Strong Prognostic Impact Research Articles

Lymph but Not Blood Vessel Invasion Is Independent Prognostic in Lung Cancer Patients Treated by VATS-Lobectomy and Might Represent a Future Upstaging Factor for Early Stages.

Simple SummaryLung cancer is the second most common cancer entity and the leading cause of cancer-related deaths worldwide despite constant advantages in immune-oncology and personalized medicine. Invasion of the lymphatic and vascular system has been investigated as a risk factor in the past and available data suggested a strong prognostic impact. However, many studies did not distinguish between the invasion of the lymphatic and the vascular system. Furthermore, this issue has not yet been studied in a homogenous cohort treated by a VATS lobectomy and staged by the most recent 8th edition of the TNM staging. We hence examined the role of lymphatic and vascular invasion as two separate risk factors in NSCLC patients treated by a modern minimal-invasive VATS lobectomy to re-encourage the scientific interest in the prognostic role of vascular invasion and to further improve NSCLC risk stratification.Lung cancer is the most frequent cause of cancer-related death worldwide. The patient’s outcome depends on tumor size, lymph node involvement and metastatic spread at the time of diagnosis. The prognostic value of lymph and blood vessel invasion, however, is still insufficiently investigated. We retrospectively examined the invasion of lymph vessels and blood vessels separately as two possible prognostic factors in 160 patients who underwent a video-assisted thoracoscopic lobectomy for non-small-cell lung cancer at our institution between 2014 and 2019. Lymph vessel invasion was significantly associated with the UICC stage, lymph node involvement, tumor dedifferentiation, blood vessel invasion and recurrence. Blood vessel invasion tended to be negative prognostic, but missed the level of significance (p = 0.108). Lymph vessel invasion, on the other hand, proved to be a prognostic factor for both histological subtypes, adenocarcinoma (p < 0.001) as well as squamous cell carcinoma (p = 0.018). After multivariate analysis apart from the UICC stage, only lymph vessel invasion remained independently prognostic (p = 0.018). Remarkably, we found analogue survival curve progressions of patients with stage I, with lymph vessel invasion, compared to stage II non-small-cell lung cancer. After further validation in prospective studies, lymph vessel invasion might be considered as an upstaging factor in resectable lung cancer. Especially in the early-stage of the disease, it might represent an additional risk factor to consider adjuvant therapy after surgical resection.

Tertiary lymphoid structures critical for prognosis in endometrial cancer patients

B-cells play a key role in cancer suppression, particularly when aggregated in tertiary lymphoid structures (TLS). Here, we investigate the role of B-cells and TLS in endometrial cancer (EC). Single cell RNA-sequencing of B-cells shows presence of naïve B-cells, cycling/germinal center B-cells and antibody-secreting cells. Differential gene expression analysis shows association of TLS with L1CAM overexpression. Immunohistochemistry and co-immunofluorescence show L1CAM expression in mature TLS, independent of L1CAM expression in the tumor. Using L1CAM as a marker, 378 of the 411 molecularly classified ECs from the PORTEC-3 biobank are evaluated, TLS are found in 19%. L1CAM expressing TLS are most common in mismatch-repair deficient (29/127, 23%) and polymerase-epsilon mutant EC (24/47, 51%). Multivariable Cox regression analysis shows strong favorable prognostic impact of TLS, independent of clinicopathological and molecular factors. Our data suggests a pivotal role of TLS in outcome of EC patients, and establishes L1CAM as a simple biomarker.

Risk Stratification Before and During Treatment in Newly Diagnosed Multiple Myeloma: From Clinical Trials to the Real-World Setting.

Multiple Myeloma (MM) is a hematologic malignancy characterized by a wide clinical and biological heterogeneity leading to different patient outcomes. Various prognostic tools to stratify newly diagnosed (ND)MM patients into different risk groups have been proposed. At baseline, the standard-of-care prognostic score is the Revised International Staging System (R-ISS), which stratifies patients according to widely available serum markers (i.e., albumin, β 2-microglobulin, lactate dehydrogenase) and high-risk cytogenetic abnormalities detected by fluorescence in situ hybridization. Though this score clearly identifies a low-risk and a high-risk population, the majority of patients are categorized as at “intermediate risk”. Although new prognostic factors identified through molecular assays (e.g., gene expression profiling, next-generation sequencing) are now available and may improve risk stratification, the majority of them need specialized centers and bioinformatic expertise that may preclude their broad application in the real-world setting. In the last years, new tools to monitor response and measurable residual disease (MRD) with very high sensitivity after the start of treatment have been developed. MRD analyses both inside and outside the bone marrow have a strong prognostic impact, and the achievement of MRD negativity may counterbalance the high-risk behavior identified at baseline. All these techniques have been developed in clinical trials. However, their efficient application in real-world clinical practice and their potential role to guide treatment-decision making are still open issues. This mini review will cover currently known prognostic factors identified before and during first-line treatment, with a particular focus on their potential applications in real-world clinical practice.

Comparison of Immune Response Assessment in Colon Cancer by Immunoscore (Automated Digital Pathology) and Pathologist Visual Scoring.

Simple SummaryThe immune response to colon cancer (CC) is highly variable among patients and is clinically relevant. In this study, we compared the immune response assessment for early-stage CC, as measured by Immunoscore (IS), to pathologist visual scoring of the CD3+ and CD8+ T-cell densities at the tumor site (T-score). The objectives were to determine the inter-observer agreement between pathologists and the concordance between the two methods. Agreement between pathologists was minimal to weak. Moreover, a weak concordance between the two methods was observed, leading to misclassification of 48% of cases by pathologist scoring. Due to the high level of immune infiltrate heterogeneity resulting in disagreement of interpretation among pathologists, IS is unlikely to be reproduced via non-standardized methods.Adjunction of immune response into the TNM classification system improves the prediction of colon cancer (CC) prognosis. However, immune response measurements have not been used as robust biomarkers of pathology in clinical practice until the introduction of Immunoscore (IS), a standardized assay based on automated artificial intelligence assisted digital pathology. The strong prognostic impact of the immune response, as assessed by IS, has been widely validated and IS can help to refine treatment decision making in early CC. In this study, we compared pathologist visual scoring to IS. Four pathologists evaluated tumor specimens from 50 early-stage CC patients and classified the CD3+ and CD8+ T-cell densities at the tumor site (T-score) into 2 (High/Low) categories. Individual and overall pathologist scoring of immune response (before and after training for immune response assessment) were compared to the reference IS (High/Low). Pathologists’ disagreement with the reference IS was observed in almost half of the cases (48%) and training only slightly improved the accuracy of pathologists’ classification. Agreement among pathologists was minimal with a Kappa of 0.34 and 0.57 before and after training, respectively. The standardized IS assay outperformed expert pathologist assessment in the clinical setting.

Aberrant expression of the esophageal carcinoma related gene 4 as a prognostic signature for hepatocellular carcinoma

Background and objectiveHepatocellular carcinoma (HCC) is a lethal cancer with increasing incidence, yet the molecular biomarkers that have strong prognostic impact and also hold great therapeutic promise remain elusive. MethodsData mining approaches with a set of publicly accessible databases and immunohistochemistry were used to provide a novel insight into the expression pattern and prognostic significance of the esophageal cancer-related gene (ECRG) family members in HCC. ResultsWe found that elevated mRNA expression levels of ECRG factors were correlated with better overall survival, relapse-free survival and progression-free survival rates in patients with HCC. Subgroup analyses showed significant associations between ECRG expression and survival outcome in select HCC patients. In addition, immunohistochemical and multivariate analysis confirmed increased ECRG4 expression as an independent prognostic indicator for survival. ConclusionsOur data suggest that ECRG factors have significant impacts on the survival of HCC patients. The expression of ECRG factors may be involved in HCC progression and could serve as novel biomarkers for predicting more accurate prognosis.

Differential impact of clinicopathological risk factors within the 2 largest ProMisE molecular subgroups of endometrial carcinoma.

ObjectiveTo assess whether the prognostic impact of conventional risk factors and ancillary biomarkers differs across the 2 largest ProMisE molecular subgroups of endometrial carcinoma (EC).MethodsDirect sequencing of POLE exonuclease domain hot spots and immunohistochemistry for MLH1, PMS2, MSH2, MSH6 and p53 were performed on 745 unselected endometrioid ECs to identify mismatch repair deficient (MMR-D, n = 264) and no specific molecular profile (NSMP, n = 206) ECs. Molecular group-specific survival analyses and interaction analyses were performed to determine the prognostic relevance of clinicopathological factors and various biomarkers (L1 cell adhesion molecule, estrogen and progesterone receptor, beta-catenin, p16, E-cadherin, KRAS) within the subgroups.ResultsMolecular subgroup did not have an independent effect on disease-specific survival after adjustment for conventional risk factors (P = 0.101). High grade (G3) and p16 hyperexpression remained significant predictors of survival in NSMP. Stage II-IV, ≥50% myometrial invasion, lymphovascular space invasion and loss of E-cadherin were independent predictors in the MMR-D group. In the interaction analysis, molecular subclass significantly modified the prognostic effect of high grade and p16 hyperexpression, which showed a stronger negative effect on survival in NSMP as compared to MMR-D (P for interaction = 0.016 for grade and 0.033 for p16).ConclusionsGrade of differentiation and p16 hyperexpression appear to have a stronger prognostic impact in NSMP as compared to MMR-D EC. While these results need to be confirmed in a larger study population, they indicate that differential impact of risk factors needs to be taken into account when developing new molecular class-integrated risk stratification algorithms for EC.

Pretreatment Nutritional Status and Cardiovascular Risk Factors Affect Survival of Diffuse Large B-Cell Lymphoma Patients Treated with Immunochemotherapy

▪BackgroundPretreatment nutritional status assessed by body mass index (BMI), total cholesterol (TC), albumin, total lymphocyte count (TLC) have been noted to have prognostic significance in diffuse large B-cell lymphoma (DLBCL) patients. Along with malnutrition, higher comorbidity score was observed to affect poor treatment outcome and treatment-related toxicity in the rituximab era. These factors have mostly been assessed in a small cohort of single center.MethodFive hundred and twenty-five patients with newly diagnosed DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in 6 centers of South Korea from January, 2007 to March, 2016 were analyzed. Pretreatment nutritional status was assessed by controlling nutritional status (CONUT) score, which has been suggested to have strong prognostic impact in resectable solid cancer patients. The CONUT score was calculated by adding scores of the serum albumin concentration (score 0: ≥ 3.5 g/dL, score 2: 3.00-3.49 g/dL, score 4: 2.50-2.99 g/dL, score 6: < 2.50 g/dL), the TLC (score 0: ≥ 1600/mm3, score 1: 1200-1599/mm3, score 2: 800-1199/mm3, score 3: < 800/mm3), and the TC concentration (score 0: ≥ 180 mg/dL, score 1: 140-179 mg/dL, score 2: 100-139 mg/dL, score 3: < 100 mg/dL). Cardiovascular risk factors screened for the analysis were: diabetes mellitus (DM), hypertension, previous history of myocardial infarction and cerebrovascular infarction.ResultThe median follow-up duration was 29.47 months (range: 0.60 - 139.03 months) and the median age was 62 years (range: 20-89 years). By univariate analysis, BMI ≤ 20 kg/m2 (hazard ratio [HR], 2.20; 95% confidence interval [CI], 1.32-3.66, p= 0.003), TC < 140 mg/dL (HR, 1.76; 95% CI, 1.11-2.79, p= 0.017), albumin < 3.0 g/dL (HR, 4.86; 95% CI, 2.80-8.46, p= 0.000), TLC < 1200/mm3(HR, 1.69; 95% CI, 1.09-2.62, p= 0.019), CONUT score ≥ 4 (HR, 3.22; 95% CI, 2.03-5.10, p= 0.000), and cardiovascular risk factors ≥ 1 (HR, 2.53; 95% CI, 1.63-3.91, p= 0.000) significantly affected overall survival (OS). In multivariate analysis, BMI ≤ 20 kg/m2 (HR, 1.93; 95% CI, 1.12-3.33, p= 0.019), albumin < 3.0 g/dL (HR, 2.50; 95% CI, 1.27-4.94, p= 0.008), CONUT score ≥ 4 (HR, 2.32; 95% CI, 1.15-4.66, p= 0.019), and cardiovascular risk factors ≥ 1 (HR, 2.15; 95% CI, 1.34-3.45, p= 0.001) were significantly associated with OS. In terms of factors affecting progression-free survival (PFS), there were significant association with albumin < 3.0 g/dL (HR, 1.99; 95% CI, 1.04-3.82, p= 0.038), TLC < 1200/mm3 (HR, 1.47; 95% CI, 1.00-2.15, p= 0.048) and CONUT score ≥ 4 (HR, 1.76; 95% CI, 1.16-2.69, p= 0.008) but none of these factors had prognostic impact on PFS in multivariate analysis.ConclusionMalnourishment status indicated by BMI ≤ 20 kg/m2 and CONUT score ≥ 4 and at least one or more cardiovascular risk factors at diagnosis poorly affect survival in DLBCL patients treated with Rituximab-based regimen. DisclosuresNo relevant conflicts of interest to declare.

Prognosis impact of serous metastases (SMs) in clear cell renal cell carcinoma patients in the GETUG-AFU-26 NIVOREN phase II trial.

e16566 Background: Nivolumab monotherapy (N) is a standard of care for patients with metastatic clear cell renal cell carcinoma (ccRCC) after failure of antiangiogenic therapies. IMDC criteria is the established prognostic model in anyline of systemic treatment including with N. While liver, bone and brain have been reported to convey a dismal prognosis, little is known about the pejorative prognostic impact of serous metastatic sites (pleura, peritoneum, pericardium) in patients receiving anti-PD (L) -1 treatment. Methods: We aimed to assess survival, and activity of N in patients included in the GETUG-AFU 26 NIVOREN phase II prospective trial ( NCT03013335 ), according to serous metastases (SMs). Results: Overall, 720 patients with metastatic ccRCC, and treated with N. Baseline RECIST metastases data were available for 708 patients included in this analysis. Among them, 142 (20%) had SMs (pleura, n=91 ; peritoneum, n=50 ; pericardium, n=1). Median PFS (4.5 vs 2.6 mo ; HR :1.31 ; p=0.0079), and OS (26.1 vs 15 mo ; HR :1.67 ; p&lt;0.0001) were significantly lower in patients with SMs. The dismal prognostic impact was observed both with pleura and peritoneum SMs. These 2 sites were not significantly associated. Using multivariate Cox models, SMs remained significantly associated with poor survival, independently of IMDC category, gender, age, and number of previous lines of therapy. Objective response rate in patients with SMs was not significantly different from others patients (16.4 vs 22.1%; p=0.147). SMs were not statistically associated with known poor prognosis metastatic sites (cerebral, bone, and liver.) Conclusions: SMs are a strong independent prognostic impact in patients receiving N for metastatic ccRCC Poor prognostic metastatic sites should be considered when assessing the prognosis of patients with metastatic ccRCC

Morphology Matters: A Critical Reappraisal of the Clinical Relevance of Morphologic Criteria From the 2019 WHO Classification in a Large Colorectal Cancer Cohort Comprising 1004 Cases.

The 2019 World Health Organization (WHO) classification of colorectal carcinoma (CRC) profoundly reclassified CRC subtypes and introduces tumor budding as a second major grading criterion, while condensing conventional grade into a 2-tiered system. So far it remains largely unexplored how these parameters interact with each other and whether they truly have an independent impact on patient prognosis. We reclassified a large single-center cohort of 1004 CRCs spanning 2 decades for adjusted WHO grade (low vs. high), tumor budding (Bd1/Bd2/Bd3), and CRC subtype (adenocarcinoma not otherwise specified, micropapillary, mucinous, serrated, medullary, adenoma-like, signet-ring cell, mixed adenoneuroendocrine carcinoma/neuroendocrine carcinoma, undifferentiated) according to the criteria of the 2019 WHO classification. We investigated the interaction of these parameters, their connection to stage/microsatellite status, and their significance for patient survival in the different subgroups. Specific subtypes other than adenocarcinoma not otherwise specified represented one third of all CRCs and were unevenly distributed throughout stage and microsatellite subgroups. Subtypes, WHO grade and tumor budding profoundly impacted all survival parameters (P<0.001 for all analyses), with CRC subtypes and tumor budding-but not WHO grade-being stage-independent prognosticators for all survival comparisons. WHO grade had very limited prognostic value in CRC subtypes, while tumor budding retained its strong prognostic impact in most scenarios. Accurate delineation of CRC subtypes introduced in the 2019 WHO classification provides strong stage-independent prognostic information, arguing that they should be considered in pathology reports and in clinical trials. Of the morphology-based grading schemes included in the 2019 WHO, tumor budding outperforms WHO grade.

Clinical Implications of Inflammation in Acute Myeloid Leukemia.

Recent advances in the description of the tumor microenvironment of acute myeloid leukemia, including the comprehensive analysis of the leukemic stem cell niche and clonal evolution, indicate that inflammation may play a major role in many aspects of acute myeloid leukemia (AML) such as disease progression, chemoresistance, and myelosuppression. Studies on the mechanisms of resistance to chemotherapy or tyrosine kinase inhibitors along with high-throughput drug screening have underpinned the potential role of glucocorticoids in this disease classically described as steroid-resistant in contrast to acute lymphoblastic leukemia. Moreover, some mutated oncogenes such as RUNX1, NPM1, or SRSF2 transcriptionally modulate cell state in a manner that primes leukemic cells for glucocorticoid sensitivity. In clinical practice, inflammatory markers such as serum ferritin or IL-6 have a strong prognostic impact and may directly affect disease progression, whereas interesting preliminary data suggested that dexamethasone may improve the outcome for AML patients with a high white blood cell count, which paves the way to develop prospective clinical trials that evaluate the role of glucocorticoids in AML.

Genomic heterogeneity in core-binding factor acute myeloid leukemia and its clinical implication.

Core-binding factor (CBF) acute myeloid leukemia (AML) encompasses AML with inv(16)(p13.1q22) and AML with t(8;21)(q22;q22.1). Despite sharing a common pathogenic mechanism involving rearrangements of the CBF transcriptional complex, there is growing evidence for considerable genotypic heterogeneity. We comprehensively characterized the mutational landscape of 350 adult CBF-AML [inv(16): n = 160, t(8;21): n = 190] performing targeted sequencing of 230 myeloid cancer-associated genes. Apart from common mutations in signaling genes, mainly NRAS, KIT, and FLT3, both CBF-AML entities demonstrated a remarkably diverse pattern with respect to the underlying cooperating molecular events, in particular in genes encoding for epigenetic modifiers and the cohesin complex. In addition, recurrent mutations in novel collaborating candidate genes such as SRCAP (5% overall) and DNM2 (6% of t(8;21) AML) were identified. Moreover, aberrations altering transcription and differentiation occurred at earlier leukemic stages and preceded mutations impairing proliferation. Lasso-penalized models revealed an inferior prognosis for t(8;21) AML, trisomy 8, as well as FLT3 and KIT exon 17 mutations, whereas NRAS and WT1 mutations conferred superior prognosis. Interestingly, clonal heterogeneity was associated with a favorable prognosis. When entering mutations by functional groups in the model, mutations in genes of the methylation group (ie, DNMT3A, TET2) had a strong negative prognostic impact.

The cutoff for estrogen and progesterone receptor expression in endometrial cancer revisited: a European Network for Individualized Treatment of Endometrial Cancer collaboration study

There is no consensus on the cutoff for positivity of estrogen receptor (ER) and progesterone receptor (PR) in endometrial cancer (EC). Therefore, we determined the cutoff value for ER and PR expression with the strongest prognostic impact on the outcome. Immunohistochemical expression of ER and PR was scored as a percentage of positive EC cell nuclei. Cutoff values were related to disease-specific survival (DSS) and disease-free survival (DFS) using sensitivity, specificity, and multivariable regression analysis. The results were validated in an independent cohort. The study cohort (n=527) included 82% of grade 1-2 and 18% of grade 3EC. Specificity for DSS and DFS was highest for the cutoff values of 1-30%. Sensitivity was highest for the cutoff values of 80-90%. ER and PR expression were independent markers for DSS at cutoff values of 10% and 80%. Consequently, three subgroups with distinct clinical outcomes were identified: 0-10% of ER/PR expression with, unfavorable outcome (5-year DSS = 75.9-83.3%); 20-80% of ER/PR expression with, intermediate outcome (5-year DSS = 93.0-93.9%); and 90-100% of ER/PR expression with, favorable outcome (5-year DSS = 97.8-100%). The association between ER/PR subgroups and outcomes was confirmed in the validation cohort (n=265). We propose classification of ER and PR expression based on a high-risk (0-10%), intermediate-risk (20-80%), and low-risk (90-100%) group.

Outcomes of Patients with Down Syndrome and CRLF2-Overexpressing Acute Lymphoblastic Leukemia (ALL): A Report from the Children's Oncology Group (COG)

Background: Patients with Down syndrome (DS) have an approximately 10-fold increased risk of developing ALL, and the spectrum of genetic alterations differs from that of non-DS ALL. Rearrangement and/or overexpression of cytokine receptor-like factor 2 (CRLF2+) occurs in 50% of DS ALL, compared to only 5-10% CRLF2+ cases in non-DS children and adolescents. JAK2 or JAK1 mutations co-occur in about half of CRLF2+ cases in both DS and non-DS ALL. The prognostic significance of CRLF2+ ALL also appears to differ in the limited data reported to date, with less adverse impact in patients with DS compared to non-DS ALL. Here, we report the clinical characteristics and prognostic significance of B-ALL with CRLF2 overexpression and JAK alterations in children and adolescents/young adults (AYA) with DS who were treated on Children's Oncology Group (COG) clinical trials from 2003-2016. Methods: We analyzed clinical, laboratory, and outcome data for 317 patients with DS B-ALL treated on standard risk (SR) trials AALL0331 and AALL0932 and high risk (HR) trials AALL0232 and AALL1131, for whom CRLF2 status and rearrangement partners (IGH or P2RY8) were ascertained by flow cytometric assessment of surface expression; fluorescence in situ hybridization; and/or polymerase chain reaction (PCR) testing. JAK mutations were ascertained in a subset by PCR and sequencing. Minimal residual disease (MRD) was assessed by flow cytometry at the end of induction (EOI) and at end of consolidation (EOC) for a subset of EOI MRD+ patients. Results: We identified 168/317 (53.0%) CRLF2+ cases, and among those assessed for CRLF2 partner, 17/73 (23.3%) were IGH-CRLF2 and 56/73 (76.7%) were P2RY8-CRLF2. In the subset of 165 cases tested for JAK mutations (85 CRLF2- and 80 CRLF2+), 42/165 (25.4%) had JAK mutations, all of which co-occurred in CRLF2+ cases. CRLF2 positivity was significantly associated with younger age at diagnosis: 140/168 (83.3%) of CRLF2+ cases were under 10 years old, versus 106/149 (71.1%) of CRLF2- cases, p&amp;lt;0.01. P2RY8-CRLF2 cases were significantly more likely than IGH-CRLF2 cases to be associated with age under 10 years at diagnosis (92.9% vs 29.4%, p&amp;lt;0.0001), initial white blood count (WBC) &amp;lt;50x103 (80.4% vs 52.9%, p&amp;lt;0.024), National Cancer Institute (NCI) standard risk status (73.2% vs 23.5%, p&amp;lt;0.0002), and day 29 MRD &amp;lt;0.01% (67.9% vs 37.5%, p&amp;lt;0.028). There were no significant associations between JAK mutation status and any clinical features assessed (sex, initial WBC, central nervous system or testicular involvement, NCI risk group, or EOI/EOC MRD). Among patients with neutral cytogenetics (defined as neither favorable [ETV6-RUNX1, double trisomies of chromosomes 4 and 10] nor unfavorable [BCR-ABL1, KMT2A-rearranged, hypodiploid, iAMP21]), survival did not significantly differ between CRLF2+ and CRLF2- patients (Figure 1A,B), either for 5-year event-free survival (EFS) (79.1 +3.6% vs 77.6 +4.7%, p=0.856) or 5-year overall survival (OS) (89.5 ±2.8% vs 84.9 ±4.1%, p=0.674). There were also no significant differences in EFS or OS based on JAK mutation status or CRLF2 partner, although there were trends toward poorer outcomes in the CRLF2+/JAK+ and IGH-CRLF2 subgroups (Figure 1C). Finally, there was no significant difference in 5-year cumulative incidence of relapse (CIR) according to CRLF2 status (CRLF2+ 16.0 +3.0%, CRLF2- 10.6 +2.6%, p=0.179), although there were non-significant trends toward more relapses in CRLF2+ cases overall and in the NCI HR subgroup analysis. Discussion: Whereas CRLF2 and JAK alterations are associated with higher MRD, poorer survival, and increased CIR in patients with high-risk ALL without DS, these alterations do not demonstrate strong adverse prognostic impact in children and AYAs with DS-ALL treated on recent frontline COG trials, although larger sample sizes are needed to adequately assess for possible poorer prognoses associated with the CRLF2+/JAK+ and IGH-CRLF2 subgroups. Regardless, given the frequency of these targetable lesions and the increased risk of relapse and chemotherapy-associated toxicities in patients with DS-ALL, targeted therapies currently under investigation for these genetic lesions may be beneficial to replace some intensive blocks of therapy in DS-ALL with CRLF2 and/or JAK alterations, both to enhance anti-leukemic efficacy and decrease intensive chemotherapy-associated toxicities. Figure 1 Disclosures Tasian: Gilead Sciences: Research Funding; Incyte Corporation: Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees. Borowitz:Amgen: Honoraria. Mullighan:Illumina: Consultancy, Honoraria, Speakers Bureau; AbbVie, Inc.: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau. Raetz:Celgene: Other: DSMB member; Pfizer: Other: Institutional research funding. Loh:Pfizer: Other: Institutional Research Funding; Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hunger:Novartis: Consultancy; Amgen: Current equity holder in publicly-traded company, Honoraria.

High B7-H3 expression is linked to increased risk of prostate cancer progression.

B7-H3 is a member of the B7 superfamily of immune checkpoint molecules. B7-H3 up regulation has been linked to cancer development and progression in many tumors including prostate cancer. To clarify the potential utility of B7-H3 as a prognostic biomarker, B7-H3 expression was analyzed by immunohistochemistry in more than 17 000 prostate cancers. Normal prostatic glands were largely B7-H3 negative, while membranous B7-H3 immunostaining was seen in 47.0% of analyzed cancers. B7-H3 immunostaining was weak in 12.3%, moderate in 21.1% and strong in 13.5% of cases. High B7-H3 expression was associated with pT, Gleason score, lymph node metastasis, high Ki67 labeling index and early prostate-specific antigen recurrence (P < 0.0001 each). High B7-H3 expression was also linked to high androgen receptor expression and TMPRSS2:V-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusions (P < 0.0001 each). Multivariate analyses showed a strong independent prognostic impact of high B7-H3 expression in all cancers and in the ERG negative subgroup. Comparison with previously analyzed frequent chromosomal deletions revealed a close association with Phosphatase and Tensin Homolog deletions. Analysis of B7-H3, alone or in combination with other markers, might be of clinical utility, especially in the subgroup of ERG negative prostate cancers.

Functional Imaging for Therapeutic Assessment and Minimal Residual Disease Detection in Multiple Myeloma.

Serum markers and bone marrow examination are commonly used for monitoring therapy response in multiple myeloma (MM), but this fails to identify minimal residual disease (MRD), which frequently persists after therapy even in complete response patients, and extra-medullary disease escape. Positron emission tomography with computed tomography using 18F-deoxyglucose (FDG-PET/CT) is the reference imaging technique for therapeutic assessment and MRD detection in MM. To date, all large prospective cohort studies of transplant-eligible newly diagnosed MM patients have shown a strong and independent pejorative prognostic impact of not obtaining complete metabolic response by FDG-PET/CT after therapy, especially before maintenance. The FDG-PET/CT and MRD (evaluated by flow cytometry or next-generation sequencing at 10−5 and 10−6 levels, respectively) results are complementary for MRD detection outside and inside the bone marrow. For patients with at least a complete response, to reach double negativity (FDG-PET/CT and MRD) is a predictive surrogate for patient outcome. Homogenization of FDG-PET/CT interpretation after therapy, especially clarification of complete metabolic response definition, is currently underway. FDG-PET/CT does not allow MRD to be evaluated when it is negative at initial workup of symptomatic MM. New PET tracers such as CXCR4 ligands have shown high diagnostic value and could replace FDG in this setting. New sensitive functional magnetic resonance imaging (MRI) techniques such as diffusion-weighted MRI appear to be complementary to FDG-PET/CT for imaging MRD detection. The goal of this review is to examine the feasibility of functional imaging, especially FDG-PET/CT, for therapeutic assessment and MRD detection in MM.

Reduced KLK2 expression is a strong and independent predictor of poor prognosis in ERG-negative prostate cancer.

Kallikrein-related peptidase 2 (KLK2)-like KLK3 (prostate-specific antigen [PSA])-belongs to the highly conserved serine proteases of the glandular kallikrein protein family (KLK family). Studies suggested that measurement of KLK2 serum levels advanced the predictive accuracy of PSA testing in prostate cancer. To clarify the potential utility of KLK2 as a prognostic tissue biomarker, KLK2 expression was analyzed by immunohistochemistry in more than 12 000 prostate cancers. Normal epithelium cells usually showed weak to moderate KLK2 immunostaining, whereas KLK2 was negative in 23%, weak in 38%, moderate in 35%, and strong in 4% of 9576 analyzable cancers. Lost or reduced KLK2 immunostaining was associated with advanced tumor stage, high Gleason score, lymph node metastasis, increased cell proliferation, positive resection margin, and early PSA recurrence (P < .0001). Comparison with previously analyzed molecular alterations revealed a strong association of KLK2 loss and presence of TMPRSS2:ERG fusion (P < .0001), most of all analyzed common deletions (9 of 11; P ≤ .03), and decreased PSA immunostaining (P < .0001 each). Cancers with combined negative or weak immunostaining of KLK2 and PSA showed worse prognosis than cancers with at least moderate staining of one or both proteins (P < .0001). Multivariate analyses including established preoperative and postoperative prognostic parameters showed a strong independent prognostic impact of KLK2 loss alone or in combination of PSA, especially in erythroblast transformation-specific-negative cancers (P ≤ .006). Loss of KLK2 expression is a potentially useful prognostic marker in prostate cancer. Analysis of KLK2 alone or in combination with PSA may be useful for estimating cancer aggressiveness at the time of biopsy.

Combined tumor plus nontumor interim FDG-PET parameters are prognostic for response to chemoradiation in squamous cell esophageal cancer.

We have investigated the prognostic value of two novel interim 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) parameters in patients undergoing chemoradiation (CRT) for esophageal squamous cell carcinoma (ESCC): one tumor parameter (maximal standardized uptake ratio rSUR) and one normal tissue parameter (change of FDG uptake within irradiated nontumor-affected esophagus ∆SUVNTO ). PET data of 134 European and Chinese patients were analyzed. Parameter establishment was based on 36 patients undergoing preoperative CRT plus surgery, validation was performed in 98 patients receiving definitive CRT. Patients received PET imaging prior and during fourth week of CRT. Clinical parameters, baseline PET parameters, and interim PET parameters (rSUR and ∆SUVNTO ) were analyzed and compared to event-free survival (EFS), overall survival (OS), loco-regional control (LRC) and freedom from distant metastases (FFDM). Combining rSUR and ∆SUVNTO revealed a strong prognostic impact on EFS, OS, LRC and FFDM in patients undergoing preoperative CRT. In the definitive CRT cohort, univariate analysis with respect to EFS revealed several staging plus both previously established interim PET parameters as significant prognostic factors. Multivariate analyses revealed only rSUR and ∆SUVNTO as independent prognostic factors (p = 0.003, p = 0.008). Combination of these parameters with the cutoff established in preoperative CRT revealed excellent discrimination of patients with a long or short EFS (73% vs. 17% at 2 years, respectively) and significantly discriminated all other endpoints (OS, p < 0.001; LRC, p < 0.001; FFDM, p = 0.02), even in subgroups. Combined use of interim FDG-PET derived parameters ∆SUVNTO and rSUR seems to have predictive potential, allowing to select responders for definitive CRT and omission of surgery.

Prognostic impact of tumor budding and EMT in periampullary adenocarcinoma: a quantitative approach.

The presence of invasive cell clusters known as tumor budding and the closely related epithelial mesenchymal transition (EMT) have a prognostic impact on cancer patients' overall survival. Interestingly, data quantitatively analyzing and correlating the amount of tumor buds and patient overall survival as well as the impact of expression of epithelial phenotype markers are missing.Periampullary carcinoma samples of 171 patients were immunohistochemically stained for E-Cadherin (ECad). Tumor cell clusters (TCC, defined from one to 50 cells) were manually quantified comprising tumor cell number and subcellular localization of ECad expression (membranous, cytoplasmic or mixed). Data analyses were performed using elastic net feature selection. Hereby, five distinct intervals of TCC sizes and corresponding fractions of cells with distinct ECad expression were identified. Prognostic features of the defined budding categories were entered into a subsequent Cox regression model together with standard clinicopathological parameters and, based on the model prediction, cases were categorized into “low and high budding” grades.Overall median TCC size was 16 cells (range: 2-36 cells). The median number of TCCs per tumor was 42 (range: 3-283). Elastic net feature selection identified TCCs of 6-10 and 31-35 cells as prognostically most relevant negative and positive features, respectively. Regarding ECad expression, cytoplasmic ECad expression in TCCs of 11-15 as well as of 26-30 cells revealed prognostic relevance. Combining TCC numbers and ECad expression, budding grade qualified as independent prognostic factor for patient overall survival (p<0.001) in a multivariable clinicopathologic Cox model.Applying an advanced modelling by machine learning on a cohort of periampullary cancers, we show that not the smallest TCCs (1-5 cells) but tumor cell nests containing 6-10 cells display the strongest negative prognostic relevance. Moreover, we demonstrate that larger TCCs might have a strong positive prognostic impact in periampullary adenocarcinomas, contributing to establishing an advanced grading system.

Prognostic impact of eosinophils in mastocytosis: analysis of 2350 patients collected in the ECNM Registry.

Systemic mastocytosis (SM) is frequently associated with eosinophilia. To examine its prevalence and clinical impact in all WHO classification-based subcategories, we analyzed eosinophil counts in 2350 mastocytosis patients using the dataset of the European Competence Network on Mastocytosis. Ninety percent of patients had normal eosinophil counts, 6.8% mild eosinophilia (0.5-1.5 × 109/l), and 3.1% hypereosinophilia (HE; >1.5 × 109/l). Eosinophilia/HE were mainly present in patients with advanced SM (17%/19%), and only rarely recorded in patients with indolent and smoldering SM (5%/1%), and some patients with cutaneous mastocytosis. The eosinophil count correlated with organomegaly, dysmyelopoiesis, and the WHO classification, but not with mediator-related symptoms or allergy. Eosinophilia at diagnosis had a strong prognostic impact (p < 0.0001) on overall survival (OS) and progression-free survival (PFS), with a 10-year OS of 19% for patients with HE, 70% for those with mild eosinophilia, and 88% for patients with normal eosinophil counts. In 89% of patients with follow-up data (n = 1430, censored at start of cytoreductive therapy), eosinophils remained stable. In those with changing eosinophil counts (increase/decrease or mixed pattern), OS and PFS were inferior compared with patients with stable eosinophil counts. In conclusion, eosinophilia and HE are more prevalent in advanced SM and are predictors of a worse outcome.

Impact of Somatic Mutations on Outcome in Patients > 60 Years Old with Newly Diagnosed AML Treated with Response-Adapted Sequential Azacitidine and Induction Chemotherapy within the DRKS00004519 Trial (RAS-AZIC) of the East German Study Group of Hematology and Oncology (OSHO)

Introduction: Old age and unfavorable cytogenetics are well-established adverse prognostic factors for outcome in patients (pts) with AML. Recently, high-throughput sequencing techniques have identified multiple somatically acquired driver mutations (muts) with a strong prognostic impact in AML. We explored the relative contribution of baseline molecular genetics versus a response-based sequential treatment approach on response and overall survival (OS) at two years in pts &amp;gt;60 years (y) with newly diagnosed AML treated within the multicenter RAS-AZIC study of the OSHO. Patients and methods: In the RAS-AZIC trial, 112 pts received priming with Azacitidine (AZA) followed by a day (d) 15 bone marrow (BM) blast count-adapted sequential treatment with AZA or intensive chemotherapy (IC). Pts with d15 blasts ≥45% received IC. If the count was &amp;lt;45%, AZA was continued at d28. The second treatment adaptation was based on d56 response. If no complete remission (CR) or CR with incomplete recovery (CRi) were documented, IC was applied followed by AZA maintenance or allogeneic hematopoietic stem cell transplantation if a remission was achieved on d90. Conventional cytogenetics, NPM1, and FLT3 mutational screening were used for genetic risk stratification following the 2010 ELN recommendations. Response [CR/CRi/Partial remission (PR)] and treatment-related mortality on d90, the two-year OS, event-free survival (EFS), and relapse-free survival (RFS) were previously presented (Jaekel N, et al; ASH 2018). Baseline BMs of 77 pts who signed the translational informed consent were analyzed by NGS using the NEOmyeloid panel of NEO New Oncology (Siemens Healthineers Company, Germany). This hybrid capture-based assay comprises 43 genes and detects point muts, small insertions and deletions in 30 genes as well as gene fusions in 18 genes. Molecular results were correlated to outcome data. Results: Median age was 70y. Secondary AML was present in 39%. Genetic risk was int-II and adverse in 25% and 27% respectively. Response on d90 was 67% (CR/CRi 58%, PR 9%). A median of 3 muts per pt were found. Mutations in DNA methylation-related-, spliceosome complex-, and chromatin-modifying-genes were 62%, 39%, and 30% respectively. Overall, muts in DNMT3A (34%), ASXL1 (25%), RUNX1 (24%), SRSF2 (23%), and TET2 (23%) were the most frequently detected (fig. 1). As expected, 72% of SRSF2 muts were associated with ASXL1 and/or RUNX1 muts. CR/CRi in the favorable and int-I 2010 ELN genetic risk groups was 81% and 57.5% in int-II and adverse risk pts. With the exception of muts in spliceosome complex-related genes, the mutational status (including the FLT3 status) seemed to have no impact on response in this cohort (table 1). In the presence of splicing factor gene muts a trend towards an inferior response of 53% compared to 77% in pts without such a mut was observed. High risk muts such as ASXL1, RUNX1, and TP53 muts which were included in the 2017 ELN adverse risk stratification were present in 20/32 (63%) of pts with favorable and int-I genetic risk. Yet, only 5/32 (16%) did not achieve a response. Similarly, CR/CRi was achieved in 7/9 (78%) pts with TP53 mut which was associated with an adverse karyotype in 8 pts. Likewise, OS tended to be similar across all molecular classes with the exception of KMT2A gene fusions with their well-known negative impact on outcome. The presence of such a fusion (n=4) was associated with a median survival time of only 8 compared to 16 months in pts without a detectable KMT2A fusion. These KMT2A gene fusions also correlated with a shorter EFS and RFS. The presence of myeloid transcription factor gene muts such as in RUNX1 (24%) and BCOR (13%) tended to be associated with an inferior EFS, while cohesin complex- (STAG2 8%), tumour suppressor-, and DNA-methylation-related gene muts with a negative RFS (table 1). Conclusions: This explorative analysis with a limited number of patients describes the pattern of genetic mutations in elderly AML treated with a response-based sequential approach that integrates epigenetic and chemotherapeutic treatments and their association with outcome. Whether such a response-based treatment mitigates the negative impact of (some) high risk mutations on outcome needs to be addressed in a much larger trial. Disclosures Jaekel: Celgene: Other: travel grant. Siebolts:Merck: Honoraria; Boehringer Ingelheim: Honoraria; MSD: Honoraria; Pfizer: Honoraria; AstraZeneca: Honoraria; Roche: Honoraria; Novartis: Honoraria; BMS: Honoraria. Pazaitis:Novartis: Consultancy. Niederwieser:Daichii: Speakers Bureau; Cellectis: Consultancy. Hänel:Amgen: Honoraria; Roche: Honoraria; Novartis: Honoraria; Takeda: Other: advisory board; Celgene: Other: advisory board. Maschmeyer:Gilead, Janssen Cilag, Astra Zeneca; BMS, Merk-Serono: Honoraria. Heukamp:NEO New Oncology GmbH: Employment. Menon:NEO New Oncology GmbH: Employment. Bertrand:NEO New Oncology GmbH: Employment. Wickenhauser:BMS: Honoraria; Merck-Serono: Honoraria; MSD: Honoraria; Böhringer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Roche: Honoraria. Brosteanu:University Leipzig: Employment. Al-Ali:Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CTI: Honoraria.