Site Of Disease Research Articles

Peptide functionalized biomimetic gene complexes enhance specificity for vascular endothelial regeneration

Gene delivery presents great potential in endothelium regeneration and prevention of vascular diseases, but its outcome is inevitably limited by high shear stress and instable microenvironment. Highly efficient nanosystems may alleviate the problem with strong dual-specificity for diseased site and targeted cells. Hence, biomimetic coatings incorporating EC-targeting peptides were constructed by platelets and endothelial cells (ECs) for surface modification. A series of biomimetic gene complexes were fabricated by the biomimetic coatings to deliver pcDNA3.1-VEGF165 plasmid (pVEGF) for rapid recovery of endothelium. The gene complexes possessed good biocompatibility with macrophages, stability with serum and showed no evident cytotoxicity for ECs even at very high concentrations. Furthermore, the peptide modified gene complexes achieved selective internalization in ECs and significant accumulation in endothelium-injured site, especially the REDV-modified and EC-derived gene complexes. They substantially enhanced VEGF expression at mRNA and protein levels, thereby enabling a wound to heal completely within 24 h according to wound healing assay. In an artery endothelium-injured mouse model, the REDV-modified and EC-derived gene complexes presented efficient re-endothelialization with the help of enhanced specificity. The biomimetic gene complexes offer an efficient dual-targeting strategy for rapid recovery of endothelium, and hold potential in vascular tissue regeneration.

Implementation of a hepatitis B screening program in patients receiving systemic anti-cancer therapy: A Canadian single center retrospective review.

e23242 Background: Cancer patients receiving non-endocrine anti-cancer therapies are at risk of hepatitis B virus (HBV) reactivation (HBVr). Medical society guidelines recommend HBV screening prior to treatment, but real-world uptake is slow and variable. The Ottawa Hospital Cancer Centre implemented a screening pilot program for all patients receiving FOLFOX based regimens or FOLFOXIRI between January and April 2023 which included incorporating HBV screening tests into treatment plan builds and specifying pharmacy and nursing pre-treatment checks. Methods: Charts were retrospectively reviewed, and patient and disease characteristics were collected. The primary endpoint was to identify the proportion of patients who underwent screening prior to treatment start. Univariate analyses assessed the association between baseline characteristics and failure to screen. We also reviewed quality metrics including time from consult to testing, time to result, number of duplicate screens, and treatment delays due to testing. Results: Baseline demographics of the 42 patients included can be found in Table 1. 32 patients (76.2%) completed screening and 5 (15.6%) had a positive screen. The majority of patients screened (78.1%) completed screening prior to first treatment as intended, however 38.1% were drawn on day of treatment. 9.52% of patients had duplicate screening inadvertently. All patients who tested positive were referred to Infectious Diseases. Of those, 1 received antivirals for chronic HBV, and 4 had resolved HBV and were recommended for monitoring. There were no treatment delays due to pending screening and no HBVr. Receipt of prior systemic therapy was significantly associated with failure to screen (55% vs 95%, OR 17.1 (95% CI 1.92-153), p = 0.011). Factors including age, sex, primary disease site, therapy intent, and regimen received were not significantly associated with screening completion or HBV positivity. Conclusions: The results of this pilot highlights the importance of building HBV screening into standardized treatment plans and engaging all team members to ensure high levels of screening. Prior systemic therapy receipt was associated with failure to screen, and thus programs should include education on the necessity of screening as recommended by medical guidelines. The prevalence of HBV in this population may also be higher than previously expected, which should be explored in future research. [Table: see text]

A phase 2 study to determine the pathological (path) response to neoadjuvant nivolumab (nivo) and relatlimab (rela) in stage I to III resectable Merkel cell carcinoma (Neo-MCC).

TPS9613 Background: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cancer of the skin with viral and sun related aetiologies, and an overall mortality rate twice that observed in cutaneous melanoma (33% vs 15%). The 5-year disease specific survival is 60% to 87% for those presenting with local disease, 39% to 62% for nodal disease and 11% to 20% for metastatic disease (1). Neoadjuvant therapy (NAT) is a powerful treatment platform to rapidly assess drug activity in resectable cancers. In melanoma, using International Neoadjuvant Melanoma Consortium (INMC) path response criteria (2), a major path response to immunotherapy (≤10% viable tumor) correlates with low risk of recurrence in resectable stage III disease (Menzies et al., 2021), and improved survival and EFS when immunotherapy is given neoadjuvantly as compared to adjuvant (adj) treatment (Patel et al., 2022). In a study of NAT anti-PD1 monotherapy with nivolumab, in patients (pts) with resectable IIA-IV MCC (N=36), 47.2% of pts achieved a complete path response (pCR) (Topalian et al., 2020). Other benefits of NAT include early insight into response, feedback to pts regarding their individual response and prognosis, ability to tailor subsequent management, and collection of translational specimens to explore mechanisms of response and resistance. The Neo-MCC trial will examine whether combination PD-1 blockade plus lymphocyte-activation 3 (LAG3) checkpoint inhibition will achieve a high rate of path response with manageable toxicity in pts with resectable stage I-III MCC. Methods: Pts with histologically confirmed resectable clinical stage I (≥ 10 mm), II or III Merkel cell carcinoma, are eligible (N=20). All pts undergo complete resection (RES) at wk 6 following NAT with 2 doses of nivo (480 mg, IV) plus rela (160 mg, IV) at wk 0 and 4. Standard of care sentinel lymph node biopsy will be completed as indicated. Pts with non-path response (>50% viable tumor) or partial path response (>10% - ≤50% viable tumor) at RES will receive adj radiotherapy (RT) to all disease sites, including the draining lymph node basin. Pts with pCR (0% viable tumor) or near-pCR response (≤10% viable tumor) will receive no further adj treatment. Pts with involved RES path margins will be considered for adj RT, following multidisciplinary team consultation to determine the role of further surgery. CT, and FDG PET/CT will be performed at baseline (BL), prior to RES to measure NAT response, and 6-monthly over a 10-year follow-up period. Tumor and fecal samples are collected at BL, RES, and recurrence. Blood samples are collected at BL, wk 4, RES, and recurrence. The primary endpoint is the rate of pCR at RES after NAT using INMC response criteria. Secondary endpoints include RFS, OS, safety/tolerability, surgical outcomes, QOL, and biomarker analyses. 1. Mistry, et al., 2022. 2. Tetzlaff et al., 2018. Clinical trial information: NCT06151236 .

Impact of comorbidity on outcome and treatment choice in patients with head and neck squamous cell carcinoma (HNSCC).

e18033 Background: Most patients (pts) with HNSCC are elderly and suffer from other diseases that, similarly to cancer, are related to smoking and alcohol habit. Therefore, these pts often may present at diagnosis with both comorbidities and other primary tumour with which they share the same risk factors. Several studies have shown that in cancer pts, the presence of comorbidities is a strong negative prognostic factor that can predict worse survival and a factor involved in changing cancer treatment choices. The Charlson Comorbidity Index (CCI) is a known tool for assessing the comorbidity burden of pts, with broad and validated prognostic value in the HNSCC population. Methods: The aim of this study is to retrospectively analyze, in a single cohort of HNSCC pts, the role of comorbidity burden on treatment choice and pts outcome.Data from the medical records of pts treated at Spaziani Hospital, FR, Italy from May 2019 to Jan 2023 for an HNSCC were collected. All pts had received a variable combination of surgery, chemo and radiotherapy for their tumor. All pts were staged according to CCI and divided into four groups of comorbidity burden. Data on treatment choice (trimodal (variable combination of surgery+chemotherapy+radiotherapy) vs non-trimodal) were also recorded for stage III-IVA pts. Results: 54 consecutive pts were enrolled. The disease sites included the oral cavity (14 pts), oropharynx (18 pts), larynx (9 pts), nasal cavity/paranasal sinuses (6 pts), occult primary (4 pts) and hypopharynx (4 pts).Of the 54 pts the 22.2% and 77.8% were female and male, respectively. Most pts (39 pts, 72.2%) had stage III-IVA disease. 35 and 40 pts, respectively received a surgical and nonsurgical primary therapy. 13 pts received a trimodal approach. The median observed PFS was 22.4 months (95% CI: 12.6-32.2). No significant differences in DFS were observed according to age (<65 vs ≥ 65 years, p 0.99), sex (p 0.45), comorbidity burden (CCI 0, CCI 1-2, CCI 3-4, CCI≥5; p 0.99), RT (yes vs no, p 0.90), CT-RT (yes vs no, p 0.62), smoking (p0.91). In our cohort, only an ECOG Performance Status 0 (0 vs ≥1; p 0.028) and HPV status (pos vs neg; p 0.002) were correlated with a better DFS. A high comorbidity burden (CCI score) was present in >85% of pts. In general, those who undergo trimodal treatment among stage III-IV pts are those with PS 0 vs ≥ 1 (40% vs 23.5%), with age < 65 vs ≥65 years (40.0% vs 26.3%), with a CCI ≤1 vs CCI >1 (47.6% vs 16.7%), absence vs presence of CV morbidity (40.6% vs 0%), female vs male (50% vs 27.6%), in the HPV+ vs HPV- (100% vs 25%). Among these, the presence of CV comorbidities (p 0.039), CCI (p 0.041) and HPV (p 0.018) are statistically significant. Conclusions: Our analysis suggests that in pts with Stage III-IVA, the presence of a higher comorbidity burden and CV morbidity are capable of influencing the choice of a trimodal treatment. A broader test is necessary due to the small sample size considered.

Phase 1b trial of IFx-Hu2.0, a novel in situ cancer vaccine, in checkpoint inhibitor-resistant Merkel cell carcinoma (MCC) and cutaneous squamous cell carcinoma (cSCC).

9592 Background: MCC and cSCC have limited treatment options when refractory to immune checkpoint inhibitor (ICI) therapy. IFx-Hu2.0 (IFx) is a plasmid DNA encoding for an immunogenic bacterial protein, Emm55, formulated with a transfection agent for direct intra-tumoral (IT) injection. In this Phase 1b study, we evaluated the safety and efficacy of different schedules of IT IFx in patients (pts) with advanced MCC or cSCC. Methods: In the first trial stage (n=9), IT IFx was administered in up to 3 lesions on 3 schedules following a 3+3 exposure escalation schema; weekly x 1, 2, or 3. In the second trial expansion stage (n=11), IT IFx was administered weekly x 3. The primary objective of the study was to establish safety and feasibility of repeated IT administrations of the investigational agent. ≥80% completion of planned study therapy was predefined as a successful feasibility outcome. Given the proposed potential for immune priming effects of IFx, we performed an unplanned exploratory analysis of post-protocol treatment efficacy to evaluate response to ICI rechallenge. Results: We treated 22 pts (MCC, 13; cSCC, 9). All pts had received prior anti-PD(L)1 based treatment with disease progression being the reason for ICI discontinuation in all patients but one. Two pts did not complete planned study therapy due to rapid clinical progression and were replaced but included in the safety analysis. IT IFx was well tolerated at all dose schedules evaluated with 1 high-grade toxicity deemed possibly treatment related (G3 hepatitis in a patient recently treated with ICI). The study therefore met predefined study endpoints for safety and efficacy. After protocol specified IT therapy, 11 MCC pts and 6 cSCC pts were treated with anti-PD(L)1 based therapy as the immediate post-protocol treatment. Five of 9 (56%) evaluable MCC patients and 1 of 7 (14%) cSCC patients experienced an objective response to this ICI rechallenge, with duration of response ongoing in 4 patients (6+, 19+, 21+, 23+ months) and the two other responses lasting 23 and 33 months. The two remaining MCC patients were not evaluable for response from IO rechallenge due to radiation administered to the only measurable disease site(s), but both remain progression free at 11+ and 13+ months with previously progressive disease. Conclusions: IT IFx-Hu2.0 is safe and feasible to administer at weekly dosing repeated up to 3 weeks. An unplanned exploratory analysis revealed frequent (56%) and durable responses in advanced MCC to ICI re-challenge despite prior resistance to this class of drug, suggesting that IFx induced an immune priming effect. Preliminary biomarker analyses to investigate this phenomenon are ongoing and will be presented. Clinical trial information: NCT04160065 .

Overall survival analysis of first line CDK4/6 inhibitors in a large real-world cohort of patients with hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer.

e13095 Background: Multiple clinical trials have demonstrated the efficacy of the commercially available CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) as upfront therapy in patients (pts) with (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC). Recently, differences in overall survival (OS) benefit in MBC and invasive disease-free survival benefit in early-stage BC suggest greater potency of abemaciclib and ribociclib compared to palbociclib. Here we report a comprehensive OS analysis of a cohort of pts with HR+/HER2- MBC treated with ribociclib, palbociclib or abemaciclib and ET in 1st line setting. Methods: We retrieved medical records of pts with HR+/HER2- MBC receiving CDK4/6i as 1st line therapy between December 2013 and October 2023 at Memorial Sloan Kettering Cancer Center. We investigated the impact of clinico-pathological characteristics and treatment type as categorical variables on OS using uni- and multivariate Cox (proportional hazard) regression model. Any p-value (p) <0.05 was deemed to be statistically significant. Results: 854 pts were included in the analysis, 838 females (98%) and 16 males at birth. The median age was 56 (IQR: 48-65). Overall, 722 (84%) pts received palbociclib, 88 (11%) abemaciclib, and 44 (5%) ribociclib. Most pts received aromatase inhibitor (AI) as ET backbone (n=634, 74%); 214 received fulvestrant (35%), and 6 received tamoxifen (1%). After a median follow-up of 3.14 years (range: 1.7-4.6), the median OS of the full cohort was 54.7 months (95%CI: 50-63.1). Clinico-pathological characteristics that resulted independently associated with worse OS were: male gender at birth (HR:2, 95%CI:1.4-4), disease-free interval ≤ 2 years (HR:1.64, 95%CI:1.11-2.44), ER-low status (HR: 2.27, 95%CI:1.42-3.63), high grade(HR: 1.28, 95%CI:1.01-1.62), liver involvement (HR: 1.48, 95%CI:1.08-2.03), and number of disease sites >3 (HR:1.35, 95%CI:1.03-1.78). HER2-low status was associated with better OS (HR: 0.75, 95%CI:0.59-0.96). In terms of type of treatment, there was a trend toward improved OS in patients receiving AI rather than fulvestrant or tamoxifen (HR:0.76, 95%: 0.58-1), while the type of CDK4/6i did not affect the outcome. Conclusions: Clinical parameters of early relapse, high disease burden, and intrinsic tumor aggressiveness seem to be the main drivers of poor prognosis in patients with HR+/HER2- MBC in 1st line setting. In this analysis, type of CDK4/6i did not have a significant impact on OS, although pts treated with abemaciclib and ribociclib were underrepresented in the cohort due to the earlier and prevalent use of palbociclib as the first-in-class FDA-approved CDK4/6i. These data are reassuring about the use of palbociclib suggesting that a switch of CKD4/6i is not needed in pts with ongoing treatment and demonstrated benefit.

Analysis of demographic and socioeconomic factors in biphasic synovial sarcoma using data from the National Cancer Database.

e23524 Background: Synovial sarcoma, a rare type of soft tissue sarcoma, can be classified into two subtypes - biphasic and spindle cell. Of the two, biphasic synovial sarcoma (BSS) has a better 5-year survivorship; however, 35% of patients diagnosed with BSS die within 5 years. Despite past controversy, adjuvant chemotherapy has been found to improve overall survival for patients with stage III BSS. The National Cancer Database (NCDB) was examined to discover the demographics of individuals diagnosed with BSS. Methods: The 2004-2020 NCDB was analyzed to conduct a retrospective cohort analysis. Patients with a histologically confirmed diagnosis of BSS (ICD-O-3 code 9043) were included (N = 92). Demographic factors like age, sex, race, Hispanic origin, insurance status, educational attainment, distance from facility, facility type, and Charles/Deyo score were evaluated using descriptive statistics and incidence trends were interpreted with regression analysis. Results: Ninety-two biphasic synovial sarcoma cases sampled between 2004 and 2020 revealed an average age at diagnosis of 47.3 years (SD = 19.9, range = 5–87), with males being more likely to be diagnosed (58%). The patients reside at an average of 42 miles from treatment facilities (SD = 108.56, range = 0.3–800.6). Primary disease sites varied, including the lower lobe of the bronchus or lung (12%), upper lobe (11%), and long bones (11%). Diagnosis frequency (2004–2020) showed minimal variation (R^2 = 0.007). Palliative care was not received in 95% of cases, and 41% of patients did not undergo a surgical procedure at the primary site. In patients who received surgery, residual tumor absence post-resection was noted in 56% of patients. Primary treatments included chemotherapy (48%) and radiation therapy (42%), with an average tumor size of 65.2 mm (SD = 42.8, range = 9–195 mm). Notably, 74% survived beyond 90 days post-surgery, with a thirty-day mortality rate of 2%. Patients survived an average of 8.5 years post-diagnosis. Facility-wise, 37% were in academic/research programs. Privately insured patients constituted 60%, with 51% of all patients residing in metropolitan areas of 1 million or more. Conclusions: This analysis addresses a critical knowledge gap, offering insights into the demographics and socioeconomic factors affecting the diagnosis and treatment of Biphasic Synovial Sarcoma (BSS). The average age of BSS diagnosis is 47.3 years with males being predominantly affected, consistent with earlier case reports. BSS patients showed diverse geographic distribution. Survival beyond 90 days post-surgery was high. Chemotherapy and radiation therapy were common treatments. Unique findings include a majority residing in metropolitan areas, and non-academic program treatments. This study underscores the necessity for further research to grasp the impact of these factors on BSS diagnosis, treatment, and overall survival.

Diagnostic performance of Cu64-dotatate-PET/CT or Ga68-dotatate-PET/CT with 18F-fluorodeoxyglucose (FDG)-PET/CT for neuroendocrine tumor evaluation.

e16285 Background: Neuroendocrine tumors (NETs) may be imaged for theranostics with somatostatin receptor (SSTR)-PET/CT like Cu64- or Ga68-dotatate-PET/CT. NETs may also be imaged with 18F-Fluorodeoxyglucose (FDG)-PET/CT based on disease state and insurance coverage. FDG+ and SSTR- disease predicts poor response to Lu177-dotatate therapy, making both scans of possible value. The diagnostic performance of performing both PET/CT studies in close temporal proximity in NET patients is assessed. Methods: This NIH-funded and IRB-approved imaging trial provided FDG- and SSTR-PET/CT in NET patients with RECIST 1.1 measurable disease. A board-certified nuclear radiologist documented detection of the primary NET (if not resected), local, and distant metastatic disease. Each PET/CT pair was assessed for FDG- and SSTR-PET/CT discordant lesions, with location of discordant uptake tabulated. Results: 30 individuals completed FDG-PET/CT and SSTR-PET/CT with either Cu64-dotatate (n = 15) or Ga68-dotatate (n = 15). Studies were performed within 2.4 days average (range 1-10 days). Primary NET site was bowel (n = 15), pancreas (n = 7), lung (n = 7) and unknown (n = 1), with tumor grade 1 (n = 11), grade 1-2 (n = 1), grade 2 (n = 17) and grade 3 (n = 1). Primary NET was detected on FDG-PET/CT in 7/12 cases (58.3%) and on SSTR-PET/CT in 12/12 cases (100%), significantly higher ( p= 0.017). Primary NET was surgically resected in the remaining 18 cases. Local metastases were detected on FDG-PET/CT in 12/30 cases (40%) and on SSTR-PET/CT in 19/30 cases (63.3%), significantly higher ( p= 0.006). Distant metastases were detected on FDG-PET/CT in 19/30 cases (63.3%) and on SSTR-PET/CT in 24/30 cases (80%), trending significantly higher ( p= 0.057). Discordant detection (yes/no for any disease) of primary, local, and/or distant disease was seen in 13/30 cases (43.3%). An equal number of lesions were detected between FDG- and SSTR-PET/CT in 4/30 cases (13.3%), more lesions on FDG-PET/CT in 1/30 (3.4%), and more lesions on SSTR-PET/CT in 25/30 (83.3%). For SSTR-PET/CT, more lesions were detected in the liver (n = 16), lymph nodes (n = 15), bone (n = 6) and bowel (n = 5) than on paired FDG-PET/CT. Disease was exclusively detected on SSTR-PET/CT in 5/30 (16.7%), and in no case on FDG-PET/CT. FDG-PET/CT showed 2/30 (6.7%) cases with exclusively FDG+ liver disease, both in patients with primary lung NETs (2/7, 28.9%). Conclusions: SSTR-PET/CT showed superior detection of primary and locoregional disease, and detected more distant disease sites than FDG-PET/CT. Discordant uptake between PET/CT studies was identified in nearly half of cases, with highest discordance noted in liver and lymph nodes. Discordant FDG+ and SSTR- disease was only seen in patients with primary lung NET, which is a negative prognostic factor for Lu177-dotatate therapy, and may justify the need for having both scans in this group.

Genomic profiling in a subgroup analysis of patients (pts) with diffuse large B-cell lymphoma (DLBCL) and extranodal (EN) sites of involvement in the phase 3 Pola-R-CHP versus R-CHOP (POLARIX) study.

7061 Background: The prognosis and survival outcomes of pts with EN involvement remain a challenge for DLBCL management. In the Phase 3 POLARIX study (NCT03274492), Pola-R-CHP demonstrated significantly improved progression-free survival (PFS) compared with R-CHOP in previously untreated DLBCL (Tilly et al. 2022). This retrospective analysis assessed clinical outcomes and genomic patterns of pts with DLBCL and EN disease. Methods: POLARIX methods were previously described (Tilly et al. 2022). Using a data cutoff of June 15, 2022, this analysis assessed pts with EN involvement as determined by investigators. Additional outcomes and genomics analyses were performed on pts whose EN status was confirmed from documented radiographic lesions or bone marrow biopsy with denotation of EN disease sites. Hazard ratios (HRs) for investigator-assessed PFS were adjusted for age (≤60 vs >60) and sex. Cell of origin (COO) by NanoString, mutation analysis by whole exome sequencing, and global gene expression profiling by RNAseq were performed centrally. Results: In POLARIX, 616/879 pts (70%) had identified EN involvement. After a median follow-up of 39.7 months, pts showed improved PFS with Pola-R-CHP vs R-CHOP (HR 0.72, 95% confidence interval [CI]: 0.55–0.96), with a 2-year PFS of 75% vs 66%. A total of 556 pts (Pola-R-CHP, n=279; R-CHOP, n=277) had confirmed sites of EN involvement, defined as pts with EN radiographic lesions or bone marrow disease. In these pts, PFS favored Pola-R-CHP vs R-CHOP but the difference was not statistically significant (HR 0.84, 95% CI: 0.63–1.13). Of pts with confirmed EN disease, 429 had COO results (activated B-cell, 145 [34%]; germinal center B-cell, 223 [52%]; unclassified DLBCL, 61 [14%]). Mutation data and frequencies of select clinically relevant mutations (Ptashkin, 2023) across EN sites were available for 364 pts (Table). Gene expression data were available for 418 pts; genes involved in proliferation (E2F or PI3K signaling targets and checkpoint genes) and regulated by IRF4, OCT2 and XBP1, were commonly upregulated in pts with EN disease. Conclusions: Results in pts with DLBCL with EN involvement suggest superior PFS with Pola-R-CHP vs R-CHOP. Ongoing analyses will further assess the independent impact of EN status on outcome. POLARIX represents the largest cohort of pts with annotated EN disease and systematic genomic analysis, providing new insights into the genomics of these pts. Clinical trial information: NCT03274492 . [Table: see text]

Age-normed patient-reported outcome measures among cancer survivors.

11122 Background: Patient-reported outcome measures (PROMs) are instruments used to collect health-related outcomes that are derived completely from the patient without interpretation from healthcare providers. Monitoring and subsequent intervention based on PROMs collection has demonstrated efficacy in clinical trial settings. This has resulted in implementation of PROMs in routine clinical cancer practices throughout the nation. PROMs have been normed to the general population, but establishing the norms among cancer patients is essential to understanding how PROMs can be evaluated on an individual basis in routine clinical cancer care. This study aims to characterize age-normed PROMs scores among survivors of cancer using the National Institute of Health’s Patient-Reported Outcome Measures Information System (PROMIS) depression, fatigue, pain interference, and physical function domains. Methods: Routine collection of PROMs using 4 domains (depression, fatigue, pain interference, and physical function) of PROMIS were offered to all patients with a diagnosis of cancer of any disease site at visits with an oncologic provider using computer adaptive testing. All patients ≥18 years old with a completed PROM at least 2 years since their diagnosis of cancer were eligible for inclusion in the analysis. Only completed PROMs were included in the final analysis. Generalized estimating equation models were used to assess the relationship between age and the estimated mean T-score for each PROMs domain, considering repeat measures within a single patient. Results: A total of 3,636 patients were included in this retrospective cohort study with a total of 26,173 completed PROMs among all 4 domains. Mean age at diagnosis was 61.2 years (SD=12.44), 64% (n=2324) were female, 68% (n=2,461) identified as White, and 25% (n=893) identified as Black. For fatigue, mean T-score ranged from 48.4 points (SD=9.6) among 18-29 years olds to 56.5 points (SD=10.1) among 90-99 years olds, with no significant change with age (p=0.27). For depression, mean T-score ranged from 48.9 points (SD=9.0) among 60-69 year olds to 51.1 points (SD=8.8) among 80-89 year olds with a 0.3 point/decade decrease in T-score (p=0.01). Pain interference T-scores ranged from 48.6 points (SD=10.5) among 18-29 year olds to 55.0 points (SD=9.4) among 80-89 year olds with a 0.4 point/decade average increase (p<0.001). The largest differences were observed in physical function, where scores ranged from 53.5 points (SD=11.0) among 18-29 year olds to 34.3 points (SD=9.2) among 90-99 year olds. There was a 2.1 point/decade decrease in T-score (p<0.001). Conclusions: Among survivors of cancer, mean PROMIS scores differed by age in the depression, pain interference, and physical function domains but not fatigue. These age-normed PROMIS T-scores, which are required to understand individualized assessments of PROMs, are essential as PROMs are integrated into routine cancer care.

The impact of admitting ward on resource utilization and outcomes among hospitalized cancer survivors.

1550 Background: With improvements in the early detection and treatment of cancer, there is a growing population of cancer survivors; with a corresponding increase in acute care use among cancer survivors. However, models of inpatient care delivery for cancer survivors differ between hospitals and regions, which may impact resource use and outcomes. Understanding how different models influence outcomes may help define optimal models for inpatient care delivery for this population. Methods: We created a multicenter cohort of all cancer patients admitted to medical wards across 26 hospitals in Ontario, Canada from 2015 to 2022, and deterministically linked population-level administrative data including ambulatory oncology data, with each hospital’s patient-level electronic information (pharmacy, orders, notes, laboratory/imaging and results). Multivariable regression models compared characteristics and outcomes between patients admitted on oncology wards vs non-oncology wards adjusting for age, sex and co-morbidity scores. Results: In total, there were 370,118 hospitalizations from 191,990 unique patients. Among these hospitalizations, 38,075 episodes (10.3%) were on an oncology ward. The median time from cancer diagnosis to hospitalization was 4 years. The most common disease sites were genitourinary (21%), gastrointestinal (20%), breast (12%), and lung (10%). The most discharge diagnoses from oncology wards were inpatient chemotherapy (9%), febrile neutropenia (7%), non-Hodgkin’s lymphoma (4%), acute myeloid leukemia (4%), myeloma (3%); while for non-oncology wards were heart failure (5%), palliative care (4%), UTI (2%), pneumonia (2%), acute renal failure (2%). In general, cancer patients admitted on oncology wards were younger (64 vs 76), had shorter length of stay (LOS; 9.6 vs 10.1 days), less in-hospital mortality (7.5% vs 11.4%), greater 30-day re-admission rates (29% vs 14%) and were also more likely to undergo CTs (28% vs 21%), MRIs (11% vs 9%) and interventional procedures (8% vs 6%) (all comparisons, p<0.001). Subgroup analysis focusing on the top 5 discharge diagnoses from non-oncology wards, showed that despite higher in-hospital mortality rates (aOR 1.27 95% CI [1.15-1.40] p<0.001), admission to a non-oncology ward for those diagnoses was associated with a shorter LOS (aOR 0.96 [0.92-1.00] p=0.03), reduced 30-day re-admission rates (aOR 0.77 [0.69-0.87] p<0.001), and reduced use of CTs (aOR 0.74 [0.68-0.82] p<0.001), MRIs (aOR 0.80 [0.68-0.95] p=0.01), and interventional procedures (aOR 0.84 [0.69-1.01] p=0.07). Conclusions: There are differences in both resource use and outcomes for cancer survivors hospitalized on oncology versus non-oncology wards, including for patients with the same discharge diagnosis. To optimize inpatient cancer care delivery for hospitalized cancer survivors, further exploration is needed.

Tolerability and outcomes of neuroendocrine tumors treated with PRRT and SBRT.

There is interest in optimizing peptide receptor radionuclide therapy (PRRT) for the management of metastatic neuroendocrine neoplasms (NEN). The addition of stereotactic body radiation therapy (SBRT) may provide synergistic benefits by targeting specific sites of disease that may represent areas of tumor heterogeneity. Little is known about the efficacy or potential toxicity of this approach; understanding the outcomes of patients treated with these two modalities in a sequential fashion will provide insights into the appropriateness of embarking on a combined therapy strategy. An institutional retrospective review of 21 patients with NEN treated with sequential PRRT and SBRT (64 targets) was performed. Median overall survival and progression-free survival were 19.6 months and 12.8 months, respectively. Median time to local recurrence at the SBRT site was not reached, with rates at 12 and 24 months of 1.8% and 5.9%, respectively. The toxicity profile remains favorable. Given the safety and efficacy of sequential SBRT and PRRT, further trials evaluating a concurrent treatment approach may be warranted.

Quantification of the environmental impact of radiotherapy and associated secondary human health effects: a multi-institutional retrospective analysis and simulation

The health-care industry is a substantial contributor to global greenhouse gas emissions, yet the specific environmental impact of radiotherapy, a cornerstone of cancer treatment, remains under-explored. We aimed to quantify the emissions associated with the delivery of radiotherapy in the USA and propose a framework for reducing the environmental impact of oncology care. In this multi-institutional retrospective analysis and simulation study, we conducted a lifecycle assessment of external beam radiotherapy (EBRT) for ten anatomical disease sites, adhering to the International Organization for Standardization's standards ISO 14040 and ISO 14044. We analysed retrospective data from Jan 1, 2017, to Oct 1, 2023, encompassing patient and staff travel, medical supplies, and equipment and building energy use associated with the use of EBRT at four academic institutions in the USA. The primary objective was to measure the environmental impacts across ten categories: greenhouse gases (expressed as kg of carbon dioxide equivalents [CO2e]), ozone depletion, smog formation, acidification, eutrophication, carcinogenic and non-carcinogenic potential, respiratory effects, fossil fuel depletion, and ecotoxicity. Human health effects secondary to these environmental impacts were also estimated as disability-adjusted life years. We also assessed the potential benefits of hypofractionated regimens for breast and genitourinary (ie, prostate and bladder) cancers on US greenhouse gas emissions using an analytic model based on the 2014 US National Cancer Database for fractionation patterns and patient commute distances. We estimated that the mean greenhouse gas emissions associated with a standard 25-fraction EBRT course were 4310 kg CO2e (SD 2910), which corresponded to 0·0035 disability-adjusted life years per treatment course. Transit and building energy usage accounted for 25·73% (1110 kg CO2e) and 73·95% of (3190 kg CO2e) of total greenhouse gas emissions, respectively, whereas supplies contributed only 0·32% (14 kg CO2e). Across the other environmental impact categories, most of the environmental impact also stemmed from patient transit and energy use within facilities, with little environmental impact contributed by supplies used. Hypofractionated treatment simulations suggested a substantial reduction in greenhouse gas emissions-by up to 42% for breast and 77% for genitourinary cancer-and environmental impacts more broadly. This comprehensive lifecycle assessment of EBRT delineates the environmental and secondary health impacts of radiotherapy, and underscores the urgent need for sustainable practices in oncology. The findings serve as a reference for future decarbonisation efforts in cancer care and show the potential environmental benefits of modifying treatment protocols (when clinical equipoise exists). They also highlight strategic opportunities to mitigate the ecological footprint in an era of escalating climate change and increasing cancer prevalence. Mount Zion Health Fund.

Enhanced therapeutic potential of Flotillins-modified MenSCs by improve the survival, proliferation and migration.

Menstrual blood-derived endometrial stem cells (MenSCs) have attracted increasing interest due to their excellent safety, and lack of ethical dilemma as well as their ability to be periodically obtained in a noninvasive manner. However, although preclinical research as shown the therapeutic potential of MenSCs in several diseases, their poor cell survival and low engraftment at disease sites reduce their clinical efficacy. Flotillins (including Flot1 and Flot2) are implicated in various cellular processes, such as vesicular trafficking, signal transduction, cell proliferation, migration and apoptosis. In this study, we aimed to determine the effects of Flotillins on MenSCs survival, proliferation and migration. Our experimental results show that MenSCs were modified to overexpress Flot1 and/or Flot2 without altering their intrinsic characteristics. Flot1 and Flot2 co-overexpression promoted MenSC viability and proliferation capacity. Moreover, Flot1 or Flot2 overexpression significantly promoted the migration and inhibited the apoptosis of MenSCs compared with the negative control group, and these effects were stronger in the Flot1 and Flot2 gene co-overexpression group. However, these effects were significantly reversed after Flot1 and/or Flot2 knockdown. In conclusion, our results indicate that Flot1 and Flot2 overexpression in MenSCs improved their proliferation and migration and inhibited their apoptosis, and this might be an effective approach to improve the efficiency of cell-based therapies.

Ocular findings in patients with histiocytosis and association with clinical and molecular features

Background/aimsOcular manifestations of histiocytosis and their genetic underpinnings are poorly characterised. This study characterises ocular sites of histiocytosis, notate genetic alterations and correlates to histiocytosis clinical features including subtype and...

HeredERA Breast Cancer: a phase III, randomized, open-label study evaluating the efficacy and safety of giredestrant plus the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with previously untreated HER2-positive, estrogen receptor-positive locally advanced or metastatic breast cancer

BackgroundHER2-positive, estrogen receptor-positive breast cancer (HER2+, ER+ BC) is a distinct disease subtype associated with inferior response to chemotherapy plus HER2-targeted therapy compared with HER2+, ER-negative BC. Bi-directional crosstalk leads to cooperation of the HER2 and ER pathways that may drive treatment resistance; thus, simultaneous co-targeting may optimize treatment impact and survival outcomes in patients with HER2+, ER+ BC.First-line (1L) treatment for patients with HER2+ metastatic BC (mBC) is pertuzumab, trastuzumab, and taxane chemotherapy. In clinical practice, dual HER2 blockade plus a fixed number of chemotherapy cycles are given as induction therapy to maximize tumor response, with subsequent HER2-targeted maintenance treatment given as a more tolerable regimen for long-term disease control. For patients whose tumors co-express ER, maintenance endocrine therapy (ET) can be added, but uptake varies due to lack of data from randomized clinical trials investigating the superiority of maintenance ET plus dual HER2 blockade versus dual HER2 blockade alone. Giredestrant, a novel oral selective ER antagonist and degrader, shows promising clinical activity and manageable safety across phase I–II trials of patients with ER+, HER2-negative BC, with therapeutic potential in those with HER2 co-expression.MethodsThis phase III, randomized, open-label, two-arm study aims to recruit 812 patients with HER2+, ER+ locally advanced (LA)/mBC into the induction phase (fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] plus a taxane) to enable 730 patients to be randomized 1:1 to the maintenance phase (giredestrant plus PH FDC SC or PH FDC SC [plus optional ET]), stratified by disease site (visceral versus non-visceral), type of LA/metastatic presentation (de novo versus recurrent), best overall response to induction therapy (partial/complete response versus stable disease), and intent to give ET (yes versus no). The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include overall survival, objective response rate, clinical benefit rate, duration of response, safety, and patient-reported outcomes.DiscussionheredERA BC will address whether giredestrant plus dual HER2 blockade is superior to dual HER2 blockade alone, to inform the use of this combination in clinical practice for maintenance 1L treatment of patients with HER2+, ER+ LA/mBC.Trial registrationClinicalTrials.gov, NCT05296798; registered on March 25, 2022. Protocol version 3.0 (November 18, 2022). Sponsor: F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124 4070, Basel, Switzerland.

Local Ablative Therapy Combined With Pembrolizumab in Patients With Synchronous Oligometastatic Non-Small Cell Lung Cancer: A Recursive Partitioning Analysis

Purpose: This study aimed to evaluate the efficacy of local ablative therapy (LAT) combined with pembrolizumab in patients with synchronous oligometastatic non-small cell lung cancer (NSCLC) and to identify patients who would most benefit from LAT.Methods and Materials: We retrospectively identified patients diagnosed with synchronous oligometastatic NSCLC (≤5 metastatic lesions and ≤3 organs involved) and treated with first-line pembrolizumab between January 2017 and December 2022. Patients who underwent LAT, including surgery or radiotherapy at all disease sites, were compared with those who did not undergo LAT. A recursive partitioning analysis (RPA) model was developed using prognostic factors for progression-free survival (PFS).Results: Among the 258 patients included, 78 received LAT with pembrolizumab and 180 received pembrolizumab alone. The median follow-up duration was 15.5 months (range, 3.0–71.2). In the entire cohort, LAT was independently associated with significantly improved PFS (hazard ratio [HR], 0.64; P = 0.015) and overall survival (OS) (HR, 0.61; P = 0.020). In the propensity score-matched cohort (N = 74 in each group), the median PFS was 19.9 months and 9.6 months, respectively (P = 0.003), and the median OS was 42.2 months and 20.5 months, respectively (P = 0.045), for the LAT and non-LAT groups. Based on the RPA model, incorporating the number of metastatic lesions, performance status, and PD-L1 expression level, patients were stratified into three risk groups with distinct PFS. LAT significantly improved PFS and OS in the low- and intermediate-risk groups; however, no difference was observed in the high-risk group. LAT was more effective as a consolidative treatment following pembrolizumab initiation than as an upfront therapy.Conclusion: LAT combined with pembrolizumab was associated with higher PFS and OS compared to pembrolizumab alone in selected patients with synchronous oligometastatic NSCLC. The RPA model could serve as a valuable clinical tool for identifying appropriate patients for LAT.

Nontuberculous mycobacterial disease in children: A systematic review and meta-analysis

BackgroundThe prevalence of nontuberculous mycobacterial (NTM) disease in children is increasing worldwide. The clinical manifestations of pediatric NTM patients are significantly different from those of adult patients, but the knowledge of the disease is generally poor. MethodsEnglish databases (PubMed, Web of Science, Embase, BIOSIS) and Chinese databases (CNKI, Wanfan, VIP) were searched on October 15th, 2022. All the articles of cross-sectional and cohort studies reporting the species composition and lesion site of the NTM disease in children using well-recognized NTM species identification methods were taken into account. Using a random effects model, we assessed the disease lesion sites and the prevalence of different NTM species in pediatric NTM disease. Sources of heterogeneity were analyzed using Cochran's Q and the I2 statistic. All analyses were performed using CMA V3.0. ResultsThe prevalence rates of NTM disease in children ranged between 0.6 and 5.36/100,000 in different countries, and Europe reported the highest prevalence rate. The most common clinical lesion site was lymph node, accounting for 71.1 % (55.0 %–83.2 %), followed by lung (19.3 %, 9.8%–34.4 %）and then skin and soft tissue (16.6 %,13.5%–20.3 %). Mycobacterium avium complex (MAC) was the most isolated NTM pathogen in children, accounting for 54.9 % (39.4%–69.6 %). Inconsistent with adult patients, Mycobacterium avium accounted for a dominant proportion in MAC than Mycobacterium intracellulare. ConclusionsThe lymph node was the most affected organ in pediatric NTM disease, while Mycobacterium avium was the most isolated pathogenic species in children.

Effects of Total Body Irradiation on Hematopoietic Cell Transplantation Outcomes in Pediatric Acute Myeloid Leukemia with Prior Central Nervous System Involvement

The implications of previous central nervous system (CNS) involvement in children with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT) remain inadequately understood. Patients with CNS disease require more upfront CNS-directed intrathecal therapy, but little is known about whether transplant conditioning regimens should be intensified or if previous CNS involvement impacts post-HCT outcomes. While total body irradiation (TBI) remains standard for pediatric acute lymphoblastic leukemia myeloablative conditioning, it has been largely replaced with chemotherapy-only myeloablation in pediatric AML, primarily due to toxicity and late effects associated with TBI. In the setting of previous CNS involvement, it has been suggested that TBI-based myeloablation may have advantages due to superior CNS tissue penetration and thus decreased rates of AML relapse post-HCT. We analyzed a publicly available dataset derived from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry to characterize the impact of TBI in HCT preparative regimens in pediatric AML patients with a history of CNS involvement. The study dataset was obtained from the CIBMTR data repository. The study cohort included patients aged ≤21 years who underwent initial allogeneic HCT with myeloablative conditioning for de novo AML in the first or second complete remission (CR) between 2008 and 2016, who provided consent for research. Patients with mismatched related donor transplants and noncalcineurin inhibitor graft-versus-host disease (GVHD) prophylaxis were excluded. The dataset was further modified by excluding patients with missing disease site data or those with non-CNS extramedullary disease. Patients were categorized as CNS-positive or -negative AML (AML-CNS(+) and AML-CNS(-), respectively) based on the disease status at diagnosis. The Cox regression model and Fine-Grey methods were employed to delineate the effects of TBI and CNS disease on key HCT outcomes. The study cohort comprised 550 pediatric AML patients, of which 25% (n = 136) were AML-CNS(+). CNS involvement was more prevalent in patients aged 0 to 3 years, patients who were in the second CR, and those with a mismatched unrelated donor or umbilical cord blood. AML-CNS(+) patients demonstrated a lower relapse rate (hazard ratio: 0.50, 95% confidence interval: 0.33 to 0.76) compared to AML-CNS(-) patients, with comparable disease-free survival (DFS) and overall survival (OS) (P = .10 and 0.20, respectively) in the two cohorts. The entire TBI-treated cohort showed an association with increased risks of grade 2 to 4 acute GVHD, bloodstream infections, and endocrine dysfunction. TBI use within the AML-CNS(+) cohort was associated with a lower relapse rate but increased risks of nonrelapse mortality and a trend of higher grade 3 to 4 acute GVHD. In this population-based analysis of pediatric patients with de novo AML undergoing HCT, TBI-based conditioning regimens did not confer an advantage in DFS or OS compared to non-TBI regimens, irrespective of CNS disease status. However, TBI use was associated with increased risks of short- and long-term comorbidities. These findings underscore the need for careful consideration of TBI in pediatric AML.

Mesoporous silica nanoparticles as a drug delivery mechanism.

Research in intelligent drug delivery systems within the field of biomedicine promises to enhance drug efficacy at disease sites and reduce associated side effects. Mesoporous silica nanoparticles (MSNs), characterized by their large specific surface area, appropriate pore size, and excellent biocompatibility, have garnered significant attention as one of the most effective carriers for drug delivery. The hydroxyl groups on their surface are active functional groups, facilitating easy functionalization. The installation of controllable molecular machines on the surface of mesoporous silica to construct nanovalves represents a crucial advancement in developing intelligent drug delivery systems (DDSs) and addressing the issue of premature drug release. In this review, we compile several notable and illustrative examples of MSNs and discuss their varied applications in DDSs. These applications span regulated and progressive drug release mechanisms. MSNs hold the potential to enhance drug solubility, improve drug stability, and mitigate drug toxicity, attributable to their ease of functionalization. Furthermore, intelligent hybrid nanomaterials are being developed, featuring programmable properties that react to a broad spectrum of stimuli, including light, pH, enzymes, and redox triggers, through the use of molecular and supramolecular switches.