 0.006, and -0.043, 95% CI -0.067 to -0.018, p = 0.0007, respectively). RV function and RV-PA coupling measures were prognostic in isolation, but did not add incremental value to REVEAL (p > 0.50 for all). Findings were similar in patients with group 2 PH (n = 239). Stratification by the REVEAL Lite 2 score non-invasively identified non-group 1 PH with more advanced PVD with worse exercise capacity, RV-PA uncoupling, ventricular interdependence and impaired cardiac output reserve (p < 0.05 for all). Non-invasive REVEAL risk predicts mortality in non-group 1 PH without incremental prognostic value from detailed RV function or RV-PA coupling assessment. Baseline REVEAL Lite 2 risk stratification non-invasively identifies greater pulmonary vascular dysfunction and right heart-related exercise limitation, which may help guide patient selection for targeted pulmonary vascular therapies in non-group 1 PH.

Is it possible to detect cribriform adverse pathology in prostate cancer with magnetic resonance imaging machine learning-based radiomics?

Rationale and objectives: Cribriform patterns are accepted as aggressive variants of prostate cancer. These adverse pathologies are closely associated with early biochemical recurrence, metastasis, castration resistance, and poor disease-related survival. A few publications exist to diagnose these two adverse pathologies with multiparametric magnetic resonance imaging (mpMRI). Most of these publications are retrospective and are not studies that have made a difference in diagnosing adverse pathology. It is also known that fusion biopsies taken from lesions detected in mpMRI are insufficient to detect these adverse pathologies. Our study aims to diagnose this adverse pathology using machine learning-based radiomics data from MR images. Materials and methods: A total of 88 patients who had pathology results indicating the presence of cribriform pattern and prostate adenocarcinoma underwent preoperative MRI examinations and radical prostatectomy. Manual slice-by-slice 3D volumetric segmentation was performed on all axial images. Data processing and machine learning analysis were conducted using Python 3.9.12 (Jupyter Notebook, Pycaret Library). Results: Two radiologists, SE and MAG, with 7 and 8 years of post-graduate experience, respectively, evaluated the images using the 3D-Slicer software without knowledge of the histopathological findings. One hundred seventeen radiomic tissue features were extracted from T1 weighted (T1W) and apparent diffusion coefficient (ADC) sequences for each patient. The interobserver agreement for these features was analyzed using the intraclass correlation coefficient (ICC). Features with excellent interobserver agreement (ICC &gt; 0.90) were further analyzed for collinearity between predictors using Pearson’s correlation. Variables showing a very high correlation (r ≥ ±0.80) were disregarded. The selected features for T1W and ADC images were First-order maximum, First-order skewness, First-order 10th percentile for ADC, and Gray level size zone matrix, Large area low gray level emphasis for T1W.As a result of the classification of PyCaret, the three best models were found. A single model was obtained by blending these three models. AUC, accuracy, recall, precision, and F1 scores were 0.79, 0.77, 0.85, 0.82, and 0.83, respectively. Conclusion: ML-based MRI radiomics of prostate cancer can predict the cribriform pattern. This prognostic factor cannot be determined through qualitative radiological evaluation and may be overlooked in preoperative histopathological specimens.

Breast cancer orbital metastases: Clinical, histopathological features and disease related survival in a retrospective case series

PurposeTo analyze the clinical, radiological and histopathological features, and long-term follow-up of patients with orbital metastases originating from a primary breast carcinoma. Main outcomes were: demographic characteristics of the population, clinical ophthalmological presentation, histological features, orbital metastasis latency, disease related survival, mortality rate. DesignA retrospective observational case-series. MethodsThe medical records of 10 female patients affected by orbital metastases originating from a primary breast carcinoma referring at our tertiary referral center from 01/2016 to 12/2023, were reviewed. ResultsThe median age was 63 (71.50 - 57.25) years (time of orbital biopsy). The prevalent histotype of orbital metastases of breast cancer was lobular 9.00 (90 %). The median orbital metastasis latency time in months was 9 months (IQR: 11 - 5) (in one case the orbital metastases were the first manifestation of an unknown primary tumor). The median Disease Related Survival (DRS) during the observation period was 17.50 months and the 24 months survival rate 57.14 %. The overall Mortality Rate in our population was 60 %. ConclusionsThe most frequent histotype of breast cancer orbital metastasis is the lobular one. The primary tumor precedes the onset of orbital metastasis in the majority of cases and tends to present with the classic symptoms of a mass occupying and infiltrating space. Orbital metastases are a sign that the disease is at an advanced stage, the mortality rate is high and DRS low.

Risk Factors Associated with Occult Nodal Metastasis and Outcomes for cT1-2N0 Maxillary and Mandibular gingival Carcinoma: A Retrospective Study.

This study aims to identify the rate of occult nodal metastasis (ONM), risk factors associated with ONM, and compare regional recurrence (RR), 2-year disease-free survival (DFS) in patients treated with elective neck dissection (END) versus expectant management (OBS) for primary T1-T2 gingival squamous cell carcinoma (GSCC) of the maxilla and mandible. A retrospective analysis was conducted and included patients from 2014 to 2021 who were treated at a tertiary referral center. Twenty patients underwent END and 36 were managed expectantly, with a mean follow-up period of 28months. ONM was observed in 26% of the study cohort with 16.7% occurring in the maxilla and 36.4% in the mandible. No specific histopathologic features were predictive for ONM. No regional recurrence occurred. Local recurrence occurred in 5% and 2.8% of END and OBS groups, respectively. Two-year DFS were comparable between the END (93.8%) versus OBS (83.9%) as well as maxilla (90.9%) versus mandible (83.4%), P > 0.05. ONM remains variable in cT1-T2N0 GSCC with a greater incidence occurring in the mandible when compared to the maxilla, respectively. An END should be strongly considered for mandibular GSCC. Overall, END for the N0 neck has been shown to provide significant overall and disease-free survival benefits. However, further prospective randomized studies are needed to verify risk factors for ONM and validate the disease-related survival benefit of an elective neck dissection in this patient population.

Long-term impact of sarcopenia in older patients undergoing gastrectomy for gastric cancer: a systematic review and meta-analysis.

Sarcopenia is an inevitable problem in older patients. After gastrectomy, patients often have an inadequate dietary intake and easily fall into sarcopenia. However, the impact of preoperative sarcopenia on long-term outcomes after gastrectomy has not been analyzed. A systematic review was conducted for all relevant articles identified on PubMed, the Cochrane Library, Web of Science, and ClinicalTrials.gov until April 2023. Adjusted hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the fixed or random effects model according to the heterogeneity. The Newcastle-Ottawa Scale was used to quantify study quality. Seven studies involving 1,831 patients aged ≥65 years who underwent gastrectomy for gastric cancer were analyzed. Four hundred twelve patients (22.5%) were diagnosed with sarcopenia. The analysis showed that preoperative sarcopenia was significantly associated with poor overall survival (OS) (HR =1.93; 95% CI:1.60-2.34; P<0.001). Two of the included studies also showed that preoperative sarcopenia was significantly correlated with disease-related survival: one with disease-specific survival (DSS) (HR =4.00; 95% CI: 1.20-13.3, P=0.024) and the other with non-cancer specific survival (HR =3.27; 95% CI: 1.61-6.67; P=0.001). Furthermore, sarcopenic patients experienced more severe complications than non-sarcopenic patients (OR =1.80; 95% CI: 1.10-2.95; P=0.019). This meta-analysis suggested that preoperative sarcopenia is useful as a prognostic factor of impaired OS in older patients after gastrectomy. Preoperative evaluation and intervention for skeletal muscle loss should be considered. Further studies of sarcopenic impact on disease-related survival are required.

Uric Acid, Serum Urea, Creatinine, And Profiling In Oral Cancer: A Prospective Comparative Study

Introduction: Oral squamous cell carcinoma (OSCC) is a prevalent global malignancy, imposing substantial social and financial burdens. Understanding the fundamental processes driving OSCC may yield novel therapeutic avenues to enhance disease management and patient survival. Our study seeks to evaluate serum urea, creatinine, and uric acid levels in oral cancer patients compared to a healthy control group. Methodology: In this prospective comparative study, we enrolled 60 OSCC patients and 60 healthy controls. We assessed serum urea, creatinine, and uric acid levels at OSCC diagnosis and collected clinical and laboratory data. Subsequently, we examined these serum concentrations, correlating them with the disease's clinic pathological features. Results: In our study, we observed that OSCC patients (mean age: 54.48±11.52 years) outnumbered controls (mean age: 53.24±10.19 years) with a male predominance (68.33%). Significant differences existed in smoking and alcohol use between the groups. TNM stage 4 (41.67%) was the most prevalent among cases, and most had advanced disease (TNM 3-4, 60.00%). Lymph node metastasis was frequent in positive neck cases (53.33%), and histological, most cases were moderately differentiated (65.00%). Most cases were alive (71.67%) concerning disease-related survival. In linear regression analysis, OSCC patients displayed significantly lower serum urea levels compared to controls, with age, smoking, and lymph node invasion significantly influencing urea levels. Multiple linear regression confirmed these variables' impact on serum urea levels. Conclusion: Patients with advanced OSCC exhibit reduced serum urea levels correlated with lymph node metastasis. Dysregulation of protein catabolism processes may potentially enhance the invasive characteristics of OSCC, fostering their aggressive behavior.

Molecular prognostication in Ph-negative MPNs in 2022.

The application of genomic techniques, including cytogenetics and DNA sequencing, to decipher the molecular landscape of patients with myeloproliferative neoplasms (MPNs) has radically modified diagnostic approach and management through improved risk stratification. Three driver mutated genes (JAK2, MPL, CALR) are variably harbored by >80% of patients and associated with clinical characteristics, as well as major disease-related complications and different survival outcomes. Therefore, JAK2 V617F mutation is included in the revised International Prognosis Score of Thrombosis for Essential Thrombocythemia score for prediction of thrombosis in patients with essential thrombocythemia and prefibrotic primary myelofibrosis, while a CALR type 1 mutated genotype constitutes a favorable variable for survival in patients with myelofibrosis (MF). Novel, integrated clinical and cytogenetic/mutation scores (Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients with Primary Myelofibrosis [MIPSS70/v2], genetically inspired prognostic scoring system [GIPSS], Myelofibrosis Secondary to PV and ET- Prognostic Model [MYSEC-PM]) have been devised that guide selection of stem cell transplantation candidates with MF or help predict the risk associated with the transplant procedure (Myelofibrosis Transplant Scoring System), with greater performance compared with conventional scores based on hematologic and clinical variables only. On the other hand, several clinical needs remain unmet despite the great amount of molecular information available nowadays. These include the prediction of evolution to acute leukemia in a clinically actionable time frame, the identification of patients most likely to derive durable benefits from target agents, in primis JAK inhibitors, and, conversely, the significance of molecular responses that develop in patients receiving interferon or some novel agents. Here, we discuss briefly the significance and the role of genomic analysis for prognostication in patients with MPNs from a clinician's point of view, with the intent to provide how-to-use hints.

Nuclear Expression of β-Catenin Is Associated with Improved Outcomes in Endometrial Cancer.

Beta-catenin is involved in intercellular adhesion and participates in the Wnt signaling pathway. This study evaluated the expression pattern and prognostic value of β-catenin in a series of endometrial carcinoma patients. Immunohistochemical analyses were used to assess the expression and subcellular localization of β-catenin from tissue sections of 74 patients with endometrial carcinoma. No correlation was found between beta-catenin expression and clinicopathological parameters. Patients expressing nuclear β-catenin (n = 13; 16%) showed a more favorable prognosis than patients expressing membranous β-catenin; the 5-year disease-related survival rate was 100% for cases expressing nuclear β-catenin, compared with 73.8% (SE 0.08) of cases expressing membranous β-catenin (p = 0.04). Although statistical significance was not reached (p = 0.15), cases expressing nuclear β-catenin showed a 5-year disease-free survival rate of 90.9% (SE 0.08) compared with 67.4% (SE 0.08) of cases expressing membranous β-catenin. Univariate Cox analysis revealed that membranous β-catenin expression was found to be associated with a relative risk of death of 33.9 (p = 0.04). The stage of disease (p = 0.0006), histology (p = 0.003), and grading (p = 0.008) were also significantly correlated with disease-free survival according to univariate Cox analyses. Determining β-catenin expression and localization patterns may predict survival in patients with endometrial cancer and, therefore, should be considered a potential prognostic marker of disease.

Preoperative myocardial fibrosis is associated with worse survival after alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy: A delayed enhanced cardiac magnetic resonance study

BackgroundPrior studies have shown that myocardial fibrosis can be detected by late gadolinium enhancement (LGE) of cardiac magnetic resonance (CMR) and might be associated with higher mortality risk in hypertrophic cardiomyopathy (HCM). The objective of this study was to examine the prognostic utility of CMR in patients with hypertrophic obstructive cardiomyopathy (HOCM) undergoing alcohol septal ablation (ASA).Materials and methodsWe conducted a retrospective study which consisted of 183 consecutive patients with symptomatic drug-refractory HOCM who underwent CMR for assessment of myocardial fibrosis before ASA. The cardiovascular disease related survival was evaluated according to LGE-CMR status.ResultsThe cohort comprised 74 (40.4%) women with a mean age of 51 ± 8 years. Preoperative myocardial fibrosis was detected in 148 (80.9%) patients. After a median of 6 years (range 2–11 years) follow-up, adverse clinical events occurred in 14 (7.7%) patients. Multivariate-adjusted Cox regression analyses revealed that age [hazard ratio (HR) 1.142 (1.059–1.230), p = 0.001] and LGE [HR 1.170 (1.074–1.275), p < 0.001] were independent predictors of cardiovascular mortality during follow-up.ConclusionPreoperative myocardial fibrosis measured by LGE-CMR was an independent predictor of increased adverse clinical outcomes in patients with HOCM undergoing ASA and could be used for the pre-operative evaluation of risk stratification and long-term prognosis after ASA in these patients.

Physical Comorbidities and Their Relationship with Cancer Treatment and Its Outcomes in Older Adult Populations: Systematic Review.

BackgroundCancer is one of the predominant causes of morbidity and mortality in older adult populations worldwide. Among a range of barriers, comorbidity particularly poses a clinical challenge in cancer diagnosis, prognosis, and treatment owing to its heterogeneous nature. While accurate comorbidity assessments and appropriate treatment administration can result in better patient outcomes, evidence related to older adult cancer populations is limited as these individuals are often excluded from regular clinical trials due to age and comorbid conditions.ObjectiveTo determine the prevalence of physical comorbidity and the impact of physical comorbidities and rurality on treatment and its outcomes in older adult cancer populations.MethodsScientific databases Embase and PubMed were searched for published scientific literature on physical comorbidity and older adult cancer patients. Google Scholar was searched for scholarly literature published in nonindexed journals. Snowballing was utilized to identify research papers missed in the above searches. Included studies : (1) reported on original research involving cancer patients; (2) included patients aged 65 years or older; (3) had patients receiving cancer-related treatment and (4) cancer survivors; (5) reported on physical comorbidity as a variable; (6) were published in English; and (7) conducted from any geographical location.ResultsIn total, 29 studies were selected for data extraction, evidence synthesis, and quality assessment. In these, comorbidities ranged from 37.9%-74.3% in colorectal cancer, 74%-81% in head and neck cancer, and 12.6%-49% in breast cancer. Moderate comorbidities ranged from 13%-72.9%, and severe comorbidities from 2.5%-68.2%. Comorbidity increased with age, with comorbidity affecting both treatment choice and process. Physical comorbidities significantly affected treatment initiation, causing delay, toxicity, and discontinuation. Older adult cancer patients were given less vigorous and nonstandard treatments and were also less likely to be offered treatment. Where patients are given more vigorous treatment, several studies showed better survival outcomes. Appropriate treatment in older adult cancer patients increased both overall and disease-related survival rates. None of the studies noted rurality as a distinct variable.ConclusionsThis systematic review concludes that there is evidence to substantiate the adverse effect of comorbidity on treatment and survival outcomes. However, the mechanism by which comorbidity impedes or impacts treatment is unknown in many cases. Some low-quality evidence is available for considering the functional status and biological age in treatment decisions. Future studies that substantiate the value of comprehensive older adult assessments before treatment initiation in cancer patients, including assessing the nature and severity of comorbidities, and additional consideration of rurality as a factor, could lessen the effect of comorbidities on the treatment process.

Elevated Flt3L Predicts Long-Term Survival in Patients with High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms.

Simple SummaryNeuroendocrine tumors of the gastrointestinal tract (GEP-NEN) are a rare type of tumor with considerable variability in the course of disease, which makes clinical management particularly challenging. Biomarkers that are able to guide personalized treatment decisions would be of importance, but are not yet available. In this study, we demonstrate that tissue expression, as well as circulating levels of the cytokine Flt3L in advanced and aggressive tumors, predict survival and time to progression. Increased tumoral Flt3L was also associated with upregulation of genes related to immune activation, suggesting Flt3L as a surrogate marker of host anti-tumor immunity. Therefore, Flt3L measurements in serum may hold promise as a biomarker of disease outcome that could support personalized treatment decisions in GEP-NEN patients, potentially guiding researchers towards viable immunotherapies.Background: The clinical management of high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is challenging due to disease heterogeneity, illustrating the need for reliable biomarkers facilitating patient stratification and guiding treatment decisions. FMS-like tyrosine kinase 3 ligand (Flt3L) is emerging as a prognostic or predictive surrogate marker of host tumoral immune response and might enable the stratification of patients with otherwise comparable tumor features. Methods: We evaluated Flt3L gene expression in tumor tissue as well as circulating Flt3L levels as potential biomarkers in a cohort of 54 patients with GEP-NEN. Results: We detected a prominent induction of Flt3L gene expression in individual G2 and G3 NEN, but not in G1 neuroendocrine tumors (NET). Flt3L mRNA expression levels in tumor tissue predicted the disease-related survival of patients with highly proliferative G2 and G3 NEN more accurately than the conventional criteria of grading or NEC/NET differentiation. High level Flt3L mRNA expression was associated with the increased expression of genes related to immunogenic cell death, lymphocyte effector function and dendritic cell maturation, suggesting a less tolerogenic (more proinflammatory) phenotype of tumors with Flt3L induction. Importantly, circulating levels of Flt3L were also elevated in high grade NEN and correlated with patients’ progression-free and disease-related survival, thereby reflecting the results observed in tumor tissue. Conclusions: We propose Flt3L as a prognostic biomarker for high grade GEP-NEN, harnessing its potential as a marker of an inflammatory tumor microenvironment. Flt3L measurements in serum, which can be easily be incorporated into clinical routine, should be further evaluated to guide patient stratification and treatment decisions.

AML-291: Treatment Response and Outcome in DNMT3A-mutated Acute Myeloblastic Leukemia

<h3>Introduction:</h3> Mutations in DNMT3A have been associated with clonal hematopoiesis. Among patients with DNMT3A-mutated AML, prior reports of the prognostic impact of mutations at the R882 residue versus non-R822 mutations have been conflicting. <h3>Objective:</h3> To identify the prognostic impact of DNMT3A mutations and whether mutations at codon R882 (DNMT3A-R882) <i>versus</i> mutations at codons other than R882 (non-R882) have clinically relevant differences. <h3>Design:</h3> We retrospectively reviewed the clinical records of 236 patients with newly diagnosed AML with DNMT3A mutations who presented to our institution from 2012 to 2020. The study population was classified into two age groups (<65 years <i>vs</i> >65 years). We analyzed the disease-related characteristics, response rates (CR/CRi), and survival of those with DNMT3A-R882 versus non-R882 mutations. <h3>Results:</h3> Patients <65 years with DNMT3A-R882 had a median age of 55 years compared to 58 years in the non-R882 group (p=0.04). There were no additional significant differences in this group. Similarly, among patients >65 years, those with DNMT3A-R882 showed a median age of 70 years versus 74 years in those with non-R882 (p=0.01). Moreover, DNMT3A-R882 presented with a diploid karyotype (69%) and complex karyotype (11%, p=0.06). The presence of concomitant mutations was not significantly different, and the most frequently co-occurring mutations were NPM1, FLT3-ITD, IDH2, and IDH1. TP53-mutated was overrepresented in the non-R882 group (21% <i>vs</i> 8% in DNMT3A-R882; p=0.009). There was a trend for a higher CR/CRi rate among those with DNMT3A-R882 treated with cladribine plus low-dose cytarabine (93%; p=0.08) or hypomethylating agents with venetoclax (87%; p=0.21). Finally, concomitant TP53 mutation significantly increased the risk of death (HR; 4; 95% CI: 0.47–2.27, p<0.01). Among patients >65 years, DNMT3A non-R822 was associated with worse survival, although it was not statistically significant. Secondary or therapy-related AML had a two-fold increased risk of death (p=0.01 and p=0.04, respectively). HMA-Ven or Clad-LDAC-Ven showed a survival advantage. <h3>Conclusions:</h3> DNMT3A mutations do not have an independent prognostic impact in patients diagnosed with AML across age groups. Patients >65 years with DNMT3A-R882 had a trend toward longer OS. Clad-LDAC-Ven and HMA-Ven provided better CR/CRi and survival advantage. Co-occurrence of TP53 mutations was associated with a negative prognostic impact in all patients.

Multicenter analysis of geriatric fitness and real-world outcomes in older patients with classical Hodgkin lymphoma

AbstractWe performed a multicenter retrospective analysis across 10 US academic medical centers to evaluate treatment patterns and outcomes in patients age ≥60 years with classic Hodgkin lymphoma (cHL) from 2010-2018. Among 244 eligible patients, median age was 68, 63% had advanced stage (III/IV), 96% had Eastern Cooperative Oncology Group performance status (PS) 0-2, and 12% had documented loss of ≥1 activity of daily living (ADL). Medical comorbidities were assessed by the Cumulative Illness Rating Scale–Geriatric (CIRS-G), where n = 44 (18%) had total scores ≥10. Using multivariable Cox models, only ADL loss predicted shorter progression-free (PFS; hazard ratio [HR] 2.13, P = .007) and overall survival (OS; HR 2.52, P = .02). Most patients (n = 203, 83%) received conventional chemotherapy regimens, including doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; 56%), AVD (14%), and AVD with brentuximab vedotin (BV; 9%). Compared to alternative therapies, conventional regimens significantly improved PFS (HR 0.46, P = .0007) and OS (HR 0.31, P = .0003). Survival was similar following conventional chemotherapy in those ages 60-69 vs ≥70: PFS HR 0.88, P = .63; OS HR 0.73, P = .55. Early treatment discontinuation due to toxicity was more common with CIRS-G ≥10 (28% vs 12%, P = .016) or documented geriatric syndrome (28% vs 13%, P = .02). A competing risk analysis demonstrated improved disease-related survival with conventional therapy (HR 0.29, P = .02) and higher mortality from causes other than disease or treatment with high CIRS-G or geriatric syndromes. This study suggests conventional chemotherapy regimens remain a standard of care in fit older patients with cHL, and highlights the importance of geriatric assessments in defining fitness for cHL therapy going forward.

Arginase Pathway Markers of Immune-Microenvironment in Thymic Epithelial Tumors and Small Cell Lung Cancer

BackgroundKey regulators of antitumor immunity such as arginase-1 and the adenosine pathway may have an important role in modulating the effect of immunotherapy. Here, we investigated the expression profile of these immune-related biomarkers in thymic epithelial tumors (TETs) and small cell lung cancer (SCLC), 2 solid tumors where immune checkpoint inhibitors have activity. Materials and MethodsImmunohistochemical staining was performed using tissue microarrays of 123 TET (110 thymoma and 13 thymic carcinoma) and 125 SCLC cases. The expression profile of the following immune-related biomarkers was assessed: arginase-1, CD39, CD73, A2AR, PD-L2, and CD15. The expression profile was also correlated with clinical data. ResultsNo sample was positive for arginase-1. In the adenosine pathway, the prevalence of positive staining for CD39, CD73, and A2AR was 4.9%, 2.5%, and 69.2%, in TETs and 0%, 1.7%, and 50.8%, in SCLC. The multivariate analysis showed that CD39 expression was significantly associated with worse disease related survival (hazard ratio [HR], 10.36; 95% confidence interval [CI]: 2.01-53.47; P= .005) and a shorter time-to progression (HR, 11.35; 95% CI, 2.11-61.23; P = .005) in TETs. Other biomarkers were not associated with disease related survival or time to progression in TETs. No biomarker was associated with survival in SCLC. ConclusionArginase-1 was not detectable in TETs and SCLC. Expression of markers in the adenosine pathway were present in both TETs and SCLC. CD39 expression in tumor cells may identify subsets of patients with TETs with an unfavorable prognosis.

Oncologic and survival outcomes in elderly patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy and total mesorectal excision.

The efficacy of the addition of neoadjuvant chemotherapy to neoadjuvant chemoradiotherapy and total mesorectal excision for locally advanced rectal cancer in elderly patients has not been established. A total of 3096 locally advanced rectal cancer patients who received neoadjuvant chemotherapy, along with neoadjuvant chemoradiotherapy and total mesorectal excision, with or without adjuvant chemotherapy, between January 2010 and December 2018, were studied retrospectively. Patients were divided into elderly (>75years) and younger (≤75years) groups, and propensity score matching was used to balance a potentially confounding clinical bias. Overall survival, cancer-specific survival, disease-free survival, distant metastasis-free survival and local recurrence-free survival rates for the two groups were compared. Hazard ratios (HR) with 95% confidence intervals (CI) for different clinicopathological variables were calculated to determine predictors of 3-year overall survival. Mean follow-up was 39.0 (range, 5-140) months. The overall 3-year overall survival, cancer-specific survival, disease-free survival, distant metastasis-free survival and locoregional relapse-free survival rates were 86.1, 87.6, 80.0, 82.4 and 95.4%, respectively. Only 3-year overall survival rates differed significantly between the elderly (77.2%) and younger (88.9%) groups (P=0.01). Cancer-specific survival, disease-free survival, distant metastasis-free survival and locoregional relapse-free survival rates did not differ significantly between the two groups. Significant negative independent prognostic factors for 3-year overall survival were age>75years (HR=2.016, 95% CI 1.157-23.511, P=0.01) and high pathologic TNM stage (yp stage III, P<0.001). For elderly locally advanced rectal cancer patients who have good health and performance status, the addition of neoadjuvant chemotherapy to neoadjuvant chemoradiotherapy and total mesorectal excision can result in disease-related survival rates and oncological outcomes similar to those experienced by younger patients. The decision to use this treatment approach in elderly patients should not be based solely on chronological age.

The Proper Ki-67 Cut-Off in Hormone Responsive Breast Cancer: A Monoinstitutional Analysis with Long-Term Follow-Up.

IntroductionBreast cancer is a heterogeneous disease. Our study focuses on a monoinstitutional series of patients affected by Hormone Responsive carcinomas (luminal A and luminal B) and aims to define an optimal Ki-67 cut-off, to correctly stratify these patients into risk classes, using the ImmunoHistoChemical (IHC) surrogates of the Molecular Subtypes, according to the St. Gallen guidelines.MethodsWe analyzed 1685 patients. These patients underwent both radical and conservative surgeries with Sentinel Lymph Node Biopsy eventually followed by Axillary Dissection (AD). Furthermore, all the patients underwent adjuvant therapies according to the guidelines. A retrospective univariate analysis was performed and survival curves (Disease-Related Survival, DRS, and Disease-Free Survival, DFS) were carried out according to the following ki-67 risk classes: Low Risk (Ki-67 ≤ 14%); Intermediate Risk (Ki-67 15% ÷ 20%); High Risk (Ki-67 > 20%).Results14 yy DRS was 98% in LA and 85% in LB with a ki-67 cut-off of 14% (p=0.037) vs 95% (LA) and 83% (LB) with a ki-67 cut-off of 20% (p=0.003). 14yy DFS was 85% in LA and 72% in LB with a ki-67 cut-off of 14% (p=0.017) vs 83% (LA) and 66% (LB) with a ki-67 cut-off of 20% (p<0.000).DiscussionOur results confirmed that the 20% Ki-67 cut-off is more reliable in differentiating patients at low or high risk of recurrence and death, and stratifying patients eligible for adjuvant chemotherapy. Thus, despite its poor reproducibility, the identification of the most accurate ki-67 index assumes a pivotal relevance in guiding a tailored strategy among patients with this specific profile of breast cancer, as well as the molecular surrogates, in order to avoid harmful overtreatments.

Coagulation Abnormalities in Light Chain Amyloidosis

ObjectiveTo assess the prevalence of coagulation abnormalities in patients with systemic light chain (AL) amyloidosis and their association with disease-related characteristics, disease progression, and survival. Patients and MethodsThis is a retrospective study of patients with AL amyloidosis seen at Mayo Clinic, Rochester, Minnesota, from January 1, 2006, to December 31, 2015. We studied the association between abnormal coagulation parameters and baseline characteristics and their association with survival outcomes. ResultsThe study included 411 patients. Abnormalities at diagnosis included prolonged clotting times and coagulation factor deficiencies; prolonged prothrombin time (PT) and factor X (FX) deficiency were found in 19% (73 of 390) and 43% (177 of 411) of patients, respectively. The FX deficiency was associated with higher Mayo stage, involvement of more than 1 organ, liver and cardiac involvement, and greater than 10% bone marrow plasma cells. On univariate analysis, the risk for disease progression or death was higher in patients with abnormal values for PT and factor V, factor VII (FVII), FX, and factor XII compared with those with normal values. Prolonged PT and FVII and FX deficiencies were independent predictors of death after adjusting for Mayo stage and more than 1 organ involvement. Only 106 patients had repeat testing after treatment; no clear relationship was found between treatment response and changes in coagulation parameters. ConclusionCoagulation abnormalities occur in a significant proportion of patients with AL amyloidosis and are associated with advanced disease and inferior outcomes. Larger studies are needed to establish whether a relationship exists between treatment response and improvement in individual parameters.

Contributions and Prognostic Values of N6-Methyladenosine RNA Methylation Regulators in Hepatocellular Carcinoma.

IntroductionThe methylation at position N6 of adenine is called N6-methyladenosine (m6A). This transcriptional RNA modification exerts a very active and important role in RNA metabolism and in other biological processes. However, the activities of m6A associated with malignant liver hepatocellular carcinoma (LIHC) are unknown and are worthy of study.Materials and MethodsUsing the data of University of California, Santa Cruz (UCSC), the expression of M6A methylation regulators in pan-cancer was evaluated as a screening approach to identify the association of M6A gene expression and 18 cancer types, with a specific focus on LIHC. LIHC datasets of The Cancer Genome Atlas (TCGA) were used to explore the expression of M6A methylation regulators and their clinical significance. Gene Ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA) were used to explore the underlying mechanism based on the evaluation of aberrant expression of m6A methylation regulators.ResultsThe expression alterations of m6A-related genes varied across cancer types. In LIHC, we found that in univariate Cox regression analysis, up-regulated m6A modification regulators were associated with worse prognosis, except for ZC3H13. Kaplan–Meier survival curve analysis indicated that higher expression of methyltransferase-like protein 3 (METTL3) and YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) genes related to the worse survival rate defined by disease-related survival (DSS), overall survival (OS), progression-free interval (PFI), and disease-free interval (DFI). Up-regulated m6A methylation regulator group (cluster2) obtained by consensus clustering was associated with poor prognosis. A six-gene prognostic signature established using the least absolute shrinkage and selection operator (LASSO) Cox regression algorithm performed better in the early (I + II; T1 + T2) stages than in the late (III + IV; T3 + T4) stages of LIHC. Using the gene signature, we constructed a risk score and found that it was an independent predictive factor for prognosis. Using GSEA, we identified processes involved in DNA damage repair and several biological processes associated with malignant tumors that were closely related to the high-risk group.ConclusionIn summary, our study identified several genes associated with m6A in LIHC, especially METTL3 and YTHDF1, and confirmed that a risk signature comprised of m6A-related genes was able to forecast prognosis.