Risk Of Early Progression Research Articles

The burden and care cascade in young and middle-aged patients with diabetes hypertension comorbidity with abdominal obesity in India: A nationally representative cross-sectional survey.

We ascertained the burden, determinants, and care cascade in the young and middle-aged patients having co-existing hypertension (HTN), Diabetes Mellitus (DM), and abdominal obesity in India from a secondary data analysis of nationally representative data. The study examined cross-sectional data from the National Family Health Survey (NFHS-5) conducted in India from 2019 to 2021 in 788974 individuals aged 15-49 years including 695707 women and 93267 men. The weighted prevalence of DM-HTN comorbidity with high waist circumference in the sample was 0.75% (95% CI: 0.71 to 0.79) including 46.33% (95% CI: 44.06 to 48.62) newly diagnosed cases detected for HTN and high blood sugars. The weighted prevalence of Metabolic syndrome as per NCEP ATPIII criteria was found to be 1.13% (95% CI: 1.08 to 1.17). Only 46.16% existing cases were treated with both anti-diabetes and antihypertensive medication (full treatment), while 34.71% cases were untreated. On adjusted analysis, increasing age, females, higher wealth index, high fat diet, obesity and comorbidities were significantly associated with having DM-HTN comorbidity along with high-waist circumference. More than half of young and middle aged-population in India with DM-HTN-abdominal obesity triad are not initiated on treatment for DM and HTN comorbidities, while a majority of the previously diagnosed cases have uncontrolled blood pressure and poor glycemic control. The poor cascade of care for DM and HTN in these high-risk group of patients may substantially increase their risk for early progression and severity of microvascular and macrovascular complications especially cardiovascular disease.

Diffuse large B-cell lymphoma: strokes to the epidemiological portrait. A review

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous orphan lymphoproliferative disease with an aggressive course, which accounts for 30–40% of all non-Hodgkin lymphomas. Approximately 3,000 new cases of DLBCL are diagnosed annually in Russia. The trend towards a steady increase in DLBCL incidence worldwide and the rapidly changing treatment landscape with the introduction of innovative options require the updating of epidemiological data. Despite a deeper understanding of the lymphomagenesis and molecular heterogeneity of DLBCL, the R-CHOP regimen remains the first-line standard of care for the vast majority (74%) of patients in Russia and worldwide. The effectiveness of this approach varies greatly and depends on several clinical, biological, and genetic factors. Currently, the most effective and simple prognostic model is the International Prognostic Index (IPI), according to which approximately 20% of patients are at intermediate/high risk of early progression (IPI3-5) and require therapy modification. After the first-line standard immunochemotherapy, 60–70% of DLBCL patients achieve long-term remission with the potential for cure. However, the occurrence of relapse or refractory disease in the remaining 40% of patients is associated with an abysmal prognosis with a median overall survival of about 6 months, which tends to decrease with each subsequent line, warranting an urgent need for new innovative treatments for patients with relapsed DLBCL.

Abstract 964: Genomic and clinical predictors of early disease progression and chemoimmunotherapy benefit in advanced NSCLC

Abstract Background: Immune checkpoint inhibitors (ICIs) as monotherapy (ICI-mono) or with chemotherapy (ICI-chemo) are standard first-line treatment in NSCLC patients lacking targetable driver mutations. Biomarkers to identify patients at risk for early progression on ICI-mono or those who would maximally benefit from upfront ICI-chemo have not been defined. Methods: We queried the GEMINI database to identify metastatic NSCLC patients without targetable EGFR/ALK alterations who were treated with ICI-mono or ICI-chemo. Mutational profiling was performed on tissue or blood using targeted NGS. Outcome measures were defined as clinical progression free survival (PFS) or early progressive disease (PD) rate (defined as rate of 3-month progression), and their association with variables was assessed via Cox Proportional Hazards regression (PFS) or logistic regression (early PD). Predictive deep learning models were used to integrate clinicopathological factors and genomic profile. Results: 735 patients were included in this study, 269 treated with ICI-chemo and 466 with ICI-mono; 446 were treated in the first-line setting. TP53 was the most frequently altered gene (60%), followed by KRAS (37%), AR (21%), and STK11 (19%). In ICI-mono patients, alterations in STK11, ERBB2, ARID1A and CDK6 were associated with a higher likelihood of early PD; only STK11 was associated with early PD (29% vs 17%, P = 0.04) on ICI-chemo. In all patients, low PD-L1 expression and high disease burden (stage IVb and liver metastases) associated with early PD, but there were borderline significant treatment effects in favor of ICI-chemo in never smokers and patients with liver metastases and stage IVb. Shorter PFS was observed in the ICI-chemo group who had CDKN2A alterations vs wild type (median PFS: 5.1 vs 9.0 months; HR: 1.72; P = 0.01). A subgroup analysis of patients with CDKN2A alterations demonstrated preferentially worse outcomes in ICI-chemo compared to ICI-mono, with the best PFS achieved in the ICI-mono treated patients with CDKN2A point mutation. Integration of clinicogenomic features into a multivariate model with feature selection to predict early PD demonstrated a predictive performance of AUC 0.73 (vs PD-L1 alone, AUC 0.60) in the ICI-mono group, driven by liver metastases, stage IVb disease, PD-L1 expression, and STK11 alterations. These features were less predictive in ICI-chemo-treated patients, indicating a protective effect against early PD in these patients from combination chemoimmunotherapy. Conclusions: Low PD-L1, high disease burden, and STK11 alterations are markers of early PD on ICI-mono, and patients with these features may particularly benefit from upfront combination treatment with ICI-chemo to protect against early progression. Citation Format: Lingzhi Hong, Muhammad Aminu, Xuetao Lu, Maliazurina B. Saad, Pingjun Chen, Waree Rinsurongkawong, Amy Spelman, Yasir Y. Elamin, Marcelo V. Negrao, Ferdinandos Skoulidis, Carl M. Gay, Tina Cascone, Mara B. Antonoff, Boris Sepesi, Jeff Lewis, Don L. Gibbons, Ara A. Vaporciyan, Xiuning Le, J.Jack Lee, Sinchita Roy-Chowdhuri, Mark J. Routbort, John V. Heymach, Jia Wu, Jianjun Zhang, Natalie I. Vokes. Genomic and clinical predictors of early disease progression and chemoimmunotherapy benefit in advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 964.

Efficacy and clinicogenomic correlates of response to immune checkpoint inhibitors alone or with chemotherapy in non-small cell lung cancer

The role of combination chemotherapy with immune checkpoint inhibitors (ICI) (ICI-chemo) over ICI monotherapy (ICI-mono) in non-small cell lung cancer (NSCLC) remains underexplored. In this retrospective study of 1133 NSCLC patients, treatment with ICI-mono vs ICI-chemo associate with higher rates of early progression, but similar long-term progression-free and overall survival. Sequential vs concurrent ICI and chemotherapy have similar long-term survival, suggesting no synergism from combination therapy. Integrative modeling identified PD-L1, disease burden (Stage IVb; liver metastases), and STK11 and JAK2 alterations as features associate with a higher likelihood of early progression on ICI-mono. CDKN2A alterations associate with worse long-term outcomes in ICI-chemo patients. These results are validated in independent external (n = 89) and internal (n = 393) cohorts. This real-world study suggests that ICI-chemo may protect against early progression but does not influence overall survival, and nominates features that identify those patients at risk for early progression who may maximally benefit from ICI-chemo.

Monitoring of Circulating Tumor DNA Predicts Response to Treatment and Early Progression in Follicular Lymphoma: Results of a Prospective Pilot Study.

Follicular lymphoma (FL) is the most frequent indolent non-Hodgkin lymphoma. Around 20% of patients suffer early disease progression within 24 months (POD24) of diagnosis. This study examined the significance of circulating tumor DNA (ctDNA) in predicting response to therapy and POD24 in patients with FL. We collected 100 plasma samples, before and during the treatment, from 36 patients with FL prospectively enrolled in 8 Spanish hospitals. They were treated with a chemotherapy-rituximab regimen and followed up for a median of 3.43 years. We performed targeted deep sequencing in cell-free DNA (cfDNA) and tumor genomic DNA from 31 diagnostic biopsy samples. Of the alterations detected in the diagnostic tissue samples, 73% (300/411) were also identified in basal cfDNA. The mean numbers of alterations per basal cfDNA sample in patients who suffered progression of disease within 24 months (POD24-pos) or did not achieve complete response (non-CR) were significantly higher than in POD24-neg or CR patients (unpaired samples t test, P = 0.0001 and 0.001, respectively). Pretreatment ctDNA levels, as haploid genome equivalents per milliliter of plasma, were higher in patients without CR (P = 0.02) and in POD24-pos patients compared with POD24-neg patients (P < 0.001). Dynamic analysis showed that ctDNA levels decreased dramatically after treatment, although the reduction was more significant in patients with CR and POD24-neg patients. Basal ctDNA levels are associated with the risk of early progression and response to treatment in FL. cfDNA monitoring and genotyping during treatment and follow-up predict response to treatment and early progression.

Abstract LB120: Comprehensive biomarkers analysis to explain resistances to PD1-L1 ICIs: The precision immuno-oncology for advanced non-small cell lung cancer (PIONeeR) trial

Abstract Background: Resistance to PD1/L1 immune checkpoint inhibitors (ICIs) in advanced NSCLC patients is observed in about 80% of individuals with no robust predictive biomarker yet. The PIONeeR trial (NCT03493581) aims to predict such resistances through a comprehensive multiparametric biomarkers analysis. Methodology: Among the &amp;gt;300 advanced NSCLC patients (pts) recruited in PIONeeR, we focused on the first 137 ≥2nd line ECOG PS0-1 pts treated with single-agent nivolumab, pembrolizumab or atezolizumab. Tumor tissue was collected at baseline and pts were re-biopsied at 6 weeks, and blood-sampled every cycle throughout the 24 weeks post C1D1. Response to PD1/L1 ICIs was assessed by RECIST 1.1 every 6 weeks. Immune contexture was characterized in tumor &amp; blood of each pt through FACS for circulating immune cell subtypes quantification and endothelial activation, blood soluble factors dosage, dual- &amp; multiplex IHC/digital pathology to quantify immune cells infiltrating the tumor, WES for TMB &amp; ICI plasma dosage, leading to 331 measured biomarkers in addition to routine clinical parameters. Multivariable (MV) logistic regression was used to examine the association of each biomarker (controlled by sex, age, smoking status, histological type &amp; PDL1+ Tumor Cells) with the risk of Early Progression (EP), i.e. within 3.5 months of treatment. Multivariable Cox regression analysis was conducted for association with PFS and OS. Results: Overall, the 137 pts were mainly male (64%), smokers (92%) and &amp;lt;70yrs (68%). Tumors were mainly non-squamous (79%) with &amp;gt;1% PDL1+ TC in 36% of the cases, and 21% of pts were still on treatment at data cut-off. Archived samples were available for 80% of pts at inclusion and re-biopsy was available in 52.9% of these cases. The median follow up was 19.8 months, 22.5% of pts did not progress at data cut-off while 62% presented EP. Tumor Cytotoxic T-cells density, especially PD1+ were lower in EP (MV OR=0.45, p=0.022); conversely, higher proportions of circulating cytotoxic T-cells and activated T-cells (HLA-DR+) were observed in EP (MV OR=3.8, p&amp;lt;0.001). Among other biomarkers, Tregs (MV OR=0.44, p=0.018), NK cell subsets (MV OR≤0.44, p&amp;lt;0.05), albumin (MV OR=0.4, p&amp;lt;0.01) and PDL1 TC % (MV OR=0.27, p&amp;lt;0.01) were decreased whereas alkaline phosphatase was increased (OR=3, p=0.018). &amp;gt;65% inter-pt variability was observed in plasma exposures for all ICIs, with 8-10% of pts displaying trough levels below the target engagement threshold. Data will be presented through unsupervised clustering algorithms &amp; multi-modal supervised learning methods. Changes after 6 weeks of treatment will be analyzed to further investigate drugs mechanisms of action. Conclusion: The PIONeeR trial provides with the 1st comprehensive biomarkers’ analysis to establish predictive models of resistance in advanced NSCLC pts treated with PD1/L1 ICIs and highlights how tumor and circulating biomarkers are complementary. Citation Format: Laurent Greillier, Florence Monville, Vanina Leca, Frédéric Vely, Stephane Garcia, Joseph Ciccolini, Florence Sabatier, Gilbert Ferrani, Nawel Boudai, Lamia Ghezali, Marcellin Landri, Clémence Marin, Mourad Hamimed, Laurent Arnaud, Melanie Karlsen, Kevin Atsou, Sivan Bokobza, Pauline Fleury, Arnaud Boyer, Clarisse Audigier-Valette, Stéphanie Martinez, Hervé Pegliasco, Patrice Ray, Lionel Falchero, Antoine Serre, Nicolas Cloarec, Louisiane Lebas, Stephane Hominal, Patricia Barre, Sarah Zahi, Ahmed Frikha, Pierre Bory, Maryannick Le Ray, Lilian Laborde, Virginie Martin, Richard Malkoun, Marie Roumieux, Julien Mazieres, Maurice Perol, Eric Vivier, Sebastien Benzekry, Jacques Fieschi, Fabrice Barlesi. Comprehensive biomarkers analysis to explain resistances to PD1-L1 ICIs: The precision immuno-oncology for advanced non-small cell lung cancer (PIONeeR) trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB120.

Abstract 5142: Clinical and genomic correlates of survival outcomes in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving intensified androgen deprivation therapy (ADT) in a real-world population

Abstract Introduction: Use of upfront chemotherapy or novel hormonal therapy (NHT) in patients (pts) with mCSPC has been approved based on improved outcomes. Baseline clinical and genomic correlates associated with inferior outcomes on intensified therapy would help identify pts at high risk for early progression or death, may improve patient counselling and guide drug development. Methods: In this IRB-approved study, pt-level data were collected retrospectively. Eligibility: mCSPC pts undergoing ADT plus NHT or docetaxel with available pre-treatment tumor comprehensive genomic profiling from a CLIA-certified lab. Study endpoint: progression-free survival (PFS) per PCWG-2, is defined as PSA, or radiographic, or clinical progression or death whichever occurred first. Variants of unknown significance and mutated genes present in ≤5% pts were excluded. Cox proportional hazards was used to evaluate the relationship between PFS and age at diagnosis, Gleason score, volume of disease (per CHAARTED), presence of visceral mets, PSA at baseline and genomic alterations. Significance was pre-set at p ≤ 0.05. Results: 106 pts with mCSPC were included: median follow-up was 20 months. Median age at diagnosis was 62 yrs (58 - 68); 85 pts (80%) had a Gleason score ≥8; 67 pts (63%) had de-novo metastatic disease; 69 pts (56%) had high-volume disease; and 20 (19%) had visceral metastases at time of diagnosis of metastatic disease. Most frequently mutated genes: TP53 (28%, n=30), TMPRSS2 (27%, n=29), and PTEN (21%, n=22). See table for COX regression results. Conclusion: In this real-world cohort of mCSPC pts undergoing intensified ADT we identify clinical and genomic markers that are significantly associated with a an inferior PFS. These hypothesis-generating data need external validation. Hazard Ratio (95% CI) P Age 0.98 (0.94-1.02) 0.40 De Novo 1.28 (0.61-2.62) 0.52 Gleason Score ≥8 2.61 (0.98-6.93) 0.05 Log-PSA at Baseline 1.17 (1.03-1.33) 0.02 High Vol of Disease 2.47 (1.23-4.99) 0.01 Visceral Mets 1.25 (0.54-3.92) 0.60 Mutated Genes MYC 5.17 (1.39-19.27) 0.01 KDM6A 0.97 (0.20-4.52) 0.97 RB1 3.14 (0.97-10.17) 0.06 PTEN 1.07 (0.48-2.36) 0.87 TMPRSS2 1.09 (0.55-2.14) 0.81 TP53 0.89 (0.47-1.74) 0.74 Citation Format: Nicolas Sayegh, Bennet Peterson, Nishita Tripathi, Beverly Chigarira, Haoran Li, Kamal Kant Sahu, Deepika Sirohi, Roberto Nussenzveig, Benjamin L. Maughan, Neeraj Agarwal, Umang Swami. Clinical and genomic correlates of survival outcomes in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving intensified androgen deprivation therapy (ADT) in a real-world population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5142.

Polymorphism of Baculoviral Inhibitor of Apoptosis Repeat-Containing 5 (BIRC5) Can Be Associated with Clinical Outcome of Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) comprises about 85% of all lung cancers. Currently, NSCLC therapy is based on the analysis of specific predictors, whose presence qualifies patients for appropriate treatment. Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5), also known as “survivin”, is a protein whose expression is characteristic for most malignant tumors and fetal tissue, while absent in mature cells. The biological role of BIRC5 is to counteract apoptosis by inhibiting the initiating and effector activities of caspases and binding to microtubules of the mitotic spindle. In our study, we looked for a relationship between BIRC5 gene polymorphism and the effectiveness of platinum-based chemotherapy. The study group consisted of 104 patients with newly diagnosed locally advanced or metastatic NSCLC. DNA was isolated from pretreatment blood samples, and SNPs of BIRC5 gene were analyzed. All patients received first-line platinum-based chemotherapy. Univariate analysis showed that a specific BIRC5 genotype was significantly associated with a higher risk of early progression (homozygous GG vs. heterozygous CG or CC: 28.9% vs. 11.9%). The presence of a homozygous GG genotype of the BIRC5 gene was insignificantly related to PFS shortening and TTP shortening. Moreover, significantly higher risk of overall survival shortening was associated with the BIRC5 homozygous GG genotype. Thus, studies on polymorphisms of selected genes affecting apoptosis may have a practical benefit for clinicians who monitor and treat NSCLC.

Early Progressing Follicular Lymphoma.

Follicular lymphoma is an indolent lymphoma which does not limit life expectancy in most patients; however, approximately 20% of patients will experience progression of disease within 24months (POD24) of diagnosis and have inferior survival outcomes. To date, no clinical, genetic, or tumor microenvironment prediction models have been able to definitively predict which patients will experience POD24 which limits the ability to alter frontline management of patients suspected to be at high risk of early progression. Here, we review recent literature regarding novel prediction models and management recommendations for POD24 patients. Recent studies have revealed novel clinicopathologic prediction models which may be closer to identifying patients at risk of POD24. In addition, several clinical trials utilizing novel therapies such as tazemetostat, obinutuzumab, PI3K inhibitors, and lenalidomide have been performed which help further guide treatment. Ongoing trials seek to identify the optimal management of these patients, and data from bispecific antibodies and CAR T cell therapies is forthcoming. With ongoing research efforts, hope remains that we are closer to being able to predict which patients will experience early progressing follicular lymphoma and have an improved management plan for those who do in order to improve survival outcomes.

Malignant transformation of pleomorphic xanthoastrocytoma in pregnant patient: Clinical case and ethical dilemma

Background: Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic tumor, accounting for <1% of astrocytic tumors. Due to its rarity, etiology, natural history, and biologic behavior is not completely explained. We present a case of malignant transformation of a PXA to glioblastoma in pregnant patient 6 month after tumor biopsy.Case Description: A 28-year-old female patient was presented with a newly onset of headache, nausea, and right-sided hemiparesis at 21st week of pregnancy. Magnetic resonance imaging (MRI) revealed cystic mass in the left frontal region. Patient underwent biopsy to confirm pathohistological analysis; the tumor tissue corresponded to an anaplastic PXA. Two weeks after initial biopsy, open surgery along with gross total tumor removal was performed confirming pathohistological analysis. Six months later, after childbirth, and control MRI revealed a recurrent tumor mass: the patient underwent surgical resection and the tumor tissue corresponded to a glioblastoma. The patients were further treated with radiation and chemotherapy according to oncologist.Conclusion: Distinguishing between PXA patients who have a good prognosis and those at risk for early progression is very important for the PXA clinical management. Despite cellular pleomorphism, mitotic index and the extent of resection are shown to be the main predictors for recurrence-free survival and overall survival rates. The standard therapy management is not yet established. Our patient treatment was associated with a significant ethical dilemma. Respecting patient’s wishes to deliver a baby, nor radio or chemo treatments were done. Further studies are necessary to provide factors responsible for malignant transformation of PXA. In addition, in ethically sensitive situation, such as tumor in pregnant patient, good communication, respecting patient’s wishes, and a multidisciplinary teamwork is the key for better outcome.

Combined Immune Score of Lymphocyte to Monocyte Ratio and Immunoglobulin Levels Predicts Progression-Free Survival of Myeloma Patients after Autologous Transplant

Although autologous stem cell transplant (ASCT) remains an important therapy for myeloma, outcomes are highly variable. MM is characterized by the loss of central mediators of immune surveillance and the development of an immunologic milieu that promotes disease progression and resistance to treatment. We aimed to analyze the impact of various clinically available immune-related markers on progression-free survival (PFS) after ASCT and formulate a combined immune score that could be used to predict early progression.One hundred and thirty patients who received melphalan 200 mg/m2 and ASCT between 2002 and 2016 were included in the final analysis. The median age was 59 (range: 34-77) years with the majority of patients being male (n=71, 55%), African-American (n=61, 47%), IgG subtype (n=65, 50%), and ISS stage 3 at diagnosis (n=55, 57%). Sixteen (12%) patients were diagnosed with high risk FISH/karyotype. Median number of prior treatments was 2 (range: 1-5), the majority of which were IMiD- (n=82, 63%) or PI- (n=72, 55%) based. The median time to transplant was 8 months (range: 3-144), and approximately half of patients received post-ASCT maintenance treatment (n=60, 46%). Pre-transplant response was VGPR (n=23, 23%) or PR (n=52, 51%) in most patients.We collected the following values at baseline (Day -2) and at Day +90 post-ASCT: absolute lymphocyte count (ALC); absolute monocyte count (AMC); lymphocyte to monocyte ratio (LMR); and the number of immunoglobulin (Ig) levels suppressed. Values were separated into upper and lower quartiles for analysis. A low ALC, AMC, and LMR were defined as less than 1100 cells/μL, 300 cells/μL, and 2.4 respectively. A high ALC, AMC, and LMR were defined as more than 2400 cells/μL, 500 cells/μL, and 5.7 respectively. For the entire cohort, the median PFS was 25 months. Baseline ALC, AMC, LMR, or Ig levels did not predict PFS. However, at Day +90, we found that a low ALC (18 versus 23 months, p=0.04) or AMC (13 versus 25 months, p=0.02) predicted for worse PFS. When combined as the LMR, a low ratio strongly predicted for worse PFS when compared to a high ratio (16 versus 52 months, p=0.004). Finally, patients with 2 or 3 suppressed Ig levels were found to have significantly worse PFS compared to those with normal levels (17 versus 51 months, p=0.04).When LMR and Ig levels were combined, we were able to divide patients into poor risk (low LMR and 2-3 suppressed Ig), good risk (high LMR and 0-1 suppressed Ig) and intermediate risk (all other patients) groups. Median PFS for poor, intermediate and high risk groups was 7.5 versus 27 versus 79 months respectively (see figure, p=0.0004). In a multivariate analysis adjusted for prognostic factors (protein subtype, ISS stage, number of prior treatments, novel agents induction, and use of maintenance treatment), low LMR (95% CI 0.01-0.15, HR 0.01; p=0.001) and suppressed Ig levels (95% CI 1.45-39.71, HR 7.58; p=0.017) were strong independent predictors of poor PFS.Here we demonstrate that clinically available markers related to immune recovery post-ASCT can predict PFS. We observed that at Day +90 a low LMR and suppressed Ig levels strongly predicted for a worse PFS. We propose an immune score combining these readily available immune-related tests to stratify patients at risk for early progression and identify those who may benefit from intensified post-ASCT consolidation and maintenance. Future investigation will focus not only on validating this score in an independent cohort of patients but also on identifying the important cell subsets upon which to focus clinical interventions. [Display omitted] DisclosuresPatel:Celgene: Consultancy, Honoraria.

First-Line Pembrolizumab with or Without Platinum Doublet Chemotherapy in Non-Small-Cell Lung Cancer Patients with PD-L1 Expression ≥50%

Pembrolizumab plus chemotherapy is currently used in the first-line treatment of advanced non-small-cell lung cancer without EGFR mutations or ALK rearrangements, regardless of PD-L1 expression status. A study comparing chemotherapy plus pembrolizumab versus pembrolizumab alone has never been performed in patients with PD-L1 ≥50%. The aim of this trial is to perform such a comparison as first-line treatment in patients not eligible for locally advanced treatment who have expression of PD-L1 on ≥50% of tumor cells. The expected results are a reduction in the risk of early progression. A higher objective tumor response is also expected with the combination of chemotherapy and pembrolizumab compared with pembrolizumab alone. The study will allow a direct comparison of the proportion of patients who derive long-term benefit from the treatment. Clinical trial number: EudraCT (2020-002626-86); ClinicalTrials.gov (NCT04547504).

Proliferative function of endothelium in local scleroderma, gender and age characteristics of the disease

Objective — to investigate the variability of vascular endothelial growth factor (VEGF) in localized scleroderma (LS), characteristics of the disease in different age groups. Materials and methods. The study included the clinical evaluation of 78 patients (27 men, 51 women) with localized scleroderma aged (43.2 ± 7.28) years. All patients underwent clinical, laboratory, and enzyme immunoassay investigation of VEGF. The criteria for inclusion in the study were: the presence of localized scleroderma and the absence of signs of a systemic process. Results and discussion. It has been proven that localized scleroderma is gender­related, more often recorded in women (65.4 %, p &lt; 0.05), with an attributive risk of 50.0 % compared to men. Late diagnosis of the disease was proven in 78.2 % of patients. The age and gender characteristics of this pathology were determined — men are more likely to get sick at a young age (up to 20 years; 22.2 % of the surveyed), however, women over the age of 55 prevail (p &lt; 0.05). Women sought dermatological help earlier compared to men (29.4 %; p &lt; 0.05), but had a higher risk of early progression (p &lt; 0.05). Among the clinical forms of localized scleroderma, most of the cases (70.5 %) were of the plaque form. In 15.4% of cases, a linear form was diagnosed, in 9.0% ­ lichen sclerosus, in 5.1 % — Pasini—Pierini idiopathic atrophoderma. The plaque form of LS was significantly more often detected in women (80.3 %), and the linear form and lichen sclerosus — in men (22.2 % each). The average number of lesions was 2.8 ± 1.12. Three lesions were found in almost half (43.6 %) of the patients, one lesion – in 23.1%, two lesions – in 16.7%, four lesions – in 11.5%. Five or more lesions were present in 4 (5.1 %) patients. It has been found that the highest content of VEGF was observed in classic plaque form (p &lt; 0.05), the lowest — in Pasini—Pierini idiopathic atrophoderma (p &lt; 0.05). U­shaped age dependence of the disease was determined: high content of VEGF­A in patients under the age of 20 (p &lt; 0.05), with a significant decrease of VEGF­A in patients aged 20—35 years (p &lt; 0.05) and further increase in those aged 35 to 55 years (p &lt; 0.05). It was established that VEGF­A level increased at patients with early progression of the disease — in the first 2 years after the start of clinical manifestations against the group of patients with slow progression — more than 6 years (p &lt; 0.05). In assessment of gender dependence, we found a higher content of VEGF­A in female patients compared to male patients (p &lt; 0.05). Conclusions. Localized scleroderma has gender and age­related characteristics and is 50.0 % more often recorded in women. Among men, young patients predominate. Studying the pathogenesis of LS and assessing the proliferative function of the endothelium of the disease will make it possible to predict the course of the disease, improve the diagnosis and treatment.

EXPERIENCE IN THE TREATMENT OF REFRACTORY HODGKIN’S LYMPHOMA

Background. The use of modern induction chemotherapy programs for primary Hodgkin’s lymphoma allows achievement of high long-term outcomes even in patients with initially poor prognosis. However, the toxicity of treatment is quite high. Despite the effectiveness of chemotherapy, the frequency of relapses and resistant forms varies from 20 to 30 %. In extremely rare cases, the use of intensive chemotherapy regimens, including high-dose chemotherapy, leads to long-term remissions.Description of the clinical case. We present a case of advanced-stage Hodgkin’s lymphoma in a young patient with symptoms of intoxication and adverse risk factors, such as: massive lesion in the mediastinum, increased ES R, infiltration of soft tissues, pleura, pericardium, multiple lesions of both lungs, damage to more than 3 areas of the lymphatic collectors. Given all these factors, the disease prognosis was extremely unfavorable, with a low probability of achieving remission and a high risk of early progression. The use of the intensive EACOPP -14 program allowed the achievement of short-term partial remission. Due to poor treatment tolerance, but taking into account the achievement of a partial response, further treatment was continued using the ABVD chemotherapy regimen. Follow-up examination revealed disease progression. Further courses of chemotherapy using various combinations of chemotherapy drugs resulted in a short-term positive effect with subsequent disease progression. Considering the fact that the disease was resistant to most basic chemotherapeutic agents, immunotherapy with nivolumab (PD -1 inhibitor) was administered. This alternative treatment method allowed the disease to be stabilized.Conclusion. The use of the immunological drug in a patient with chemoresistant Hodgkin’s lymphoma made it possible to stop the progression of the disease and to improve the patient’s quality of life, without significant infectious complications and adverse events.

P0036THE EFFECT OF CKD ASSOCIATED SNPS ON THE PROGRESSION OF AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Abstract Background and Aims Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most frequent, inherited, cystic kidney disease. It is characterized by formation and growth of renal cysts obstructing normal tubules leading to a decline in renal function and eventually end stage renal disease (ESRD). The disease is mainly caused by mutations in either PKD1 or PKD2. Both the involved genes and the type of mutation have been shown to provide significant prognostic information in relation to the risk of early progression to ESRD. However, even within families, progression of disease varies widely between individuals with the same disease causing mutation. This variation might be explained by other genetic components. Previous studies have suggested genetic components affect the progression of Chronic Kidney Disease (CKD) and ESRD. To explain the variation in disease progression, not accounted for by the disease causing gene, 15 Single Nucleotide Variants (SNPs) associated to CKD and/or ESRD were chosen for further analysis. In addition, 3 SNPs within CFTR was included, since variants within this gene is known to affect the progression of ADPKD. Method A cohort of 120 Danish individuals suffering from ADPKD was sequenced using targeted Next Generation Sequencing (NGS). The targeted NGS panel included PKD1, PKD2, rs13538, rs12460876, rs17319721, rs10109414, rs653178, rs267734, rs1260326, rs347685, rs11959928, rs6420094, rs7805747, rs4744712, rs626277, rs881858, rs12917707, rs213950, rs213965, rs1042180. If no causative variant was identified using the NGS panel, Multiplex Ligation-dependent Probe Amplification was performed to identify larger deletions and duplications. In addition, clinical information was obtained to divide patients into two established or predicted progression groups; fast or slow. Results Based on clinical information we identified 39 patients with established or predicted fast progression and 81 with slow progression. The distribution of SNPs in the fast progression group was compared to the distribution within a European population. Out of 18 SNPs, one was significantly different distributed among the fast progressive ADPKD patients, rs13538 (p=0.01); however, in contrast to expected the frequency of the SNP was lower in the fast progression group compared to the European population. To examine if the shift could be associated to a specific disease causing mutation type, the distribution of each SNP within different mutation types were analysed. The mutations were divided into three groups; PKD1 truncating, PKD1 nontruncating and PKD2. A significant difference was observed in all three groups. Conclusion A single SNP associated to progression of CKD was observed to have a different distribution in the fast progressive ADPKD patients. The distribution differed for all analysed mutation types, thus no specific mutation type or gene could explain the shift in distribution alone. Hence, none of the analysed SNPs seem to influence the rate of progression in the analysed cohort of ADPKD patients.

Association of dynamic susceptibility magnetic resonance imaging at initial tumor diagnosis with the prognosis of different molecular glioma subtypes

PurposeThe updated 2016 CNS World Health Organization classification differentiates three main groups of diffuse glioma according to their molecular characteristics: astrocytic tumors with and without isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deleted oligodendrogliomas. The present study aimed to determine whether dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) is an independent prognostic marker within the molecular subgroups of diffuse glioma.MethodsFifty-six patients with treatment-naive gliomas and advanced preoperative MRI examination were assessed retrospectively. The mean and maximal normalized cerebral blood volume values from DSC-MRI within the tumors were measured. Optimal cutoff values for the 1-year progression-free survival (PFS) were defined, and Kaplan-Meier analyses were performed separately for the three glioma subgroups.ResultsIDH wild-type astrocytic tumors had a higher mean and maximal perfusion than IDH-mutant astrocytic tumors and oligodendrogliomas. Patients with IDH wild-type astrocytic tumors and a low mean or maximal perfusion had a significantly shorter PFS than patients of the same group with high perfusion (p = 0.0159/0.0112). Furthermore, they had a significantly higher risk for early progression (hazard ratio = 5.6/5.1). This finding was independent of the methylation status of O6-methylguanin-DNA-methyltransferase and variations of the therapy. Within the groups of IDH-mutant astrocytic tumors and oligodendrogliomas, the PFS of low and highly perfused tumors did not differ.ConclusionHigh perfusion upon initial diagnosis is not compellingly associated with worse short-term prognosis within the different molecular subgroups of diffuse glioma. Particularly, the overall highly perfused group of IDH wild-type astrocytic tumors contains tumors with low perfusion but unfavorable prognosis.

Prediction of early progression (EP) to CDKIs first line treatment in ER+/HER2- metastatic breast cancer (MBC) using machine learning.

e13040 Background: The treatment of luminal MBC has undergone a substantial change with the use of cyclin dependent kinase 4/6 inhibitors (CDKIs). Nevertheless, there is not a clearly defined subgroup of patients who do not initially respond to CDKIs and show EP. Methods: MBC ER+/HER2- patients who have received at least one line of treatment were eligible. The event of interest was disease progression within 6 months of first line treatment according to the type of therapy administered. The first line treatments were categorized in chemotherapy (CT), hormonal therapy (HT), CT plus maintenance HT and HT plus CDKIs. Free text data from clinical visits registered in our Electronic Health Record were obtained until the date of first treatment in order to generate a feature vector composed of the word frequencies for each visit of every patient. Six different machine learning algorithms were evaluated to predict the event of interest and to obtain the risk of EP for every type of therapy. Area under the ROC curve (AUC), True Positive Rate (TPR) and True Negative Rate (TNR) were assessed using 10-fold cross validation. Results: 610 RE+/HER2- MBC treated between November 1991 and August 2019 were included. Median follow up for metastatic disease was 28 months. 17426 clinical visits were analyzed (per patient: range 1-173; median 30). 119 patients received CT as first line treatment, 311 HT, 117 CT plus maintenance HT and 63 HT plus CDKIs. There were 379 patients with disease progression, from which 126 were within 6 months from first line treatment (54 events with CT, 57 with HT, 4 with CT plus maintenance HT and 11 with HT plus CDKIs). The model that yields the best results was the GLMBoost algorithm: AUC 0.72 (95%CI 0.67-0.77), TPR 70.85% (95%CI 70.63%-71.06%), TNR 66.27% (95% 66.08%-66.46%). Conclusions: Our model based on unstructured data from real-world patients predicts EP and establishes the risk for each of the different types of treatment for MBC ER+/HER2-. Obviously an additional validation is needed, but a tool with these characteristics could help to select the best available treatment when that decision has to be made, avoiding those therapies that are probably not to be effective.

Combined immune score of lymphocyte to monocyte ratio and immunoglobulin levels predicts treatment-free survival of multiple myeloma patients after autologous stem cell transplant.

Outcomes after ASCT are highly variable making it difficult to predict risk of disease progression. We analyzed the impact of clinically available immune-related biomarkers on treatment-free survival (TFS) in 130 patients receiving Mel200 and ASCT. Absolute lymphocyte count (ALC), monocyte count (AMC), neutrophil count (ANC), and immunoglobulin (Ig) levels were collected on day -2 and 90 of ASCT. The lymphocyte-monocyte (LMR) and neutrophil-lymphocyte ratios (NLR) were then derived. At Day +90, we found that low ALC (18 versus 23 months, p = 0.04) or AMC (13 versus 25 months, p = 0.02) predicted for worse TFS. A low LMR predicted for worse TFS (16 versus 52 months, p = 0.004). Patients with two or three suppressed Ig levels had worse TFS (17 versus 51 months, p = 0.04). Median TFS for poor (low LMR and 2-3 suppressed Ig), intermediate, and good (high LMR and 0-1 suppressed Ig) risk groups was 7.5 versus 27 versus 79 months, respectively (p = 0.0004). In a multivariate analysis, a low LMR and suppressed Ig levels were strong independent predictors of poor TFS. We propose an immune score combining these available tests to stratify patients at risk for early progression and identify those who may benefit from intensified post-ASCT consolidation or immunotherapy based approaches.

Periacetabular Osteotomy for the Treatment of Skeletally Mature Acetabular Dysplasia

Acetabular dysplasia is a common cause of persistent hip pain and limited function in young mature patients. Literature has shown that these patients with acetabular dysplasia are an increased risk for early progression to osteoarthritis. Periacetabular osteotomy, with the appropriate indications, can significantly improve both pain and function, as well as help to prevent the development of early osteoarthritis. Throughout this review we will discuss the indications, surgical technique, and outcomes of periacetabular osteotomy for the treatment of acetabular dysplasia in mature patients.

Early progression after bendamustine-rituximab is associated with high risk of transformation in advanced stage follicular lymphoma

AbstractDespite widespread use of bendamustine and rituximab (BR) as frontline therapy for advanced-stage follicular lymphoma (FL), little is known about the risk of early progression or incidence of histological transformation. We performed a retrospective analysis of a population-based cohort of 296 patients with advanced-stage FL treated with frontline BR and maintenance rituximab. As previously demonstrated, outcomes with this regimen are excellent, with 2-year event-free survival estimated at 85% (95% confidence interval [95% CI], 80-89) and 2-year overall survival 92% (95% CI, 88-95). Progression of disease within 24 months (POD24) occurred in 13% of patients and was associated with a significantly inferior outcome with 2-year overall survival of 38% (95% CI, 20-55). The only significant risk factor for POD24 at baseline was elevated lactate dehydrogenase (P < .001). Importantly, the majority of POD24 patients (76%) had transformed disease. Compared with a historical cohort treated with rituximab, cyclophosphamide, vincristine, and prednisone, event-free survival has improved and the risk of POD24 has decreased, but a higher proportion of patients with POD24 harbor transformation. The overall incidence of transformation appears unchanged. The presence of occult or early transformation is the main driver of POD24 in FL patients treated with frontline BR. Identification of biomarkers and improved management strategies for transformation will be crucial to improving outcomes.