Overall Survival In Such Patients Research Articles

Does liver cirrhosis affect outcomes in non-metastatic esophageal squamous cell carcinoma (ESCC) undergoing radiotherapy-based treatment?

89 Background: Liver cirrhosis frequently coexists with esophageal squamous cell carcinoma (ESCC), as both conditions share alcohol consumption as a common etiological factor. Surgical intervention is often contraindicated or associated with significant morbidity in patients with non-metastatic ESCC and liver cirrhosis. Consequently, radiotherapy-based therapy is commonly employed. This study aims to investigate prognostic factors for overall survival in such patients undergoing radiotherapy-based therapy. Additionally, we will evaluate predictors for the 90-day mortality rate, proposed as a measure to mitigate treatment-related toxicity and prevent unwarranted or excessive medical interventions. Methods: From January 2001 to December 2021, we conducted a retrospective review of the medical records of 1298 patients diagnosed with esophageal squamous cell carcinoma (ESCC). Within this cohort, we identified 103 patients with concomitant liver cirrhosis, diagnosed through abdominal ultrasonography, computerized tomography, and/or liver biopsy, as appropriate. Of these individuals, 78 patients with non-metastatic ESCC and liver cirrhosis were included in our analysis. We collected clinicopathologic parameters and examined their correlation with overall survival and the 90-day mortality rate. Results: Univariate analysis revealed several factors significantly associated with inferior overall survival: Child-Pugh classification B/C (P<0.001, compared to A), radiotherapy alone (P=0.03, compared to chemoradiotherapy), prothrombin time prolonged by ≥2 seconds (P=0.024), albumin levels ≤3.5g/dl (P<0.001), controlled/refractory ascites (P=0.01, compared to no ascites), and total bilirubin levels ≥1.5mg/dl (P=0.004). In multivariate analyses, albumin levels ≤3.5g/dl (P=0.001, odds ratio: 2.500) and total bilirubin levels ≥1.5mg/dl (P=0.019, odds ratio: 2.012) were identified as independent prognostic factors. Among the 78 patients receiving radiotherapy-based therapy, the 90-day mortality rate was 10.3% (n=8). Clinical 8th AJCC stage IVA (P=0.02), clinical T classification T3/4 (P=0.049), prothrombin time prolonged by ≥4 seconds (P=0.009), and albumin levels ≤3.5g/dl (P=0.027) were significantly correlated with higher 90-day mortality rate. The logistic model indicated that albumin levels ≤3.5g/dl (P=0.015, odds ratio: 16.129) and clinical 8th AJCC stage IVA (P=0.012, odds ratio: 17.544) were independently associated with higher 90-day mortality rate. Conclusions: In patients undergoing radiotherapy-based therapy for non-metastatic esophageal squamous cell carcinoma (ESCC) and liver cirrhosis, pretreatment hypoalbuminemia has been associated with increased 90-day mortality and unfavorable prognosis.

ОЦЕНКА БЕЗОПАСНОСТИ И ЭФФЕКТИВНОСТИ МЕТОДИКИ МОБИЛИЗАЦИИ И СБОРА ГЕМОПОЭТИЧЕСКИХ СТВОЛОВЫХ КЛЕТОК У ДЕТЕЙ РАЗНЫХ ВОЗРАСТНЫХ ГРУПП СО ЗЛОКАЧЕСТВЕННЫМИ НОВООБРАЗОВАНИЯМИ: ОПЫТ ОДНОГО ЦЕНТРА

High dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation (auto-HSCT) is used currently as a consolidating stage in cancer treatment protocols for children from different age groups with various malignant neoplasms. Auto-HSCT can improve both progression-free survival and overall survival of such patients. At the same time the optimization of the collection of autologous hematopoietic stem cells (HSCs) seems to be an important factor in the successful implementation of auto-HSCT. The purpose of this research was to evaluate the safety and effectiveness of the HSCs mobilization and collection method in children from different age groups with various malignancies. Materials and methods used: a single-center retrospective cohort study of 258 pediatric patients (median body weight 20.0 [13.8; 42.0] (7.0-95.0) kg and median height 116 [97; 155] (55.0-189) cm) with various cancers aged 1 to 18 y/o (median 78.0 [36; 144] (3-215) months old) who received treatment in Jan. 2020-Jan. 2023 at the Research Institute of Pediatric Oncology and Hematology named after Academician L.A. Durnov with the N.N. Blokhin Russian Cancer Research Center (Moscow, Russia). Patients were divided into 3 age groups: younger than 1 y/o, 1 to 10 y/o and 11 to 18 y/o. Results: 242 (93.8%) of HSC apheresis procedures were successful on the first attempt, 16 patients underwent repeated apheresis (a total of 274 procedures were performed). The median number of CD34+ cells obtained was 110.95 [45.6; 276.4] (0.70-2338.2) cells/µl, median apheresis duration was 253.5 [189; 338] (82-575) min. No serious complications were observed during the HSCs mobilization and collection in any patient. None of the patients developed hemodynamic disturbances. The main criteria for effectiveness was the CD34+/kg level, the median of which was 5.1 [2.4; 12.7] (0.01-95.6)•106. One of the safety criteria for the patients from all the three age groups was the absence of hemodynamic disorders and citrate reactions in the form of numbness, cyanosis of the skin and respiratory disorders. Another important safety criteria were the absence of a significant decrease in both platelet and hemoglobin levels. The median platelet levels prior to the procedure was 125.5 [68; 210] (14.0-815)•109/l and 129 [73; 210] (17.0-823)•109/l at the end of the procedure (p<0.001). Hemoglobin levels before and after the procedure were 100 [94; 110] (75-242) g/l and 99 [93; 109] (70-142) g/l, respectively (p<0.001). Considering it safe to reduce hemoglobin (g/l) and/or platelets (•109/l) by no more than 10 units in each measurement, in 87.6±4.1% (83.0-91.1) of observed cases the procedure was safe without statistically significant differences in all age groups. The effectiveness of the HSCs mobilization and collection method proposed by the Authors in children of the older age group (11 to 18 y/o) was the lowest and was statistically significantly different from the effectiveness in the group of children aged 1 to 10 y/o (p<0.001) with cancer and amounted to 84.5±4.4% (79.6-88.4). Conclusion: with the multidisciplinary team of practitioners, HSC apheresis in children is a safe and effective technique used as part of the complex cancer treatment in patients from poor prognosis groups. The apheresis algorithm that the Authors have proposed allows high-quality collection of CD34+ positive cells in amounts sufficient for further auto-HSCT.

Sarcopenia in Men With Bone-Predominant Metastatic Castration-Resistant Prostate Cancer Undergoing Ra-223 Therapy.

Osteosarcopenia is the progressive loss of musculoskeletal structure and functionality, contributing to disability and mortality. Despite complex interactions between bone and muscle, osteosarcopenia prevention and treatment in men with metastatic castration-resistant prostate cancer (mCRPC) focuses predominantly on bone health. It is unknown whether Radium-223 (Ra-223) therapy affects sarcopenia. We identified 52 patients with mCRPC who had received Ra-223 and had a baseline plus ≥1 follow-up abdominopelvic CT scan. The total contour area (TCA) and averaged Hounsfield units (HU) of the left and right psoas muscles were obtained at the inferior L3 endplate, and the psoas muscle index (PMI) was calculated therefrom. Intrapatient musculoskeletal changes were analyzed across various time points. TCA and PMI gradually declined over the study period (P = .002, P = .003, respectively), but Ra-223 therapy did not accelerate sarcopenia, nor the decline of HU compared to the pre-Ra-223 period. The median overall survival of patients with baseline sarcopenia was numerically worse (14.93 vs. 23.23 months, HR 0.612, P = .198). Ra-223 does not accelerate sarcopenia. Thus, worsening muscle parameters in men with mCRPC undergoing Ra-223 therapy are attributable to other factors. Further research is needed to determine whether baseline sarcopenia predicts poor overall survival in such patients.

The Prognostic Utility of a Geriatric Assessment for Patients with Pancreatic Cancer Receiving Gemcitabine-based Chemotherapy: A Prospective Observational Study.

Objective To evaluate the effect of a pretreatment geriatric assessment on the clinical outcomes in older patients with unresectable or recurrent pancreatic ductal adenocarcinoma (PDAC) scheduled to receive gemcitabine (GEM)/GEM+nab-paclitaxel (GnP). Patients Older patients with unresectable PDAC scheduled to receive GEM/GnP who visited Kyorin University Hospital and cooperating institutions were enrolled and followed from April 2015 to March 2020. The maximum observation period was two years. All patients underwent a cancer-specific geriatric assessment (CSGA) and optional geriatric assessment (GA) before treatment initiation and two months after the start of treatment. The patients' background characteristics, tumor progression, tumor site, and regimen (GEM/GnP) were examined in a Cox proportional hazards model. The relationship between the overall survival (OS) and GA score was also determined. Eligible patients (age ≥70 years old with histopathologically confirmed unresectable or recurrent PDAC) were scheduled to receive first-line chemotherapy. Results The performance status (PS) and activities of daily living (ADL)/instrumental ADL (IADL) scores at baseline correlated with the OS. Furthermore, even in cases with normal baseline values, lower Frontal Assessment Battery scores and higher Geriatric Depression Scale-Short Form scores after treatment initiation were significantly correlated with OS. Conclusion The baseline PS, ADL, and IADL may be prognostic factors in older PDAC patients. In addition, a normal frontal lobe function and depression scores prior to treatment initiation that rapidly worsened during treatment were independently associated with a reduced OS. Selecting appropriate interventions and improving the therapeutic environment may prolong the OS in such patients.

The Co-expression of HER Family Members and CD109 is common in Pancreatic Cancer.

In the absence of biomarkers for the early detection of pancreatic cancer and the development of more effective therapeutic interventions, pancreatic cancer is projected to become the second leading cause of death from cancer in the Western world. In the past four decades, aberrant expression and activation of human epidermal growth factor receptor (EGFR, also called HER) family members have been reported in a wide range of human cancers. Currently, of the various types of drugs targeting one or more members of the HER family, only the EGFR-specific tyrosine kinase inhibitor erlotinib and more recently Zenocutuzumab, a HER-2/HER3 bispecific antibody, were granted breakthrough therapy designation by the FDA for the treatment of patients with pancreatic cancer. However, the therapeutic benefit may be modest in some patients. Hence there is an urgent need for the identification of biomarkers as prognostic indicators, therapeutic targets, and for the response to therapy and the development of more effective therapeutic agents for this highly heterogeneous cancer. In this study, for the first time, we investigated the relative expression and prognostic significance of all members of the HER family, the type-III EGFR mutant (EGFRvIII), and CD109 in tissue microarrays (TMAs) and whole tumour specimens (WTS) from pancreatic cancer patients by immunohistochemistry. We found the positive expression of wild-type EGFR (wt-EGFR) (63%, 4.7%), HER2 (75%, 14%), HER3 (none, 14%), HER4 (45%, 21%), EGFRvIII (5%, 3%), and CD109 (67%, 55%) in TMAs (USA) and WTS (UK) from pancreatic cancer patients respectively. Our results also show that the co-expression of HER family members with CD109 occurs frequently in patients with pancreatic cancer. In addition, the co-expression of HER4/CD109 may also be associated with poorer overall survival in such patients. In this article, we shall discuss these findings and their implications and future opportunities for more effective targeting of HER positive pancreatic cancer using the HER inhibitors in combination with other drugs and therapeutic interventions.

Retrospective Analysis of Prognostic Factors in Pediatric Patients with Adrenocortical Tumor from Unique Tertiary Center with Long-Term Follow-Up.

Pediatric adrenocortical tumors (PACTs) represent rare causes of malignancies. However, the south/southeast regions of Brazil are known to have a high incidence of PACTs because of the founder effect associated with a germline pathogenic variant of tumor suppressor gene TP53. We aimed to retrospectively analyze the types of variables among hormone production, radiological imaging, tumor staging, histological and genetic features that were associated with the occurrence of malignancy in 95 patients (71% females) with PACTs from a unique center. The worst prognosis was associated with those aged > 3 years (p < 0.05), high serum levels of 11-desoxicortisol (p < 0.001), tumor weight ≥ 200 g (p < 0.001), tumor size ≥ 5 cm (p < 0.05), Weiss score ≥ 5 (p < 0.05), Wieneke index ≥ 3 (p < 0.001) and Ki67 ≥ 15% (p < 0.05). Furthermore, patients with MacFarlane stage IV had an overall survival rate almost two times shorter than patients with other stages (p < 0.001). Additionally, the subtractions of BUB1B-PINK1 (<6.95) expression (p < 0.05) and IGF-IR overexpression (p = 0.0001) were associated with malignant behavior. These results helped identify patients who are likely to have an aggressive course; further multicenter prospective studies are required to confirm our results. In conclusion, PACTs with these patterns of prognostic factors could be treated using an adjuvant approach that may improve the overall survival in such patients.

Abstract LB035: Understanding the mechanism of neuropilin2 upregulation in advanced prostate cancer

Abstract Background: Prostate cancer management involves administering Androgen Deprivation Therapy (ADT). Patients with advanced form of the disease become resistant to ADT and progress to a lethal phenotype called Castration Resistant Prostate Cancer (CRPC). Neuropilin-2 is upregulated in advanced prostate cancer. It has been implicated in decreasing the overall survival of such patients by inducing therapy-resistance. Significance: Understanding how NRP2 is differentially expressed will uncover molecular pathways that can be targeted to develop a specific treatment strategy for better management of patients. Experimental Design: We checked NRP2 expression in different prostate cancer cell lines {LNCaP, C4-2 and C4-2 P53/RB1 null cells (DKD cells)} and the level of methylation of the NRP2 promoter in these cells by pyrosequencing. We demethylated the NRP2 promoter by treatment with 5’Azacytidine and checked NRP2 mRNA expression. We analyzed the NRP2 promoter activity under demethylated conditions by transfecting cells with a demethylated NRP2 promoter construct using a GLuc dual-luciferase assay. Using Biobase we found DNA sequences for binding of transcription factors within the NRP2 promoter. RNA-Seq, RT-PCR was performed to identify potential transcription factors of NRP2(highly expressed in DKD cells). To validate SOX2 as a transcription factor for NRP2, we tested its binding to NRP2 promoter by ChIP-q-PCR. Requirement of SOX2 in transcribing NRP2 mRNA in C4-2 and DKD cells was tested by both knocking down or ectopically expressing SOX2. To determine whether demethylation of NRP2 promoter is a prerequisite for SOX2 binding, SOX2 was overexpressed in LNCaP cells following 5’Azacytidine and monitored the change in the NRP2 expression. Results: NRP2 expression was low in LNCaP cells. It steadily increased in C4-2 cells with a steep rise in the DKD cells. Pyrosequencing showed a high level of DNA methylation in LNCaP cells compared to C4-2 cells. On treatment with 5’Azacytidine, NRP2 mRNA expression was upregulated in the LNCaP cells and it significantly rose in the C4-2 cells. Our dual-luciferase assay showed us that in C4-2 cells, the promoter activity of NRP2 upon demethylation went up causing a significant rise in Luciferase expression. RNA-seq and RT-PCR analysis showed high SOX2 levels in DKD cells indicating that SOX2 might play a role in elevating NRP2 expression in these cells. ChIP q-PCR indicated enriched binding of SOX2 in the NRP2 promoter in DKD cells. On silencing SOX2 in DKD cells, the expression of NRP2 was decreased. Analogous to this finding, overexpressing SOX2 in C4-2 cells caused significant rise in NRP2 expression, whereas in LNCaP cells, there was no change. Demethylation of NRP2 promoter and simultaneous overexpression of SOX2 in LNCaP lead to a significant increase in NRP2 mRNA suggesting the requirement of demethylated NRP2 promoter for SOX2 function. Conclusion: The differential expression of NRP2 in advanced prostate cancer is a two-step process of initial demethylation of the DNA in the NRP2 promoter region, followed by binding of SOX2 Citation Format: Sanika Bodas, Ridwan Islam, Sreyashi Bhattacharya, Juhi Mishra, Dipanwita Das, Michael Muders, Samikshan Dutta, Benjamin A. Teply, Kaustubh Datta. Understanding the mechanism of neuropilin2 upregulation in advanced prostate cancer [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 LB035.

Abstract P066: Gain and loss of function genome-wide CRISPR screens identify Hippo signalling as an important driver of resistance in EGFR mutant lung cancer

Abstract Drug resistance is ultimately the cause of death for most cancer patients – even initially strong responses to treatment are usually followed by the emergence of resistance over time. This suggests the existence of residual or persistent cancer cells, creating a reservoir that ultimately gives rise to stable resistance. These drug tolerant persisters (‘the deadly survivors’) have been described for over a decade in numerous studies; they are often present as a minor fraction of the total tumour population and may exploit non-genetic (transcriptional) programs to allow the cells to survive drug treatment. 10-20% of lung adenocarcinoma patients harbour activating mutations in EGFR. Although treatment with the EGFR kinase inhibitor osimertinib has improved overall survival in such patients, almost all patients ultimately develop drug resistance. We carried out parallel genome-wide CRISPR gain and loss of function screens in EGFR mutant lung cancer cell lines treated with EGFR inhibitors, to identify the genes and pathways that may be important in enabling the survival of persister cells. We observed recurrent resistant genes in previously identified resistance pathways including PI3K (PTEN, TSC1, TSC2), MAPK (KRAS, NF1, MET), cell death (BCL2L11, BAX), the mediator complex (MED24, MED19) and ubiquitination (KCTD5, KEAP1). A secondary screen of 63 resistance genes that combined high content microscopy with CRISPR gene knockout demonstrated that 21% (13/63) of genes were associated with increased nuclear localisation of YAP1/WWTR1, key activators of the Hippo pathway. A closer review of the CRISPR screen data confirmed that many resistance hits are members of this pathway - upstream regulators (NF2, AMOTL2), core signalling genes (LATS1, LATS2), main effectors (WWTR1, YAP1), transcriptional co-effectors (TEAD3, FOSL1, VGLL4) and the SWI/SNF complex (ARID2, SMARCA4, SMARCB1, PBRM1). Hippo signalling is mediated through YAP1 and WWTR1 which bind to TEAD transcription factors and activate transcriptional programs affecting cell proliferation and apoptosis. We confirmed using CRISPR that knockout (NF2) or overexpression (YAP1, WWTR1) of key Hippo genes in the EGFR mutant lung cancer cell lines PC-9, HCC827 and HCC4006 resulted in up to 60-fold increased resistance to osimertinib and increased expression of canonical Hippo transcriptional targets. We therefore reasoned that the Hippo pathway might be involved in maintaining the survival of drug tolerant persister cells in this setting. Acute treatment of EGFR mutant cell lines with osimertinib was associated with increased nuclear localisation of YAP1 and WWTR1 and increased expression of canonical Hippo transcriptional targets. Furthermore, the combination of osimertinib and a TEAD inhibitor (K-975) almost completely abolished the survival of drug tolerant persister cells following treatment, indicating that this pathway is an important survival mechanism following drug treatment. Consequently, we propose Hippo signalling as an important target mechanism for the prevention of resistance to osimertinib. Citation Format: Matthias Pfeifer, Jonathan Brammeld, Stacey Price, Matthew Martin, Hannah Thorpe, Aurelie Bornot, Ercia Banks, Nin Guan, Shanade Dunn, Maria Lisa Guerriero, Daniel O'Neill, James Pilling, Davide Gianni, James Brownell, Paul Smith, Ultan McDermott. Gain and loss of function genome-wide CRISPR screens identify Hippo signalling as an important driver of resistance in EGFR mutant lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P066.

Abstract 1100: Gain and loss of function genome-wide CRISPR screens identify Hippo signaling as an important driver of resistance in EGFR mutant lung cancer

Abstract 10-20% of lung adenocarcinoma patients harbour activating mutations in EGFR. Although treatment with the EGFR kinase inhibitor osimertinib has improved overall survival in such patients, almost all patients ultimately develop drug resistance. In many cases the molecular resistance mechanisms remain unknown. A systematic identification of the involved genes and pathways is critical to overcome osimertinib resistance. To define the resistance landscape of EGFR kinase inhibition we performed genome-wide gain and loss of function CRISPR screens in EGFR mutant lung cancer cell lines treated with osimertinib. Resistance hits were enriched for genes in previously identified resistance pathways including PI3K (PTEN, TSC2), MAPK (NF1, MET), cell death (BCL2L11, BAX), the mediator complex (MED24, MED19) and ubiquitination (KCTD5, LZTR1). A secondary screen of 63 resistance genes that combined high content microscopy with CRISPR gene knockouts demonstrated that 21% (13/63) of genes were associated with increased nuclear localisation of YAP1/WWTR1, indicating transcriptional activation of the Hippo pathway. According to our screening data, many resistance hits mapped onto the Hippo signaling axis - upstream regulators (NF2, AMOTL2), core signaling genes (LATS1, LATS2), main effectors (WWTR1, YAP1), transcriptional co-effectors (TEAD3, FOSL1, VGLL4) and the SWI/SNF complex (ARID2, SMARCA4, SMARCB1, PBRM1). Hippo signaling is mediated through YAP1 and WWTR1 which bind to TEAD transcription factors and activate transcriptional programs affecting cell proliferation and apoptosis. We confirmed using CRISPR that knockout (NF2) or overexpression (YAP1, WWTR1) of key Hippo genes in the EGFR mutant lung cancer cell lines PC-9, HCC827 and HCC4006 resulted in up to 60-fold increased resistance to osimertinib and elevated activity of a TEAD reporter system, indicating activation of Hippo transcriptional programs. To maintain osimertinib resistance, expression of both YAP1 and WWTR1 was necessary, suggesting non-redundant roles for both Hippo main effectors in mediating osimertinib resistance. The combination of osimertinib and a TEAD inhibitor (MYF-01-37) reversed the resistance phenotype in NF2 KO cell line models in long-term proliferation assays and also substantially repressed the emergence of drug-tolerant persister cells in PC-9, HCC827 and HCC4006 cell lines following osimertinib treatment. These cells exhibited an enhanced apoptotic response when treated with combination of osimertinib and TEAD inhibitor. Consequently, we propose Hippo signaling as an important target mechanism for the prevention of resistance to osimertinib. Citation Format: Matthias Pfeifer, Jonathan S. Brammeld, Stacey Price, Matthew Martin, Hannah Thorpe, Aurelie Bornot, Erica Banks, Nin Guan, Shanade Dunn, Maria Luisa Guerriero, Daniel O'Neill, James Pilling, Davide Gianni, James Brownell, Paul Smith, Ultan McDermott. Gain and loss of function genome-wide CRISPR screens identify Hippo signaling as an important driver of resistance in EGFR mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1100.

Sarcopenia is associated with poor prognosis after chemoradiotherapy in patients with stage III non-small-cell lung cancer: a retrospective analysis

We intended to investigate whether muscle and adipose masses were associated with prognosis among patients with stage III non-small-cell lung cancer (NSCLC) who were undergoing chemoradiotherapy (CCRT). We retrospectively explored data of patients with stage III NSCLC who underwent definitive CCRT (≥ 60 Gy) between January 2004 and March 2018 at our hospital. We examined the relationship of overall survival (OS) with body mass index (BMI), skeletal muscle index (SMI), psoas muscle index (PMI), visceral adipose tissue index (VAI), subcutaneous adipose tissue index (SAI), and visceral-to-subcutaneous adipose tissue area ratio (VSR) using log-rank tests for the univariate analysis and Cox proportional hazard models for the multivariate analysis. Overall, 16, 32, and 12 patients had stage IIIA, IIIB, and IIIC NSCLC, respectively. The total radiotherapy dose ranged from 60 Gy/30 fractions to 66 Gy/33 fractions. In the univariate analysis, the performance status (PS), BMI, and SMI were associated with OS, whereas the PMI, VAI, SAI, and VSR were not. In the multivariate analysis, the PS and SMI were associated with OS. The hazard ratios and 95% confidence intervals were 2.91 and 1.28–6.64 for PS, and 2.36 and 1.15–4.85 for SMI, respectively. The 1, 3, and 5-year OS rates were 92.1%, 59.6%, and 51.0% in patients with high SMI, and 63.6%, 53.8%, and 17.9% in patients with low SMI, respectively. The SMI correlated with prognosis in our study population, whereas adipose mass did not. Therefore, sarcopenia should be considered while predicting the OS in such patients.

Диагностика функциональной недостаточности поджелудочной железы

Exo- and/or endocrine pancreatic insufficiency are the complications and diagnostic criteria of chronic pancreatitis. Recently expanded surgical activity in pancreatic diseases prolongs overall survival in such patients. However, patients’ quality of life decreases due to exo- and endocrine pancreatic insufficiency. Timely diagnosis and adequate treatment of the conditions are based on the lab assessment of pancreatic function. The paper presents diagnostic methods, their sensitivity, specificity, and diagnostic role.

POS-379 CARDIOVASCULAR INJURY MARKERS IN LONG-TERM HEMODIALYSIS PATIENTS: A SINGLE-CENTER STUDY

Heart failure and related sudden cardiac death are the main causes of death in dialysis patients, so searching for cardiovascular injury (CV) indicators may improve the overall survival of such patients. The aim was to identify the N-terminal pro-brain natriuretic peptide (NT-proBNP) cut-off points associated with increased survival in dialysis patients and select echocardiographic markers of CV injury and increased mortality. A single-center prospective trial included 13 hemodialysis (HD) patients without any medical history of CV disease with an age at dialysis onset <65 years old and dialysis vintage of 5-22 years. In April 2018, all patients underwent echocardiography (Echo); serum NT-proBNP level was also carried out. Depending on the NT-proBNP level, 2 groups of patients were identified: the 1st group included patients with NT-proBNP value >3000 pg/ml, the 2d group had value ≤3000 pg/ml. At the end of a follow-up period of 2.5 years, the outcomes were evaluated. A summary of patients' characteristics is shown in the table below. In the 1st group, patients were older and more often were men. 62.5% of these patients had resting wall motion abnormalities (RWMA), 25% had mitral annular calcification (MAC). All patients who had these abnormalities died during the follow-up. In the 2d group, patients didn't have any RWMA or MAC. During follow-up, 75% of patients from the 1st group died, 25% were transplanted, and were alive after transplantation. Among the patients of the 2nd group, 40% underwent kidney transplantation (of which 1 patient died after transplantation due to acute liver failure), 60% were alive and were on HD. Tabled 1Parameter1st group2d groupNT-proBNP, pg/ml>3000≤3000Number, N (%)8 (61.5)5 (38.5)Male, N (%)5 (62.5)1 (20)Median [25%;75%]Age, years55.5 [47;58.5]29 [24;43]Dialysis vintage, years8 [6;9.5]10 [6;11]EchoRWMA, N (%)5 (62.5)0MAC, N (%)2 (25)0OutcomesDied, N (%)6 (75)0Transplanted, N (%)2 (25)2 (40)Alive, undergoing HD, N (%)03 (60) Open table in a new tab NT-proBNP level of ≤3000 pg/ml may be an optimal cut-off point for overall survival, but this requires clarification and research on more dialysis patients. The NT-proBNP level is not affected by dialysis vintage but depends on age. The presence of RWMA and MAC increases the risk of death in dialysis patients and is associated with higher NT-proBNP levels.

Expression of bone morphogenetic protein 10 in cases with endometrial carcinoma and its clinical significance.

To investigate the expression of bone morphogenetic protein 10 (BMP-10) in patients with endometrial carcinoma (EC) and its clinical significance. Totally 143 cancer tissue specimens were sampled from patients with EC and retrospectively analyzed. The immunohistochemical method was adopted for quantifying BMP-10 in EC tissues. Then the patients were assigned to high and low BMP-10 expression groups. The Kaplan-Meier method and log-rank test were adopted to compare the difference of tumor-free survival (TFS) rate and overall survival (OS) rate between the two groups. The COX proportional hazard model was used to analyze independent risk factors affecting the TFS rate and OS rate of patients with EC. There were 80 patients (55.94%) with low BMP-10 expression and 63 patients with high BMP-10 expression (54.06%). BMP-10 expression was significantly correlated with International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.001), myometrial invasion depth (P < 0.001), histological grade (P < 0.001), and lymph node metastasis (P = 0.009). Additionally, TFS rate (P = 0.004) and OS rate (P = 0.003) in the low BMP-10 expression group were notably lower than those in the high BMP-10 expression group. Multivariate analysis showed that BMP-10 expression (HR: 13.712, 95% CI 1.823-103.158, P = 0.011) was an independent risk factor for the TFS of patients with EC. FIGO stage (P = 0.001) and BMP-10 expression (HR: 8.655, 95% CI 1.098-68.215, P = 0.020) were independent risk factors for the OS of such patients. BMP-10 can be adopted as a molecular marker for predicting the poor prognosis of patients with EC.

Abstract PR006: Correlation of immunohistochemistry with TP53 sequence and clinical outcomes in GOG-086P

Abstract Introduction: GOG-086P was one of the first attempts to combine molecular inhibitors such as bevacizumab or temsirolimus with chemotherapy in patients with advanced endometrial cancer. An exploratory analysis of this study indicates that bevacizumab combined with chemotherapy is superior to temsirolimus plus chemotherapy in patients with TP53 mutated tumors as determined by next generation sequencing. The functional status of p53 in a tumor can be inferred by sequence analysis and/or by immunohistochemistry (IHC). In this next study of the GOG-086P cohort, we sought to determine whether p53 IHC alone or integrated with TP53 sequencing was similarly predictive of outcome and whether IHC was predictive of the sequence analysis. Methods: A total of 349 patients were enrolled on GOG-086P. Two hundred and forty-three patients have TP53 sequence data, and 213 have p53 protein expression data measured by IHC. Tumor histology and sequence data were correlated with p53 IHC categorizing each case as p53 negative or null, wild type (WT) or over-expressed (OE), and these variables were further correlated with progression-free survival (PFS) and overall survival (OS) in the chemotherapy + bevacizumab arms versus the chemotherapy + temsirolimus arm. Results: The majority of patients (118) had tumors with WT p53 protein expression by IHC and non-mutated or WT TP53 sequence, with expected concordance between IHC and sequence analysis. However, there were five discordant cases with OE p53 protein in the absence of a TP53 mutation. Fourteen patients had null IHC protein expression and a concordant TP53 sequence mutation expected to result in the total loss of protein. Four cases that were p53 null by IHC had a discordant WT TP53 sequence. Seventeen patients had tumors with a missense TP53 mutation but had WT p53 protein expression by IHC, reflecting a potential discordance between sequencing and IHC versus a missense mutation that did not result in loss of protein function. Six of these 17 discordant cases may be explained by co-mutations in TP53 and POLE or microsatellite instability where p53 proteins, though mutated, function more like WT. Reassuringly and as expected, high concordance was found in the 55 cases that had OE protein by IHC and a missense mutation in TP53. On integrated analysis, a TP53 mutation with p53 protein OE was associated with significantly lower hazard ratio for PFS (HR=0.41; 95% CI 0.22-0.83) and OS (HR=0.28; 95% CI 0.14-0.59), i.e., longer PFS and OS, for patients receiving bevacizumab + chemotherapy relative to temsirolimus + chemotherapy. Conclusions: Mutations in TP53, which are common in patients with advanced endometrial cancer, represent a developing platform upon which to design personalized treatment regimens. We demonstrate that IHC is often but not always predictive of the TP53 sequence. However, most cases with over-expressed p53 protein by IHC had a mutation in TP53, and bevacizumab + chemotherapy prolonged PFS and OS in such patients. Citation Format: Kristina W. Thiel, Eric J. Devor, Virginia Filiaci, Douglas A. Levine, Fanny Dao, Narciso Olvera, David Mutch, Carol Aghajanian, Kimberly K. Leslie. Correlation of immunohistochemistry with TP53 sequence and clinical outcomes in GOG-086P [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PR006.

Multi-level En Bloc Resection as a Preferred Salvage Therapy for Recurrent Thoracolumbar Chondrosarcoma: A Comparative Study With Piecemeal Resection.

A retrospective analysis was performed. The aim of this study was to evaluate the feasibility and effectiveness of multilevel en bloc resection versus piecemeal resection for recurrent thoracolumbar chondrosarcoma (CHS). Multilevel en bloc resection for recurrent thoracolumbar CHS is rarely performed. Included in this retrospective study were 27 patients with recurrent thoracolumbar CHS who received either multilevel en bloc resection or piecemeal resection as a salvage revision procedure in our center between 2010 and 2018. Relevant data between the two methods were compared. Relapse-free survival (RFS) and overall survival (OS) were analyzed by log-rank analysis. Our series comprised 16 males and 11 females with a mean age of 40.7 years. Multilevel en bloc resection was performed in 17 patients, and piecemeal resection in 10 patients. Of the 17 patients receiving multilevel en bloc resection, five patients experienced recurrence, of whom three died, whereas in the 10 patients receiving piecemeal resection, seven experienced recurrence and all of them died, showing a significant difference between the two groups (P = 0.04 for recurrence, P = 0.007 for death). Complications occurred more frequently in the patients receiving multilevel en bloc resection (P = 0.04), but RFS and OS were prolonged significantly in this group of patients as compared with piecemeal resection group (56.8 ± 9.7 vs. 17.2 ± 4.2, P = 0.016; 67.3 ± 8.4 vs. 21.4 ± 3.5, P = 0.002). Multilevel en bloc resection as a salvage therapy for recurrent thoracolumbar CHS is technically challenging with high risk of complications, but it can significantly prolong RFS and OS of such patients as compared with piecemeal resection. 4.

Influence of body mass index on the therapeutic efficacy of gemcitabine plus cisplatin and overall survival in lung squamous cell carcinoma

BackgroundGemcitabine plus cisplatin (GP) is commonly used to treat lung squamous cell carcinoma (SCC); however, it is not clear which subgroup of lung SCC patients could benefit most from GP treatment. We explored the predictive factors in lung SCC patient cohorts.MethodsSeventy‐eight lung SCC patients treated with a first‐line GP regimen were enrolled in this retrospective cohort study. Progression‐free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Classification tree models were used to explore the risk factors for PFS and OS in these patients.ResultsThe median PFS and OS in SCC patients treated with a GP regimen were 6.0 and 13.6 months, respectively. Three terminal subgroups were formed for both PFS and OS. The subgroup with a body mass index (BMI) > 23.94 kg/m2 and aged ≤ 54.5 had the longest PFS (9.0 months); the subgroup with a BMI < 23.94 kg/m2 and aged ≤ 54.5 had the shortest PFS (4.05 months). Patients with an objective response (partial or complete response) to treatment had the longest OS (20.0 months), while patients with a BMI ≤ 26.92 kg/m2 and stable or progressive disease as the best response had the shortest OS (11.2 months).ConclusionsBMI and age may be predictors of PFS in lung SCC patients who receive GP treatment. BMI and best response to GP treatment predicts OS in such patients. Patients’ clinical pathological characteristics may be used to predict the therapeutic efficacy of chemotherapy and survival.

Expressions and Clinical Significances of Angiopoietin-1, Angiopoietin-2, and Tie-2 Receptor in Patients With Colorectal Cancer

PurposeAngiopoietin-1 (Ang-1) plays a crucial role in vascular and hematopoietic development, mainly through its cognate receptor, Tie-2. Increased levels of Ang-2 have been shown to be correlated with abnormal tumor angiogenesis in several malignancies. Hence, we estimated the increased expression of Ang-2 relative to Ang-1 in patients with colorectal cancer and correlated our finding with prognosis in order to investigate the relationships between the expressions of Ang-1/Ang-2/Tie-2 receptor and the clinical parameters or overall survival of such patients.MethodsWe retrospectively analyzed 114 tissue samples from patients with colorectal cancer by using immunohistochemistry (IHC) to examine Ang-1, Ang-2, and Tie-2 expressions and to investigate the relationship between those expressions and clinical parameters or overall survival of such patients. A Western blot analysis was used for Ang-2 expression.ResultsIHC staining showed a link between Ang-1 and Tie-2 (P = 0.018), as well as meaningful correlations between Ang-2 and Tie-2 receptor (P = 0.022) and between lymph-node metastasis and Ang-2 (P = 0.025). The stronger the IHC staining for Ang-2 expression was, the shorter the cumulative survival was (P = 0.016).ConclusionA relationship was found to exist between Ang-2 and Tie-2 expressions. The Ang-2 was correlated with lymph-node metastasis, and high expression of Ang-2 was indicative of poor overall survival. These findings suggest that Ang-2 is a useful prognostic marker in the management of patients with colorectal cancer. In addition, we suggest that Ang/Tie-2 signaling plays an important role in the progression of colorectal cancer.

Association of long-term survival in pancreatic cancer (PDAC) with increased proliferative and anti-apoptotic protein activation.

254 Background: 5 year (yr) overall survival (OS) for resected PDAC is typically 20%. To test the potential for molecular prediction of &gt; 5 yr OS in such patients (pts), we analyzed proteomic activation (phosphorylation) patterns in both cancer and stromal cells from initial surgical specimens prior to adjuvant therapy (Rx). Methods: Formalin-fixed, paraffin-embedded tissue from 40 pts (20 pts each with long-term actual disease-free OS [median 65 mo, range 26-137 mo] [LTS] and with early relapse/death &lt; 2 yrs [STS]) with de novo resected PDAC formed the test cohort. All pts received adjuvant Rx (chemo Rx with/without chemoradiation). Laser Capture Microdissection enabled directed cancer and stromal cell isolation. Retrospective blinded protein activation analysis for both was performed via Reverse Phase Protein Array (RPPA). Differences in baseline protein signaling of LTS vs. STS were evaluated via two-way ANOVA analysis. Results: Analysis of &gt; 50 signal transduction proteins (STPs) for activation (phosphorylation) showed these significant differences for LTS vs. STS in cancer cells: 1) Activation of proliferation markers Sox2/ Ki 67 were higher (p&lt;0.0001). 2) Activation of anti-apoptotic signal transducer and activator of transcription 3 (p-STAT 3) ( p=0.047) and p-SRC kinase (p=0.039) were higher. 3) Activated p-m-TOR expression was higher (p=0.021). 4) Activation of mitotic marker histone H3S10 was lower (p=0.03). In stromal cells, activation of the survival marker Mek S298 was lower (p=0.021). For other STPs, differences for LTS vs. STS (e.g. Livin, PCNA) were not seen. Conclusions: 1) LTS and STS of de novo resected PDAC show clear differences in cancer cell protein activation re key markers of proliferation and apoptosis (Sox2, Ki67, STAT3, SRC kinase, H3S10). 2) For stromal cells, protein activation was largely similar, but a difference in activation of one stromal protein (Mek S298) was seen. 3) For these pts, differences in protein activation prior to adjuvant Rx could enhance current prognostic models and/or identify new pharmacological targets designed to improve OS. 4) These findings require further validation: a second 60 sample validation cohort is now under anaylsis.

Hepatic Resection for Hepatocellular Carcinoma with Tumor Thrombus in the Major Portal Vein

Background: The prognosis of hepatocellular carcinoma (HCC) with tumor thrombus in the major portal vein has been extremely poor. We investigated the outcome of hepatic resection in HCC with major portal vein tumor thrombus (PVTT). Methods: We retrospectively evaluated 52 consecutive patients who underwent hepatic resection for HCC with tumor thrombi in the first branch or trunk of the portal vein. Factors related to disease-free survival (DFS) and overall survival (OS) were analyzed. Results: The median DFS and OS times were 8.9 and 27.6 months for the whole cohort, respectively. Multiple tumors (hazard ratio 2.12; 95% CI 1.11-4.33; p = 0.023), positive surgical margins (hazard ratio 2.45; 95% CI 1.19-4.81; p = 0.016), and non-adjuvant hepatic arterial infusion chemotherapy (HAIC; hazard ratio 2.07; 95% CI 1.11-3.90; p = 0.023) were independent risk factors for DFS. Non-adjuvant HAIC (hazard ratio 1.84; 95% CI 1.01-3.37; p = 0.047) was an independent risk factor for OS. Conclusions: Macroscopically curative resection seems to be of benefit to HCC patients with PVTT, even with tumor thrombi in the first branch or trunk of the portal vein. Adjuvant postoperative HAIC might improve DFS and OS in such patients.

The Nature and Function of Immunogenic Tumor Proteins That Characterize Pancreatic and Colorectal Cancer: A Review

The use of immunotherapy as it relates to the treatment of solid tumor malignancies appears to be an effective approach for managing many patients who present with both recurrent and metastatic disease. This holds true, especially in those cases where patients have failed current chemotherapeutic protocols and evidence of tumor progression is noted. In such instances, the delivery of the proper immunotherapeutic agents may be effective either alone or in combination with chemotherapy. The ideal approach would be in the identification of an immunogenic protein that characterized and was specific for the tumor system to be treated. One of the first attempts to utilize specific active immunotherapy for treating cancer patients with advanced disease was by Ariel Hollinshead. She produced several vaccine preparations composed of tumor associated antigen (TAA) derived from pooled allogeneic tumor membrane preparations. These vaccines, obtained from operative specimens were shown to exhibit varying degrees of improvement in the overall survival of such patients. They were employed in treating patients with advanced malignancies including those having lung cancer, colon cancer and malignant melanoma. For most who received the vaccine following resection of an advanced disease process, survival results demonstrating 80-90% freedom of disease at 5 years could be achieved. These results were considered significant when compared to other therapeutic protocols available at the time. Further use in clinical trials were held back at the suggestion of the FDA due to possible viral contamination in the next set of vaccine preparations if any tumor specimen used contained the possible presence virulent strains of virus such as hepatitis, AIDS and HPV. At this point recombinant vaccines were felt to be essential if such vaccines were to be used in future clinical trials. Monoclonal antibodies were therefore developed against each of the pooled vaccine preparations and used for affinity purification and sequencing of the antigens. In reviewing our survival data results it became apparent that those who failed therapy were patients unable to mount an effective IgG1 response and not related to the presence of CD8 T cells. The mAbs were now produced in GMP format and clinical trials as such were initiated for patients with recurrent colon and pancreatic Ca having failed standard chemotherapy.