Adverse Features Research Articles

Retrospective Self-Reported Childhood Experiences in Enriched Environments Uniquely Predict Prosocial Behavior and Personality Traits in Adulthood.

What features of people's childhood environments go on to shape their prosocial behavior during adulthood? Past studies linking childhood environment to adult prosocial behavior have focused primarily on adverse features, thereby neglecting the possible influence of exposure to enriched environments (e.g., access to material resources, experiences with rich cooperative relationships, and interactions with morally exemplary role models). Here, we expand the investigation of childhood environmental quality to include consideration of enriching childhood experiences and their relation to adult prosociality. In two cross-sectional studies, we found promising evidence that enriched childhood environments are associated with adult moral behavior. In study 1 (N = 1,084 MTurk workers), we adapted an existing measure of enriched childhood environmental quality for retrospective recall of childhood experiences and found that subjects' recollections of their enriched childhood experiences are distinct from their recollections of adverse childhood experiences. In Study 2 (N = 2,208 MTurk workers), we found that a formative composite of subjects' recollections of enriched childhood experiences is positively associated with a variety of morally relevant traits in adulthood, including agreeableness, honesty-humility, altruism, endorsement of the principle of care, empathic responding to the plights of needy others, and charitable donations in an experimental setting, and that these associations held after controlling for childhood environmental adversity, childhood socioeconomic status, sex, and age. We also found evidence suggesting that some, but not all, of the relationship between enrichment and adult prosociality can be explained by a shared genetic correlation. We include a new seven-item measure as an appendix.

Cardiovascular complications of Cushings syndrome: Impact on morbidity and mortality.

Cardiovascular complications of Cushings syndrome: Impact on morbidity and mortality.

Prognostic significance of A-kinase interacting protein 1 expression in various cancers: A meta-analysis based on the Chinese population.

Background:Cumulative evidence suggests that A-kinase interacting protein 1 (AKIP1) plays an important role in tumor progression. However, the prognostic value of AKIP1 expression in various cancers remains unclear. Here, we conducted a meta-analysis to evaluate the prognostic value of AKIP1 expression in patients with cancer.Methods:The PubMed, Web of Science, EMBASE, CNKI, and Wanfang databases were systematically searched to identify studies in which the effect of AKIP1 expression on prognosis (overall survival or disease-free survival) was investigated. Hazard ratios (HRs) with 95% confidence intervals (CIs) were combined to assess the effect of AKIP1 expression on patient survival. Odds ratios (ORs) with 95% CIs were pooled to estimate the association between AKIP1 expression and clinicopathological characteristics of patients with cancer.Results:Nineteen eligible studies, encompassing 3979 patients, were included in the meta-analysis. AKIP1 expression was negatively associated with overall survival (HR = 1.86, 95% CI: 1.58–2.18, P < .001) and disease-free survival (HR = 1.69, 95% CI: 1.53–1.87, P < .001) in patients with cancer. Moreover, AKIP1 overexpression was positively correlated with adverse clinicopathological features, such as tumor size (OR = 2.22, 95% CI: 1.67–2.94, P < .001), clinical stage (OR = 2.05, 95% CI: 1.45–2.90, P < .001), depth of tumor invasion (OR = 2.98, 95% CI: 2.21–4.02, P < .001), and degree of lymph node metastasis (OR = 2.12, 95% CI: 1.75–2.57, P < .001).Conclusions:High AKIP1 expression is an unfavorable prognostic biomarker and may serve as a potential therapeutic target in patients with cancer.

S146: VENETOCLAX IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA WITH 17P DELETION: 6-YEAR FOLLOW-UP AND GENOMIC ANALYSES IN A PIVOTAL PHASE 2 TRIAL

Background: Patients (pts) with chronic lymphocytic leukemia (CLL) with del(17p) and/or mutated TP53 have adverse prognosis and are a population of interest for improving outcomes. In a pivotal Phase 2 study (NCT01889186) evaluating venetoclax (Ven; a selective oral BCL2 inhibitor) monotherapy in del(17p) CLL (N=158), overall response rate (ORR) was 77% (median time on study, 26.6 mo; Stilgenbauer. J Clin Oncol. 2018;17:1973). Aims: To report final analyses after 5 y from last pt enrolled, including post-hoc subgroup analyses of prognostic markers. Methods: Adults with R/R or previously untreated del(17p) CLL received Ven 400 mg (via ramp-up) orally daily until progressive disease (PD) or intolerance. Main cohort comprised pts with R/R CLL; safety expansion cohort included pts with R/R or untreated CLL. Primary endpoints were ORR (main) and safety (safety expansion). Peripheral blood (PB) and bone marrow (BM) were analyzed pre-Ven for somatic mutations via targeted next-generation sequencing (NGS). Minimal residual disease (MRD) was assessed by flow cytometry, ASO-PCR, and/or clonoSEQ NGS; undetectable MRD (uMRD) is reported at <10−4. Results: In all, 158 pts received Ven (main, n=107; safety expansion, n=51). Data cutoff was 15 December 2020. Pts had median 2 (range, 0−10) prior lines of therapy (LOT); 5 had untreated CLL (first-line [1L]). Common mutations (n/N) were TP53 (113/138 [82%]; 35/113 [31%] had >1), SF3B1 (28/137 [20%]) NOTCH1 (22/137 [16%]), ATM (11/120 [9%]), and BIRC3 (6/120 [5%]); 93/115 (81%) had unmutated IGHV and 118/158 (75%) had ≥20% del(17p). Median time on Ven was 27.4 (range, 0–79.3) mo. At study close, 77 pts were alive; 26 remained on Ven. No new safety signals were observed. With 70 mo median follow-up (f/u), investigator-assessed ORR was 77% (95% CI, 70−84); 21% achieved complete remission (CR)/CR with incomplete blood count recovery (CRi). Median duration of response was 39.3 mo (95% CI, 31.1−50.5); 28% had ongoing response at 60 mo. Of 61 evaluable pts with a PB MRD assessment, 25% had uMRD at ~2 y (24−30 mo). Median progression-free survival (mPFS) was 28.2 mo (95% CI, 23.4−37.6; Figure). Median overall survival (mOS) was 62.5 mo (95% CI, 51.7−NR; 5-y PFS and OS rates, 24% and 52%). Of 5 1L pts, 4 were alive and progression-free. In pts with CR/CRi (n=37), mPFS was 62.2 mo (95% CI, 53.1−NR); in pts with partial remission (PR)/nodular PR (n=85), mPFS was 27.6 mo (95% CI, 22.8−38.0). Overall, 98/158 (62%) pts had PD, including 24/158 (15%) with Richter transformation. Of pts with PD (n=98) or whose disease was refractory to Ven (n=11), 73 received another LOT, most commonly ibrutinib (n=41); mOS from ibrutinib initiation was 28.0 mo. In pts with both del(17p) and TP53 mutation (n=111) vs those with either (n=19), ORR was 75% vs 79%; mPFS was 27.4 vs 22.8 mo (P=.8). In pts with mutated (n=22) vs unmutated IGHV (n=93), mPFS was 40.4 vs 26.9 mo (P=.11). No significant difference in ORR, PFS, or OS was observed in pts with vs without ≥20% del(17p), >1 TP53 mutation, NOTCH1, ATM, or BIRC3 mutations; mPFS was shorter in pts with mutated SF3B1 (n=28) vs without (n=109; 16.4 vs 30.2 mo [P=.0071]). Multivariate analysis is ongoing. Image:Summary/Conclusion: At end of study (median f/u, 70 mo), 48% of pts were alive, 24% were progression-free, and 16% remained on Ven, confirming the long-term activity of Ven in this high-risk population with del(17p) CLL and median 2 prior LOT. Except SF3B1 mutation, other adverse features (eg, >1 TP53 mutation, NOTCH1 mutations, unmutated IGHV) did not influence outcomes with Ven treatment in this cohort.

P508: REAL LIFE EXPERIENCE USING FRONT-LINE CPX-351 FOR THERAPY-RELATED AND AML-MRC: RESULTS FROM THE SPANISH PETHEMA REGISTRY.

Background: Acute Myeloid Leukemias arising after cytotoxic therapy (t-AML) or with myelodysplasia-related changes (AML-MRC) share adverse risk features and poor outcomes after standard 3 + 7 chemotherapy. In a randomized clinical trial, CPX-351 has shown superior overall survival (OS) compared to standard anthracycline-cytarabine schedule in these AML subtypes. Aims: to evaluate the effectiveness of CPX-351 treatment in a real-world setting. Methods: adult t-AML and AML-MRC patients who have been treated upfront with CPX-351 in 35 Spanish centers between 2018 and 2021. All patients were included in the PETHEMA registry (NCT02606825). Primary end-point was OS. Secondary end points were complete remission with or without hematological recovery (CR/CRi), proportion of minimal residual negativity (MRD), rate of allogeneic hematopoietic stem cell transplant (HSCT) and safety. Results: CPX-351 was administered to 74 patients as first induction chemotherapy. Median age was 67 (63-71) years, with 40% (30/74) of female patients. ECOG performance status score was 0-1 in 85% (53/62) patients. A diagnosis of t-AML was present in 30% (22/74) patients. Hypomethylating agents were used for MDS or CMML phase in 15%. Hematopoietic Transplant Comorbidity Index was low, intermediate and high in 14% (10/74), 43% (32/74) and 43% (32/74) patients. ELN17 risk classification was favourable, intermediate, adverse and indeterminate in 9% (7/74), 38% (28/74), 46% (34/74) and 5% (4/74). CR/CRi was obtained in 43% (32/74) patients after first cycle with CPX-351. Three additional patients achieved Morphological Leukemia Free Status. A second induction with CPX-351 was administered in 5 patients with 100% CR (CR/CRi after 2 cycles 37/74, 50%). MRD was evaluated in 97% (36/37) of CR/CRi patients, being low (<0.1%) in 47% (17/36) of them. In univariate analysis, no factor was associated with response. However, 71% (5/7) response rate was observed in the favourable ELN17 genetic risk group compared to 48% (32/67) in the non-favourable. HSCT was performed in 27% (20/74) patients, in 1st CR/CRi in 70% (14/20), MLFS in 15% (3/20) and active disease in 10% (2/20). With median follow up of 11.9 months (7.2-23.6) from HSCT, median OS was not reached (95% CI 9.5-NR months (Figure). In univariate analysis no factors were significantly associated with OS after HSCT. Median time to absolute neutrophil count ≥0.5 x109/L and platelets ≥50 x109/L were 30.5 (25-35) and 30 (26-39) days, respectively. Deaths within the first 30 days after induction occurred in 12% (9/74) patients. Causes of early death: infection in 5 patients, haemorrhage in 3 and respiratory failure in 1. With 6.1 (1.8-14) months of median follow up, median OS was 10.5 (6.9-NR) months, with significant differences between HSCT and non-HSCT patients [NR, (95% CI: 12.7-NR), vs. 6 months, (95% CI: 4-NR), P<0.001]. In univariate analysis, factors associated with lower OS were non-favourable ELN17 [8.9 vs 23.5, P=0.04]; ECOG≥2 [0.7 vs 12., P=0.002]; age ≥65 [7.9 vs NR, P=0.007] and male [6.6 vs NR, P= 0.007]. In multivariate analysis, age above 65 years [HR 1.6, P<0.001], male [HR -0.9, P=0.02] and ECOG≥2 [HR 1.9, P<0.001] were associated with OS. Image:Summary/Conclusion: Our real-life cohort was comparable to the target population of the pivotal trial including patients diagnosed with sAML (t-AML, AML-MRC and ELN17 high risk AML), obtaining similar outcomes than the CPX-351 phase 3 trial arm. To optimize treatment outcomes CPX-351 should be preferably offered to t-AML and AML-MRC patients who are suitable for HSCT.

P1270: IMMUNE REGULATORY CELLS IN B-CELL LYMPHOMAS: SIGNIFICANT HETEROGENEITY ACROSS HISTOLOGIC TYPES.

Background: Immune regulatory cell populations play a fundamental role in tumor development and tumor immune evasion. Myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) considered as dominant suppressor cells which are significantly enriched in blood, bone marrow (BM), or tumor sites of patients with hematologic malignancies and often associate with high tumor burden, adverse clinical features, and outcome. Studies in lymphoma patients however, have generated conflicting results, regarding the function and phenotype of MDSC and Tregs mainly due to large heterogeneity of the disease as well as due to the lack of a unanimous nomenclature of these cell subsets in human samples. Furthermore, the molecular mechanisms via which MDSCs and Tregs contribute to clinical outcomes of disease and how they interfere with response to therapy remain elusive. Aims: To investigate the prevalence of immune suppressive population in B-cell lymphomas according to histologic, subtype providing the basis for further analysis of their biologic properties and association with clinical features and outcome of specific lymphoma subtypes. Methods: Peripheral blood (PB) and BM samples were collected from healthy individuals (n= 22) and lymphoma patients (n=50). Specifically, lymphoma subtypes were as follows:Marginal Zone (MZL, N=19), Diffuse Large B-cell Lymphoma (DLBCL, N=18) and Follicular Lymphoma (FL, N=13). Peripheral blood mononuclear cells (PBMCs) were isolated with ficoll gradient and subjected to flow cytometry analysis. MDSC characterization was based on HLADR-/lowCD11b+CD33- expression with CD14+CD15- for M-MDSCs and CD14-CD15+ for PMN-MDSCs. In addition, Treg cells were denoted as CD4+CD25highCD127-Foxp3+. Expression of PDL1 and PD1 on MDSCs and Tregs respectively, was also determined by flow cytometry. M-MDSCs and PMN-MDSCs were sorted from BM samples, RNA was extracted in order to subjected to transcriptomic analysis (RNAseq). Informed consent was obtained. Results: Frequencies of MDSCs were significantly increased in PB of all lymphoma patients compared to healthy individuals, with MZL subtype exhibiting the most prominent increase of MDSCs (p<.0001). Notably numbers of M-MDSCs were increased in FL and MZL patients and to a lesser extend in DLBCL patients while PMN-MDSCs were elevated in all subtypes with MZL displaying the higher frequencies. Regarding the Treg cells, although all lymphoma patients exhibited increased absolute numbers of CD4+CD25highCD127- Treg cells, Foxp3-expressing Tregs were significantly increased in the PB of DLBCL and MZL patients, but not in FL patients. Of interest, CD4+ and CD8+ T cells in the PB of DLBCL patients exhibited increase expression of PD1 compared to respective cell subsets from healthy individuals. Summary/Conclusion: Our findings comprehensively demonstrate enhanced numbers of MDSC and Treg immune suppressive cells in the PB of B-cell lymphoma patients while an increased heterogeneity was observed among the different histological lymphoma types. Functional characterization of MDSCs and Tregs by transcriptomic (RNAseq) and proteomic analysis are ongoing.

Effect of E-cadherin on Prognosis of Colorectal Cancer: A Meta-Analysis Update.

The effect of E-cadherin on colorectal cancer is still controversial. In order to clarify the effect of E-cadherin on the prognosis and clinicopathological features of colorectal cancer, a meta-analysis was conducted. PubMed, Embase and Cochrane Library were used to collect all relevant literature published before November 2021, and the corresponding data was extracted to analyze the correlation between the expression of E-cadherin and the prognosis and clinicopathological features of colorectal cancer. In addition, the Gene Expression Profiling Interactive Analysis (GEPIA) was used to validate our results. Fifty-two studies, including 9591 patients, were included in this meta-analysis. According to the meta-analysis, low expression of E-cadherin was significantly associated with shorter overall survival (OS) (hazard ratio [HR] 2.09, 95% confidence interval [CI]1.67-2.62; Z=6.42, p=0.000) and disease-free survival (DFS) (HR 2.03, 95%CI 1.71-2.42; Z=7.95, p=0.000). In addition, low expression of E-cadherin resulted in higher risk of low differentiation (odds ratio [OR] 0.35, 95% CI 0.25-0.50; p=0.000), high risk of distant metastasis (OR 0.45, 95% CI 0.35-0.58; p=0.000), high risk of vascular invasion (OR 0.61, 95% CI 0.45-0.83; p=0.002), higher risk of lymph node metastasis (OR 0.54, 95% CI 0.42-0.69; p=0.000), high risk of lymphatic invasion (OR 0.56, 95% CI 0.40-0.80; p=0.001), high risk of deep infiltration (OR 0.63, 95% CI 0.50-0.80; p=0.000), later TNM stage (OR 0.60, 95% CI 0.46-0.78; p=0.000) and late Dukes' stage (OR 0.35,95% CI 0.25-0.49; p=0.000), but wasn't associated with tumor size (OR 0.90, 95% CI 0.71-1.15; p=0.406).The results of GEPIA showed that E-cadherin mRNA expression in colorectal cancer tumor tissues and normal tissues had no difference, and had no effect on OS and DFS. Although not supported by GEPIA, our meta-analysis provided abundant data to suggest that low expression of E-cadherin is associated with poor prognosis in colorectal cancer patients and is an important factor influencing adverse clinicopathological features. Therefore, E-cadherin may be used to predict the prognosis of colorectal cancer and provide guidance for clinical treatment.

Clinical outcomes of multifocal papillary thyroid cancer: A systematic review and meta-analysis.

ObjectivePapillary thyroid cancer (PTC) is the most common endocrine malignancy with a steadily increasing incidence. Researches have reported that tumor multifocality occurs in an extensive number of cases. Nevertheless, the clinical characteristics and prognostic value remained controversial. This study was performed to investigate the relationship between multifocal PTC and adverse clinicopathologic features and the prognosis.MethodsA systematic review and meta‐analysis were conducted based on three electronic databases up to December 31, 2021. Parameters of interest included five clinical features (extrathyroidal extension, lymphovascular invasion, central lymph node metastasis, lateral lymph node metastasis, distant metastasis) and were pooled into risk ratios (RRs). Time‐to‐event data (recurrence‐free survival and all‐cause mortality) were evaluated using hazard ratios (HRs). Publication bias was examined using funnel plots and Egger's test.ResultsA total of 23 articles were included according to the inclusion criteria; all of the studies were retrospective cohorts. In comparison with unifocality, multifocality showed an increased risk of extrathyroidal extension (RR 1.38, 95% CI 1.25–1.53), lymphovascular invasion (RR 1.27, 95% CI 1.04–1.55), central lymph node metastasis (RR 1.21, 95% CI 1.12–1.30), lateral lymph node metastasis (RR 1.86, 95% CI 1.62–2.14), and distant metastasis (RR 1.35, 95% CI 1.03–1.76). Multifocal patients were predisposed to postoperative recurrence (HR 1.76, 95% CI 1.50–2.07). The rate of all‐cause mortality did not reach a statistical difference.Level of Evidence2.ConclusionMultifocal PTC is more aggressive in contrast to unifocal PTC and is accompanied by an increased risk of recurrence. They were usually diagnosed in higher grades and stages. To achieve the maximal benefit, we recommend personalized therapy and close follow‐up for multifocal PTC patients. Further prospective studies will clarify the best‐fitted treatment plans.

NTRK -Rearranged Uterine Sarcomas: Clinicopathologic Features of 15 Cases, Literature Review, and Risk Stratification.

NTRK -rearranged uterine sarcomas are rare spindle cell neoplasms that typically arise in the uterine cervix of young women. Some tumors recur or metastasize, but features which predict behavior have not been identified to date. Distinguishing these tumors from morphologic mimics is significant because patients with advanced stage disease may be treated with TRK inhibitors. Herein, we present 15 cases of NTRK- rearranged uterine sarcomas, the largest series to date. Median patient age was 35 years (range: 16 to 61). The majority arose in the uterine cervix (n=14) and all but 2 were organ-confined at diagnosis. Tumors were composed of an infiltrative, fascicular proliferation of spindle cells and most showed mild-to-moderate cytologic atypia. All were pan-TRK positive by immunohistochemistry (13/13); S100 (11/13) and CD34 (6/10) were usually positive. RNA or DNA sequencing found NTRK1 (10/13) and NTRK3 (3/13) fusions with partners TPR , TPM3 , EML4 , TFG , SPECC1L , C16orf72 , and IRF2BP2 . Unusual morphology was seen in 2 tumors which were originally diagnosed as unclassifiable uterine sarcomas, 1 of which also harbored TP53 mutations. Follow up was available for 9 patients, of whom 3 died of disease. By incorporating outcome data of previously reported tumors, adverse prognostic features were identified, including a mitotic index ≥8 per 10 high-power fields, lymphovascular invasion, necrosis, and NTRK3 fusion. Patients with tumors which lacked any of these 4 features had an excellent prognosis. This study expands the morphologic spectrum of NTRK -rearranged uterine sarcomas and identifies features which can be used for risk stratification.

The impact of interval between surgery and postoperative radiotherapy in major salivary gland carcinoma

BackgroundRadiotherapy following primary operation is strongly recommended for salivary gland carcinomas (SGCs) with adverse features. The interval between surgery and the initiation of radiotherapy (SRT) varied and a prolonged SRT may cause failure of cancer treatment. However, the association of SRT with survival is unclear in major SGCs. MethodsThis retrospective study included a total of 346 patients who underwent radiotherapy after the primary operation from Fudan University Shanghai Cancer Center from 2005 to 2020. The best cutoff value of the SRT was determined by the maximum log-rank statistic method. The primary endpoint of the study was overall survival (OS). Correlations between variables and OS were conducted by the univariable analysis using the Log-rank method, and a multivariate Cox proportional hazards regression was performed to identify the independent prognostic factors associated with OS. The estimated survival rates were captured using the Kaplan-Meier method. ResultsWith a median follow-up time of 70.31 months, the estimated 5-year OS, LRFS, and DMFS were 83.3%, 80.1%, and 75.9%, respectively. The cutoff value for SRT was 8.5 weeks, while age, T stage, N stage, perineural invasion (PNI), pathological aggression, chemotherapy, and SRT were associated with OS in the univariable analysis. The Cox regression analysis demonstrated that older age (P < 0.001), T3-4 tumors (P = 0.007), positive N stage (P < 0.001), pathological aggression (P = 0.014), and longer SRT (P = 0.009) were independent prognostic factors for major SGCs. Using the stratification model, we observed that delay in the SRT was associated with worse OS (P = 0.006) in the high-risk group, whereas no significant difference was observed in the low-risk subgroup (P = 0.61). ConclusionsThe delay in the initiation of postoperative radiotherapy may be a prognostic factor for patients with major SGCs. It was suggested that radiotherapy should be delivered within 8.5 weeks following the operation, especially for patients with ≥2 risk factors, including older age, high pathological aggression, T3-4 tumors, and positive N stage.

Characterizing the longitudinal course of symptoms and functioning in bipolar disorder.

The course of Bipolar Disorder (BD) is highly variable, with marked inter and intra-individual differences in symptoms and functioning. In this study, we identified illness trajectories across major clinical domains that could have etiological, prognostic, and therapeutic relevance. Using the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, we performed univariate and multivariate trajectory modeling of depressive symptoms, manic symptoms, and psychosocial functioning. Multinomial regression was performed to identify baseline variables associated with poor outcome trajectories. Depressive symptoms predominated, with most subjects being found in trajectories characterized by various degrees of depressive symptoms and 13% of subjects being classified in a poor outcome 'persistently depressed' trajectory. Most subjects experienced few manic symptoms, although approximately 10% of subjects followed a trajectory of persistently manic symptoms. Trajectory analysis of psychosocial functioning showed impairment in most of the sample, with little improvement during follow up. Multi-trajectory analyses highlighted significant impairment in subjects with persistently mixed and persistently depressed trajectories of illness. In general, poor outcome trajectories were marked by lower educational attainment, higher unemployment and disability, and a greater likelihood of adverse clinical features (rapid cycling and suicide attempts) and comorbid diagnoses (anxiety disorders, PTSD, and substance abuse/dependence disorders). Subjects with BD can be classified into several trajectories of clinically relevant domains that are prognostically relevant and show differing degrees of associations with a broad range of negative clinical risk factors. The highest level of psychosocial disability was found in subjects with chronic mixed and depressive symptoms, who show limited improvement despite guideline-based treatment.

Impact of radiotherapy on the immune landscape in oesophageal adenocarcinoma.

BACKGROUNDIn the contemporary era of cancer immunotherapy, an abundance of clinical and translational studies have reported radiotherapy (RT) and immunotherapies as a viable option for immunomodulation of many cancer subtypes, with many related clinical trials ongoing. In locally advanced disease, chemotherapy or chemoradiotherapy followed by surgical excision of the tumour remain the principal treatment strategy in oesophageal adenocarcinoma (OAC), however, the use of the host immune system to improve anti-tumour immunity is rapidly garnering increased support in the curative setting.AIMTo immunophenotype OAC patients’ immune checkpoint (IC) expression with and without radiation and evaluate the effects of checkpoint blockade on cell viability.METHODSIn the contemporary era of cancer immunotherapy, an abundance of studies have demonstrated that combination RT and IC inhibitors (ICIs) are effective in the immunomodulation of many cancer subtypes, with many related clinical trials ongoing. Although surgical excision and elimination of tumour cells by chemotherapy or chemoradiotherapy remains the gold standard approach in OAC, the propagation of anti-tumour immune responses is rapidly garnering increased support in the curative setting. The aim of this body of work was to immunophenotype OAC patients’ IC expression with and without radiation and to establish the impact of checkpoint blockade on cell viability. This study was a hybrid combination of in vitro and ex vivo models. Quantification of serum immune proteins was performed by enzyme-linked immunosorbent assay. Flow cytometry staining was performed to evaluate IC expression for in vitro OAC cell lines and ex vivo OAC biopsies. Cell viability in the presence of radiation with and without IC blockade was assessed by a cell counting kit-8 assay.RESULTSWe identified that conventional dosing and hypofractionated approaches resulted in increased IC expression (PD-1, PD-L1, TIM3, TIGIT) in vitro and ex vivo in OAC. There were two distinct subcohorts with one demonstrating significant upregulation of ICs and the contrary in the other cohort. Increasing IC expression post RT was associated with a more aggressive tumour phenotype and adverse features of tumour biology. The use of anti-PD-1 and anti-PD-L1 immunotherapies in combination with radiation resulted in a significant and synergistic reduction in viability of both radiosensitive and radioresistant OAC cells in vitro. Interleukin-21 (IL-21) and IL-31 significantly increased, with a concomitant reduction in IL-23 as a consequence of 4 Gray radiation. Similarly, radiation induced an anti-angiogenic tumour milieu with reduced expression of vascular endothelial growth factor-A, basic fibroblast growth factor, Flt-1 and placental growth factor.CONCLUSIONThe findings of the current study demonstrate synergistic potential for the use of ICIs and ionising radiation to potentiate established anti-tumour responses in the neoadjuvant setting and is of particular interest in those with advanced disease, adverse features of tumour biology and poor treatment responses to conventional therapies.

Management of neuroendocrine tumors of the rectum

Rectal neuroendocrine tumors (NETs) have increased in prevalence due to increased detection via endoscopic screening for colorectal neoplasia, advances and availability of imaging tools along with the indolent nature of the tumor. Imaging techniques to identify rectal NETs include computed tomography, magnetic resonance imaging, and endoscopic rectal ultrasound. Rectal NETs are typically categorized by tumor size to determine if they should undergo endoscopic resection, local excision or transanal excision, or a radical resection, as per National Comprehensive Cancer Network guidelines. However, while examining the literature, multiple studies have examined outcomes for patients who did not adhere to these guidelines and had similar recurrence rates and survival as those patients who did. Therefore, we propose less aggressive treatment for rectal NETs in the absence of adverse features.

Elevated IsoPSA Selects for Clinically Significant Prostate Cancer Without a Preference for Any Particular Adverse Histopathologic or Radiographic Feature

OBJECTIVETo explore if elevated IsoPSA selects for particular adverse radiographic or histopathologic features among men destined to undergo radical prostatectomy (RP) because of clinically significant prostate cancer identified at biopsy. MATERIALS AND METHODSSingle center, retrospective review of patients who had undergone IsoPSA testing, prostate biopsy and RP at our institution from 2019-2021. A consecutive cohort of patients whom had undergone RP within the same period without pre-operative IsoPSA served as controls. Pre-operative prostate Magnetic Resonance Imaging (MRI) was included in our analysis. Adverse histopathologic and MRI features were compared between both groups. Concordance, downstaging, and upstaging grade group rates (GG) was evaluated. Pearson Chi-Square test was used to compare categorical variables, Wilcoxon-Rank sum test for quantitative variables, and binary logistic regression to identify predictors of upstaging at RP. RESULTSEighty-three patients underwent IsoPSA and RP while 44 patients were controls. The IsoPSA group had significantly higher pre-operative PSA (IsoPSA group: 7.8 ng/mL vs Control group: 5.2 ng/mL, P<.001 ). Elevated IsoPSA index (>6.0) did not select for any specific adverse histopathologic features at RP. Excluding PSA density, elevated IsoPSA was not selective for adverse MRI features. There were no differences in concordance, downstaging, and upstaging GG rates from biopsy to RP. IsoPSA testing was not a predictor of GG upstaging (Odds Ratio: 0.63, P .58). CONCLUSIONElevated IsoPSA is a diagnostic tool that can detect clinically significant prostate at the time of biopsy. In doing so, it does not select for any particular adverse prostate MRI or pathologic feature at RP.

A pilot study of neoadjuvant cemiplimab with platinum-doublet chemotherapy and cetuximab in patients with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC).

TPS6109 Background: Definitive treatment of locally advanced HNSCC can require radical surgery and reconstruction often resulting in unacceptable functional consequences. Radiotherapy, often with concurrent chemotherapy, is administered postoperatively to achieve the best chance for cure. Induction chemotherapy has previously been shown to reduce the extent of surgical resection and need for adjuvant radiation (RT). The purpose of this trial is to evaluate if an induction regimen combining cytotoxic chemotherapy, EGFR targeting, and immune checkpoint blockade can pathologically downstage resectable HNSCC sufficiently to decrease surgical morbidity and justify omission of adjuvant RT-based therapy. Compared to standard docetaxel, cisplatin, and 5-FU (TPF), docetaxel, cisplatin, and cetuximab (TPC) has been shown to be a therapeutic alternative with a more favorable toxicity profile. Targeting PD-1 alone can induce significant pathologic responses in resectable HNSCC patients. Combining PD-1 inhibitors with cetuximab has shown promising activity in incurable HNSCC; cetuximab may optimize the tumor immune microenvionment for PD-1 therapy by stimulating IFN-gamma secretion to increase dendritic cell maturation and CD8 T cell expression of PD1. Based on this rationale, we are evaluating the novel induction regimen of platinum, docetaxel, cetuximab plus cemiplimab (anti-PD1 antibody). Methods: This is a 10-patient pilot study for locally advanced, resectable HNSCC patients for whom standard management requires adjuvant RT +/- chemotherapy. Patients will receive neoadjuvant treatment with a loading dose of cetuximab and cemiplimab followed by 3 cycles of cisplatin or carboplatin, docetaxel, cetuximab and cemiplimab followed by definitive surgical resection of the primary site +/- neck dissection(s). Post-operative RT +/- radiosensitizing agent(s) will be administered per standard of care (SOC) based on pathologic staging (rather than clinical staging at presentation). If the pathologic stage following induction and surgery is ypT0-2N0 without adverse features, adjuvant RT will not be administered and 6 months of adjuvant cemiplimab will be given. Otherwise, patients will receive SOC adjuvant RT-based treatment. The primary endpoint is safety and tolerability. Secondary endpoints include feasibility assessed by the number of patients whose definitive surgery was delayed due to toxicity and quantifying the number in whom clinical to pathologic downstaging is achieved and the planned surgery and/or need for adjuvant-RT based therapy is modified. Exploratory endpoints include evaluating the association between biomarkers in the tumor microenvironment and peripheral blood with pathologic response. 8 of 10 patients have been enrolled. Clinical trial information: NCT04722523.

18F-FluorThanatrace (18F-FTT) positron emission tomography (PET/CT) in prostate cancer measures in vivo PARP-1 expression and is associated with adverse clinicopathologic features.

5030 Background: We performed the first clinical trial to evaluate expression of PARP-1, the target of PARP-inhibitors (PARPi), in prostate cancer (PC) using 18F-FluorThanatrace (18F-FTT), a novel radiopharmaceutical that selectively measures PARP-1 expression with PET/CT. Approvals for PARPi in metastatic castrate resistant prostate cancer (mCRPC) have improved clinical outcomes in men with homologous recombination deficient (HRD) associated PC. Patient selection using genetic biomarkers such as HRD and PARP-1 IHC are insufficient PARPi biomarkers. We report the first trial of assessment of PARP-1 expression in men with prostate cancer. Methods: Men with localized PC with planned prostatectomy were included. Patients were required to have 2+ biopsy cores with &gt; 50% involvement, OR &gt; 1cm dominant prostate lesion on MRI. Men received a single pre-operative [18F]FTT scan. [18F]FTT is. Patients received a single injection of 8-12 mCi [18F]FTT and underwent 60 minutes dynamic scanning and static scan at 90 minutes post-injection. Ex vivo IHC, autoradiography, and germline/somatic genomic testing was performed after surgical removal. The study was approved by the University of Pennsylvania IRB (UPCC #13817, ClinicalTrials.gov, NCT03334500). Results: 30 men consented for participation (29 with presurgical MRI) from 6/2019 to 12/2020. Mean PSA was 9.8 ng/mL (range 2.35 – 60). Gleason Grade (GG) groups included: GG 1 (n = 1), GG 2 (n = 10), GG 3 (n = 5), GG 4 (n = 7), and GG 5 (n = 7). Stages included: pT2 (n = 12), pT3a (n = 10), pT3b (n = 8). Two patients had pN1 disease (cN0 by MRI). Mean injected dose was 10.32 mCi (range 7.52 – 11.62). There were no serious adverse events noted for any patient. Of patients with presurgical MRI, a range of uptake on the PET/CT correlated to the dominant lesion on MRI. The mean and median SUVMax of all lesions was 3.52 and 3.46, respectively (range 1.03 – 6.56). Both patients cN0 on MRI, had those nodes identified on the [18F]FTT scan. SUVMax was significantly associated with increasing Gleason Grade group Rs = 0.37298, p (2-tailed) = 0.04. SUVMax was significantly associated with Decipher scores (GenomeDx Biosciences, San Diego, CA) Rs = 0.63077, p (2-tailed) = 0.02. Ex vivo IHC showed PARP1 localization to the dominant region on the MRI. Ex vivo autoradiography using [I125]KX1, a FTT analogue, and correlation to genomic HRD (DDR aberrations and HRD scores) is underway. Conclusions: [18F]FTT detects in vivo PARP-1 expression in prostate cancer and SUVMax is associated with higher Gleason Grade groups and Decipher scores, This tracer may be used as an imaging biomarker for PARP-1 expression in men with prostate cancer, the target of PARPi. A follow-up study to assess change in [18F]FTT uptake before and after administration of PARPi in men with mCRPC is underway to test [18F]FTT as a biomarker PARPi (UPCC #08821). Clinical trial information: NCT03334500.

Impact of induction approach on post-stem cell transplant (SCT) outcomes in older adults with newly diagnosed acute myeloid leukemia (AML).

7038 Background: The optimal induction regimen for older patients (pts) with AML who are eligible for SCT is not well-established. Methods: This is a retrospective analysis of 127 pts age ≥60 years with newly diagnosed AML who underwent allogeneic SCT in first remission between 9/2012 and 7/2021 at our institution. Pts with previously treated secondary AML were excluded. Pts were divided according to induction therapy received: intensive chemotherapy (IC) (n = 44), lower-intensity therapy (LIT) without venetoclax (VEN) (n = 36), and LIT with VEN (n = 47). We compared overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) according to the induction regimen received. Results: Pts who received IC were younger than those who received LIT with or without VEN (median age: 63 vs. 68 years; P &lt; 0.0001) and were more likely to have an ECOG performance status of 0 at time of AML diagnosis (34% vs. 14%; P = 0.02). Cytomolecular risk was well-balanced between the 3 arms; the rates of adverse cytomolecular features in the IC, LIT without VEN and LIT with VEN groups were 43%, 50%, and 55%, respectively. Donor sources and degree of HLA matching were similar in the 3 groups. Most pts (92%) in the LIT with VEN group received reduced-intensity conditioning prior to SCT, compared with 54% and 58% in the IC and LIT without VEN groups, respectively. The majority of pts achieved CR/CRi prior to SCT (IC cohort:100%, LIT without VEN: 94%, LIT with VEN: 92%); the rest had MLFS as best response. The rate of measurable residual disease (MRD) negativity by flow cytometry prior to SCT was higher in the LIT with VEN group (69%), compared with IC (58%) and LIT without VEN (49%) (P = 0.14). The median number of cycles of chemotherapy prior to SCT was 3 in all groups. The median post-SCT follow-up was 37 months. The 2-year CIR was similar in pts who received IC or LIT with VEN (18% and 19%, respectively) and was highest in pts who received LIT without VEN (36%). The 2-year NRM was lowest in pts with LIT with VEN (11%), as compared with IC or LIT without VEN (27% and 22%, respectively) (P = 0.02 for IC vs. LIT with VEN). The 1-year post-SCT RFS for pts who received IC, LIT without VEN and LIT with VEN was 58%, 50%, and 75%, respectively, and the 2-year RFS was 54%, 42% and 62%. The 1-year post-SCT OS was 63%, 58%, and 84%, respectively, and the 2-year OS was 58%, 44% and 73%. OS was statistically superior for LIT with VEN compared with LIT without VEN (P = 0.02) and there was a trend towards superior OS with LIT with VEN compared to IC (P = 0.17). Conclusions: LIT with VEN was associated with similar rates of CIR and lower NRM compared with IC. Despite the older age of pts in the LIT with VEN cohort, their post-SCT survival outcomes were noninferior, and possibly superior, to those who received IC. These results suggest that LIT with VEN is a valid induction strategy for older SCT-eligible pts with newly diagnosed AML.

Subcutaneous daratumumab (DARA SC) versus active monitoring in patients (pts) with high-risk smoldering multiple myeloma (SMM): Randomized, open-label, phase 3 AQUILA study.

TPS8075 Background: Standard of care for SMM includes active monitoring until progression to multiple myeloma (MM); however, recent evidence suggests pts with high-risk features may benefit from early treatment. DARA is a human IgGκ monoclonal antibody targeting CD38 that is approved as monotherapy for relapsed/refractory MM (RRMM) or in combination with standard of care for RRMM or newly diagnosed MM. Results from the phase 3 COLUMBA study showed that DARA SC demonstrated similar efficacy to intravenous (IV) DARA but with a lower rate of infusion-related reactions and shorter administration time. Based on the promising single-agent activity observed with IV DARA in intermediate- or high-risk SMM pts during the phase 2 CENTAURUS study, we hypothesized that DARA SC may delay progression to MM versus active monitoring in pts with high-risk SMM. Methods: AQUILA is an ongoing, randomized, open-label, multicenter phase 3 study of DARA SC versus active monitoring in pts with high-risk SMM. DARA SC (DARA 1,800 mg + recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; Halozyme]) is administered by manual injection over approximately 5 minutes at alternating locations on the abdomen weekly in Cycles 1 and 2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter until 39 cycles (28 days/cycle), up to 36 months, or until disease progression. Eligibility criteria include confirmed diagnosis of SMM for ≤5 years, factors indicating high risk of progression to MM (clonal bone marrow plasma cells [BMPCs] ≥10% and ≥1 of the following: serum M protein ≥30 g/L, IgA SMM, immunoparesis with reduction of 2 uninvolved Ig isotypes, serum involved:uninvolved free light chain ratio ≥8 to &lt; 100, or clonal BMPCs &gt; 50% to &lt; 60% with measurable disease), and ECOG performance status ≤1. The primary endpoint is progression-free survival (PFS), assessed by an independent review committee, with disease progression defined according to International Myeloma Working Group diagnostic criteria for MM. Secondary endpoints include time to biochemical or diagnostic (SLiM-CRAB) progression, overall response rate, complete response rate, duration of response, time to response, time to first-line treatment for MM, PFS on first-line treatment for MM (PFS2), overall survival, and incidence of MM with adverse prognostic features. The study completed enrollment on May 6, 2019; 390 pts have been randomly assigned to DARA SC or active monitoring. The primary efficacy analysis will be performed after approximately 165 PFS events have been observed. Clinical trial information: NCT03301220.

A new and automated risk prediction of coronary artery disease using clinical endpoints and medical imaging-derived patient-specific insights: protocol for the retrospective GeoCAD cohort study.

IntroductionCoronary artery disease (CAD) is the leading cause of death worldwide. More than a quarter of cardiovascular events are unexplained by current absolute cardiovascular disease risk calculators, and individuals without clinical risk factors have been shown to have worse outcomes. The ‘anatomy of risk’ hypothesis recognises that adverse anatomical features of coronary arteries enhance atherogenic haemodynamics, which in turn mediate the localisation and progression of plaques. We propose a new risk prediction method predicated on CT coronary angiography (CTCA) data and state-of-the-art machine learning methods based on a better understanding of anatomical risk for CAD. This may open new pathways in the early implementation of personalised preventive therapies in susceptible individuals as a potential key in addressing the growing burden of CAD.Methods and analysisGeoCAD is a retrospective cohort study in 1000 adult patients who have undergone CTCA for investigation of suspected CAD. It is a proof-of-concept study to test the hypothesis that advanced image-derived patient-specific data can accurately predict long-term cardiovascular events. The objectives are to (1) profile CTCA images with respect to variations in anatomical shape and associated haemodynamic risk expressing, at least in part, an individual’s CAD risk, (2) develop a machine-learning algorithm for the rapid assessment of anatomical risk directly from unprocessed CTCA images and (3) to build a novel CAD risk model combining traditional risk factors with these novel anatomical biomarkers to provide a higher accuracy CAD risk prediction tool.Ethics and disseminationThe study protocol has been approved by the St Vincent’s Hospital Human Research Ethics Committee, Sydney—2020/ETH02127 and the NSW Population and Health Service Research Ethics Committee—2021/ETH00990. The project outcomes will be published in peer-reviewed and biomedical journals, scientific conferences and as a higher degree research thesis.

Outcomes of Richter’s syndrome in patients with chronic lymphocytic leukemia (CLL) treated with platinum or anthracycline based chemotherapy with or without a BTK inhibitor (BTKi).

e19511 Background: Richter’s syndrome (RS) is a rare complication of chronic lymphocytic leukemia (CLL) and the median survival is generally poor. Evidence is limited regarding the biology of the disease, treatment and outcomes. Methods: We retrospectively reviewed pts diagnosed (dx) with pathologically confirmed RS who presented at the University of Miami Sylvester Cancer Center between 2011 and 2020. Informed consent was provided through IRB-approved protocols. Descriptive statistics were utilized and overall survival (OS) was calculated from RS diagnosis to death or last follow-up by Kaplan-Meier. Results: 33 patients with RS, including 87.9% diffuse large B-cell lymphoma-type RS and 12.1% Hodgkin lymphoma-type RS were identified. Median time from CLL dx to RS transformation was 37months (m). Most patients presented with elevated LDH 75%, bulky lymphadenopathy 66%, and adverse genetic features, such as TP53 disruption 52% or complex karyotype 81%. FISH at RS dx: del(17p) 37%, del(11q) 17%, trisomy 12 58%. ORR to first line therapy was 75.8% (55% CR, 27% PR), but of those who achieved CR, 44% relapsed. Median PFS (mPFS) was 10m for the anthracycline-based chemotherapy group (ABC) with a CR of 50%, compared to 15.5 m for the platinum-based chemotherapy group (PBC) and a CR of 60%. Similar OS were observed regardless of the chemotherapy regimen with median OS (mOS) of 60 m in the ABC group vs 59.5 m in the PBC group. Notably, the addition of a BTKi to chemoimmunotherapy lead to a mOS of more than 10 years in BTKi-naïve pts compared to 5.1 years in BTKi-exposed pts and 1.8 years in pts who did not receive a BTKi for RS treatment. Conclusions: Patients who develop RS often have high risk CLL, especially complex cytogenetics. Although a large proportion of pts with RS respond to frontline therapy, almost half relapse. While mOS is similar for anthracycline and platinum-based chemotherapies, platinum-based chemotherapy can lead to superior CR and PFS. BTKi-naïve pts who receive a BTKi with chemotherapy for RS treatment have superior mOS.