Median Survival Of Patients Research Articles

Myc rearrangement and concurrent high protein expression of C-Myc/Bcl2 carry an adverse prognosis in diffuse large B-cell lymphoma

PurposeDiffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of non-Hodgkin lymphoma, characterized by a variety of clinicopathological, histomorphological, immunophenotypic, and molecular genetic features. The subtype of DLBCL known as double-expressor lymphoma (DEL) is associated with an adverse prognosis when treated with R-CHOP. Our study aimed to investigate the clinicopathologic features of DEL and the prognostic roles of Myc rearrangement and C-Myc expression in DEL patients. Patients and methodsWe conducted a retrospective study of 145 patients who were identified through fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) testing. ResultsWe found that DEL patients were more likely to have a non-germinal center B-cell (GCB) subtype, stage III/IV disease, and a high International Prognostic Index (IPI) score. Our survival analysis indicated that Myc rearrangement and C-Myc expression were associated with poor prognosis. Although DEL patients with Myc rearrangement exhibited trends towards worse survival compared with patients without Myc rearrangement, the differences were not statistically significant (P = 0.4008). The median overall survival (OS) of DEL patients with ≥70 % C-Myc expression (DEL-C-Mychigh) was 5 months. In the DEL-C-Mychigh group, the non-GCB subtype showed nonsignificant trends towards poorer survival compared with the GCB subtype (P = 0.1042). ConclusionIn conclusion, our study shows that a cut-off of ≥70 % for C-Myc expression in DEL patients can improve risk stratification, and suggests that more intensive treatment regimens may be necessary to improve survival in this high-risk population.

Correlation Analysis between Thyroid Function Abnormality and Efficacy in Patients with Advanced Non-small Cell Lung Cancer after Immunotherapy

Thyroid function abnormality (TFA) is one of the common adverse reactions in patients with advanced non-small cell lung cancer (NSCLC) treated with immunotherapy, but the risk factors of TFA and its relationship with efficacy are not completely clear. The purpose of this study was to explore the risk factors of TFA and its relationship with efficacy in patients with advanced NSCLC after immunotherapy. The general clinical data of 200 patients with advanced NSCLC in The First Affiliated Hospital of Zhengzhou University from July 1, 2019 to June 31, 2021 were collected and analyzed retrospectively. χ² test and multivariate Logistic regression were used to explore the risk factors of TFA. Kaplan-Meier curve was drawn and Log-rank test was used for comparison between groups. Univariate and multivariate Cox analysis was used to explore the efficacy factors. A total of 86 (43.0%) patients developed TFA. Logistic regression analysis showed that Eastern Cooperative Oncology Group Performance Status (ECOG PS), pleural effusion and lactic dehydrogenase (LDH) were factors influencing TFA (P<0.05). Compared with normal thyroid function group, the median progression-free survival (PFS) of patients in the TFA group was significantly longer (19.0 months vs 6.3 months, P<0.001), and the objective response rate (ORR) (65.1% vs 28.9%, P=0.020) and disease control rate (DCR) (100.0% vs 92.1%, P=0.020) of the TFA group were better than those of the normal thyroid function group. Cox regression analysis showed that ECOG PS, LDH, cytokeratin 19 fragment (CYFRA21-1) and TFA were factors influencing prognosis (P<0.05). ECOG PS, pleural effusion and LDH may be risk factors affecting the occurrence of TFA and TFA may be a predictor of the efficacy of immunotherapy. Patients with advanced NSCLC who have TFA after immunotherapy may obtain better efficacy.

Association of Copresence of Pathogenic Variants Related to Amyotrophic Lateral Sclerosis and Prognosis.

Despite recent advances, it is not clear whether the various genes/genetic variants related to amyotrophic lateral sclerosis (ALS) interact in modifying patients' phenotype. The aim of this study was to determine whether the copresence of genetic variants related to ALS has interactive effects on the course of the disease. The study population includes 1,245 patients with ALS identified through the Piemonte Register for ALS between 2007 and 2016 and not carrying superoxide dismutase type 1, TAR DNA binding protein, and fused in sarcoma pathogenic variants. Controls were 766 Italian participants age-matched, sex-matched, and geographically matched to cases. We considered Unc-13 homolog A (UNC13A) (rs12608932), calmodulin binding transcription activator 1 (CAMTA1) (rs2412208), solute carrier family 11 member 2 (SLC11A2) (rs407135), and zinc finger protein 512B (ZNF512B) (rs2275294) variants, as well as ataxin-2 (ATXN2) polyQ intermediate repeats (≥31) and chromosome 9 open reading frame 72 (C9orf72) GGGGCC intronic expansions (≥30). The median survival time of the whole cohort was 2.67 years (interquartile range [IQR] 1.67-5.25). In univariate analysis, only C9orf72 (2.51 years, IQR 1.74-3.82; p = 0.016), ATXN2 (1.82 years, IQR 1.08-2.33; p < 0.001), and UNC13A C/C (2.3 years, IQR 1.3-3.9; p < 0.001) significantly reduced survival. In Cox multivariable analysis, CAMTA1 also emerged to be independently related to survival (hazard ratio 1.13, 95% CI 1.001-1.30, p = 0.048). The copresence of 2 detrimental alleles/expansions was correlated with shorter survival. In particular, the median survival of patients with CAMTA1 G/G+G/T and UNC13A C/C alleles was 1.67 years (1.16-3.08) compared with 2.75 years (1.67-5.26) of the patients not carrying these variants (p < 0.001); the survival of patients with CAMTA1 G/G+G/T alleles and ATXN2 ≥31 intermediate polyQ repeats was 1.75 years (0.84-2.18) (p < 0.001); the survival of patients with ATXN2 ≥31 polyQ repeats and UNC13A C/C allele was 1.33 years (0.84-1.75) (p < 0.001); the survival of patients with C9ORF72 ≥30 and UNC13A C/C allele was 1.66 years (1.41-2.16). Each pair of detrimental alleles/expansions was associated to specific clinical phenotypes. We showed that gene variants acting as modifiers of ALS survival or phenotype can act on their own or in unison. Overall, 54% of patients carried at least 1 detrimental common variant or repeat expansion, emphasizing the clinical impact of our findings. In addition, the identification of the interactive effects of modifier genes represents a crucial clue for explaining ALS clinical heterogeneity and should be considered when designing and interpreting clinical trials results.

Pertuzumab as second‑ or later‑line therapy for human epidermal growth factor receptor 2‑positive metastatic breast cancer: A clinical experience.

Trastuzumab and pertuzumab with taxane-based chemotherapy are considered the first-line standard therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC). Pertuzumab is also a later-line therapy for mBC in Switzerland, although limited safety and efficacy data are available. The present study assessed the therapeutic regimens, toxicities and clinical outcomes after second- or later-line pertuzumab therapy in patients with mBC who did not receive pertuzumab as a first-line therapy. Physicians from nine major Swiss oncology centers retrospectively completed a questionnaire for each pertuzumab-naive patient who was treated with pertuzumab as a second- or later-line therapy. Of 35 patients with HER2-positive mBC (median age, 49 years; range, 35-87 years), 14 received pertuzumab as a second-line therapy, 6 as a third-line therapy, and 15 as a fourth- or later-line therapy. A total of 20 patients (57%) died during the study period. The median overall survival was 74.2 months (95% confidence interval, 47.6-139.8 months). Grade (G) 3/4 adverse events (AEs) were reported in 14% of patients, with only 1 patient discontinuing therapy due to pertuzumab-related toxicities. The most common AE was fatigue (overall, 46%; G3, 11%). Overall, congestive heart disease occurred in 14% of patients (G3, 6%), nausea in 14% of patients (all G1), and myelosuppression in 12% of patients (G3, 6%). In conclusion, the median overall survival of patients who underwent second- or later-line pertuzumab treatment was similar to that reported for patients who underwent first-line pertuzumab treatment, and the safety profile was acceptable. These data support the use of pertuzumab for second- or later-line therapy when it was not administered as first-line therapy.

Histone deacetylase-based dual targeted inhibition in multiple myeloma.

Despite enormous advances in terms of therapeutic strategies, multiple myeloma (MM) still remains an incurable disease with MM patients often becoming resistant to standard treatments. To date, multiple combined and targeted therapies have proven to be more beneficial compared to monotherapy approaches, leading to a decrease in drug resistance and an improvement in median overall survival in patients. Moreover, recent breakthroughs highlighted the relevant role of histone deacetylases (HDACs) in cancer treatment, including MM. Thus, the simultaneous use of HDAC inhibitors with other conventional regimens, such as proteasome inhibitors, is of interest in the field. In this review, we provide a general overview of HDAC-based combination treatments in MM, through a critical presentation of publications from the past few decades related to in vitro and in vivo studies, as well as clinical trials. Furthermore, we discuss the recent introduction of dual-inhibitor entities that could have the same beneficial effects as drug combinations with the advantage of having two or more pharmacophores in one molecular structure. These findings could represent a starting-point for both reducing therapeutic doses and lowering the risk of developing drug resistance.

Outcome of immune checkpoint inhibitors in patients with extensive-stage small-cell lung cancer and brain metastases.

Brain metastases (BMs) are common in extensive-stage small-cell lung cancer (SCLC) and are underrepresented in pivotal clinical trials that demonstrate the efficacy of immune checkpoint inhibitors (ICIs). We conducted a retrospective analysis to assess the role of ICIs in BM lesions in less selected patients. Patients with histologically confirmed extensive-stage SCLC who were treated with ICIs were included in this study. Objective response rates (ORRs) were compared between the with-BM and without-BM groups. Kaplan-Meier analysis and the log-rank test were used to evaluate and compare progression-free survival (PFS). The intracranial progression rate was estimated using the Fine-Gray competing risks model. A total of 133 patients were included, 45 of whom started ICI treatment with BMs. In the whole cohort, the overall ORR was not significantly different for patients with and without BMs (p = 0.856). The median progression-free survival for patients with and without BMs was 6.43 months (95% CI: 4.70-8.17) and 4.37 months (95% CI: 3.71-5.04), respectively (p =0.054). In multivariate analysis, BM status was not associated with poorer PFS (p = 0.101). Our data showed that different failure patterns occurred between groups, with 7 patients (8.0%) without BM and 7 patients (15.6%) with BM having intracranial-only failure as the first site progression. The cumulative incidences of brain metastases at 6 and 12 months were 15.0% and 32.9% in the without-BM group and 46.2% and 59.0% in the BM group, respectively (Gray's p<0.0001). Although patients with BMs had a higher intracranial progression rate than patients without BMs, the presence of BMs was not significantly associated with a poorer ORR and PFS with ICI treatment in multivariate analysis.

ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma.

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA-mutations showed increased sensitivity to ONC201, while those harboring TP53-mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.

Real-world clinical outcomes in patients with multiple myeloma treated with isatuximab after daratumumab treatment

Isatuximab and daratumumab are anti-CD38 monoclonal antibodies used to treat refractory multiple myeloma. Isatuximab is often used after unsuccessful daratumumab treatment; however, the clinical benefits of receiving isatuximab after daratumumab treatment have not been fully evaluated. Therefore, this retrospective cohort study assessed the clinical outcomes of 39 patients with multiple myeloma who were administered isatuximab after daratumumab. The median follow-up period was 8.7months (range 0.1-25.0months). The overall response rate was 46.2% (18 patients). The 1-year overall survival was 53.9%, with a median progression-free survival of 5.6months. The median progression-free survival in patients with high and normal lactate dehydrogenase levels was 4.5 and 9.6months, respectively (P = 0.004). The median progression-free survival in patients with and without triple-class refractory disease was 5.1months and not reached, respectively (P = 0.001). The median overall survival in patients with high and normal lactate dehydrogenase levels was not reached and 9.3months, respectively (P = 0.001). The median overall survival in patients with and without triple-class refractory disease was 9.9months and not reached, respectively (P = 0.038). Our findings provide insight into the optimal use and timing of anti-CD38 antibody therapy.

Comprehensive Genomic Profiling Detects Hereditary Cancers and Confers Survival Advantage in Patients With Gynaecological Cancers.

The clinical benefits of comprehensive genomic profiling (CGP) of tumours in patients with gynaecological cancers remain unknown. We investigated the utility of CGP in assessing patient survival and its efficacy in detecting hereditary cancers in gynaecological patients. We retrospectively analysed the medical records of 104 gynaecological patients who underwent CGP between August 2018 and December 2022. The detection of actionable and accessible genomic alterations and administration of targeted therapy, as recommended by the molecular tumour board (MTB), were assessed. The overall survival (after second-line treatment in cervical and endometrial carcinomas and after platinum-resistant recurrence in ovarian carcinoma) was compared between patients with or without administration of MTB-recommended genotype-matched therapy. Germline findings were assessed using a variant allele frequency-tumour content graph. Among 104 patients, actionable and accessible genomic alterations were observed in 53 patients. Matched therapy was applied in 21 patients, comprising administration of repurposing itraconazole (n=7), immune checkpoint inhibitors (n=7), poly (ADP-ribose) polymerase inhibitors (n=5), and others (n=2). The median overall survival of patients receiving and not receiving matched therapy were 19.3 months and 11.2 months, respectively (p=0.036, hazard ratio=0.48). Among 12 patients with hereditary cancers, 11 patients were previously undiagnosed. Seven patients had hereditary breast and ovarian cancer, and five had other cancer. The implementation of CGP testing prolonged overall survival in gynaecological cancer as well as provided an opportunity for genetic counselling for newly-diagnosed patients with hereditary cancers and their families.

What Is the Prosthetic Survival After Resection and Intercalary Endoprosthetic Reconstruction for Diaphyseal Bone Metastases of the Humerus and Femur?

Large metastatic lesions of the diaphysis can cause considerable pain and result in difficult surgical challenges. Resection and cemented intercalary endoprosthetic reconstruction offer one solution to the problem, but it is an extensive operation that might not be tolerated well by a debilitated patient. The risk of aseptic loosening and revision after intercalary endoprosthetic replacement has varied in previous reports, which have not examined the risk of revision in the context of patient survival. (1) In a small case series from one institution, what is the survivorship of patients after cemented intercalary endoprosthetic replacement for diaphyseal metastasis, and what is the cumulative incidence of revision for any reason? (2) What are the complications associated with cemented intercalary reconstruction? (3) What is the functional outcome after the procedure as assessed by the MSTS93 score? We retrospectively studied 19 patients with diaphyseal long bone metastases who were treated with resection and cemented intercalary endoprosthetic reconstruction by five participating surgeons at one referral center from 2006 to 2017. There were 11 men and eight women with a median age of 59 years (range 46 to 80 years). The minimum follow-up required for this series was 12 months; however, patients who reached an endpoint (death, radiographic loosening, or implant revision) before that time were included. One of these 19 patients was lost to follow-up but was not known to have died. The median follow-up was 24 months (range 0 to 116 months). Eight of the 19 patients presented with pathologic fractures. Ten of 19 lesions involved the femur, and nine of 19 were in the humerus. The most common pathologic finding was renal cell carcinoma (in 10 of 19). Survival estimates of the patients were calculated using the Kaplan-Meier method. A competing risks estimator was used to evaluate implant survival, using death of the patient as the competing risk. We also estimated the cumulative incidence of aseptic loosening in a competing risk analysis. Radiographs were analyzed for radiolucency at the bone-cement-implant interfaces, fracture, integrity of the cement mantle, and component position stability. Complications were assessed using record review that was performed by an individual who was not involved in the initial care of the patients. Functional outcomes were assessed using the MSTS93 scoring system. Patient survivorship was 68% (95% CI 50% to 93%) at 1 year, 53% (95% CI 34% to 81%) at 2 years, and 14% (95% CI 4% to 49%) at 5 years; the median patient survival time after reconstruction was 25 months (range 0 to 116 months). In the competing risk analysis, using death as the competing risk, the cumulative incidence of implant revision was 11% (95% CI 2% to 29%) at 1 year and 16% (95% CI 4% to 36%) at 5 years after surgery; however, the cumulative incidence of aseptic loosening (with death as a competing risk) was 22% (95% CI 6% to 43%) at 1 year and 33% (95% CI 13% to 55%) at 5 years after surgery. Other complications included one patient who died postoperatively of cardiac arrest, one patient with delayed wound healing, two patients with bone recurrence, and one patient who experienced local soft tissue recurrence that was excised without implant revision. Total MSTS93 scores improved from a mean of 12.6 ± 8.1 (42% ± 27%) preoperatively to 21.5 ± 5.0 (72% ± 17%) at 3 months postoperatively (p < 0.001) and 21.6 ± 8.5 (72% ± 28%) at 2 years postoperatively (p = 0.98; 3 months versus 2 years). Resection of diaphyseal metastases with intercalary reconstruction can provide stability and short-term improvement in function for patients with advanced metastatic disease and extensive cortical destruction. Aseptic loosening is a concern, particularly in the humerus; however, the competing risk analysis suggests the procedure is adequate for most patients, because many in this series died of disease without undergoing revision. Level IV, therapeutic study .

RNA cytosine methyltransferase NSUN5 promotes protein synthesis and tumorigenic phenotypes in glioblastoma.

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. The standard treatment achieves a median overall survival for GBM patients of only 15 months. Hence, novel therapies based on an increased understanding of the mechanistic underpinnings of GBM are desperately needed. In this study, we show that elevated expression of 28S rRNA (cytosine-C(5))-methyltransferase NSUN5, which methylates cytosine 3782 of 28S rRNA in GBM cells, is strongly associated with the poor survival of GBM patients. Moreover, we demonstrate that overexpression of NSUN5 increases protein synthesis in GBM cells. NSUN5 knockdown decreased protein synthesis, cell proliferation, sphere formation, migration, and resistance to temozolomide in GBM cell lines. NSUN5 knockdown also decreased the number and size of GBM neurospheres in vitro. As a corollary, mice harboring U251 tumors wherein NSUN5 was knocked down survived longer than mice harboring control tumors. Taken together, our results suggest that NSUN5 plays a protumorigenic role in GBM by enabling the enhanced protein synthesis requisite for tumor progression. Accordingly, NSUN5 may be a hitherto unappreciated target for the treatment of GBM.

Morphological parameters of uterine body leiomyosarcoma associated with survival rates

Background. Uterine leiomyosarcomas are highly aggressive tumors with a poor prognosis. The main prognostic factors are the stage of the disease, the size of the primary tumor, and the grade of malignancy. It is well known that the clinical course and prognosis of uterine leiomyosarcoma do not correlate with the FNCLCC histological grade, based on assessment of the mitotic index and the presence and amount of necrosis in sarcomas. There is published data on a more unfavorable course of non-spindle cell uterine leiomyosarcomas.Aim. To evaluate the influence of pathological factors (histological subtype, mitotic index, necrosis and its type) on survival rates in uterine leiomyosarcoma.Materials and methods. The study included 58 patients who underwent radical surgery for uterine leiomyosarcoma. The following morphological parameters were evaluated on histological slides: histological subtype, mitotic index, the presence of necrosis in the tumor and its type. Further, the analysis of the influence of these morphological characteristics on the indicators of progression-free survival and overall survival was carried out. Statistical analysis was carried out using the IBM SPSS Statistics Professional 20.0 statistical software package. Long-term results are presented in the form of actuarial survival calculated by the Kaplan–Meier method.Results. Most cases of uterine leiomyosarcoma were of the spindle-cell variant (82.8 %), had a mitotic index &gt;20 per 10 high power field (93.1 %) and large foci of necrosis (70.7 %), coagulation necrosis was more often detected (43.1 %). There was a significant difference in the median overall survival of patients with spindle-cell variant of uterine leiomyosarcoma and non-spindle-cell variants (epithelioid or myxoid): 77 months vs. 49 months (p = 0.05). There was no significant relationship between the mitotic index of the primary tumor, the size of necrosis foci in the tumor and survival rates. The presence of coagulative necrosis in the tumor was significantly associated with a deterioration in progression-free survival (9 months vs. 14 months, p = 0.05) and overall survival (51 months vs. 104 months, p = 0.05).Conclusion. The spindle-cell variant of leiomyosarcoma is associated with higher overall survival rates compared to other histological subtypes. The presence of coagulative necrosis in the tumor in comparison with other types of necrosis is an unfavorable prognostic factor associated with a decrease in both progression-free survival and overall survival.

Mortality and Survival of Patients with Central Nervous System Disorders: Prognostic Factors of at the University Hospital Point G, Bamako, Mali

The department of infectious and tropical diseases is the referral for all HIV positive patients in need of hospitalization. HIV has modified the epidemiology of central nervous system (CNS) disorders in Mali. Objective: Our objective was to study the prognostic factors of the mortality and survival of patients with CNS disorders in the department of infectious and tropical diseases at the University hospital Point G, Bamako, Mali. Methods: We collected data retrospectively from the medical records inpatients between 1st January 2013 and 31st December 2017 and we used R software version 2.12.2 to analyze data. Results: In five (5) years, we registered 1,315 hospital admissions with CNS disorders with a morbidity rate of 21.14% (278/1315) and 71.7% (125/278) were HIV positive. In bivariate analysis (Log-rank test), there was a statistically significant difference between survival and alcohol consumption (p=0.001) and smoking (p&lt;0.001); history of tuberculosis (p=0.006); presence of dementia syndrome (p&lt;0.001) and positive HIV serology (p=0.01). Multivariate analysis (Cox model) identified dementia [adjusted Hazard Risk, HR=13.02 (2.62 - 64.8)], previous tuberculosis [adjusted HR=13.33 (1.05 - 102.63)], alcohol use [adjusted HR=3.08 (1.67 - 5.69)] and smoking [adjusted HR= 2.9 (1.05 - 7.99)] as poor prognostic factors for survival. According to the Kaplan Meier method, the overall median survival of patients was 37 days [CI 95%; (35-55 days)]. Conclusion: Notion of TB, alcohol use and smoking were poor prognostic factors of the survival of HIV positive inpatients with CNS disorders.

Abstract CT131: Initial preclinical and clinical experience of autologous engineered monocytes in T cell lymphoma patients

Abstract For many patients with T cell lymphomas (TCL), sustained clinical benefit with standard treatment options is elusive. Myeloid cells, such as monocytes, dendritic cells and macrophages, readily accumulate in tumors, whereby they support tumor progression. The ability to harness the capability of myeloid cells to penetrate into tumors, and to subsequently program them to activate and elicit broad anti-tumor immunity has the potential to transform cancer therapies. With this goal we developed the first engineered monocyte cell product, by manipulating autologous monocytes to express a novel chimeric antigen receptor (CAR). This CAR contains a tumor recognition domain fused to a CD8 hinge domain, Fcγ and PI3K intracellular signaling domains. In addition to imparting tumor specificity, the Fcγ and PI3K signaling domains promote phagocytosis, cytokine production and antigen presentation upon activation. In a rodent model of melanoma (gp75+ B16/F10-OVA), Ly6C+ monocytes engineered with this receptor were able to phagocytose tumor cells and cross present antigen in vitro. In vivo infusion of engineered monocytes was associated with significant suppression of tumor growth. FACS analysis of tumor-infiltrates demonstrated that engineered monocytes preferentially infiltrated tumors and differentiated into antigen presenting cells. Adoptive T cell transfer of CFSE-labeled OT-I CD8+ T cells confirmed that treatment was also associated with increased accumulation of tumor specific T cells in tumor and spleen. Based on these promising data, MT-101 is being assessed in humans in the Phase 1, open-label, first-in-human trial in patients with refractory or relapsed T cell lymphoma, IMAGINE trial (NCT05138458). The primary objective is the assessment of safety and tolerability at Day 28, following 3 weekly cycles of 2 infusions. Secondary objectives include assessment of correlative markers of response, pharmacokinetics, and efficacy. In the first 3 subjects, MT-101 has been well-tolerated, with no evidence of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or infusion reactions. Examination of biomarkers by CyTOF in one subject shows changes in circulating leukocytes, including B cells. In this subject, survival has been greater than 10 months, while the median overall survival of patients with R/R PTCL is 5.5 months. Continued patient enrollment and data collection is ongoing to confirm these observations. Citation Format: Michele Gerber, Thomas Prod'homme, Yuxiao Wang, Kyong-Rim Kieffer-Kwon, Neha Diwanji, Josephine D'Alessandro, Xing Du, Edward Cochran, Michael Gorgievski, Zheng Ling, Nicholas King, Siddhartha Mukherjee, Daniel Getts. Initial preclinical and clinical experience of autologous engineered monocytes in T cell lymphoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT131.

Cystic fibrosis - Ways to improve the quality of life of patients

Introduction Cystic fibrosis (CF) is a serious, multi-system disease. In the Caucasian population CF is the most common autosomal recessive disease, which happens for 1 person in 3,500 births [1]. In the course of CF, there is a dysfunction of many organs, mainly the respiratory and digestive systems. Symptomatic treatment of cystic fibrosis is very important. The change in daily eating habits, the use of proper breathing techniques and psychotherapy also have an impact on improving the quality of life of patients. In the past patients died at a young age. The progress in the diagnosis and treatment of cystic fibrosis has meant that nowadays more and more people are reaching adulthood. In recent years, the median survival of patients has increased to 46.2 years. [2] Purpose The aim of this review is to present the current state of knowledge about ways to improve the quality and length of life of patients with CF. Methods The literature available in the Pubmed and Google Scholarship databases was reviewed using key phrases. Results Additional methods of treatment, such as: learning the correct breathing technique, oxygen therapy, physical exercise or proper nutrition, significantly improve the living conditions of patients.

Clinical impact of weight loss on mortality in patients with idiopathic pulmonary fibrosis: a retrospective cohort study

Patients with idiopathic pulmonary fibrosis (IPF) often experience weight loss during the follow-up period. However, the prevalence and clinical impact of weight loss in these patients still need to be elucidated. This retrospective single-center study reviewed 134 consecutive patients diagnosed with IPF. Weight loss of 5% or more over 1 year was defined as significant weight loss. Clinical data of patients were compared according to the significant weight loss. We analyzed whether the clinical impact of significant weight loss differed regarding the pirfenidone dose. The median follow-up period was 22.1 months. The mean age of patients was 67.3 years, and 92.5% were men. Of the 134 patients, 42 (31.3%) showed significant weight loss. Multivariate cox regression analysis revealed that significant weight loss was independently associated with mortality (hazard ratio [HR]; 2.670; 95% confidence interval [CI] 1.099–6.484; p = 0.030) after adjusting for lung function and other significant risk factors (6-min walk test distance: HR, 0.993; 95% CI 0.987–0.998; p = 0.005). The median survival of patients with significant weight loss (n = 22) was relevantly shorter than that of those without significant weight loss (n = 43) in the reduced dose pirfenidone group (28.2 ± 3.3 vs. 43.3 ± 3.2 months, p = 0.013). Compared with patients without significant weight loss (n = 38), patients with significant weight loss (n = 15) also showed a marginally-significant shorter survival in the full-dose pirfenidone group (28.9 ± 3.1 vs. 39.8 ± 2.6 months, p = 0.085). Significant weight loss is a prognostic factor in patients with IPF regardless of pirfenidone dose. Vigilant monitoring might be necessary to detect weight loss during the clinical course in these patients.

Value of thyroid cancer history in the prognosis of pancreatic cancer: a SEER population-based study

Thyroid cancer patients have a good prognosis, and their long survival increases the likelihood of developing a second primary tumor. Meanwhile, pancreatic cancer (PC) has a poor prognosis and therapeutic efficacy. However, the association between prior thyroid cancer and the subsequent PC prognosis is unknown. Herein, we selected pathologically diagnosed PC patients older than 17 between 2010 and 2015 from the SEER database. We used propensity score matching (PSM) to reduce confounding factors between groups and matched each PC patient with a history of thyroid cancer with 10 PC patients without a history of thyroid cancer. Finally, we selected 103 PC patients with prior thyroid cancer and 1030 PC patients without prior thyroid cancer. Then, we analyzed the factors influencing the overall survival (OS) and the cancer-specific survival (CSS) of PC patients. The median overall survival of PC patients with and without a history of thyroid cancer was 12 and 9 months, respectively. The history of thyroid cancer in PC patients reduced the PC-specific mortality (p < 0.05). Prior thyroid cancer might be a favorable prognostic factor for PC-specific mortality in PC patients.

RANKL acts an unfavorable prognostic biomarker and potential target in advanced KRAS‐mutated lung adenocarcinoma

Advanced lung cancers carrying Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation remain a group that lacks effective treatments. Receptor activator of nuclear factor-κB ligand (RANKL) has been demonstrated to drive malignant phenotypes in lung cancer; however, its role in KRAS-mutant (mt) lung adenocarcinoma (LUAD) is not yet fully elucidated. The data used to explore expression and prognosis were obtained from The Cancer Genome Atlas, Genotype-Tissue Expression databases, and from our hospital. The proliferation, invasion, and migration capacities of KRAS-mt LUAD cells were evaluated. The prediction model was established via Lasso regression method. RANKL is strongly expressed in advanced KRAS-mt LUAD, and significantly distinct association exists between high RANKL expression and poor survival. The enriched expression of RANKL in advanced KRAS-mt LUAD was confirmed by specimens from our hospital. Further, although not statistically significant, our clinical cohort (n = 57) revealed a longer median progression-free survival in advanced KRAS-mt LUAD patients treated with RANKL inhibitor than those without (300 vs. 133 days, p = 0.210), but not in KRAS-wt ones (208 vs. 250 days, p = 0.334). Decrease of KRAS-mt LUAD cells' capacity for proliferation, invasion, and migration was observed when RANKL was knocked down. Enrichment analysis suggested distinct roles of RANKL between KRAS-mt and KRAS-wt LUAD, with adhesion-related pathways and molecules significantly downregulated in the KRAS-mt RANKL-high tumors. Finally, a model for predicting overall survival of KRAS-wt LUAD was established according to four related key genes (BCAM, ICAM5, ITGA3, and LAMA3), which had good performance in prediction concordance. RANKL acts as an unfavorable prognostic biomarker for patients with advanced KRAS-mt LUAD. Inhibition of RANKL may be a feasible strategy for this subset of patients.

Impact of chemoradiotherapy on the survival of unresectable locally advanced pancreatic cancer: a retrospective cohort analysis

BackgroundThe role of chemoradiotherapy in unresectable locally advanced pancreatic cancer is still unclear.MethodsData from patients with unresectable locally advanced pancreatic cancer were extracted from the Surveillance, Epidemiology, and End Results Program database. Univariate and multivariate Cox regression analyses were conducted to identify the independent prognostic factors of survival. Propensity score matching was carried out to minimize the interference of confounding factors. Subgroup analysis was performed to screen the characteristics of patients who would benefit from chemoradiotherapy.ResultsA total of 5002 patients with unresectable locally advanced pancreatic cancer were included. Among them, 2423 (48.4%) received chemotherapy, and 2579 (51.6%) received chemoradiotherapy. The median overall survival of all patients was 11 months. Multivariate Cox analysis showed that age (p < 0.001), marital status (p < 0.001), tumor size (p = 0.001), N stage (p = 0.015) and radiotherapy (p < 0.001) were independent prognostic factors of survival. Both before (HR, 0.817; 95% CI, 0.769–0.868; p < 0.001) and after (HR, 0.904; 95% CI, 0.876–0.933; p < 0.001) propensity score matching, chemoradiotherapy significantly improved the median overall survival of patients from 10 to 12 months. Subgroup analysis showed that chemoradiotherapy was significantly associated with improved survival regardless of sex, primary site or N stage. In addition, the following subgroups all significantly benefited from chemoradiotherapy: age ≥ 50 years, not divorced, grade 2–4, tumor size > 2 cm, adenocarcinoma, mucinous adenocarcinoma and white race.ConclusionsChemoradiotherapy is highly recommended for patients with unresectable locally advanced pancreatic cancer.

Abstract 4734: BRD8-driven EP400 complex hijacks H2AZ to maintain proliferation in glioblastoma

Abstract Glioblastoma (GBM) is the most notorious primary brain tumor. The median survival of GBM patients is only about one year and about 95% patients succumb after five years. This gloomy picture has not been improved for decades, even with extensive treatments including surgery, radiotherapy, and chemotherapy. Hence, a better understanding of the mechanisms underlying GBM development may provide new therapeutic opportunities. Primary GBM generally harbors a low mutational load when compared to other human cancers. Even P53—the guardian of the genome that is essentially disabled in nearly all human cancers, remains unmutated in about 71% of GBM cases. Moreover, these P53 wildtype GBM cases are as aggressive as those with P53 mutations. To explore the mechanism by which P53 wildtype GBM thrive in the presence of intact P53, we performed CRISPR screens in a panel of human cancer cell lines using an sgRNA library specifically targeting the functional domains of ~200 chromatin regulators. We discovered that BRD8’s bromodomain—a druggable domain as shown by the tremendous success in preclinical and clinical trial in diverse cancers—is a vulnerability specifically in P53 wildtype GBM cases. Our mechanistic studies demonstrate that BRD8 functions through the EP400 chromatin remodeling complex and hijacks the histone variant H2AZ at P53 target loci, enforcing a compact chromatin state that blocks P53’s accessibility to its targets. We show that targeting the BRD8 bromodomain releases H2AZ, opens up chromatin, engages P53-mediated transactivation, and triggers growth arrest. Consistent with these findings, BRD8 is highly expressed with H2AZ in patient-derived proliferating GBM cells, and is inversely correlated with the expression of P53 targets. Our work solves a long-standing mystery in P53 wildtype GBM, and presents a promising therapeutic target for the majority of GBM patients. Citation Format: Sherine Xueqin Sun, Olaf Klingbeil, Christopher Vakoc, Alea Mills. BRD8-driven EP400 complex hijacks H2AZ to maintain proliferation in glioblastoma. [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 4734.