Central Pathology Research Articles

Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial

The KEYNOTE-057 trial evaluated activity and safety of pembrolizumab in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer who were ineligible for or declined radical cystectomy. In cohort A (patients with carcinoma in situ, with or without papillary tumours) of the KEYNOTE-057 study, pembrolizumab monotherapy led to a complete response rate of 41% at 3 months, and 46% of responders maintained a response lasting at least 12 months. Here, we evaluate pembrolizumab monotherapy in cohort B of patients with papillary tumours without carcinoma in situ. KEYNOTE-057 is a single-arm, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. Cohort B eligible patients were aged 18 years and older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had BCG-unresponsive high-risk non-muscle-invasive bladder cancer with papillary tumours (high-grade Ta or any-grade T1) without carcinoma in situ. Transurethral resection of bladder tumour within 12 weeks of first pembrolizumab dose was required. Patients received pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles. Primary endpoint was 12-month disease-free survival of high-risk non-muscle-invasive bladder cancer or progressive disease as assessed by cystoscopy, cytology, and central pathology and radiology review. Activity was assessed in all patients who received at least one dose of the study drug and had a baseline evaluation. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. Between April 12, 2016, and June 17, 2021, 132 patients (104 [79%] men and 28 [21%] women) who had received a median of ten (IQR 9-15) previous BCG instillations were enrolled into cohort B of the study. Patients received a median of 10 cycles (IQR 6-27) of pembrolizumab. At data cutoff date, Oct 20, 2022, median follow-up was 45·4 months (IQR 36·4-59·3) and five (4%) of 132 patients remained on treatment. The 12-month disease-free survival was 43·5% (95% CI 34·9-51·9). Treatment-related adverse events occurred in 97 (73%) of 132 patients; 19 (14%) had a grade 3 or 4 treatment-related adverse event; the most common grade 3 or 4 treatment-related adverse events were colitis (in three [2%] patients) and diarrhoea (in two [2%]). 17 (13%) of 132 patients experienced serious treatment-related adverse events, of which colitis (three patients [2%]) was most common. No treatment-related deaths occurred. Pembrolizumab monotherapy showed antitumour activity and manageable toxicity in patients with BCG-unresponsive high-risk Ta or T1 bladder cancer without carcinoma in situ and could potentially be a suitable treatment option for patients who decline or are ineligible for radical cystectomy. Findings will need to be confirmed in a randomised controlled trial. Merck Sharp & Dohme.

Abstract PO1-14-11: Different molecular processes are associated with recurrence in the clinical high- genomic low risk (cH/gL) and clinical low- genomic high risk (cL/gH) groups of the MINDACT clinical trial

Abstract Background: Despite the growing understanding of estrogen receptor positive/HER2-negative (ER+/HER2-) breast cancer (BC) biology, many unknowns remain regarding the mechanisms of disease recurrence. While several multigene prognostic signatures have shown clinical utility in identifying those patients at high or low genomic risk of recurrence, they can present with some limitations. In this retrospective analysis of the MINDACT trial, we interrogated the available transcriptomic data to understand which biological characteristics of the tumor are associated with recurrence in patients from the clinical high- genomic low risk (cH/gL) and clinical low- genomic high risk (cL/gH) groups (where the clinical and genomic risk were defined by a modified version of Adjuvant Online! and the 70-gene signature, respectively). Methods: These analyses focused on the subset of patients with ER+/HER2- tumors of no special type (NST) who received endocrine therapy (which comprised the majority of this NST ER+/HER2- sub-cohort) and for which central pathology and gene expression data were available (n= 1245). Scores of gene expression modules associated with key biological processes in breast cancer defined in a collection of previous publications were computed from the gene expression matrix using the formula described in Desmedt et al. (Clin. Cancer Res. 2008). Gene Set Variation Analysis method (R package ‘GSVA’ – version 1.40.1) was used to derive the enrichment scores of fifty hallmark gene sets available in the ‘H’ collection of the MSigDB database (version 7.5.1). Survival analyses were performed for disease-free survival (DFS) and distant recurrence-free survival (DRFS). Univariable and multivariable regression models, implemented by Cox regression and Fine-Gray subdistribution hazard regression methods, were performed to evaluate the association of enrichment of hallmarks and gene modules with DFS and DRFS, respectively (covariates =age, nodal status, KI67, tumor size, chemotherapy, radiotherapy). Results: DFS event occurred in 150/913 (16.4%) and 51/332 (15.4%) NST ER+/HER2- patients in the cH/gL and cL/gH groups, respectively. DRFS event occurred in 70/913 (7.7%) and 21/332 (6.3%) NST ER+/HER2- patients in the cH/gL and cL/gH groups, respectively. In the cH/gL group, we observed an association of hallmarks related to cell cycle and downregulation of gene modules related to lymphocyte-centric immune activities with worse prognosis (Table). For the cL/gH, we did not observe an association between hallmarks related to cell cycle and worse prognosis but an enrichment of hallmarks related to PI3K/AKT/mTOR signaling as well as several metabolic hallmarks related to insulin activities (Table). Of interest, in this group of patients, higher scores of the HER2-associated gene expression signature were also associated with worse prognosis. Across the two groups effects were more pronounced for DRFS than DFS. Conclusion: Different molecular processes are associated with progression in these two distinct groups of patients. The association of hallmarks related to cell cycle with survival in the cH/gL group supports the observation that adjuvant chemotherapy could benefit a subset of these patients. In the cL/gH group, the association of signatures associated with PI3K pathway and HER2 can have potential clinical relevance given their current targetability in the metastatic setting. This retrospective study is funded by the Breast Cancer Research Foundation. Table. Representative hallmarks and gene expression modules independently associated with prognosis in NST ER+/HER2- patients in the cH/gL group and in the cL/gH group #p-values reported were not corrected for multiple testing Citation Format: Christine Desmedt, Ha-Linh Nguyen, François Richard, Marion Maetens, Coralie Poncet, Laura De Meulemeester, Kim Aalders, Mauro Delorenzi, Suzette Delaloge, Jean-Yves Pierga, Etienne Brain, Suzan Vrijaldenhoven, Peter A Neijenhuis, Emiel Rutgers, Florentine Hilbers, Laura Van ’t Veer, Giuseppe Viale, Christos Sotiriou, Martine Piccart, Fatima Cardoso. Different molecular processes are associated with recurrence in the clinical high- genomic low risk (cH/gL) and clinical low- genomic high risk (cL/gH) groups of the MINDACT clinical trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-14-11.

Abstract LBO1-05: Impact of age and ovarian function suppression (OFS) on endocrine response to short preoperative endocrine therapy (ET): Results from the multicenter ADAPTcycle trial (n=4,334)

Abstract Background: In HR+/HER2- early breast cancer (EBC), short preoperative endocrine therapy (ET) is a promising tool for ET-efficacy assessment based on Ki67-decrease after 2-4 weeks of ET. Low post-endocrine Ki67 (Ki67post) is associated with good prognosis in large prospective trials. WSG-ADAPT demonstrated that ET-response is a valid criterion for decisions in uncertain adjuvant chemotherapy indications, e.g., in premenopausal patients (pts) with N0 and Recurrence Score (RS, Oncotype DX®) RS 16-25 or with N1 and RS ≤25. Preliminary results from the phase III ADAPTcycle trial indicated higher efficacy of preoperative ET in premenopausal pts. if ovarian function suppression (OFS) was used together with tamoxifen (TAM) or aromatase inhibitors (AI). In the final screening population, we are now able to confirm these results and investigate the influence of age subgroups, RS, individual biological markers, and OFS on ET-response. Methods: In ADAPTcycle (n=5,290 screened, 1,670 randomized by 06/23; 84 sites in Germany), N0-1 pts with RS >25 or N2-3 pts with RS ≤25 and ET-response were randomized to (neo)adjuvant chemotherapy (CT) followed by ET vs. ribociclib + AI (premenopausal: +GnRH). In premenopausal pts, participation with N1-disease and RS ≤25 or N0 and RS 16-25 was allowed irrespective of ET-response, but randomization recommended only for ET-responders; in the preoperative phase, OFS+TAM or AI for ET-response assessment was protocol-recommended. Results: This analysis includes all pts with complete baseline characteristics (including RS) and ET-response data (n=4,334); ET-response was defined as Ki67post ≤10% (central pathology) after 2-4 weeks (if OFS: 4 weeks) of therapy. ER, PR, and HER2-levels were analyzed by IHC and mRNA. Median age was 56 years (22-87y). 55% had cT2-4 tumors; 28% had cN+ disease; 42% were G3 (central lab). Median RS was 20, median baseline Ki67 25%. n=1,368 were ≤50y and premenopausal (“≤50y”): n=314 (23.0%) and 255 (18.6%) were treated by AI+OFS and TAM+OFS, respectively. 2,966 were >50y or postmenopausal (“ >50y”), of whom 2,565 received AI (86.5%). ET-response occurred in 48.2% of “≤50y” vs. 72.7% in “ >50y” pts (p< 0.001). We observed significant differences in ET-response rates between “≤50y” vs. “ >50y” with TAM alone (34.7% vs. 46.4%); In “≤50y” pts, 55.7% ET-response occurred with TAM+OFS vs. 76.4% with AI+OFS, comparable to 76.8% in “ >50y” patients with AI. Moreover, OFS led to higher ET-response rates (by uni- and multivariable analysis) even in the small (n=78) group of premenopausal pts >50y. Remarkably, even in pts with RS >25, substantial ET-response rates were observed with AI: 66.7% (“≤50y”, AI+OFS), 55.6% (“ >50y”, AI) vs. lower rates with TAM alone (>50y: 18.2%; < 50y: 15.8%). ET-response rate in “≤50y” pts was associated with ET type, RS, and baseline Ki67 in both uni- and multivariable analysis, but not age subgroup (≤40 vs. 41-50y). ER, PR, and HER2 expression by IHC or RT-PCR were associated with ET-response by univariable (but not multivariable) analysis. In “ >50y” pts, by uni- and multivariable analysis, again ET-type, RS, and baseline Ki67, as well as ER-expression (by IHC) and ESR1, PR, and HER2-expression (by RT-PCR) were associated with higher ET-response rates. Conclusions: With about 10,000 pre- and postmenopausal pts, ADAPT and ADAPTcycle provide the largest international database regarding ET-response. ADAPTcycle confirms ADAPT ET-response rates in pts receiving TAM or AI; adding OFS to either improves ET-response, irrespective of RS. ET-response measurement adds value in therapy decisions, particularly in ≤50y N0-1 pts. ET-response might provide key information even in pts with high RS; outcome data of ADAPTcycle will reveal potential clinical consequences. Optimal preoperative ET, especially in premenopausal pts, might even enable sparing chemotherapy in additional pts. Citation Format: Oleg Gluz, Matthias Christgen, Ulrike Nitz, Sherko Küemmel, Michael Braun, Marc Thill, Rachel Wuerstlein, Pauline Wimberger, Andreas Hartkopf, Christian Schem, Matthias Zaiss, Vesna Bjelic-Radisic, Marianne Just, Kristina Veselinovic, Myriam Vincent, Monika Graeser, Katja Krauss, Oliver Hoffmann, Kerstin Lüdtke-Heckenkamp, Ronald Kates, Christine zu Eulenburg, Katarzyna Jozwiak, Sandy Burmeister, Rick Baehner, Peter Schmid, Hans-Heinrich Kreipe, Nadia Harbeck. Impact of age and ovarian function suppression (OFS) on endocrine response to short preoperative endocrine therapy (ET): Results from the multicenter ADAPTcycle trial (n=4,334) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr LBO1-05.

Abstract PS16-01: Comparison of an Atezolizumab monotherapy window followed by Atezolizumab and chemotherapy vs. Atezolizumab and chemotherapy alone in triple negative breast cancer (TNBC) – final analysis of the neoadjuvant neoMono trial

Abstract Background: Improvement of systemic therapy of TNBC still is a medical need. Exploratory data from the neoadjuvant GeparNuevo trial suggested a benefit from an immune checkpoint inhibitor (ICI) monotherapy window in TNBC. The neoMono trial prospectively analyzed whether the addition of a preceding Atezolizumab monotherapy window prior to Atezolizumab and chemotherapy (CTX) improves pCR rates among patients (pts) with early TNBC. In an interim analysis after 100 pCR events, patients with unselected TNBC did not show a significant benefit from an Atezolizumab monotherapy window, while an exploratory analysis suggested a highly clinically relevant benefit among pts with PD-L1 positive TNBC. Here we present the final primary endpoint analysis. Methods: NeoMono is a phase 2 randomized multicenter trial that was planned to recruit a maximum of 458 female and male pts with primary TNBC (defined as ER/PR < 10% and HER2 negative) with tumor stages cT1c – cT4d (cN0 and cN+). As the protocol mandated termination of trial recruitment based on the results of the interim analysis, the final ITT population was limited to 359 pts. PD-L1 status had to be identifiable by central pathology by means of the VENTANA PD-L1 (SP142) assay and was defined by PD-L1 expression on immune cells (IC). Neoadjuvant treatment in both study arms consisted of Atezolizumab 1200 mg every 3 weeks in addition to neoadjuvant CTX (12 x Carboplatin/Paclitaxel q1w followed by 4x Epirubicin/Cyclophosphamide q3w). Combination therapy in arm A was preceded by an Atezolizumab monotherapy window of 840 mg once two weeks prior to initiation of combination therapy, while patients in arm B received no immune monotherapy window. Study goals are to compare the efficacy of neoadjuvant CTX + Atezolizumab with versus without a two-week atezolizumab monotherapy window preceding CTX + ICI (primary endpoint: pCR) and to identify biomarkers for response and resistance through analysis of sequential tissue and liquid biopsies. The neoMono statistical design uses Bayesian posterior probabilities (uniform prior distribution) and logistic regression to analyze the primary endpoint. Results: 180 pts in arm A and 179 in arm B from 34 study sites were included in the final primary endpoint analysis. Demographics and baseline characteristics as well as drug exposure were well-balanced in both arms. Posterior mean pCR rates in the ITT population in study arms A and B were 65.7% (95% high posterior density interval (HPDI): 58.5%, 72.5%) and 69% (62.2%, 75.9%), respectively. In an exploratory analysis stratified by PD-L1 IC status (negative: < 1% versus positive: ≥ 1%), pCR rates in arm A were 91.5% in the PD-L1 IC-positive group and 56.1% in the PD-L1 IC-negative group, the corresponding pCR rates in arm B were 82.2% and 64.5%, respectively. In a multivariate analysis of the ITT population including tumor size, nodal status, tumor grade, age and PD-L1 status, the odds ratio for achieving a pCR was 4.77 (p < 0.001) for PD-L1-positive and 2.36 (p=0.023) for grade 3 tumors. In an exploratory analysis including HER2 status, odds for achieving a pCR were significantly higher for patients with HER2-negative (IHC 0) vs. HER2-low tumors (OR 1.73, p=0.036). No new safety signals were observed. Conclusion: The final primary endpoint analysis of the neoMono trial demonstrated the highest pCR rates ever reported in a phase II/III trial in TNBC. While a significant impact of an ICI monotherapy window on the pCR rate after combination of CTX + ICI in an unselected ITT population could not be demonstrated, neoMono indicates for the first time in a randomized prospective setting that patients with immune active TNBC might derive particular benefit from a preceding ICI monotherapy window. The results of the neoMono trial are mainly justifying the conduction of a confirmative trial in immune active TNBC. However, our results underscore the potential role of pre-therapeutic ICI monotherapy window as part of future therapeutic concepts in TNBC. Citation Format: Hans-Christian Kolberg, Johannes Schumacher, Ramona Erber, Michael Braun, Peter A. Fasching, Eva-Maria Grischke, Christian Schem, Michael P. Lux, Mustafa Deryal, Oliver Hoffmann, Bernhard Heinrich, Georg Kunz, Kristina Lübbe, Petra Krabisch, Arndt Hartmann, Philip Raeth, Sabine Kasimir-Bauer, Cornelia Kolberg-Liedtke. Comparison of an Atezolizumab monotherapy window followed by Atezolizumab and chemotherapy vs. Atezolizumab and chemotherapy alone in triple negative breast cancer (TNBC) – final analysis of the neoadjuvant neoMono trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS16-01.

Case Report: Pendular Nystagmus Presenting in Usher Syndrome Type I.

We describe a 42-year-old patient with reported "shaking" vision referred due to concerns of possible vestibular system dysfunction. The patient has known history of Usher syndrome type I, bilateral cochlear implants, and severe vision impairment. This case describes an unusual nystagmus previously only reported in individuals with central demyelinating disorders, significant light deprivation, or in congenital / early-onset visual pathway impairment. Case study. Retrospective chart review of vestibular function. Vestibular function was likely absent in this case. There was no evidence of vestibular (jerk) nystagmus for sinusoidal harmonic acceleration stimuli or repeatable responses for cervical vestibular evoked myogenic potentials. Significant pendular low amplitude high frequency oscillations of approximately 6 Hz were present for horizontal and vertical tracings throughout testing. Nystagmus may not always be associated with vestibular system impairment. In this case, the patient's reported "shaking" vision was attributed to pendular low amplitude high frequency nystagmus and hypothesized to relate to long-standing significant vision impairment. This presentation is unusual in adults and has historically been associated with individuals with significant central pathology or in those with long duration light deprivation.

Abstract PO5-19-01: The HER2-RADiCAL study (Response ADaptive CAre pLan) – Tailoring treatment for HER2 positive early breast cancer

Abstract Background The presence or absence of residual disease following neoadjuvant systemic anti-cancer therapy (neoSACT) for HER2-positive early breast cancer (HER2+ EBC) provides powerful prognostic information. Pathological complete response (pCR) following neoSACT, particularly in patients with earlier clinical TNM stage at diagnosis, identifies a population with excellent survival outcomes in whom the balance of toxicity associated with the current treatment pathway may be disproportionate to absolute clinical benefit. Aims >HER2-RADiCAL seeks to reduce the treatment burden and healthcare costs of treating HER2+ EBC by testing the hypothesis that pCR can be used as a functional response biomarker to select patients who can safely receive less systemic therapy with minimal/no loss of efficacy. Trial design and eligibility criteria HER2-RADiCAL is a response-directed interventional cohort/threshold-crossing design study embedded within a real-world data-driven clinical pathway model. Patients with ER-positive or negative HER2+ EBC with cT1N1 or cT2N0-1 stage at diagnosis are eligible after completion of standard of care neoSACT and locally determined pCR (ypT0/Tis ypN0). Patients with pathological features consistent with previous malignant involvement in >4 nodes are not eligible. Adjuvant trastuzumab +/- pertuzumab may have continued prior to study entry provided no more than 9 cycles of trastuzumab are received. After registration all participants receive a total of 9 cycles of trastuzumab including those administered prior to study entry. Participants receive no further pertuzumab and no adjuvant chemotherapy. Adjuvant endocrine therapy and radiotherapy are given as per standard of care. Central pathology review of pCR status will be conducted in a subset of cases. A Study Within a Trial (SWAT) will explore identification of factors influencing patient decision-making for participation in studies of response-adapted treatment. Statistical methods The primary endpoint is relapse-free interval. Recruitment of 720 participants over 3.5 years will provide 90% power to exclude an event rate >6.5% at 3 years (expected event rate ≤4%). Secondary endpoints include relapse-free survival, invasive breast cancer-free survival, invasive disease-free survival, distant recurrence-free interval, breast cancer-free interval, overall survival, treatment pathway adherence and cost-effectiveness. An interventional cohort is preferred to a randomised non-inferiority trial based on the known event rate in this population which is sufficiently low such that any deviation from this expected event rate would indicate failure of the reduced therapy strategy. Real-world data driven clinical pathway model Health economic modelling will compare the protocol-driven study cohort with two comparator pathways: a non-response adapted maximum therapy pathway (the standard clinical pathway prior to the study) and a real-world representative pathway derived from anonymised data for all patients treated for HER2+ EBC within the UK NHS. Patient and public involvement Our PPI partners continue to shape this research, holding key roles as trial management group members, overseeing progress of the study, contributing to protocol amendment development, and design and implementation of the SWAT. Current status The first patient was enrolled in December 2021. At 10th July 2023, 25 research sites have opened with 39 participants recruited. Site opening continues with a minimum target of 40. Responding to continued use of anthracycline-based regimens in UK practice, eligibility criteria have recently been extended to permit entry of patients who have received anthracycline-containing neoSACT. For further information contact her2radical-icrctsu@icr.ac.uk. Citation Format: Iain Macpherson, Stuart McIntosh, Lucy Kilburn, Holly Tovey, Laura Moretti, Katie Goddard, Indrani Bhattacharya, Clinton Boyd, Cliona Kirwan, Ciara O'Brien, Duncan Wheatley, Jennifer Glendenning, Mairead MacKenzie, Hilary Stobart, Claire Snowdon, Andrew Wardley, Abeer Shaaban, Peter Hall, David Cameron, Judith Bliss. The HER2-RADiCAL study (Response ADaptive CAre pLan) – Tailoring treatment for HER2 positive early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-01.

Abstract PS09-02: Event-free Survival by Residual Cancer Burden (RCB) and Intratumor HER2 Heterogeneity after Neoadjuvant T-DM1 and Pertuzumab for Early-stage HER2-positive Breast Cancer

Abstract Background: Intratumor HER2 heterogeneity (ITH-HER2) predicates resistance to targeted anti-HER2-based therapy, and understanding its impact on response to HER2-directed therapies is particularly important with regimens that rely solely on targeted anti-HER2 therapies without chemotherapy. Methods: To determine the effect of ITH-HER2 on response to therapy, we conducted a single-arm phase II study in which patients (pts) with centrally confirmed HER2+ early-stage breast cancer received six cycles of preoperative T-DM1 plus pertuzumab. Baseline image-guided biopsies allowed central pathology evaluation of ITH HER2, defined as an area with HER2 amplification in >5% but < 50% of tumor cells or a HER2-negative area by FISH. The study met its primary endpoint by demonstrating inferior pathologic complete response (pCR) measured by Residual Cancer Burden (RCB) in the subset of ITH-HER2 pts. Single-cell ERBB2 FISH analysis identified the fraction of ERBB2 nonamplified cells as a factor associated with therapeutic resistance (Metzger et al. Cancer Discovery 2021). Secondary endpoints included event-free survival (EFS), invasive disease-free survival (iDFS), and breast cancer-specific survival (BCSS) by ITH-HER2 status and RCB scores. Results: 163 pts were enrolled and received treatment in the study from Jan 2015 to Jan 2018. Central pathology evaluation of HER2 heterogeneity was successful in 96% (157/163) of cases, with 16 classified as ITH-HER2. RCB-0 or -I rate in the ITH-HER2 vs. not was (25% v. 67%, OR = 5.6, p = 0.002). Median follow-up, including all treated pts (n =163), was 65.4 months (IQR, 60.3-76.6). The 5yr EFS, iDFS, and BCSS were 91% [86.5% - 95.6%], 89.4% [84.5% - 94.5%], and 96% [92.9% - 99.2%], respectively. ITH-HER2 was associated with numerically inferior outcomes for EFS, iDFS, and BCSS (Table 1). The subset of pts with non-ITH-HER2 at baseline (n= 141) and RCB-0 or -I (n = 95/141, 67%) had a 5-yr IDFS of 94.2% [89.3% - 99.3%]. A sensitivity analysis describing survival outcomes by chemotherapy use in the adjuvant setting will be presented at the meeting, along with translational research results evaluating the association of HER2DX assay with pCR and survival outcomes. Conclusions: The inferior pCR rates among cases classified as ITH-HER2 translated into numerically inferior outcomes for both EFS and iDFS. The number of events is small; therefore, our results are exploratory. Selecting pts whose tumors lack ITH-HER2 can increase the chances of achieving RCB 0/I with neoadjuvant TDM1 + pertuzumab. Neoadjuvant TDM1 + pertuzumab, followed by adjuvant HER2-directed therapy without classic chemotherapy agents, could represent an optimal regimen for non-ITH-HER2 pts experiencing RCB 0/I at the time of surgery and deserves further study. Table 1. 5-year survival estimates by ITH-HER2 Citation Format: Otto Metzger, Se Eun Kim, Nabihah Tayob, Giuseppe Viale, Denise Yardley, Aleix Prat, Vandana Abramson, Laura Spring, Adrienne Waks, Eileen Wrabel, Michelle DeMeo, Aditya Bardia, Patrizia Dell'Orto, Leila Russo, Tari King, Franziska Michor, Eric Winer, Kornelia Polyak, Sara Tolaney, Ian Krop. Event-free Survival by Residual Cancer Burden (RCB) and Intratumor HER2 Heterogeneity after Neoadjuvant T-DM1 and Pertuzumab for Early-stage HER2-positive Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS09-02.

Abstract GS01-03: Adding atezolizumab to adjuvant chemotherapy for stage II and III triple-negative breast cancer is unlikely to improve efficacy: interim analysis of the ALEXANDRA/IMpassion030 phase 3 trial

Abstract Background: Early stage triple negative breast cancer (TNBC) is associated with a high risk of distant relapse. ALEXANDRA/IMpassion030 is a global, prospective, randomized, open-label, phase 3 trial that investigated the efficacy, safety and pharmacokinetic profile of adjuvant atezolizumab plus standard anthracycline/taxane chemotherapy (arm A) versus chemotherapy alone (arm B) in early-stage TNBC. Methods: ALEXANDRA/IMpassion030 (NCT03498716) aimed to randomize (1:1) 2300 patients with operable stage II-III TNBC, confirmed by central pathology review. Patients were stratified by type of surgery (breast conserving versus mastectomy), nodal status (0 versus 1-3 versus >=4 nodes), and centrally assessed PD-L1 status (IC 0 vs >=1% ). Adjuvant chemotherapy consisted of weekly paclitaxel 80 mg/m2 for 12 weeks followed by dose dense anthracycline (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2) and cyclophosphamide 600 mg/m2 for 4 doses every 2 weeks given concomitantly with atezolizumab 840 mg every 2 weeks followed by maintenance atezolizumab 1200 mg every 3 weeks until completion of 1 year of atezolizumab (Arm A) or the same chemotherapy regimen (T-EC/AC) alone (Arm B). The primary endpoint was invasive disease-free survival (iDFS); secondary endpoints included, iDFS in the PD-L1 positive and lymph node-positive subpopulations, overall survival, safety, patient functioning and health related quality of life (HRQoL). On the 14th of November 2022, following an IDMC recommendation, the study accrual was temporarily stopped. In February 2023, the protocol was amended in order for the IDMC to perform an early interim analysis of efficacy and futility, at approximately 62% of the planned (390) iDFS events. The futility boundary was set to a Hazard Ratio (HR) > 1. Results: The IDMC recommendations of 15th March 2023 reported that the primary endpoint crossed the futility boundary, accrual to the study was permanently stopped and the experimental treatment was discontinued. Between August 2018 and November 2022, the study enrolled 2199 patients, with 1101 randomised to the atezolizumab arm (A) and 1098 to the control arm (B). At a median follow-up of 25.3 months, 239 (10.9%) iDFS events were observed in the 2199 enrolled patients; 127 versus 112 iDFS events were observed (61.3% of 390) in the A versus B arms respectively, HR 1.12, (95% confidence interval, CI, 0.87, 1.45). In the PD-L1 positive subgroup, (1567/2199 patients, 71.3%), 77 versus 73 iDFS events were observed in the A versus B arms respectively, HR 1.03, (95% CI 0.75, 1.42). Among patients with lymph node positive tumors (1066/2199 patients, 48.5%), 86 versus 66 iDFS events were observed in the A versus B arm respectively, HR 1.41, (95% CI 1.02, 1.96). Incidence of adverse events grade >=3 was 58.01% versus 48.15% in the A versus B arms, including death in 1.01% (11) and 0.55% (6) of patients, respectively. Conclusions: Crossing the pre-specified futility boundary of HR > 1 provides evidence that adjuvant atezolizumab is very unlikely to improve invasive disease-free survival when added to adjuvant anthracycline and taxane based chemotherapy in patients with stage II-III triple-negative breast cancer. With longer treatment exposure in the atezolizumab arm (A), adverse events were more frequent but consistent with the atezolizumab safety profile. No new or unexpected safety issue was identified. Citation Format: Michail Ignatiadis, Andrew Bailey, Heather McArthur, Sarra El-Abed, Evandro de Azambuja, Otto Metzger, Steve Chui, Max Dieterich, Thomas Perretti, Guenther Steger, Jacek Jassem, Soo Chin Lee, Michaela Higgins, José Zarbá, Marcus Schmidt, Henry Gomez, Angel Guerrero-Zotano, Luca Moscetti, Joanne Win Yang Chiu, Carter DuFrane, Vanessa Honvault, Rosa Altarcheh, Luciana Molinero, Andrew Ellingson, Elisabetta Munzone, Noa Efrat Ben-Baruch, Emilio Bajetta, Shinji Ohno, Seock-Ah Im, Gustavo Werutsky, Einav Gal-Yam, Xavier Gonzalez-Farré, Ling-Ming Tseng, William Jacot, Oleg Gluz, Zhimin Shao, Yaroslav Shparyk, Ivan Sinielnikov, Zimina Anastasia, Aleksandr Vasiliev, Esther Shearer-Kang, Eric Winer, Diogo Martins-Branco, Shona Fielding, David Cameron, Giuseppe Viale, Shigehira Saji, Richard Gelber, Martine Piccart. Adding atezolizumab to adjuvant chemotherapy for stage II and III triple-negative breast cancer is unlikely to improve efficacy: interim analysis of the ALEXANDRA/IMpassion030 phase 3 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS01-03.

Abstract PO3-18-10: Impact of age and ovarian function suppression (OFS) on endocrine response to short preoperative endocrine therapy (ET): Results from the multicenter WSG-ADAPTcycle trial (n=5,290)

Abstract Background In HR+/HER2- early breast cancer (EBC), short preoperative endocrine therapy (ET) offers a promising tool for assessment of ET-efficacy based on Ki67-decrease after 2-4 weeks of treatment. Low post-endocrine Ki67 (Ki67post) is associated with good prognosis in several large prospective trials. WSG-ADAPT demonstrated that Ki67post is a promising tool for decision making in cases with uncertain adjuvant chemotherapy indication, e.g., in premenopausal patients (pts.) with N0 and Recurrence Score (RS, Oncotype DX®) RS 16-25 or N1 and RS ≤25. Preliminary results from the phase III ADAPTcycle trial indicated higher efficacy of preoperative ET in premenopausal pts. if ovarian function suppression (OFS) was used together with tamoxifen (TAM) or aromatase inhibitors (AI). In the ADAPTcycle screening population, we are now able to validate these results and investigate the influence of age subgroups, Recurrence Score, and individual biological markers, as well as OFS on ET-response. Methods In ADAPTcycle (n=5,290 screened until 06/23 at 84 sites in Germany), N0-1 pts. with RS >25 or N2-3 pts with RS ≤25 and ET-response (Ki67post ≤10%) were randomized to (neo)adjuvant standard chemotherapy (CT) or ribociclib + AI +/- GnRH-analog (n=1,670 randomized). Participation of premenopausal pts. with N1-disease and RS ≤25 or N0 and RS 16-25 was allowed irrespective of ET-response, but randomization recommended only for ET-responders. Use of OFS + TAM or AI for ET response assessment in the preoperative phase was protocol-recommended. This analysis includes all patients with baseline RS and data on ET-response. Ki67-response is defined as Ki67post ≤10% (central pathology assessment) after 2-4 weeks of therapy (OFS-use recommended for 4 weeks). ER-, PR-, and HER2-levels are analyzed by IHC and mRNA. Results Results on ET-response according to age and clinicopathological as well as tumor biological characteristics will be presented at the meeting. So far, ADAPTcycle with >5,000 pts. screened is the largest trial worldwide to look at ET response assessment in pre- and postmenopausal pts. with HR+/HER2- EBC. The results thus have the potential to impact clinical practice. Contact Information oleg.gluz@wsg-online.com Citation Format: Oleg Gluz, Matthias Christgen, Ulrike Nitz, Sherko Küemmel, Michael Braun, Marc Thill, Rachel Wuerstlein, Pauline Wimberger, Andreas Hartkopf, Christian Schem, Matthias Zaiss, Vesna Bjelic-Radisic, Marianne Just, Kristina Veselinovic, Myriam Vincent, Monika Graeser, Katja Krauss, Oliver Hoffmann, Kerstin Lüdtke-Heckenkamp, Ronald Kates, Christine zu Eulenburg, Peter Schmid, Rick Baehner, Hans-Heinrich Kreipe, Nadia Harbeck. Impact of age and ovarian function suppression (OFS) on endocrine response to short preoperative endocrine therapy (ET): Results from the multicenter WSG-ADAPTcycle trial (n=5,290) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-10.

Abstract PO4-05-06: Hormone receptor-positive HER2-low metastatic breast cancer (mBC): evolution of HER2 status after CDK4/6 inhibitor treatment

Abstract Background Trastuzumab deruxtecan (T-DXd) is approved for HER2-low but not HER2-0 mBC. Therefore, identifying HER2-low status is of great clinical importance. Prior studies have shown HER2-low status is dynamic between primary tumor and metastatic relapse and between primary tumor and post-neoadjuvant chemotherapy residual tumor, and expert recommendations are to reiterate biopsies throughout the course of the disease. However, there is no data on when to repeat these biopsies. We provide here the first data on the evolution of HER2-low status in hormone receptor-positive (HR+) mBC before and after endocrine therapy (ET) in association with CDK4/6 inhibitor (CDK4/6i). Methods: Patients with pre-CDK4/6i+ET tumor biopsy were identified from a single large academic center database. Patients with unknown HER2 status were excluded. Pathological, clinical, and demographic data were extracted from clinical files. HER2-low was defined as HER2 IHC 1+, or 2+ with non-amplified HER2 by ISH, and HER2-0 by IHC score of 0+. Pathology central review for all paired pre- and post-treatment biopsies was performed by three expert breast cancer pathologists. Results: 304 consecutive patients with HR+/HER2- mBC treated with CDK4/6i+ET and who had immediate pre-treatment biopsy were included. Of these, 117 (38%) were HER2-0, and 187 (62%) were HER2-low. Clinical and demographic data did not differ between both groups. Patients received CDK4/6i+ET as first-line treatment in 48% of cases. Among this cohort, 49 patients had paired biopsies immediately after CDK4/6i+ET treatment. The discordance rate between pre- and post-CDK4/6i+ET HER2-status was 51% with 64% of HER2-0 patients becoming HER2-low and 38% of HER2-low switching to HER2-0. Among the 49 patients with paired biopsies, 43 had available material to perform a central pathology review. Of these, 22 (51%) were HER2-0, and 21 (49%) were HER2-low. Central pathology review showed a concordance level of 82% with pathology records, resulting in a modification of HER2 status in 7 HER2-0 patients as HER2-low, leading to a total of 65% of patient’s eligibility to T-DXd. Post-CDK4/6i+ET biopsy identified a switch to HER2-low in 10 additional HER2-0 patients resulting in a total of 38/43 (88%) candidates to T-DXd. No case became HER2 3+ after treatment. Neither baseline HER2 status, nor change in HER2 status after treatment affected the clinical outcome on CDK4/6i+ET (objective response, progression-free survival, overall survival). Conclusion: HER2-low status is dynamic, and 64% of mBC HER2-0 patients switched to HER2-low after a line of CDK4/6i+ET treatment. Since such a switch would guide post-progression treatment with T-DXd in patients initially not candidate, these results suggest that biopsy should be repeated early in the course of mBC to assess eligibility for T-DXd therapy. Our central pathology review of pre-treatment biopsies reclassified 24% of HER-0 patients as HER2-low, suggesting that pathology review is a legitimate first step before repeating biopsy or in the case of difficulty to re-biopsy. In our series, 88% of patients had a biopsy sample classified as HER2-low after pathological review of pre-treatment slides, followed by post-CDK4/6i+ET rebiopsy of HER2-0 cases. Citation Format: Alexandre de Nonneville, Pascal Finetti, Laurys Boudin, Lucas Usclade, Lenaïg Mescam, Emeline Durieux, Agathe Boucraut, Frederic Viret, Emilie Mamessier, Anthony Gonçalves, François Bertucci. Hormone receptor-positive HER2-low metastatic breast cancer (mBC): evolution of HER2 status after CDK4/6 inhibitor treatment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-05-06.

Центр патологии сетчатки в рамках новой модели организационной структуры по профилю «Офтальмология» при диабетической ретинопатии.

Relevance. The most serious consequences of the global epidemic of diabetes are its systemic vascular complications, one of which is diabetic retinopathy as the most common cause of visual function loss among diabetic patients and the leading cause of blindness and visual impairment among the working population. However, with a well-organized screening system and early detection of this complication, more than 80% of cases of blindness and visual impairment can be prevented or treated. One of such approaches is the establishment of a specialized ophthalmological Center, which will elevate medical care for patients with diabetes complications to a qualitatively new level. Purpose of the study is to evaluate the functional role of the created retinal pathology centre within the framework of the new information and technological model of medical care in the profile «ophthalmology» for diabetic retinopathy in the Tomsk region. Materials and methods. The data of the federal statistical observation form No. 12 were used as materials. Statistical analysis methods: analytical; descriptive statistical method. The critical level of significance was set at p <0.05 (95%). Data processing was carried out using electronic spreadsheets «MSOffice Excel 2010» and the application package «Statistica» for Windows 10.0. Results. In the Tomsk region, a project is being implemented to introduce a unified organizational model of telemedicine service for monitoring diabetic retinopathy based on artificial intelligence technology, including a regional expert Center for retinal pathology as the main organizational and methodological unit, operating in close collaboration with healthcare institutions in the Tomsk region. Тhe Center’s task is early detection of diabetic retinopathy with further organizational and methodological support for identified cases. The activities of the Center are regulated by regional legal documentation aimed at regulating its work and adapting a new patient routing scheme for patients with diabetic retinopathy. The expected results of the project will reduce the predicted visual disability due to diabetic retinopathy in the Tomsk region to 80%, which will have a positive impact on the main performance indicators of the ophthalmological service in the region. Findings. The model allows for the integration of the Center for Retinal Pathology, prevention rooms of medical organizations, including remote municipal entities of the Tomsk region, equipped with ophthalmological fundus cameras for digital retinal photography, the ability to exchange data between networked medical organizations and the Center for Retinal Pathology. All these organizational changes will have a positive impact on reducing the overall prevalence of diabetic retinopathy in the region.

Genomic Profiling of Rare Undifferentiated Sarcomatoid Subtypes of Pancreatic Carcinomas: In Search of Therapeutic Targets

PURPOSE The highly aggressive undifferentiated sarcomatoid carcinoma (USC) subtype of pancreatic ductal adenocarcinoma (PDAC) remains poorly characterized because of its rarity. Previous case reports suggest that immune checkpoint inhibitors could be a promising treatment strategy, but the prevalence of established predictive biomarkers of response is largely unknown. The objective of this study was to leverage comprehensive genomic profiling of USC PDAC tumors to determine the prevalence of biomarkers associated with potential response to targeted therapies. METHODS USC tumors (n = 20) underwent central pathology review by a board-certified gastrointestinal pathologist to confirm the diagnosis. These samples were compared with non-USC PDAC tumors (N = 5,562). Retrospective analysis of DNA and RNA next-generation sequencing data was performed. RESULTS USC PDACs were more frequently PD-L1+ by immunohistochemistry than non-USC PDAC (63% v 16%, respectively, P < .001). Furthermore, USC PDAC had an increase in neutrophils (8.99% v 5.55%, P = .005) and dendritic cells (1.08% v 0.00%, q = 0.022) and an increased expression of PDCD1LG2 (4.6% v 1.3%, q = 0.001), PDCD1 (2.0% v 0.8%, q = 0.060), and HAVCR2 (45.9% v 21.7%, q = 0.107) than non-USC PDAC. Similar to non-USC PDAC, KRAS was the most commonly mutated gene (86% v 90%, respectively, P = 1). CONCLUSION To our knowledge, this work represents the largest molecular analysis of USC tumors to date and showed an increased expression of immune checkpoint genes in USC tumors. These findings provide evidence for further investigation into immune checkpoint inhibitors in USC tumors.

Prevalence and Antimicrobial Sensitivity Patterns of Uropathogens in Wad Medani, Sudan: A Three Years, Cross-Sectional Study.

Urinary tract infections exert a significant negative impact on an individual's quality of life and cause significant economic and public health burdens. Therefore, this study was conducted to identify the common bacterial uropathogens associated with urinary tract infections in Wad Medani patients and their susceptibility to antibiotics. This was a cross-sectional study. All urine samples were collected from patients at Wad Medani and investigated at the Pathology Center for Diagnosis and Research, Faculty of Medicine, University of Gezira, Sudan, from the 1st of January 2021 to the 15th of October 2023. A total of 2698 urine samples were analyzed during the three years study period, with a mean age of 45.29 ± 18.9 years. Among these patients, 1108 (41.8%) were positive for bacterial growth, and 888 (80.14%) were female. A total of 522 (47.1%) were gram positive bacteria (GPB), and 586 (52.9%) were gram negative bacteria (GNB). The most frequently isolated bacteria were S. aureus 42% (465/1108) and E. coli 38.5% (427/1108), while P. aeruginosa was less detected 3.4% (38/1108). Amikacin 91.5% was the most sensitive drug to isolated GPB, while cotrimoxazole 20.9% was the least sensitive drug. In particular, amikacin 94.1% (144/153) was the most sensitive drug to S. aureus, while cotrimoxazole 20.7% (80/386) was the least sensitive drug. Moreover, amikacin 91.5% was the most sensitive drug to the isolated GNB, while ampicillin 5.7% was the least sensitive drug. Notably, amikacin was the most sensitive drug to all the isolated GNB, and ampicillin was the least sensitive drug to all the isolated GNB. This study reported a moderate uropathogen isolation rate of 41.8%. S. aureus and E. coli were the most frequently isolated bacteria, most of which were from female patients. Remarkably, amikacin was the most sensitive drug to isolated GNB and GPB.

Client and staff perceptions of acceptability of MyCheck: a direct-to-pathology telehealth and e-testing service for comprehensive bloodborne virus and sexually transmissible infection screening.

Background Sydney Sexual Health Centre (SSHC) is the largest sexual health clinic in New South Wales (NSW), servicing clients at high risk of sexually transmissible infections and bloodborne viruses. SSHC piloted a direct-to-pathology pathway that facilitated bloodborne virus/sexually transmissible infection testing at one of the ~500 participating pathology collection centres located across NSW. This qualitative study sought to understand SSHC client and provider perspectives of acceptability of the MyCheck intervention. Methods Semi-structured in-depth interviews were conducted with 11 clients who underwent testing via the MyCheck pathway and eight staff members involved in implementing MyCheck. The seven components of Sekhon's Theoretical Framework of Acceptability informed this analysis. Results Participants broadly conveyed 'affective attitude' toward the MyCheck pathway. The telehealth intervention reduced client 'burden' and 'opportunity cost' through enabling greater testing convenience at a location suitable to them and provided timely results. Issues of 'ethicality' were raised by clients and staff as pathology centre staff were, on a few occasions, regarded as being judgmental of SSHC clients. 'Intervention coherence' issues were largely attributed to pathology centre personnel being unfamiliar with the intervention, with billing issues being a recurrent concern. Participants perceived MyCheck as an 'effective' testing pathway. SSHC staff were able to offer the intervention with ease through seamless IT integration ('self-efficacy'). Conclusion The MyCheck intervention was perceived by both SSHC clients and staff as an acceptable bloodborne virus/sexually transmissible infection testing pathway. However, further work is required to address stigma experienced by some clients when attending pathology collection centres.

Testicular Regression Syndrome: Histopathological Evaluation of 20 cases from Rural India with Review of Literature

ABSTRACT Context: Testicular regression syndrome (TRS), clinically termed “vanishing testes,” is a condition with atrophy of testes in late fetal or early neonatal life. The spermatic cord ends blindly or into a small fibrovascular nubbin. Histopathology reveals a fibrovascular nodule with associated hemosiderin-laden macrophages and dystrophic calcification. Few cases show the presence of seminiferous tubules and germ cells. The presence of germ cells is associated with the risk of developing a testicular germ cell tumor. Aims: To study the histopathological features of testicular nubbins and to determine the presence of germ cells and associated neoplasm. Settings and Design: It is a retro-prospective observational study carried out on patients referred to a pediatric surgical pathology center in Miraj, who were clinically diagnosed with undescended testis, over a period of 1 year. Data were collected after the study was approved by the IEC-MGCH on December 19, 2022. Materials and Methods: Twenty patients diagnosed with cryptorchidism, undescended testis, or atrophic testis were included. Findings of hematoxylin and eosin-stained slides of each case were noted, and Prussian Blue (special staining) was performed in four cases. Statistical analysis used: As this is a descriptive observational study, simple arithmetic calculations were performed. No unique statistical analysis was performed. Results: Among twenty cases of vanishing testes syndrome, 20 cases showed fibrovascular tissue only, and 1 case showed the presence of seminiferous tubules with Sertoli cells. Conclusions: Vanishing testes syndrome is a rare condition that is difficult to diagnose on clinical examination, and a definitive diagnosis may be missed if the pathologist is unaware of the condition. Also, there is a risk of germ cell tumor if there are residual germ cells in the testicular nubbin.

Dendritic cell subpopulations in carcinoma ex-pleomorphic adenoma: A multicenter study.

Carcinoma ex-pleomorphic adenoma (CEXPA) represents a malignant transformation from a recurrent or primary pleomorphic adenoma (PA), and the immune response may be essential in this process. Therefore, in this study, we aimed to identify and quantify subpopulations of dendritic cells (DCs) in CEXPA, residual PA in CEXPA (rPA), and PA. A multicenter study was performed collecting salivary gland tumor (SGT) samples from three Oral and Maxillofacial Pathology Centers. A tissue microarray containing 41 samples of CEXPA and 22 samples of PA was included in this study and submitted to immunohistochemical reactions against CD1a, CD83, CD207, and Ki67 antibodies. Both PA and rPA showed a higher quantification of CD207+ and CD83+ cells when compared to CEXPA (p < 0.001 and p < 0.01, respectively). There was also a difference when comparing the cell proliferation index between PA/rPA and CEXPA using the Ki-67 marker (p = 0.043). However, there was no difference in the DC population regarding clinical parameters such as sex, anatomical location, size, and metastases (p > 0.06). Immunohistochemical profile of DC subpopulations and cell proliferation biomarkers in SGTs can contribute as an important tool in the differentiation of benign and malignant tumors or detection of initial areas with malignant transformation.

Evaluation of Masseteric Vestibular Evoked Myogenic Potentials in Patients With Migraine.

Masseter vestibular evoked myogenic potentials (mVEMP) involve the connection between the vestibular complex and trigeminal nerve nuclei. Given the theory that migraine is caused by increased activation of the trigeminal nerve, it is believed that mVEMP responses may have influenced in migraine patients. The study included 20 individuals with migraine and 20 healthy controls. Latency, amplitude, and interaural amplitude asymmetry ratio of mVEMP responses recorded in migraine patients were compared with control group. Considering the mVEMP normalization study conducted by Başöz et al. (2021) in a similar age group and in the same clinic, latency prolongation and amplitude decrease were observed in subjects with migraines. Migraine is considered a central pathology, as shown in the cervical and ocular VEMP (cVEMP/oVEMP) literature. No difference was observed in the interaural amplitude asymmetry ratio, which is important in peripheral pathologies. Additionally, when the number of pathological ears was examined in order to understand the total exposure, it was observed that the number of pathological ears was significantly higher in the migraine group. In future studies, using mVEMP together with cVEMP and oVEMP tests, which allow evaluation of otolith organs and vestibular nuclei, will be valuable in determining the lesion location. https://doi.org/10.23641/asha.25607901.

Ethnicity and sudden cardiac death in athletes: insights from a large United Kingdom registry.

The relationship between ethnicity and causes of sudden cardiac death (SCD) in athletes is poorly understood. To investigate aetiology of SCD among different ethnicities in a large cohort of athletes. Between 1994 and November 2022, 7880 cases of SCD were consecutively referred from all over the United Kingdom to our national cardiac pathology centre; 848 (11%) were athletes. All cases underwent detailed autopsy evaluation by expert cardiac pathologists. Clinical information was obtained from referring coroners. Most of athletes were white (n = 758; 89%). Black and Asian athletes were in number of 51 (6%) and 39 (5%), respectively. A structurally normal heart, indicative of sudden arrhythmic death syndrome (SADS) was the most common autopsy finding (n = 385; 45%), followed by myocardial diseases (n = 275; 32%), atherosclerotic coronary artery disease (CAD) (n = 58; 7%), and coronary artery anomalies (n = 29; 3%). In most of cases, death occurred during exercise (n = 737; 87%). Arrhythmogenic cardiomyopathy (ACM) was more common in black (n = 13; 25%) than in white (n = 109; 14%) and Asian (n = 3; 8%) athletes (P = 0.03 between black and white athletes; P = 0.04 between black and Asian athletes); in contrast, CAD was more common in Asians (n = 6; 15% vs. n = 51; 7% in whites vs. n = 1; 2%; in blacks, P = 0.02 between Asian and black athletes). Among white athletes, ACM was more common in individuals who died during exercise than in the ones who died at rest (P = 0.005). Such a difference was not observed in Asian and black athletes. In Asian athletes, CAD was the diagnosis at autopsy in 18% of individuals who died during exercise and in none of individuals who died at rest. A structurally normal heart at autopsy and myocardial diseases are the most common findings in athletes who died suddenly. While ACM is more common in black athletes, atherosclerotic CAD is more common in Asian athletes, with a strong association with exercise-induced SCD. ACM appears to be a driver of exercise-induced SCD in white athletes, however this is not the case in black and Asian athletes.

An Uncoventional Technique: Outflow Vein Tributary access for Central Vein and Cephalic Arch Angioplasty in Dysfunctional AVF

Abstract Introduction: Central venous stenosis (CVS) is a significant and frequently encountered problem in managing hemodialysis (HD) patients. Venous hypertension, often accompanied by severe symptoms, undermines the integrity of the HD access circuit. In CVS, dialysis through an arteriovenous (AV) fistula is usually inefficient, with high recirculation rates and prolonged bleeding after dialysis. Interventions for central vein stenosis in patients with AV access are typically performed with a direct puncture of the fistula outflow vein or taking access from the femoral vein, jugular vein, axillary vein, and basilic vein. Commonly encountered complications with taking access from the fistula vein-puncture site bleeding, hematoma, pseudoaneurysm, thrombosis of arteriovenous fistula; complications noted with femoral vein access are groin hematoma, lower limb deep-vein thrombosis, need for patient immobilization, and groin compression. An alternative approach is to use the outflow vein tributary, such as the cephalic vein tributary, as an access to avoid these potential complications. Aim and Objective: The objective of this study was to evaluate the feasibility and clinical outcomes of central vein and cephalic vein arch angioplasty, utilizing an outflow vein tributary as access, for managing symptomatic CVS in dialysis patients with upper limb vascular access and significant ipsilateral limb edema. Methodology: In a Prospective interventional study conducted at 2 Tertiary care Institutes between 2022 and 2023, a total of 34 patients underwent central vein and cephalic arch angioplasty utilizing an outflow vein tributary as access. Follow-up duration varied among patients. Results: During a 1-year period, a total of 34 patients (20 male and 14 female) underwent interventions for central vein stenosis using a tributary of the outflow vein as an access. These interventions encompassed lesions in the SVC, innominate vein, subclavian vein, cephalic arch, and multisegmental disease. The technical success rate for endovascular treatment stood at 88%. However, in four patients, we encountered difficulties in crossing the lesion despite employing additional access from the great saphenous vein (GSV). Notably, in 23 cases, the entire procedure was successfully completed using access from the tributary vein, whereas in seven patients, supplementary access was obtained from the right GSV. Importantly, none of the patients experienced access site complications. Conclusion: The use of tributary veins as access allows for the use of wide bore sheaths without encountering complications when addressing central vein pathology. Our findings indicate that employing outflow vein tributaries as access for endovascular treatment is both safe and effective in managing central venous disease.

Human Glial Cells as Innovative Targets for the Therapy of Central Nervous System Pathologies.

In vitro and preclinical in vivo research in the last 35 years has clearly highlighted the crucial physiopathological role of glial cells, namely astrocytes/microglia/oligodendrocytes and satellite glial cells/Schwann cells in the central and peripheral nervous system, respectively. Several possible pharmacological targets to various neurodegenerative disorders and painful conditions have therefore been successfully identified, including receptors and enzymes, and mediators of neuroinflammation. However, the translation of these promising data to a clinical setting is often hampered by both technical and biological difficulties, making it necessary to perform experiments on human cells and models of the various diseases. In this review we will, therefore, summarize the most relevant data on the contribution of glial cells to human pathologies and on their possible pharmacological modulation based on data obtained in post-mortem tissues and in iPSC-derived human brain cells and organoids. The possibility of an in vivo visualization of glia reaction to neuroinflammation in patients will be also discussed.