Higher Rate Of Disease Progression Research Articles

Succinate promotes pulmonary fibrosis through GPR91 and predicts death in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is believed to be associated with a notable disruption of cellular energy metabolism. By detecting the changes of energy metabolites in the serum of patients with pulmonary fibrosis, we aimed to investigate the diagnostic and prognostic value of energy metabolites in IPF, and further elucidated the mechanism of their involvement in pulmonary fibrosis. Through metabolomics research, it was discovered that the TCA cycle intermediates changed dramatically in IPF patients. In another validation cohort of 55 patients with IPF compared to 19 healthy controls, it was found that succinate, an intermediate product of TCA cycle, has diagnostic and prognostic value in IPF. The cut-off levels of serum succinate were 98.36μM for distinguishing IPF from healthy controls (sensitivity, 83.64%; specificity, 63.16%; likelihood ratio, 2.27, respectively). Moreover, a high serum succinate level was independently associated with higher rates of disease progression (OR 13.087, 95%CI (2.819-60.761)) and mortality (HR 3.418, 95% CI (1.308-8.927)). In addition, accumulation of succinate and increased expression of the succinate receptor GPR91 were found in both IPF patients and BLM mouse models of pulmonary fibrosis. Reducing succinate accumulation in BLM mice alleviated pulmonary fibrosis and 21d mortality, while exogenous administration of succinate can aggravate pulmonary fibrosis in BLM mice. Furthermore, GPR91 deficiency protected against lung fibrosis caused by BLM. In vitro, succinate promoted the activation of lung fibroblasts by activating ERK pathway through GPR91. In summary, succinate is a promising biomarker for diagnosis and prognosis of IPF. The accumulation of succinate may promote fibroblast activation through GPR91 and pulmonary fibrosis.

Organelle resolved proteomics uncovers PLA2R1 as a novel cell surface marker required for chordoma growth

Chordomas are clinically aggressive tumors with a high rate of disease progression despite maximal therapy. Given the limited therapeutic options available, there remains an urgent need for the development of novel therapies to improve clinical outcomes. Cell surface proteins are attractive therapeutic targets yet are challenging to profile with common methods. Four chordoma cell lines were analyzed by quantitative proteomics using a differential ultracentrifugation organellar fractionation approach. A subtractive proteomics strategy was applied to select proteins that are plasma membrane enriched. Systematic data integration prioritized PLA2R1 (secretory phospholipase A2 receptor–PLA2R1) as a chordoma-enriched surface protein. The expression profile of PLA2R1 was validated across chordoma cell lines, patient surgical tissue samples, and normal tissue lysates via immunoblotting. PLA2R1 expression was further validated by immunohistochemical analysis in a richly annotated cohort of 25-patient tissues. Immunohistochemistry analysis revealed that elevated expression of PLA2R1 is correlated with poor prognosis. Using siRNA- and CRISPR/Cas9-mediated knockdown of PLA2R1, we demonstrated significant inhibition of 2D, 3D and in vivo chordoma growth. PLA2R1 depletion resulted in cell cycle defects and metabolic rewiring via the MAPK signaling pathway, suggesting that PLA2R1 plays an essential role in chordoma biology. We have characterized the proteome of four chordoma cell lines and uncovered PLA2R1 as a novel cell-surface protein required for chordoma cell survival and association with patient outcome.

Molecular predictors of response to first-line systemic therapies in advanced hepatocellular carcinoma.

534 Background: With numerous advances in systemic therapy for advanced hepatocellular carcinoma (HCC) over the past several years, there are now multiple first-line treatment options which can be considered. These options include combination atezolizumab with bevacizumab (atezo/bev), programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) targeted agents, and oral multikinase inhibitor monotherapy. However, further guidance is needed to predict which patients will respond to best to each regimen. Methods: We performed a single center, retrospective study to determine the association between responses to first-line therapies in advanced HCC and various molecular alterations. Patients received first-line therapy with either atezo/bev, PD-1/PD-L1 monotherapy, or oral multikinase inhibitor monotherapy with treatment responses determined by imaging. All patients underwent next-generation sequencing (NGS) with testing performed on peripheral blood or tumor tissue. Results: A total of 116 patients with advanced HCC were included in this study. For first-line therapies, 45 (38.8%) patients received atezo/bev, 41 (35.3%) received oral multikinase inhibitor monotherapy, and 30 (25.9%) received PD-1/PD-L1 monotherapy. There was no association between treatment responses and patient ethnicity, age, or underlying cirrhosis etiology for any regimen. However, when analyzing NGS results, atezo/bev recipients with telomerase reverse transcriptase (TERT) promoter alterations had significantly higher rates of disease progression (PD) compared those without TERT promoter alterations (91.7% vs 54.6%, p = 0.03). In addition, in the oral multikinase inhibitor monotherapy group, those with CTNNB1 alterations had significantly greater PD rates compared to patients without these alterations (66.7% vs 31%, p = 0.04). There were no significant correlations between molecular alterations and responses in the PD-1/PD-L1 monotherapy group (Table). Conclusions: In our study, advanced HCC patients who received first-line systemic therapies were found to have significant correlations between TERT promoter and CTNNB1 alterations and responses to atezo/bev and oral multikinase inhibitor monotherapy, respectively. Given the widespread use of these regimens in the HCC treatment paradigm, additional studies are needed to confirm these findings and determine their impact on survival outcomes.[Table: see text]

Molecular Targeting of the Human Epidermal Growth Factor Receptor-2 (HER2) Genes across Various Cancers.

Human epidermal growth factor receptor 2 (HER2) belongs to the ErbB family, a group of four transmembrane glycoproteins with tyrosine kinase activity, all structurally related to epidermal growth factor receptor (EGFR). These tyrosine kinases are involved in the transmission of cellular signals controlling normal cell growth and differentiation. If this transmission goes awry, it can lead to dysregulated growth of the cell. HER2 specifically can be implicated in the pathogenesis of at least eight malignancies. HER2 positivity quickly became a well-characterized indicator of aggressiveness and poor prognosis, with high rates of disease progression and mortality. After realizing the implication of HER2, it first became investigated as a target for treatment in breast cancer, and later expanded to areas of research in other cancer types. To this day, the most therapeutic advancements of anti-HER2 therapy have been in breast cancer; however, there have been strong advancements made in the incorporation of anti-HER2 therapy in other cancer types as well. This comprehensive review dissects HER2 to its core, incorporating the most up to date information. The topics touched upon are discussed in detail and up to 200 published sources from the most highly recognized journals have been integrated. The importance of knowing about HER2 is exemplified by the groundbreaking advancements that have been made, and the change in treatment plans it has brought to the oncological world in the last twenty years. Since its groundbreaking discovery there have been significant breakthroughs in knowledge regarding the actual receptor, the receptors biology, its mechanism of action, and advancements in tests to detect HER2 and significant strides on how to best incorporate targeted treatment. Due to the success of this field thus far, the review concludes by discussing the future of novel anti-HER2 therapy currently in development that everyone should be aware of.

Epidemiology of amyotrophic lateral sclerosis in the Krasnoyarsk region

Background. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes paralysis of muscles due to degeneration of motor neurons. According to available data, the incidence of ALS in different regions of the world is from 0.6 to 3.8 per 100,000 population per year. Data obtained during the study of the epidemiology of ALS at the regional level can be used in planning medical resources, in particular, calculating the necessary respiratory equipment and funds for nutritional support.Aim. Clinical and epidemiological analysis of ALS cases registered in the Krasnoyarsk region for the period 2018–2022.Materials and methods. A clinical and epidemiological analysis of ALS cases registered in the Krasnoyarsk region from 2018 to 2022 was conducted. To do this, we used data from the specialized office of neuromuscular pathology of the Regional Clinical Hospital in Krasnoyarsk and the Krasnoyarsk Regional Medical Information and Analytical Center. Diagnosis verification was carried out in accordance with the generally accepted El Escorial and Gold Coast criteria. The functional state and degree of neurological deficit were assessed using the ALS-FRS-R scale.Results. Over the period from 2018 to 2022, 78 cases of ALS were registered. The incidence rate was 0.54 cases per 100,000 population per year. In 2022, the prevalence rate was 1.16 cases per 100 thousand population. The time from symptom onset to diagnosis of the disease ranged from 4 to 57 months, with the average time to diagnosis being 17 months. Most patients were diagnosed with ALS when their ALS-FRS-R score decreased by 7–11 points. The division of patients into groups of rapid, moderate, and slow diagnostic correlates with life expectancy. Patients who are diagnosed quickly have a higher rate of disease progression, which results in a low life expectancy.Conclusion. The creation of specialized centers will improve the diagnosis and management of patients with ALS and plan the costs of palliative care. The increase in the incidence and detection of ALS emphasizes the need to develop new approaches to the treatment and rehabilitation of patients with ALS.

Differences in Clinical Outcomes Between Hydroxyurea-Resistant and -Intolerant Polycythemia Vera Patients.

Previous studies have suggested that patients with polycythemia vera (PV) who exhibit hydroxyurea-resistance (HU-R) and -intolerance (HU-I) may have distinct characteristics and clinical outcomes. However, to date, no studies have reported a comparison between these two groups or assessed prognostic factors in these patients. The objective of this study was to evaluate clinical outcomes and identify prognostic factors among PV patients with HU-R or HU-I. We conducted a review of PV patients who received frontline treatment with HU from nine centers and identified 90 patients with HU-R or HU-I. The cumulative incidence of thrombosis after 7 years of HU-R/I was 21.4%, and the incidence of disease progression was 22.5%. Comparing the HU-R and HU-I groups, the HU-R group had a significantly higher rate of disease progression (36.7% vs. 0.56%, P = 0.009), while there was no significant difference in thrombosis incidence (19.0% vs. 22.9%, P = 0.463). Multivariate analysis revealed that HU-R was an independent prognostic factor for progression-free survival (hazard ratio, 6.27, 95% confidence interval, 1.83-21.47, P = 0.003). Additionally, higher lactate dehydrogenase levels, multiple cardiovascular risk factors, and prior thrombosis were identified as unfavorable predictors of overall survival. These findings suggest that patients with HU-R face a higher risk of hematological transformation, but have a comparable risk of thrombosis to patients with HU intolerance. These distinctions should guide decisions on second-line treatment options and clinical trials involving these patients.

High Rate of Disease Progression in Patients with Low-Risk Myelofibrosis (MF) Enrolled in the Prospective, Real-World MOST Study

Background: Patients (pts) with low-risk MF are typically excluded from interventional clinical trials, thus data regarding the prognosis of this pt population are largely derived from retrospective analyses. The Myelofibrosis and Essential Thrombocythemia Observational Study (MOST; NCT02953704) is a prospective observational study that enrolled pts with low-risk MF defined by Dynamic International Prognostic Scoring System (DIPSS) criteria. In this analysis, we report disease progression, defined by worsening of clinical or laboratory parameters, in MF pts during the MOST study. Methods: Criteria for enrollment in MOST were confirmed locally and centrally, and included a physician-reported diagnosis of MF (PMF, post-PV, or post-ET) and lack of any DIPSS risk factors except for age >65 y. Of the 232 MF pts enrolled, 205 met this criteria upon central review and were included in this analysis as Cohort A; the remaining 27 pts were enrolled despite having ≥1 DIPSS risk factor (other than age >65 y) and were analyzed separately as Cohort B. Data were collected as previously described (Gerds A. CLML. 2022;22:e532). Disease progression on study was defined as the acquisition of 1 of the following criteria: hemoglobin (Hb) <10 g/dL, platelets <100×10 9/L, presence of constitutional symptoms (weight loss, fever, or sweats), new or worsening splenomegaly, blasts >1%, WBC count >25×10 9/L, death due to disease progression, leukemic transformation (LT), or >1 RBC transfusion. Median (range) follow-up was 52.9 months (42-68). Results: In Cohort A, 120/205 pts (58.5%) had evidence of disease progression during the study. Baseline characteristics comparing pts with vs without disease progression were similar; although compared with pts without progression, those who progressed were older at diagnosis (median [range], 65.9 [21-88] vs 62.9 [35-86] y), older at enrollment (median [range], 70.5 [35-88] vs 66.0 [35-88] y), and had longer median (range) time from diagnosis to enrollment (1.9 [0-38] vs 1.4 [0-24] y). Similar percentages of pts with vs without progression were receiving MF-directed therapy at enrollment (59.2% vs 61.2%); most common treatments were ruxolitinib (33.3% vs 14.1%) and hydroxyurea (22.5% vs 36.5%). Of pts in Cohort A tested for JAK2 mutations, 66/93 (71.0%) with disease progression and 42/65 (64.6%) without were positive. Of pts tested for CALR mutations, 16/21 (76.2%) with disease progression and 17/23 (73.9%) without were positive. Among the 120 pts with progression, 64 (53.3%) met 1 criteria, 27 (22.5%) met 2 criteria, and 29 (24.2%) met ≥3 criteria during the study. The most common progression criteria met were Hb <10 g/dL (47.5%), platelets <100×10 9/L (31.7%), constitutional symptoms (30.8%), and new/worsening splenomegaly (28.3%) (Table 1). Median (95% CI) durations to 1st, 2nd, and 3rd progression criteria were 24.9 (19.2-34.7), 28.2 (14.3-NE), and 11.6 (8.9-26.5) months, respectively (Figure 1). Of pts who progressed, 6 (5.0%) developed LT and 12 (10.0%) died due to disease progression. In Cohort B at time of enrollment, 25/27 pts (92.6%) met 1 progression criteria. The most frequent was Hb <10 g/dL (13/27 [48.1%]), followed by WBC count >25×10 9/L (7/27 [25.9%]); constitutional symptoms (4/27 [14.8%]), and blasts >1% (1/27 [3.7%]); 1 pt (3.7%) met 2 progression criteria (Hb <10 g/dL and constitutional symptoms), and 1 pt (3.7%) met 3 progression criteria (blasts >1%, constitutional symptoms, and WBC count >25×10 9/L). Eight of 27 pts (29.6%) had evidence of further disease progression while on study (Table 1). The most common new progression criteria met were Hb <10 g/dL and platelets <100×10 9/L (each 5/8 [62.5%]) and constitutional symptoms and new/worsening splenomegaly (each 3/8 [37.5%]). Conclusions: This real-world observational analysis from MOST is the first prospective analysis of disease progression in low-risk myelofibrosis. The results show that with over 4 y of follow-up, nearly 60% of pts with low-risk MF had evidence of disease progression; 17/205 pts (8.3%) developed LT or died (both occurred in 1 pt). Median time to acquisition of 1st and 2nd disease progression criteria was approximately 2 y, respectively, decreasing to approximately 1 y for the 3rd criteria; this indicates a slow but increasing rate of progression over the course of the study. These data provide real-world insight into disease progression rate in pts with low-risk myelofibrosis.

Decreased Survival Among Patients with Indolent Systemic Mastocytosis: A Population-Level Retrospective Cohort Analysis Using Healthcare Claims Dataset

Background Systemic mastocytosis (SM) is a rare, clonal mast cell disease driven by the KIT D816Vmutation in ~95% of cases and can be subdivided into two predominant subtypes - advanced SM (AdvSM) and indolent SM (ISM). AdvSM comprises ~15% of all patients and is characterized by mast cell proliferation and infiltration causing subsequent dysfunction of various organ systems, leading to reduced overall survival. Indolent systemic mastocytosis (ISM) comprises the bulk of the remaining ~85% of patients and is characterized by a less severe clinical course that is nevertheless associated with a significant symptom burden that may worsen over time, poor quality of life, and the potential for life-threatening anaphylaxis. Recent epidemiologic data indicate ISM is a heterogenous disease. A meaningful subset of patients with disease risk factors demonstrates high symptom burden, which may be associated with higher rates of disease progression and increased risk of death (Sperr, et al. Lancet Hematol. 2019). Building upon this work, we conducted an analysis to evaluate overall survival (OS) in ISM patients. Methods Using a nationally representative health claims dataset provided by Komodo Health covering 230 million US patients (2015 to 2022), we identified 8,332 patients with ISM using a claims-based algorithm. This algorithm leverages combinations of ICD-10 dx codes for SM and organ dysfunction, procedure codes (bone marrow biopsy), and use of SM-directed therapies (Mukherjee et al ASH 2022). Patients were included if full medical and pharmacy claim information was available for >12 consecutive months post-diagnosis, and median follow-up was 4.0 years. ISM was inferred as a dx if only the broad systemic mastocytosis ICD-10 code was used (D47.02) and there was no preceding evidence of AdvSM or an associated hematologic neoplasm. Disease progression to AdvSM was inferred if there was subsequent evidence of mast cell leukemia, aggressive SM, or an associated hematologic neoplasm OS was then calculated, anchored to the first observed ICD-10 dx code for SM. Mortality information was available within the claims dataset and was additionally inferred if a patient did not generate any medical or pharmacy claims for 12 or more consecutive months. Three, independent non-SM control cohorts (N=2000 each) were established for comparison, based on a stratified sampling strategy matched by gender, age, Charlson Comorbidity Index, payer status, and race/ethnicity of the ISM population. Multiple cohorts were plotted to illustrate consistency in survival across independently-sampled control cohorts. As positive control, we compared OS with a cohort of patients with ASM, a disease cohort with known increased mortality. Results We observed a statistically significant difference in OS among patients with ISM versus the matched non-SM control cohorts ( p<0.0001, with a log-rank hazard ratio of 1.64; Figure 1A). Excess mortality was noted among ISM patients with or without evidence of disease progression ( p<0.0001, with a hazard ratio of 1.44) compared to matched non-SM cohorts ( Figure 1B). As expected, OS was worst in patients with AdvSM ( p<0.0001, with a hazard ratio of 6.64). The ISM cohort presented to the emergency room (ER) 0.70 times per year, compared to 0.31 times per year for the combined non-ISM control cohorts, based on the sum of ER visits observed across the cumulative cohort observation period. Patients with ISM who died during the study interval had the highest frequency of ER visits, at a rate of 1.09 visits per year. Conclusions This is the first and the largest population-level analysis of OS in the ISM population in the US. Results demonstrate a modest but statistically significant decrease in survival among these patients even early in their disease course (first 4 years). This increase in mortality was observed even among patients with no evidence of progression to advanced SM and was additionally associated with >2x higher rates of ER visits over the observation period. These results suggest that acute, severe symptoms of SM may contribute to the excess mortality seen among patients with ISM and warrant focused research to identify specific patient characteristics or disease features in ISM that confer higher risk of mortality.

A Model of Cumulative Risk of Disease Progression Among Patients with Indolent Systemic Mastocytosis

Introduction Indolent systemic mastocytosis (ISM), a clonal mast cell disease driven by the KIT D816V mutation in ~95% of cases, can cause lifelong debilitating cutaneous, gastrointestinal, and neurocognitive symptoms with some cases progressing to advanced systemic mastocytosis (AdvSM). While several studies have quantified variable rates of disease progression from ISM to AdvSM based on the absolute frequency of these events, these studies were limited by short median follow-up time considering the long clinical course of this condition sometimes in decades, thereby leading to underestimation of the cumulate rates of progression from ISM to AdvSM. We conducted a Markov analysis using population level data in the US to estimate the lifetime risk of progression for ISM patients. Methods We modeled the total course of SM as a discrete-time Markov chain, enabling us to estimate cumulative rates of disease progression based on fixed-interval empirical observations from the literature and, where there is no literature available, expert opinion. The Markov model assumes that patients enter the model as at-risk ISM, not-at-risk ISM, or de novo AdvSM, based on the assumed relative incidence of each subtype. Not-at-risk patients will then move to death after a period of time, with an annualized risk of death from disease. At-risk patients with ISM will remain in that state, progress to AdvSM (which may be tyrosine kinase inhibitor treated or not) or die. Finally, those who progress to AdvSM will either remain in their state or die. See Figure1 for details, where each model parameter is reflected as a line between states and modeled based on an annualized rate of state transition. See Figure 2 for a full list of model parameters. Two hundred trials were performed, in which the model parameters were statistically sampled from a range of likely values, based on a triangular distribution between minimum, mode, and maximum. For each trial, the disease course for 5000 patients with SM was then simulated from initial SM diagnosis until death. Results Based on the rates of disease incidence, progression, treatment, and survival documented within various studies, we estimate the cumulative risk (± standard deviation) of disease progression from ISM to AdvSM to be 18.0% ± 3.1%, based on a probabilistic sampling of the underlying assumptions. Conclusions This study suggests that the cumulative rate of disease progression among patients with ISM may be higher than previously recognized. In our earlier work, we showed a higher rate of disease progression in ISM patients with high symptom burden (Mukherjee S, et al. ASH 2022). These data highlight the importance of close monitoring for signs of progression and warrant further research to identify subsets of ISM patients who may have a higher underlying risk of progression.

Differences in Clinical Outcomes between Hydroxyurea-Resistant and -Intolerant Polycythemia Vera Patients

Previous retrospective studies have revealed that a substantial portion of PV patients experience resistance to hydroxyurea (HU-R) and intolerance to HU (HU-I). Currently, the therapeutic options for both groups of patients do not differ, and most clinical trials investigating second-line therapies have enrolled patients with HU-R or HU-I without considering potential clinical distinctions between the two groups. Direct comparisons between patients with HU resistance and HU intolerance have not been conducted, and prognostic factors related to clinical outcomes, such as thrombosis, bleeding, disease progression, and survival, remain unclear for patients experiencing HU resistance or intolerance. A total of 90 patients with HU-R/I were retrospectively anlyzed in this study. Among them, 44 and 46 patients fulfilled the ELN criteria defining resistance or intolerance to HU, respectively. Patients with HU-R were older at the time of diagnosis of PV (66.7 ± 13.2 years, vs. 59.8 ±11.2 years in the HU-I group, P = 0.016), had longer times to developing HU-R/I, and thus, were older at the time of HU-R/I development compared with those with HU-I. The majority of the study patients continued HU treatment with dose modification or intermittent discontinuation with anagrelide added to control platelet counts until disease progression or death because of limited second-line treatment options during the observed period. The cumulative incidence of thrombosis after 7 years of HU-R/I was 21.4%, and the incidence of disease progression was 22.5%. Comparing the HU-R and HU-I groups, the HU-R group had a significantly higher rate of disease progression (36.7% vs. 0.56%, P = 0.009), while there was no significant difference in thrombosis incidence (19.0% vs. 22.9%, P = 0.463). The type of thrombosis did not differ between the two groups (P = 0.628). Multivariate analysis revealed that HU-R was an independent prognostic factor for progression-free survival (hazard ratio = 5.57, 95% CI: 1.22 - 25.54, P = 0.027). The patients in the HU-R group had significantly lower PFS (40.2% vs. 66.1% in the HU- I group, P < 0.01). They also showed a trend toward lower TFS (51.0% vs. 62.1% in the HU-I group; P = 0.055) and lower OS (57.5% vs. 67.7% in the HU-I group; P = 0.060) compared to patients with HU-I. The mortality at seven years was 42.5% in the HU-R group and 32.3% in the HU-I group (P = 0.06). Higher LDH levels, multiple cardiovascular risk factors, and prior thrombosis were identified as unfavorable predictors of overall survival. These findings suggest that HU-resistant patients have a higher risk of hematological transformation but a comparable risk of thrombosis to HU-intolerant patients. These distinctions should guide decisions on second-line treatment options and clinical trials involving these patients.

Allogeneic Transplant for CLL Richter's Transformation: Single Center Retrospective Analysis

Introduction: Richter transformation (RT) describes the emergence of an aggressive lymphoma in the setting of chronic lymphocytic leukemia (CLL). The prognosis is poor, with a median overall survival (OS) of 10 months. Treatment of RT is still challenging despite the availability of novel agents, and stem cell transplant (SCT) is commonly used as a consolidation strategy. Data on outcomes post-allogeneic-SCT for RT is limited. The OS on these reports' ranges from 41 to 75%. Methods: We conducted a retrospective study of patients diagnosed with RT at our center who underwent allogeneic SCT between 2005 and 2022. We evaluated predictors of outcome using Cox's proportional hazards regression analysis for overall and progression-free survival (PFS) and Fine and Grey regression for disease progression and non-relapse mortality (NRM). Results: 88 patients were identified, 85 had a diffuse large lymphoma histology and 3 Hodgkin's lymphoma. The median age was 61 years (range 25-74), and the majority (n=61, 69%) of patients were in complete response (CR, N=21) or partial response (PR, N=40) pre-SCT. Median follow-up among survivors was 74 months (range: 8-168); all outcomes are reported at 6 years. Overall, OS was 45% (95% CI: 34-56), and PFS 32% (95% CI: 22-43). The cumulative incidence of disease progression was 41% (95% CI: 31-53) and NRM 25% (95% CI: 17-36). In the univariate analysis, response prior to transplant was the most significant predictor of disease progression, OS, and PFS. Patients in CR/PR had a lower rate of disease progression (32% vs. 61%, HR: 0.2, 95% CI 0.2-0.6, p=0.002) and higher OS (59% vs 16%, HR: 0.3, 95% CI 0.2-0.5, p<0.001, Figure) and PFS (44% vs. 6%, HR: 0.2 (0.1-0.4), p<0.001) compared with those advanced (>CR2)or progressive disease. In addition, the presence of deletion 17p (del17p) or TP53 mutation was associated with a higher rate of disease progression (HR=3.1, 95% C 1.3 -7.3, p=0.01), but not with PFS or OS. The use of reduced intensity regimens resulted in favorable OS (HR=0.5, 95% CI 0.3-1.0, p=0.05) as compared to non-myeloablative conditioning. Age, HCT-CI score, donor type, donor-to-recipient gender, cell source, and graft-versus-host disease prophylaxis, or the presence of other cytogenetic abnormalities were not significantly associated with OS, PFS, disease progression, or NRM. There was also no advantage for any outcome when comparing individuals who achieved CR versus PR pre-SCT. The independent predictive value of CR/PR was confirmed in multivariate analysis for OS (HR=0.3, 95% CI 0.2-0.5, p<0.001) and disease progression (HR=0.4, 95% CI: 0.2-0.8, p=0.01), after adjusting for conditioning intensity for OS and deletion 17p (del17p) or TP53 mutation for disease progression. Discussion: In this single center series of patients treated with allogeneic SCT as consolidation for RT, disease status prior to SCT (CR/PR) emerged as a strong independent predictor of outcomes. The influence of tumor burden prior to SCT may be related to disease biology (e.g., patients not in CR/PR may have more aggressive RT) or may be related to decreased graft-versus-lymphoma effect. Based on our findings, we recommend that aggressive control of the disease with the goal of achieving a CR or PR should be attempted before allogeneic stem cell transplantation in patients with Richter transformation.

High BCR::ABL1 Expression Defines CD34+ Cells with Significant Alterations in Signal Transduction, Short-Proliferative Potential and Self-Renewal Ability.

Chronic Myeloid Leukemia (CML) is a clonal disorder of the hematopoietic stem cell caused by expression of the BCR::ABL1 oncoprotein. High BCR::ABL1 levels have been associated to proliferative advantage of leukemic cells, blast crisis progression and tyrosine kinase inhibitors (TKIs) inefficacy. We have previously shown that high BCR::ABL1/GUSIS transcripts measured at diagnosis are associated with inferior responses to standard dose Imatinib (IM). However, the mechanisms underlying the higher rates of disease progression and development of TKIs resistance dependent on elevated BCR::ABL1 levels remain unclear. Leukemic cells were collected from CML patients showing, at diagnosis, high or low BCR::ABL1/GUSIS. BCR::ABL1 expression levels were measured using real-time PCR. Short-term culture and long-term culture-initiating cells assays were employed to investigate the role of BCR::ABL1 gene-expression levels on proliferation, clonogenicity, signal transduction, TKIs responsiveness and self-renewal ability. Cell division was performed by carboxyfluorescein-succinimidyl ester (CFSE) assay. We found that BCR::ABL1 oncogene expression levels correlate in both PMNs and CD34+ cells. Furthermore, high oncogene levels increased both proliferation and anti-apoptotic signaling via ERK and AKT phosphorylation. Moreover, high BCR::ABL1 expression reduced the clonogenicity of leukemic CD34+ cells and increased their sensitivity to high doses IM but not to those of dasatinib. Furthermore, we observed that high BCR::ABL1 levels are associated with a reduced self-renewal of primitive leukemic cells and, also, that these cells showed comparable TKIs responsiveness with cells expressing lower BCR::ABL1 levels. Interestingly, we found a direct correlation between high BCR::ABL1 levels and reduced number of quiescent leukemic cells caused by increasing their cycling. Higher BCR::ABL1 levels improving the proliferation, anti-apoptotic signaling and reducing self-renewal properties cause an increased expansion of leukemic clone.

HIV-1 Disease Progression and Drug Resistance Mutations among Children on First-Line Antiretroviral Therapy in Ethiopia.

Background: High rates of disease progression and HIV drug resistance (HIVDR) among adults taking highly active antiretroviral treatment (HAART) in Sub-Saharan Africa were previously documented. However, children were generally not considered despite their greater risk. Hence, this study was aimed to evaluate HIV-1 disease progression and drug resistance mutation among children on first-line antiretroviral therapy in Ethiopia. Method: A longitudinal study was conducted among 551 HIV-positive children (<15 years old) recruited between 2017 and 2019 at 40 antiretroviral treatment delivery sites in Ethiopia. Disease progression was retrospectively measured over a 12-year (2007-2019) follow-up as the progress towards immunosuppression. Two consecutive viral load (VL) tests were conducted in 6-month intervals to assess virologic failure (VF). For children with VF, HIV-1 genotyping and sequencing was performed for the pol gene region using in-house assay validated at the Chinese Center for Disease Control and Prevention, and the Stanford HIVDB v9.0 algorithm was used for identification of drug resistance mutations. The Kaplan-Meier analysis and Cox proportional hazards regression model were used to estimate the rate and predictors of disease progression, respectively. Results: The disease progression rate was 6.3 per 100 person-years-observation (95% CI = 4.21-8.53). Overall immunosuppression (CD4 count < 200 cells/mm3) during the 12-year follow-up was 11.3% (95% CI = 7.5-15.1). Immunosuppression was significantly increased as of the mean duration of 10.5 (95% CI = 10.1-10.8) years (38.2%) to 67.8% at 12 years (p < 0.001). Overall, 14.5% had resistance to at least one drug, and 6.2% had multi-drug resistance. A resistance of 67.8% was observed among children with VF. Resistance to non-nucleotide reverse transcriptase inhibitors (NNRTI) and nucleotide reverse transcriptase inhibitors (NRTI) drugs were 11.4% and 10.1%, respectively. Mutations responsible for NRTI resistance were M184V (30.1%), K65R (12.1%), and D67N (5.6%). Moreover, NNRTI-associated mutations were K103N (14.8%), Y181C (11.8%), and G190A (7.7%). Children who had a history of opportunistic infection [AHR (95% CI) = 3.4 (1.8-6.2)], vitamin D < 20 ng/mL [AHR (95% CI) = 4.5 (2.1-9.9)], drug resistance [AHR (95% CI) = 2.2 (1.4-3.6)], and VF [AHR (95% CI) = 2.82 (1.21, 3.53)] had a higher hazard of disease progression; whereas, being orphan [AOR (95% CI) = 1.8 (1.2-3.1)], history of drug substitution [(AOR (95% CI) = 4.8 (2.1-6.5), hemoglobin < 12 mg/dL [AOR (95% CI) = 1.2 (1.1-2.1)] had higher odds of developing drug resistance. Conclusions: Immunosuppression was increasing over time and drug resistance was also substantially high. Enhancing routine monitoring of viral load and HIVDR and providing a vitamin-D supplement during clinical management could help improve the immunologic outcome. Limiting HAART substitution is also crucial for children taking HAART in Ethiopia.

Expression of Vascular Endothelial Growth Factor-A (VEGF-A) in Adenocarcinoma and Squamous Cell Cervical Cancer and Its Impact on Disease Progression: Single Institution Experience.

Background and Objectives: The aim of this retrospective study was to determine the difference in VEGF-A expression in adenocarcinoma and squamous cell cervical cancer and to show the influence of VEGF-A expression on clinical, pathological, and therapeutic prognostic factors on the outcome of treatment and the survival of patients. Materials and Methods: The study included patients with cervical cancer who were treated in the period from 1 January 2010 to 31 December 2021 at the Clinic for Gynecology and Obstetrics, University Hospital Centre, Osijek. The researchers conducted a retrospective analysis of data from patients' medical history, along with the pathohistological findings and oncologist findings. The study included 66 patients with cervical cancer (divided into two subgroups of 33 with adenocarcinoma or squamous cell cervical cancer). Diagnosis was based on the pathohistological status and FIGO staging. VEGF-A expression was significantly higher in adenocarcinoma. Subjects with a higher expression of VEGF-A had a significantly higher rate of disease progression and a higher possibility for lethal outcome. Results: Statistically significant prognostic factors in bivariate analysis in predicting a negative treatment outcome were: older age, greater depth of stromal invasion, FIGO IIB stage, chemotherapy, and positive lymph nodes. In the multivariate analysis, age and positive lymph nodes were shown to be significant predictors for a negative treatment outcome. Conclusions: VEGF-A has shown to be statistically more expressed in adenocarcinoma, which correlates with disease progression, but not statistically significant in multivariate regression analysis as an independent prognostic factor for poor survival of the subjects.

Clear cell sarcoma: The OSU experience.

e23554 Background: Clear cell sarcoma (CCS) is an ultra-rare translocation-driven sarcoma. Often affects young adults with no sex preponderance, and whites have a higher occurrence. Frequently present as a slow-growing mass in the extremities or trunk. The EWSR1–ATF1/CREB1 mutation is pathognomonic. The optimal treatment has not been outlined, but it is extrapolated from soft tissue sarcomas. The role of systemic therapies still needs to be fully elucidated, largely due to limited data. This is one of the largest single-institution cohorts reported. Methods: Patients evaluated at The Ohio State University James Comprehensive Cancer Center between January 1, 2010, and April 1, 2022, were included. Data collected included baseline demographic variables, pathologic and molecular features, treatment regimen, and outcomes. Due to a small cohort size, descriptive statistics were performed instead of formal power calculations. Results: A total of five patients were identified. 3 of 5 were white (60%), and 2 of 5 patients were black (40%). The mean age at diagnosis was 46 years, median at 43 years, ranging from 29 to 66 years. 3 of the 5 patients were female (60%), and 2 were male (40%). The mean size of the tumor at presentation is 5.62 cm. 2 of the 5 patients had stage 1 disease at presentation (40%), one had stage 3 (20%), and 2 had Stage 4 (40%). 3 out of 5 patients received treatment with curative intent. 4 patients had primary in the abdomen/lower back or lower extremities (80%). 4 patients received chemotherapy, and these patients received 3 to &gt; 5 cycles. 3 of the 4 on chemotherapy progressed (50%). A patient who received Sunitinib had the shortest time to progression, at 30 days (or 4.3 weeks). The patient who experienced the longest time to progression received Pazopanib, with progression occurring after 339 days (or 48 weeks). Within the early-stage patients, one of the three underwent surgery progressed (33.3%). None of the two patients that received radiation progressed (0%). 3 of 5 participants (60%) eventually expired during the study dates (2 with metastatic disease at diagnosis and 1 with localized disease). All patients received next-generation sequencing. One of these patients demonstrated positive expression levels for PD-L1. The median tumor mutation burden (TMB) value was 11.86 ranging from 2.06 to 28.16. Conclusions: We found that CCS has a high rate of disease progression despite the multimodality approach, and there is a high mortality associated with the disease. Due to the sample size of this single institution study, we cannot identify significant associations between clinical and demographic factors and treatment outcomes in clear cell sarcoma. However, these results stress the importance of multi-institutional (national and international) collaboration around ultra-rare subtypes of sarcoma to provide more significant patient data, improve outcomes, and design clinical trials for these patients.

Association between thyroid function and regorafenib efficacy in patients with relapsed wild-type IDH glioblastoma: a large multicenter study

PurposeRegorafenib demonstrated encouraging results in recurrent glioblastoma patients. Some studies showed that changes in circulating thyroid hormones (fT3, fT4, fT3/fT4 ratio) can be considered as prognostic factors in patients with various types of tumors. We designed this study to investigate the relationship between baseline thyroid variables and outcome in IDH-wild type GBM patients who were treated with regorafenib.MethodsThis multicenter retrospective study included recurrent IDH-wild-type glioblastoma patients treated with regorafenib. Only patients with baseline thyroid function values (TSH, fT3, fT4, fT3/fT4 ratio) available were evaluated. RANO criteria were used to analyze neuroradiological response. Survival curves were estimated using the Kaplan–Meier method. The relationships between baseline thyroid variables (TSH, fT3, fT4, fT3/fT4) and survival (PFS, OS) were investigated with Cox regression models.ResultsFrom November 2015 to April 2022, 134 recurrent IDH-wildtype GBM patients were treated with regorafenib and 128 of these had information on baseline thyroid function value. Median follow-up was 8 months (IQR 4.7–14.0). Objective Response Rate was 9% and Disease Control Rate was 40.9%. Median PFS was 2.7 months (95%CI 2.2–3.6) and median OS was 10.0 months (95%CI 7.0–13.0). Lower baseline TSH value in the blood was correlated with a higher rate of disease progression to regorafenib (p = 0.04). Multivariable analyses suggested a non-linear relationship between PFS (p = 0.01) and OS (p = 0.03) with baseline fT3/fT4 ratio.ConclusionIn recurrent wild-type IDH glioblastoma patients, baseline fT3/fT4 ratio showed a non-linear relationship with survival, with different impacts across the spectrum of fT3/fT4 ratio. Moreover, baseline TSH may be a predictor of regorafenib activity.

Abstract P4-03-32: Association between androgen receptor expression and recurrence free survival among locally advanced triple negative breast. Real world data from a single Institution in Mexico City

Abstract Background The androgen receptor (AR) is expressed in 12-41% of the TNBC, contributes with differentiation, proliferation, apoptosis, and angiogenesis; its expression is associated with better recurrence free survival (RFS) and overall survival (OS). Objective The aim is to determine the association between AR and pathologic complete response (PCR), recurrence free survival (RFS) in TNBC patients treated with neoadjuvant chemotherapy (neoCT). Patients and methods Cross-sectional, retrospective cohort trial. Adult women with stage II-III TNBC, treated with neoCT from 2014 to 2021 were included. Incomplete medical record, AR not-determined, secondary malignant neoplasm were excluded. AR was determined with the VENTANA assay system, &amp;gt; 1% were considered as positive. Statistical analyses included frequencies and range, comparison was done with X2, cox regression model was made for the prognostic association with a two-sided significance level of 0.05 95% CI. RFS were evaluated with Kaplan Meier method and log-rank test. Results 309 patients were analyzed; AR prevalence was 14.6%. Median age was 49 years (21-87), tumor size was 6.3 cm (0.1-22), ductal histology (95.1%) and nuclear-grade 3 (79%), these findings were not different between the AR+ vs AR-. Median Ki67 was 52% within AR+ vs 65% AR- (p=0.05). All patients were treated with neoCT, 14.9% had disease progression, PCR rates were similar among two groups (48.5% vs 42.2%) p=0.78. At a mean follow up of 19 months, 7 recurrences presented in AR+ (15.5%) vs 67 in the AR- (25.4%) p=NS. Median RFS was 54.9 (IC 95% 45.2-64-6) and 65.5 months (IC 95% 60.4-70.7), p=0.3. We analyze the prognostic factors, for RFS we found statistically significant the locally advanced stage OR 5.6 (1.4-22.9), residual cancer burden (RCB) OR 2.8 (2.1-3.9), N stage OR 1.4 (1.1-1.8) and progression during neoCT OR 2.8 (1.5-5.1); and for OS the RCB OR 2.8 (1.9-4.1) and progression during neoCT OR 3.1 (1.5-6.9). Conclusions In this trial the AR expression did not show significant association neither with PCR and RFS; main reasons are the low prevalence of AR expression, high rate of disease progression and high residual cancer burden after neoCT. We found association with other known factors (RCB, N stage, progression during neoCT and locally advanced stage), which are more important factors that determine the bad prognosis of TNBC. Citation Format: Eder Araiza Alvarado, Claudia Haydee Arce Salinas. Association between androgen receptor expression and recurrence free survival among locally advanced triple negative breast. Real world data from a single Institution in Mexico City [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-32.

Responses to first-line systemic therapies in patients with hepatocellular carcinoma with TERT promoter mutations.

589 Background: The treatment landscape of advanced hepatocellular carcinoma (HCC) has made significant advances with the use of oral multikinase inhibitors and immunotherapy-containing regimens. However, there is minimal data with regards to which biomarkers may predict treatment responses in this population. The increased use of next-generation sequencing (NGS) has identified the most frequent mutations in HCC, including TERT promoter mutations which are found in up to 65% of patients. With the high frequency of these mutations, additional studies are needed to investigate their associations with treatment outcomes. Methods: Our team performed a retrospective study to determine the association between TERT promoter mutations in HCC and responses to first-line systemic therapies. All patients in this study underwent NGS testing on tumor tissue or peripheral blood samples. Responses to treatment were determined by imaging at least 6 weeks after the start of systemic therapy. Results: There were 128 HCC patients included in this study with TERT promoter mutations found in 72 patients (56.3%). All patients received first-line therapy with either an immunotherapy-based regimen or oral multikinase inhibitor monotherapy (lenvatinib or sorafenib). When looking at responses to all first-line therapies, patients with TERT promoter mutations were found to have significantly higher rates of disease progression (PD) compared to those without TERT promoter mutations (34.7% vs 17.9%, p = 0.04). In addition, when stratifying responses by type of systemic therapy, the TERT promoter-mutated population had notably higher rates of PD with immunotherapy regimens compared to patients without TERT mutations (34.6% vs 10.8%, p = 0.01). In contrast, there was no significant difference in rates of PD with oral multikinase inhibitor monotherapy between TERT mutated and TERT non-mutated individuals (35% vs 31.6%, p = 1). See table for further details. Conclusions: In this study, HCC patients with TERT promoter mutations were found to have significantly higher rates of PD to first-line therapies and, specifically, immunotherapy-containing regimens. Given the prevalence of these mutations in the HCC population, further investigation is needed to clarify this association and its impact on patient survival.[Table: see text]

Cytomorphology and immunocytochemical features of ovarian granulosa cell tumors in ascites or peritoneal washings: A retrospective review.

To summarize the cytomorphology and immunocytochemistry features of OGCT in ascites or peritoneal washings. All cases of histology sections, cytology smears, cell block slides and immunohistochemical staining were reviewed. A panel of immunohistochemistry antibodies consisting of Inhibin, Calretinin, BerEP4 and MC was performed for diagnosis and differential diagnosis. Seven positive cases (21.2%) in ascites and peritoneal washings were identified in 33 patients with OGCT, which is higher than early studies with positive rate of 7.4%. Clinicopathologic features including tumor size and the incidence of endometrial atypical hyperplasia or carcinoma (EAH/EC) displayed no statistical difference between groups with positive and negative cytology. Immunocytochemical results usually showed typical staining pattern with α-inhibin, calretinin positive and BerEP4, MC negative. Features of granulosa cells, including nuclear hyperplasia and overlapping, can be observed in all seven positive cases. Nuclear grooves or small conspicuous nucleoli were occasionally observed in the smear. However, features of cell clusters mimicking Call-Exner bodies, cytoplasmic vacuoles or single cell necrosis were not found on smear. Call-Exner bodies and mitosis can only be found on cell blocks. All cases of follow-up information were available and three cases displayed progression and there was a statistical difference between groups with positive and negative cytology. OGCT with positive cytology in ascites and peritoneal washings tend to have a larger tumor size and higher rates of disease progression. A panel of complementary biomarkers can greatly increase the detection rate and help in differential diagnosis in ascites or peritoneal washings of OGCT.

Addition of Chromosome 17 Polysomy and HER2 Amplification Status Improves the Accuracy of Clinicopathological Factor-Based Progression Risk Stratification and Tumor Grading of Non-Muscle-Invasive Bladder Cancer.

Simple SummaryThe addition of chromosome 17 polysomy/HER2 amplification status to the updated EAU and AUA scores improves their accuracy, allowing molecular reclassification of EAU high-risk NMIBCs and G2 tumors. Based on this, we propose to reclassify the non-HER2 amplified, non-polysomic EAU 3–4 (high- and very high-risk) cases to the EAU 2 (intermediate) risk group to prevent unnecessarily strict follow-up and treatment for these patients. Furthermore, to classify Chr17 polysomic and/or HER2 amplified G2 tumors as high-grade (HG) and non-HER2 amplified, non-polysomic G2 tumors as low-grade (LG) NMIBCs (G1 and G3 tumors remain graded as low- and high-grade, respectively). Thus, the implementation of Chr17 polysomy/HER2 amplification testing would provide an immediate and simple solution to further refine the prognostic risk assessment of NMIBCs in the uro-oncology practice.Progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive disease (MIBC) significantly worsens life expectancy. Its risk can be assessed by clinicopathological factors according to international guidelines. However, additional molecular markers are needed to refine and improve the prediction. Therefore, in the present study, we aimed to predict the progression of NMIBCs to MIBC by assessing p53 expression, polysomy of chromosome 17 (Chr17) and HER2 status in the tissue specimens of the tumors of 90 NMIBC patients. Median follow-up was 77 months (range 2–158). Patients with Chr17 polysomy or HER2 gene amplification had a higher rate of disease progression (hazard ratio: 7.44; p < 0.001 and 4.04; p = 0.033, respectively; univariate Cox regression). Multivariable Cox regression models demonstrated that the addition of either Chr17 polysomy or HER2 gene amplification status to the European Association of Urology (EAU) progression risk score increases the c-index (from 0.741/EAU/ to 0.793 and 0.755, respectively), indicating that Chr17 polysomy/HER2 amplification status information improves the accuracy of the EAU risk table in predicting disease progression. HER2/Chr17 in situ hybridization can be used to select non-progressive cases not requiring strict follow-up, by reclassifying non-HER2-amplified, non-polysomic NMIBCs from the high- and very high-risk groups of EAU to the intermediate-risk group.