Central Pathology Research Articles

Central pathological review and molecular classification of medulloblastoma in countries with limited resources: A commitment to equitable access.

10062 Background: Medulloblastoma, the most common malignant pediatric brain tumor, exhibits molecular heterogeneity influencing prognosis and treatment decisions. This study focuses on feasibility the pathological review and molecular classification with cost-effective methods. Methods: From December 2018 to November 2023, we analysed samples of patients referred to our laboratory. Data were collected on patient demographics (age, gender, origin), pathological review and specific medulloblastoma subtypes identified. The study was performed without costs for parents or institutions. Results: During the study period, 146 patients were included. The predominant age groups being 0 to 4 years (20.1%) and 5 to 9 years (36.1%) The mean age was 10.2 years. 55.6% of patients were female and 43.8% were male. Ninety-three patients were from Brazil and 7% from Latin America. Of the 117 samples that could be analyzed, 43% was classified as group 4, 37% were sonic hedgehog (SHH) group, 10% were group 3 and 4% were WNT group. Five percent of the samples had inconclusive results, with two patients had diagnoses other than medulloblastoma. Seventy percent of samples had a turnaround time for molecular classification results around 30 days. Conclusions: This study highlights the importance of central review pathology and molecular classification in medulloblastoma management. Our results emphasize the feasibility of centralized pathology review and molecular classification in countries with limited resources and provide equity for all patients. Based on this experience, we have expanded for other brain and pediatric tumors. Our effort contributes to ensuring that every patient benefits from the advancements in personalized medicine and this represents a real step to offer the same chances of cure for everyone.

Histopathological features of SMARCA4-deficient thoracic malignancies: Data from resource-limited setting.

e20045 Background: SMARCA4 deficient tumors are rare malignancies that develop due to inactivating mutation in switch/sucrose-nonfermenting chromatin remodeling complexes (SWI/SNF). This is an aggressive type of non-small cell lung cancer (NSCLC) with a poor prognosis and mediocre treatment response. The trials and observational research on SMARCA4 deficient thoracic malignancies are lacking, especially in limited resource settings. This study aims to analyze pathological and immunohistochemical (IHC) profiles of patients with SMARCA4 deficient thoracic malignancies in Armenia. Methods: The current research utilizes a retrospective cohort single-center study design. The study setting was the only pathology center in Armenia that runs an IHC panel for SMARCA4/BRG1 protein evaluation. For data collection purposes, a census sampling has been done and all the pathology reports of SMARCA4 deficient thoracic malignancies were reviewed. The study timeframe was from 24 February 2021 up to 11 December 2023. Descriptive statistics through portions were done to analyze the data. Results: In total, 19 patients with SMARCA4 deficient thoracic malignancies were diagnosed. The male-to-female ratio was 15:1 and the median age was 63 years (range: 50-73 years). Of those cases, 21% (n = 4) were excluded from the current analysis as histopathological examination of those tissue samples was not performed. The diagnosis was based on an IHC evaluation to obtain a second opinion. The tissue histopathological architecture was represented: 60% (n = 9) solid, 6.67% (n = 1) trabecular, and 6.67% (n = 1) papillary. Of those samples, 66.7% (n = 10) had hyperchromatic/polymorphic nuclei and 33.3% (n = 5) pleomorphic nuclei. Similarly, the evaluated sample cells have 53.3% (n = 8) eosinophilic, 13.3% (n = 2) clear, and 13.3% (n = 2) scant cytoplasm. All 19 cases were included in the descriptive analysis of the IHC profile as examinations were performed for all the subjects. The IHC profile of the cohort is presented in the table. Ki67 was checked in 47.4% (n = 9) of cases with 70-75% median expression. In general, the most frequently examined markers were TTF1, p40, Chromogranin, and AE1/3. Conclusions: In conclusion, the study shed light on SMARCA4 thoracic tumors spread in Armenia. Considering the rarity of the disease, further research is required to investigate the actual prevalence of SMARCA4 deficient thoracic tumors and treatment approaches in Armenia. [Table: see text]

Multinational, Multicenter Evaluation of Prostate Cancer Tissue in Sub-Saharan Africa: Challenges and Opportunities.

Prostate cancer disproportionately affects men of African descent, yet their representation in tissue-based studies is limited. This multinational, multicenter pilot study aims to establish the groundwork for collaborative research on prostate cancer in sub-Saharan Africa. The Men of African Descent and Carcinoma of the Prostate network formed a pathologist working group representing eight institutions in five African countries. Formalin-fixed paraffin-embedded prostate tissue specimens were collected from Senegal, Nigeria, and Ghana. Histology slides were produced and digitally scanned. A central genitourinary pathologist (P.L.) and eight African general pathologists reviewed anonymized digital whole-slide images for International Society of Urological Pathology grade groups and other pathologic parameters. Discrepancies were re-evaluated, and consensus grading was assigned. A virtual training seminar on prostate cancer grading was followed by a second assessment on a subcohort of the same tissue set. Of 134 tissue blocks, 133 had evaluable tissue; 13 lacked cancer evidence, and four were of insufficient quality. Post-training, interobserver agreement for grade groups improved to 56%, with a median Cohen's quadratic weighted kappa of 0.83 (mean, 0.74), compared with an initial 46% agreement and a quadratic weighted kappa of 0.77. Interobserver agreement between African pathologist groups was 40%, with a quadratic weighted kappa of 0.66 (95% CI, 0.51 to 0.76). African pathologists tended to overgrade (36%) more frequently than undergrade (18%) compared with the reference genitourinary pathologist. Interobserver variability tended to worsen with a decrease in tissue quality. Tissue-based studies on prostate cancer in men of African descent are essential for a better understanding of this common disease. Standardized tissue handling protocols are crucial to ensure good tissue quality and data. The use of digital slide imaging can enhance collaboration among pathologists in multinational, multicenter studies.

Phase 3 trial of odronextamab plus lenalidomide versus rituximab plus lenalidomide in relapsed/refractory (R/R) follicular lymphoma (FL) and marginal zone lymphoma (MZL; OLYMPIA-5).

TPS7094 Background: FL and MZL are indolent B-cell non-Hodgkin lymphomas (B-NHLs) that are treated in a similar way in the R/R setting. Despite the efficacy of rituximab–lenalidomide (R2) in patients (pts) with R/R FL, and MZL to a lesser extent, a notable proportion fail to achieve an optimal, durable response. Odronextamab is an off-the-shelf, CD20×CD3 bispecific antibody. In the Phase (Ph) 1 ELM-1 study, odronextamab monotherapy showed antitumor activity and a generally manageable safety profile across R/R B-NHL subtypes, including FL and MZL (Bannerji, et al. Lancet Haematol 2022). In the Ph 2 ELM-2 study, odronextamab elicited an objective response rate of 80% and complete response (CR) rate of 73% in pts with heavily pretreated R/R FL (Villasboas, et al. ASH 2023). The rate of treatment-related adverse events leading to treatment discontinuation was 7.8%. These positive data support the evaluation of odronextamab in R/R FL and MZL in earlier lines of therapy. Combining odronextamab with lenalidomide has the potential to improve efficacy in the R/R setting compared with R2. Methods: OLYMPIA-5 (NCT06149286) is a Ph 3, open-label, randomized study of odronextamab plus lenalidomide versus R2 in pts with R/R FL and MZL. The study consists of Part 1 (safety run-in) followed by Part 2 (randomization). In Part 1, odronextamab and lenalidomide will be administered for 12×28-day cycles or until relapse, progressive disease, withdrawal of consent, or unacceptable toxicity. Odronextamab IV infusion will be administered in a step-up regimen during Cycle (C) 1 to mitigate the risk of cytokine release syndrome, followed by full dose starting from C1 Day 22. In Part 2, pts will be randomized 1:1 to receive 12 cycles of odronextamab plus lenalidomide, or R2 for the first 5 cycles followed by lenalidomide monotherapy for C6–12 per standard schedule (Leonard, et al. J Clin Oncol 2019). Key inclusion criteria: aged ≥18 years; histologically confirmed FL Grade 1–3a or MZL (nodal, splenic, or extra nodal) that is refractory or relapsed after ≥2 cycles of prior systemic therapy that included ≥1 anti-CD20 antibody; measurable disease; ECOG PS 0–2; and adequate organ function. Pts with central nervous system (CNS) lymphoma, history of or current relevant CNS pathology, histological evidence of transformation to high-grade or diffuse large B-cell lymphoma, and prior use of lenalidomide or any CD20×CD3 bispecific antibody within the past 6 months are excluded. The Part 2 primary endpoint is progression-free survival as assessed by independent central review. Key secondary endpoints are CR, best overall response, and overall survival. Minimal residual disease (by ctDNA) analysis is an exploratory endpoint. The trial is currently recruiting and is expected to enroll approximately 24–48 pts in Part 1 and 422 pts in Part 2 (352 R/R FL; 70 R/R MZL) at ~200 global sites. Clinical trial information: NCT06149286 .

Pathologic response rates to neoadjuvant pembrolizumab in locally advanced (LA) resectable cutaneous squamous cell carcinoma (cSCC).

9591 Background: Cutaneous squamous cell carcinoma (cSCC) is the second commonest cutaneous malignancy, accounting for 20% of cutaneous malignancies and 75% of non-melanoma skin cancer deaths. Anti-PD-1 is approved in unresectable and metastatic cSCC, and is associated with high rates of pathologic response in resectable locally advanced (LA) cSCC. We conducted a phase II single-arm neoadjuvant trial of pembrolizumab (P) in patients with PD-1 naïve resectable LA cSCC. Methods: Patients with AJCC/UICC ≥T3 (or T2 with ≥2 BWH high-risk features) and/or N+ disease were eligible. Patients received 2 cycles of P (200mg Q3W) prior to definitive surgery, and 15 cycles post-surgery (NCT04808999). The primary endpoint was pathologic complete response (pCR, defined as 0% residual viable tumor, RVT) per independent central pathology review. Key secondary endpoints included incidence of adverse events (AEs), recurrence-free survival (RFS), overall survival (OS), safety and unbiased spatial biomarkers. A selected panel of multiplex immunofluorescence imaging biomarkers were used by PredxBio Inc.’s computational pipeline to reveal spatial intratumor heterogeneity in the tumor microenvironment (TME). Results: Thirty patients were enrolled and received at least 1 cycle of P. The median age was 79 (59-93) years and patients were predominantly male (77%). One patient withdrew consent prior to surgery. Three patients died prior to definitive surgery: 2 from COVID-19, a third from a NSTEMI possibly related to P. Of the 26 response-evaluable patients, AJCC/UICC stage at baseline was high-risk T2, T3, N1, and N2 in 2 (8%), 12 (46%), 9 (34.5%), and 3 (11.5%) patients, respectively. We observed pCR in 15 (57%), pathologic partial response (pPR, 10% < %RVT <50%) in 2 (8%) and pathologic non-response (pNR, >50%RVT) in 8 (31%) patients. One patient is pending surgery. Postoperative radiotherapy (RT) was de-escalated in 54% of the patients (14/15 in pCR). Median RFS was 13 (pCR) versus 10.5 (non-pCR) months. One Grade 5 (NSTEMI) and two Grade 3 (hepatitis, colitis) treatment-related AEs were observed. Computational analysis identifies key spatial interactions between PDL-1+/CD68+ cells implicated in response to P. Conclusions: Neoadjuvant P is efficacious in resectable LA cSCC with a high pCR rate (57%). Three deaths were observed, including 2 unrelated to treatment and 1 possible Grade 5 cardiac irAE, reflecting the inherent risks of perioperative therapy in this patient population. RT was de-escalated in 93% of pCR patients. No relapse events in pCR patients. Spatial interactions between PDL-1+ cells and CD68+ macrophages have a role in therapeutic response and will be detailed along with other spatial analyses of the TME compartment that have an impact on outcomes. Clinical trial information: NCT04808999 .

Comprehensive analysis of TROP2, PD-L1, stromal (s)TILs, and HER2 expression patterns in patients (pts) with metastatic HR+HER2- breast cancer.

1062 Background: Immune checkpoint inhibitors (ICI) have shown limited efficacy in hormone receptor positive (HR+) metastatic breast cancer (mBC) and the optimal ICI-based combination is unknown. The TROP2 antibody-drug conjugate sacituzumab govitecan (SG) demonstrated antitumor activity with a 5.5-month median PFS in endocrine refractory HR+ mBC. Given SG's potential for anticancer immunity, we sought to evaluate expression patterns of biomarkers of interest in HR+ mBC. Methods: This retrospective study included pts with HR+HER2- mBC identified at DFCI between 10/2020 and 12/2021 who received 0-1 prior lines of chemotherapy in the metastatic setting and consented to analysis of archival FFPE tissue samples. We aimed to 1) characterize expression patterns of TROP2 (SP295 H-score), PD-L1 (22C3 CPS), sTILs and HER2 (per central pathology review) in the most recent available sample; 2) assess the prognostic value of selected biomarker combinations for overall survival (OS) defined as the time from consent to either death due to any cause or last follow-up (Cox proportional hazard models; p-value <0.05 considered significant). Results: Among 142 pts included, median age at diagnosis was 46 yrs (IQR: 40–56). Baseline characteristics are shown (Table). At least one biomarker was available for 123 subjects (86.6%). TROP2 expression (n=61) was Medium/High (M-H: 101-300) in 43 pts (70.5%) and Low (L: 0-100) in 18 (29.5%). PD-L1 central assessment (n=120) revealed CPS ≥1 (PD-L1+) in 32 pts (26.7%) and <1 (PD-L1-) in 88 (73.3%); only 7 (5.8%) pts had CPS ≥10. sTILs (n=87) were ≥10% in 14 pts (16.1%) and <10% in 73 (83.9%). When analyzing TROP2 and PD-L1 (n=61), 15 pts (24.6%) were TROP2-M-H/PD-L1+, 28 (45.9%) were TROP2-M-H/PD-L1-, 5 (8.2%) were TROP2-L/PD-L1+, and 13 (21.3%) were TROP2-L/PD-L1-. When analyzing TROP2 and sTILs (n=54), 6 pts (11.1%) were TROP2-M-H/sTILs ≥10%, 32 (59.3%) were TROP2-M-H/sTILs <10%, 2 (3.7%) were TROP2-L/sTILs ≥10% and 14 (25.9%) were TROP2-L/sTILs <10%. For TROP2 and HER2 (n=46), 26 pts (56.5%) had TROP2-M-H/HER2-low tumors, 7 (15.2%) TROP2-M-H/HER2-0, 3 (6.5%) TROP2-L/HER2-low, and 10 (21.7%) TROP2-Low/HER2-0. Median OS (n=138) was 43.8 months; stratification for selected biomarker combinations will be presented although no statistical significance was found. Correlations with NGS data and HER2DX are ongoing and will be presented. Conclusions: Analyzing biomarkers of interest in pts with HR+ mBC unveiled diverse patterns, without associations with OS. Patient characteristics. [Table: see text]

Study EV-103: Neoadjuvant treatment with enfortumab vedotin monotherapy in cisplatin-ineligible patients with muscle invasive bladder cancer (MIBC)—2-year event-free survival and safety data for Cohort H.

4564 Background: For patients (pts) with MIBC who are cisplatin-ineligible and undergoing radical cystectomy and pelvic lymph node dissection (RC+PLND), no neoadjuvant treatment options have been shown to improve survival. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer. EV, alone and in combination w/ pembrolizumab, has been shown to improve OS vs chemotherapy in pts with previously treated and untreated locally advanced or metastatic urothelial cancer, respectively (Powles NEJM 2021; Powles ESMO 2023). In Cohort H of the EV-103 phase 1b/2 study, promising results for 1-year EFS and antitumor activity, including pathological complete response (pCR) and pathological downstaging (pDS) rates, were achieved in cisplatin-ineligible pts with MIBC after neoadjuvant monotherapy EV treatment (Petrylak ASCO GU 2022; Flaig ASCO 2023). Here we report updated results, including 2-year EFS. Methods: Cohort H of the EV-103 study enrolled cisplatin-ineligible pts with MIBC (T2-T4aN0M0) and ECOG PS ≤2 who were eligible for RC+PLND. Pts received neoadjuvant EV (1.25 mg/kg) on Days 1 and 8 every 21 days for 3 cycles before undergoing RC+PLND. The primary endpoint was pCR rate (ypT0 and N0) by central pathology review. Key secondary endpoints included pDS rate (ypT0, ypTis, ypTa, ypT1, and N0), safety, and EFS per investigator assessment (radiographic progression prior to RC, failure to undergo RC, gross residual disease at time of RC, recurrence, or death). Results: 22 pts (median age 74.5 years) were enrolled and treated; 15 pts (68.2%) remain on study. Pts had stage cT2 (68.2%), cT3 (27.3%), or cT4 (4.5%) disease. 68.2% of pts had urothelial carcinoma only; 31.8% had a mixed histology. 86.4% of pts completed all 3 cycles of EV; the median duration of EV treatment was 2.1 months (range 0.7-2.3). The pCR rate was 36.4% (95% CI, 17.2-59.3) and the pDS rate was 50.0% (95% CI, 28.2-71.8). The EFS rate at 24 months was 62.0% (95% CI, 38.2-78.9). Median EFS has not been reached. All pts underwent surgery with no delays due to EV-related TEAEs. The most common EV-related TEAEs were fatigue (45.5%), dysgeusia (36.4%), and alopecia (31.8%); 18.2% of pts had grade ≥3 EV-related TEAEs. 68.2% of pts had surgery-related TEAEs: the most common were procedural pain (18.2%), anemia (13.6%), and constipation (13.6%). 3 pts died due to AEs unrelated to EV treatment. 36.4% of pts received subsequent cancer-related therapy. Conclusions: Neoadjuvant EV monotherapy treatment showed promising results for antitumor activity and 2-year EFS with a manageable safety profile in cisplatin-ineligible pts with MIBC. These results support ongoing phase 2 and 3 programs in MIBC evaluating EV alone or combined with pembrolizumab (EV-103 Cohort L, KN-905/EV-303, KN-B15/EV-304). Clinical trial information: NCT03288545 .

Menopausal hormone therapy and ovarian and endometrial cancers: Long-term follow-up of the Women’s Health Initiative randomized trials.

10506 Background: After decades of use,menopausal hormone therapy influence on ovarian and endometrial cancer remains unsettled. Therefore, we assessed the long-term influence of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) and CEE-alone use on ovarian and endometrial cancer incidence and mortality in long-term follow-up of the Women’s Health Initiative randomized, placebo-controlled clinical trials. Methods: Long-term follow-up of two placebo-controlled randomized clinical trials that recruited 27,347 postmenopausal women aged 50-79 years without prior breast cancer or invasive cancer within 10 years (and no baseline endometrial pathology in combined hormone trial participants) from 40 US centers from 1993-1998. In 16,608 women with a uterus, 8,506 were randomized to daily 0.625 mg/d of CEE plus 2.5 mg/d of MPA and 8,102, placebo. In 10,739 women with prior hysterectomy, 5,310 were randomized to daily 0.625 mg/d of CEE-alone and 5,429, placebo. Intervention was stopped for cause before the planned 8.5-year intervention after 5.6 years (CEE plus MPA) and after 7.2 years (CEE-alone). Cancers were verified by central pathology report review. Mortality findings were enhanced by serial National Death Index (NDI) queries. The primary study outcomes were ovarian cancer and endometrial cancer incidence and related mortality. Results: After 20-year follow-up, with mortality information for > 98%; in the initial WHI report on CEE-alone influence on ovarian cancer, CEE-alone, versus placebo, significantly increased ovarian cancer incidence (35 cases [0.041% annualized rate] vs 17 [0.020%]; hazard ratio [HR], 2.04; 95% CI 1.14-3.65; P = 0.01) and ovarian cancer mortality (HR 2.79 95% CI 1.30-5.99, P = 0.006). KM-estimates and cumulative hazard ratios indicate a persistent CEE-alone adverse effect on ovarian cancer incidence that emerged after 12-years follow-up and did not diminish (P = 0.006). In contrast, use of CEE plus MPA, versus placebo, did not increase ovarian cancer incidence (75 cases [0.051%] vs 63 [0.045%]; HR, 1.14; 95% CI, 0.82-1.59; P = 0.44) or ovarian cancer mortality (HR 1.21 95% CI 0.84-1.74). CEE plus MPA did significantly lower endometrial cancer incidence (106 cases [0.073%] vs 140 [0.10%]; HR, 0.72; 95% CI, 0.56-0.92; P = 0.01), without statistically significant influence on endometrial mortality (HR 0.58 95% CI 0.29-1.16) Conclusions: In randomized, placebo-controlled, clinical trial settings, CEE-alone, in women with prior hysterectomy, significantly increased ovarian cancer incidence and increased ovarian cancer mortality while CEE plus MPA, in women with a uterus, in contrast to most observational studies, did not. However, CEE plus MPA reduced endometrial cancer incidence. These findings inform decisions regarding menopausal hormone therapy use. Clinical trial information: NCT00000611 .

A phase Ia/Ib, non-randomized, open-label, dose escalation and expansion trial of the B7-H6/CD3 T-cell engager BI 765049 with or without ezabenlimab in Asian patients with advanced solid tumors.

TPS2669 Background: Bispecific T-cell engagers represent a promising therapeutic approach for patients with solid tumors; however, these agents require an appropriate target antigen. B7-H6 is an encouraging target as it is expressed on multiple solid tumors but shows only limited expression on normal tissue (1). BI 765049 is a novel immunoglobulin G (IgG)-like T-cell engager designed to simultaneously bind B7-H6-expressing tumor cells and CD3 on T-cells resulting in the formation of a cytolytic synapse that triggers apoptosis of the tumor cells. Methods: NCT06091930 is a Phase I, non-randomized, open-label, multi-center, dose escalation and expansion trial that aims to assess the safety and tolerability of BI 765049 alone or in combination with programmed cell death protein 1 inhibitor ezabenlimab, in patients with advanced or unresectable gastric cancer, colorectal cancer (CRC), pancreatic ductal adenocarcinoma, hepatocellular cancer, head and neck squamous cell carcinoma, or non-small cell lung cancer. Patients must have progressed on, or be ineligible for, standard therapies. Key inclusion criteria include confirmed B7-H6 expression (central pathology review) except in CRC; ≥1 evaluable target lesion outside of the central nervous system (Response Evaluation Criteria in Solid Tumors [RECIST] v1.1); and Eastern Cooperative Oncology Group performance status 0/1. Patients with prior B7-H6-targeted treatment are ineligible. The study is divided into four parts: dose escalation and expansion of BI 765049 monotherapy (Parts I and II, respectively), and in combination with ezabenlimab (Parts III and IV, respectively). BI 765049 dose escalation will be guided by a Bayesian logistic regression model with overdose control. Treatment will continue until progressive disease or discontinuation for other reasons, or for up to 36 months. The primary endpoint for Parts I and III is the occurrence of dose-limiting toxicities; and for Parts II and IV it is objective response (OR; determined by the investigator; RECIST v1.1). The secondary endpoints for Parts I and III are pharmacokinetic (PK) parameters and OR (RECIST v1.1); and for Parts II and IV secondary endpoints are progression-free survival, duration of response, disease control, PK measurements, and OR (immunotherapy RECIST [iRECIST]). 1. Zhang W, et al. Clin Cancer Res 2022;28(23):5190–5201. Clinical trial information: NCT06091930 .

Neoadjuvant immuno-chemo-radiotherapy in operable esophageal and gastroesophageal junction adenocarcinoma with carboplatin, paclitaxel plus radiotherapy and avelumab (anti-PDL1 antibody): Neo-CREATE trial.

4086 Background: Neoadjuvant CROSS regimen followed by adjuvant nivolumab or perioperative FLOT are current standards of care for patients with curable esophageal/ gastroesophageal (GEJ) junction adenocarcinoma. We hypothesized that adding avelumab to neoadjuvant chemo-radiation (CRT-A) before surgery can further improve outcomes. Methods: Patients with cT1-3 and N0/N1 M0 esophageal or GEJ adenocarcinomas eligible for curative surgery received weekly carboplatin and paclitaxel concurrently with radiotherapy (41.4 Gy in 23 fractions) and bi-weekly avelumab (5 doses). The trial had a run-in phase of 10 patients to evaluate feasibility and safety and a planned futility analysis after 15 patients have undergone surgery. The primary endpoint was pathological complete response (pCR) (Mandard criteria) by central pathology review, secondary endpoints were major histological response and survival outcomes. Using an A’hern single stage design for efficacy forty-seven patients were required to rule out a lower limit of a 20% pCR rate (p0) and to demonstrate an increase to a 40% pCR rate (p1), with 90% power and significance level α=0.05. Tissue, blood, and stool samples were collected for corelative analysis. Results: 48 patients were enrolled between Sept 2019 to Oct 2022 across seven Australian sites. Median age 65 [44-81], 95% were male (n=45), with majority of cancers being esophageal/GEJ type I (n = 35), with GEJ type II (n = 13). Forty-seven (97%) patients completed CRT -A and 46 (95%) had surgery. CRT-A was well tolerated, with two patients having > grade 2 adverse event of interest in the form of myocarditis attributed to avelumab. Notable toxicities included grade 2-4 myocarditis (4%), anastomotic leak (4%), infection (6%) and diarrhoea (6%). In 44 evaluable patients, pCR was 23%. MHR was 58.3% (95% CI, 43.3%-72.1%), complete or near complete response (Tumor Regression Grade 1-2) was 31%. Overall, 1-yr disease free survival was 83.8% and OS was 91.2%. 1-yr disease free survival was 91.7% for patients with MHR vs 73.3% without MHR, p=0.20. Conclusions: Combining avelumab with neoadjuvant CRT is feasible in patients with acceptable tolerability in locally advanced esophageal/ GEJ adenocarcinoma. Avelumab with CRT is active however observed pCR rate does not represent a signal of substantial improvement compared to historical controls. Exploratory analysis suggests improved outcomes in patients with optimal tumour regression after neoadjuvant CRT-A. Exploratory biomarker work to corelate with outcomes is underway. Clinical trial information: ACTRN12619000288123.

Clinical efficacy and safety of mTOR inhibitor in patients with advanced unresectable epithelioid hemangioendothelioma (EHE).

e23540 Background: Epithelioidhemangioendothelioma is a rare vascular soft tissue sarcoma, 90% of which contains WWTR1-CAMTA1 fusion gene. Studies have shown that mTOR inhibitors may have a certain effect on EHE patients. Methods: A retrospective analysis of the efficacy and safety of mTOR inhibitor everolimus in the treatment of advanced unresectable epithelioidhemangioendothelioma in our hospital in the past one year. Patients with advanced epithelioidhemangioendothelioma (EHE) confirmed by consultation in the pathological center received this regimen, everolimus 10mg, once a day orally for 28 days, every 4 weeks as a treatment cycle until the disease progressed or showed intolerable toxicity. Results: There were 3 females and 5 males, and their average age was 41.8 years old. All of them were unresectable with liver, lung, and shoulder primary lesions, and lungs, liver, pleura and bone metastasis. Ki67 is from 2% to 10%. 3 patients who received molecular pathological examination were all identified the WWTR1-CAMTA1 fusion gene, and one of them also had EWSR1 chromosome translocation. Previous antineoplastic treatments included gemcitabine, cisplatin, albumin paclitaxel, epirubicin, dacarbazine chemotherapy, anlotinib targeting, and toripalimab immune therapy. 5 patients were treated with first-line drugs, 2 cases with second-line and 1 case with third-line. In terms of overall efficacy, 1 case was not evaluated, 2 cases lost follow-up due to poor tolerance and economic factors, 2 cases were included in the clinical trails after reaching tumor control for 3 months, and the other 3 cases achieved tumor remission with a median PFS of 11.0 months, and the best curative effect was SDa. Severe oral mucositis can greatly affect the medication experience of patients, which can be relieved after symptomatic medication, or when interstitial pneumonia and hemogram decrease significantly, we can consider the oral administration of everolimus 5mg. Conclusions: At present, there is no standard treatment for EHE, we can roughly see the efficacy of mTOR inhibitor everolimus in some EHE patients, mainly disease stability. Emphasis on side effect management, improve tolerance, and systematic treatment of EHE needs to be further explored.

A Mixed Methods Approach to Explore the Experience of Pain and Its Management in People with Parkinson's Disease.

Pain in Parkinson's disease (PD) is common but poorly understood, with most research to date taking a mechanistic approach. This mixed methods study takes a broader biopsychosocial approach to assess and describe contributors of pain and explore pain management and the relationship between pain and physical activity in people with PD (PwPD) and chronic pain. A structured survey evaluated respondents' contributors of pain using standardized, self-report assessments of the following: pain, peripheral neuropathy, central nociplastic change, emotional dysregulation or pathology, and maladaptive cognitions. Semistructured individual interviews were conducted with purposively sampled survey participants and analyzed using inductive thematic analysis. Eighty-nine PwPD (mean age 67 years, 55% female) completed the survey. The most common pain contributors were maladaptive cognitions (62%), central nociplastic change (49%), and emotional dysregulation (44%). Approaches to pain management and the response to physical activity were variable within and across individuals with different pain contributors. Four themes emerged from interviews with 24 participants: (1) causative perceptions of pain are diverse; (2) sense of control influences disease acceptance and exercise self-efficacy; (3) belief in the value of therapy; and (4) pain as the unspoken PD symptom. Physical activity was used by PwPD for pain management; however, the relationship between pain and physical activity varied based on sense of control. Clinicians should screen for pain and assess its contributors to provide individualized, multidimensional pain management that considers the biological, psychological, and social factors of pain in PwPD. It is plausible that such an approach would promote a better sense of control for PwPD.

GFAP as Astrocyte-Derived Extracellular Vesicle Cargo in Acute Ischemic Stroke Patients-A Pilot Study.

The utility of serum glial fibrillary acidic protein (GFAP) in acute ischemic stroke (AIS) has been extensively studied in recent years. Here, we aimed to assess its potential role as a cargo protein of extracellular vesicles (EVs) secreted by astrocytes (ADEVs) in response to brain ischemia. Plasma samples from eighteen AIS patients at 24 h (D1), 7 days (D7), and one month (M1) post-symptoms onset, and nine age, sex, and cardiovascular risk factor-matched healthy controls were obtained to isolate EVs using the Exoquick ULTRA EV kit. Subsets of presumed ADEVs were identified further by the expression of the glutamate aspartate transporter (GLAST) as a specific marker of astrocytes with the Basic Exo-Flow Capture kit. Western blotting has tested the presence of GFAP in ADEV cargo. Post-stroke ADEV GFAP levels were elevated at D1 and D7 but not M1 compared to controls (p = 0.007, p = 0.019, and p = 0.344, respectively). Significant differences were highlighted in ADEV GFAP content at the three time points studied (n = 12, p = 0.027) and between D1 and M1 (z = 2.65, p = 0.023). A positive correlation was observed between the modified Rankin Scale (mRS) at D7 and ADEV GFAP at D1 (r = 0.58, p = 0.010) and D7 (r = 0.57, p = 0.013), respectively. ADEV GFAP may dynamically reflect changes during the first month post-ischemia. Profiling ADEVs from peripheral blood could provide a new way to assess the central nervous system pathology.

P.094 Incidence of pathologically confirmed primary malignant brain tumours in Newfoundland and Labrador: an eight-year review spanning 2015-2022

Background: Considering regional and temporal trends, we sought to explore the incidence of primary malignant brain tumours in Newfoundland and Labrador. Methods: We reviewed all primary, malignant brain tumour cases from 2015-2022 confirmed by St. John’s Health Sciences Centre pathology reports. Incidence rates were standardized using the 2011 Canadian standard population. Results: We included 362 cases. The average annual age-standardized incidence rate of primary, malignant brain tumours per 100,000 was 7.0 (95% CI: 6.3-7.7), lower than the national average (7.93; 95% CI: 7.78-8.08). The incidence of glioblastoma (5.1; 95% CI: 4.5-5.7) was significantly higher than the national average (4.05; 95% CI: 3.95-4.16). Temporal trends revealed that oligodendroglioma incidence spiked from 0.5 (95% CI: 0.2-0.7) in 2015-2019 to 1.5 (95% CI: 0.4-2.6) in 2020 before returning to baseline in 2022. Regional trends indicated a lower incidence of malignant tumours in Labrador-Grenfell (5.1; 95% CI: 2.5-7.6), compared to 6.9 (95% CI: 6.2-7.6) averaged elsewhere. Conclusions: Higher rates of glioblastoma in Newfoundland and Labrador could have a genetic or multi-factorial cause. The increased occurrence of oligodendroglioma during the COVID-19 pandemic necessitates broader investigation, potentially linked to delays in patient care during this period. Regional trends could suggest less access to care in rural populations and underestimated incidence.

#1073 Changes in endothelial function in patients with impaired central and renal hemodynamics respiratory pathology

Abstract Background and Aims To determine the degree of influence of endothelial dysfunction on the hemodynamics of renal and central vessels in respiratory pathology, as well as to determine the effectiveness of complex therapy regimens with carvedilol. Method Studies were conducted in 26 patients with chronic obstructive pulmonary disease (COPD) of II- III severity (group 1, in whom the level of glomerular filtration rate of the kidneys eGFR CKD-EPI ≥6 ml/min/1.73 m2 was determined) and 32 patients with COPD of IV severity (group 2, they were determined e GFR CKD-EPI ≥60 ml/min/1.73 m2). Patients received one course of ten-day standard therapy (GOLD, 2020) in combination with a beta–blocker drug, T. carvedilol 5 mg (Vertex). Doppler echocardiographic examination of peripheral vessels, heart and renal vessels of patients was performed. Stable metabolites of nitric oxide (Cm NO) in blood plasma, ventilation and perfusion state of the lungs were determined. Results A significant decrease in the functional state of the respiratory system was parallel with a decrease in Cm NO synthesis, which was clearly reflected in the second group (by 11%) compared with the first group (by 7%). Pronounced structural changes with remodeling of the right parts of the heart, as well as a pronounced degree of pancreatic hypertrophy in the second group were accompanied by a sharp change in renal filtration function (eGFR ≤60 ml/min/1.73 m2). When measuring the state of diastolic dysfunction of the right parts of the heart, a decrease in E/As well as an increase in the circulatory vascular resistance index and mean blood pressure were significantly higher in the first group of patients (where еGFR ≥6 ml/min/1.73 m2). After a course of treatment with t. carvedilol, based on basic treatment, normalization of endothelial function was determined, reflected in an increase in the concentration of stable metabolites of nitric oxide by 1.05 and 1.5 times (p<0.05) in the biological fluid, respectively, in the first and second groups. In the dynamics of the course of therapy in groups of patients with 75% and 35% decrease in lung ventilation capacity, mean pulmonary arterial pressure decreased by 18.1 and 14.3%, respectively, and the hemodynamic resistance index decreased by 7.9% and 5.7% in parallel (p<0.05). Conclusion When monitoring the functional state of central and renal hemodynamics and ventilation-perfusion function of the bronchopulmonary system after complex treatment with carvedilol, a long-term hypotensive effect, a decrease in endothelial dysfunction, respectively, and an improvement in central and renal hemodynamics were determined.

#1658 Association of blood dd-cfDNA levels with Banff scores and histopathological lesions in kidney allograft biopsies: results from an observational trial

Abstract Background and Aims Donor-derived cell-free DNA (dd-cfDNA) is a novel blood biomarker of kidney allograft injury. While primarily studied to discriminate rejection from no rejection, knowledge about its dynamics in other graft pathologies is scarce and merits further investigation. Previous research has highlighted its superior diagnostic performance in detecting ABMR compared to TCMR and borderline changes, however, recent studies have suggested that its increase is not limited to damage due to alloimmune injury. Therefore, we aimed to assess the association between dd-cfDNA release and diverse histopathological patterns as well as its correlation with Banff lesion scores in renal allograft biopsies. Method For this analysis, we identified all dd-cfDNA-paired allograft biopsies from a prospective observational trial of kidney transplant recipients undergoing an indication biopsy with deterioration in graft function, persistence of anti-HLA donor-specific antibodies (DSA), or proteinuria. Dd-cfDNA was collected at the time of allograft biopsy and measured using droplet-digital PCR. Both relative and absolute quantification of dd-cfDNA, with cutoffs of 0.5% and 50cp/ml, respectively, were available for clinical interpretation. All biopsy specimens were examined by a central pathologist blinded to the dd-cfDNA results. Histopathological diagnoses were assigned according to the Banff 2019 classification. Results In total, we examined 125 dd-cfDNA paired biopsies from 110 patients performed at our center between April 2020 and October 2023. Absolute levels of dd-cfDNA were significantly higher in mixed rejection (median 156 cp/mL, IQR 138-176), antibody-mediated rejection (ABMR) (median 63cp/mL, IQR 48-81), DSA-negative microvascular inflammation (DSAnegMVI) (median 74 cp/mL, IQR 35-134), and BK-virus associated nephropathy (BKVAN) (median 168cp/mL, IQR 54-311) in comparison to glomerulonephritis (median 12cp/mL, IQR 8-19; p < 0.001, <0.001, 0.02, 0.01, respectively) as well as in comparison CNI-toxicity (median 10, IQR 6-15; p <0.001, <0.001, 0.004, 0.003, respectively). Additionally, patients with mixed rejection, ABMR, and BKVAN had higher absolute dd-cfDNA levels than patients with IFTA (median 13, IQR 8-16; p 0.004, 0.004, and 0.04, respectively), as well as normal histology (median 7, IQR 7-11, p 0.004, 0.008, 0.03, respectively). Finally, absolute dd-cfDNA levels were higher in patients with mixed rejection than in those with UTI (median 14, IQR 12-16, p = 0.02) (Fig. 1). In the univariable analysis, absolute dd-cfDNA levels were significantly correlated with Banff lesion scores for glomerulitis (g), peritubular capillaritis (ptc), and tubulitis (t). In the multivariable analysis, ptc and t were independently correlated with absolute dd-cfDNA levels. Conclusion Increased donor-derived cell-free DNA is not specific for rejection, but also occurs in alternative injury patterns showing microvascular inflammation and severe tubulointerstitial inflammation, such as DSAnegMVI and BKVAN (BK-virus associated nephropathy). Interestingly, dd-cfDNA levels remain low in the setting of de novo or recurrent glomerulonephritis and CNI-toxicity, which are important differential diagnoses in patients with clinical indication biopsy.

Role of copper in central nervous system physiology and pathology.

Copper is a transition metal and an essential element for the organism, as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs, including the central nervous system. Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B, Menkes disease and Wilson's disease, respectively, and also in multifactorial neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology, reports about unbalances in copper levels and/or distribution under disease, describes relevant animal models for human disorders where copper metabolism genes are dysregulated, and discusses relevant therapeutic approaches modulating copper availability. Overall, alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.

Microsurgical central lymphatic reconstruction-the role of thoracic duct lymphovenous anastomoses at different anatomical levels.

In recent years advances have been made in the microsurgical treatment of congenital or acquired central lymphatic lesions. While acquired lesions can result from any surgery or trauma of the central lymphatic system, congenital lymphatic lesions can have a variety of manifestations, ranging from singular thoracic duct abnormalities to complex multifocal malformations. Both conditions may cause recurrent chylous effusions and downstream lymphatic congestion depending on the anatomical location of the thoracic duct lesion and are associated with an increased mortality due to the permanent loss of protein and fluid. We present a case series of eleven patients undergoing central lymphatic reconstruction, consisting of one patient with a cervical iatrogenic thoracic duct lesion and eleven patients with different congenital thoracic duct lesions or thrombotic occlusions. Anastomosis of the thoracic duct and a nearby vein was performed on different anatomical levels depending on the underlying central lymphatic pathology. Cervical (n = 4), thoracic (n = 1) or abdominal access (n = 5) was used for central lymphatic reconstruction with promising results. In 9 patients a postoperative benefit with varying degrees of symptom regression was reported. The presented case series illustrates the current rapid advances in the field of central microsurgical reconstruction of lymphatic lesions alongside the relevant literature.

Immunohistochemistry and real-time Polymerase Chain Reaction: importance in the diagnosis of intestinal tuberculosis in a Peruvian population

IntroductionThe diagnosis of intestinal tuberculosis is challenging even nowadays. This study aims to report the positivity rates of new diagnostic methods such as immunohistochemistry and Real-Time Polymerase Chain Reaction in patients with intestinal tuberculosis, as well as describe the pathological and endoscopic features of intestinal tuberculosis in our population.MethodsThis was a retrospective observational study conducted in patients diagnosed with intestinal tuberculosis, between 2010 to 2023 from the Hospital Nacional Daniel Alcides Carrion and a Private Pathology Center, both located in Peru. Clinical data was obtained, histologic features were independently re-evaluated by three pathologists; and immunohistochemistry and real-time Polymerase Chain Reaction evaluation were performed. The 33 patients with intestinal tuberculosis who fulfilled the inclusion criteria were recruited.ResultsImmunohistochemistry was positive in 90.9% of cases, while real-time Polymerase Chain Reaction was positive in 38.7%. The ileocecal region was the most affected area (33.3%), and the most frequent endoscopic appearance was an ulcer (63.6%). Most of the granulomas were composed solely of epithelioid histiocytes (75.8%). Crypt architectural disarray was the second most frequent histologic finding (78.8%) after granulomas, but most of them were mild.ConclusionSince immunohistochemistry does not require an intact cell wall, it demonstrates higher sensitivity compared to Ziehl–Neelsen staining. Therefore, it could be helpful for the diagnosis of paucibacillary tuberculosis.

Phenotypes of occupational bronchial asthma from the standpoint of molecular genetic typing (polymorphisms rs2069812 of the IL-5 gene and rs1837253 of the TSLP gene)

Introduction. Currently, occupational bronchial asthma is considered as a pheno typically and genetically heterogeneous disease. Molecular genotyping opens up new op portunities in assessing the development, predicting the characteristics of the course and personalized approach to pharmacotherapy of occupational bronchial asthma, as well as in developing an individual strategy for its prevention. The purpose of the study is to determine clinical, immunological and genetic markers of the risk of developing PrAD under conditions of exposure to sensitizing substances based on the results of assessing the rs2069812 polymorphic variants of the IL5 gene and the rs1837253 polymorphic variants of the TSLP gene. Materials and methods. The study included 170 patients with various phenotypes of PBA and 50 controls. Genotyping was performed by real-time polymerase chain reaction using primers and probes designed using PrimerQuest (Intergrated DNA Technologies, Inc.). Re sults. The study identified for the first time genetic markers of PBA risk under conditions of exposure to sensitizing substances: polymorphic variants rs2069812 of the IL-5 gene and polymorphic variants rs1837253 of the TSLP gene. This allows us to recommend the deter mination of these immunological parameters and genetic markers during in-depth periodic medical examinations of people working under conditions of exposure to sensitizing and irri tating substances, for differential diagnosis of various phenotypes of occupational bronchial asthma. Limitations of the study. The study has regional (Samara region) and professional (in terms of detailing working conditions in the comparison groups studied) limitations. Conclusion. Identified genotypic features in various phenotypes of occupational bronchial asthma, established profiles of genotypes of occupational bronchial asthma can optimize the approach to early diagnosis, prognosis and prevention and pharmacotherapy of this dis ease, as well as recommend a list of genetic studies for use during preliminary and periodic medical examinations, in-depth examination of patients occupational bronchial asthma in occupational disease clinics and occupational pathology centers, to establish a genetic pre disposition to the development of occupational bronchial asthma, rational employment in professions associated with sensitizing and irritating substances.