Standard Of Care For Patients Research Articles

The evolving treatment landscape of metastatic urothelial cancer.

Cisplatin-based chemotherapy is currently the first-line standard of care for patients with metastatic urothelial cancer (mUC); however, up to 50% of patients are ineligible for cisplatin, necessitating alternative treatment options. Immune checkpoint inhibitors have been shown to be effective in cisplatin-ineligible patients. However, despite advances in the first-line setting, the prognosis remains poor, and challenges persist in selecting optimal therapies, treatment sequences and combination regimens. Maintenance therapy with avelumab revealed improved overall (OS) and progression-free survival (PFS) compared with best supportive care alone in patients with platinum-responsive mUC. Antibody-drug conjugates and targeted therapy with fibroblast growth factor receptor (FGFR) inhibitors have shown promise in selected patients, particularly in patients with metastatic disease that has progressed despite platinum-based chemotherapy. At the European Society of Medical Oncology Congress in 2023, groundbreaking results were presented from two phase III trials, EV-302/KEYNOTE-A39 and CheckMate 901, focusing on previously untreated mUC. In the former, the combination of enfortumab vedotin and pembrolizumab showed significant improvements in OS, PFS and overall response rate compared with chemotherapy alone; the combination of nivolumab with gemcitabine-cisplatin chemotherapy demonstrated a significant extension in median OS, PFS and overall response rate compared with chemotherapy alone. Inaddition, erdafitinib therapy resulted in significantly longer OS than chemotherapy among patients with mUC and FGFR alterations after previous treatment with immune checkpoint inhibitors. This comprehensive summary of the current treatment landscape for mUC incorporates clinical trial evidence and discussion of agents that are currently under investigation to provide support for clinical decision making and understanding of future therapeutic approaches.

Assess The Workload Management Model and Enhanced Quality Control in The Central Sterile Supply Department: A Study Protocol.

Introduction The Central Sterile Supply Department (CSSD) plays a crucial role in ensuring the safety and efficacy of medical instruments and equipment used in healthcare settings. Effective workload management and quality control are essential for maintaining high standards of patient care and minimizing the risk of healthcare-associated infections. This study protocol aims to assess the implementation and impact of a new workload management model and enhanced quality control measures in a CSSD setting. Methods The study will employ a mixed-methods approach, including quantitative analysis of workload data, qualitative interviews with CSSD staff, and observational assessments of workflow and quality control procedures. The workload management model under investigation involves the allocation of resources based on demand patterns and the implementation of scheduling algorithms to optimize staff efficiency. Enhanced quality control measures include the implementation of advanced sterilization technologies, rigorous inspection protocols, and continuous staff training initiatives. Results The study expects to provide insights into the effectiveness of the workload management model in optimizing resource allocation and improving staff productivity. Additionally, it aims to evaluate the impact of enhanced quality control measures on the reliability and safety of instrument sterilization processes. Findings from this study will inform recommendations for further improvements in CSSD operations and contribute to the advancement of best practices in sterile supply management. Conclusion The successful implementation of an effective workload management model and enhanced quality control measures in the CSSD is crucial for maintaining patient safety and ensuring the efficient functioning of healthcare facilities. By systematically evaluating the implementation and impact of these interventions, this study protocol seeks to contribute to the ongoing improvement of CSSD operations and the enhancement of healthcare quality.

Abstract PO2-19-11: NOBLE – Neoadjuvant Olaparib and Durvalumab for patients with BRCA-associated TripLE Negative Breast Cancer

Abstract Background The standard of care for patients with early triple-negative breast cancer (TNBC) is neoadjuvant chemotherapy followed by surgery. Recently, immune checkpoints inhibitors (ICI) added to neoadjuvant chemotherapy have shown efficacy. Among TNBC, BRCA mutations and other homologous recombination deficiency (HRD) signals are relatively frequent. As opposed to other types of breast cancer, TNBC show a high neoantigen load, a large number of tumour infiltrating lymphocytes (TILs), and a high PD-L1 expression. In BRCA/HRD breast cancer, PARP inhibitors (PARPi) exhibit a distinct anticancer activity. In addition, they show immunomodulatory effects by promoting PD-L1 expression and DNA damage, increasing neoantigen load. Chemotherapy-free regimens combining PARPi and ICI result in promising synergistic activity as shown in the metastatic setting, supporting investigation in the neoadjuvant setting. Trial design NOBLE is an EORTC phase 2, randomized, international, multicentre, open label, clinical trial. Eligible patients will undergo central screening for tumoral BRCA/HRD (Institute Curie, 455 patients), 152 patients will be randomized 1:1 between olaparib vs olaparib and durvalumab for 4 cycles (16 weeks) of neoadjuvant treatment. Thereafter, patients will undergo surgery. All patients will be followed-up to 2 years (y) after surgery. The trial will be conducted in 3 steps (screening/randomization): Step 1 – Feasibility (60/20): to assess the central testing failure rate, the turn-around time for central testing and the prevalence of tBRCA/HRD; Step 2 (193/64) – Futility; and Step 3 (202/152) – Expansion of recruitment. The primary endpoint is the rate of pathologic complete response (pCR) at the time of surgery, defined as ypT0/is ypN0. Secondary endpoints are response based on RECIST v1.1, surgery rate, 2-y event-free-survival, 2-y overall survival, safety, and quality of life. The study is expected to be activated in early autumn 2023 and the primary endpoint will be available approximately 5 years after the screening of the first patient. Main inclusion criteria Histologically confirmed primary TNBC, defined as: - ER and PgR ≤ 10% - HER2-negative per ASCO CAP guidelines Stage T1c-T2 N0-N1 M0 BRCA mutation and/or HRD based on methylation as determined by central testing ECOG status 0-1 Written informed consent Age ≥18 years No prior systemic therapy nor surgery for the current Main exclusion criteria Previous treatment with a PARPi or an immune-checkpoint inhibitor History of previous invasive breast cancer Bilateral and/or multifocal and/or multicentric BC Autoimmune or inflammatory disease Specific aims The aim of this study is to provide a safe and effective neoadjuvant treatment free of chemotherapy to a distinct subpopulation among patients with TNBC. We will evaluate the pCR after neoadjuvant treatment with olaparib alone and with olaparib in combination with durvalumab in patients with TNBC showing a BRCA1/2 mutation or HRD based on methylation. Statistical methods The sample size was calculated based on the minimax Simon two-stage design including an interim analysis for futility of the primary endpoint. Decision rules are pre-specified in the study protocol. Each treatment arm will be analyzed independently. There will be no formal comparison between the two experimental treatment arms. A minimization technique will be used for random treatment allocation stratifying for the type of HRD alteration, PD-L1 expression level and for TILs. Accrual We expect to start recruiting in September 2023. We aim to screen 455 patients to randomize 152 patients. Contact information for people with a specific interest in the trial Etienne Brain (study coordinator): etienne.brain@curie.fr Anne-Sophie Hamy-Petit (study co-coordinator): anne-sophie.hamy-petit@curie.fr Citation Format: Emanuel Buhrer, Eleni Xenophontos, Anne-Sophie Hamy-Petit, Jose Casas-Martin, Céline Callens, Thomas Meyskens, Coralie Poncet, Anastasia Lanzi, Etienne Brain. NOBLE – Neoadjuvant Olaparib and Durvalumab for patients with BRCA-associated TripLE Negative 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 PO2-19-11.

Abstract PS12-04: Inhibition of GPX4 enhances CDK4/6 inhibitor activity in breast cancer

Abstract Background: Cyclin D-dependent kinases 4 and 6 (CDK4/6) inhibitors (CDK4/6i) including palbociclib, ribociclib and abemaciclib in combination with endocrine therapy are the standard of care for patients with estrogen receptor-positive (ER+). Despite the success of these treatments, cytostasis is frequently observed, and novel strategies that enhance efficacy are required to eradicate residual cancer in the clinic. Methods: In the search of an effective drug combinations to enhance the efficacy of CDK4/6 inhibitors in breast cancer, we performed a whole genome CRISPR-Cas9 suppressor screen in MCF-7, an ER+ model. We also carried out transcriptomics, proteomics, and functional molecular biology analysis of breast cancer models treated with palbociclib to identify resistant mechanisms. Results: The whole genome CRISPR-Cas9 screen revealed that multiple genes involved in oxidative stress and ferroptosis modulated palbociclib sensitivity, being GPX4 the top sensitizing hit. GPX4 is a key glutathione peroxidase that protects again ferroptosis by catalysing the reduction of phospholipid and cholesterol hydroperoxides. CRISPR-depletion or drug inhibition of GPX4 increased sensitivity to palbociclib in ER+ breast cancer models, and in addition sensitised triple negative breast cancer models to palbociclib. Moreover, GPX4 null xenografts were highly sensitive to palbociclib in vivo. Transcriptomics and proteomics analysis showed that palbociclib upregulate pathways involved in oxidative stress and lipid metabolism promoting a redox-lipid imbalance. Palbociclib induced lipid peroxidation leading to a ferroptosis vulnerable state with GPX4 preventing cell death. Polyunsaturated fatty acids (PUFAs) are highly susceptible of lipid peroxidation, and pathways that regulate their abundance in membrane phospholipids were explored. Interestedly, in ER+ breast cancer models, lipid peroxidation relied on a peroxisome AGPAT3-dependent pathway rather than the classical ACSL4 pathway. Conclusion: Our studies demonstrate that quiescence induced by palbociclib results in a ferroptosis-vulnerable state that could be exploited through combination with GPX4 inhibitors to enhance sensitivity to CDK4/6 inhibition in breast cancer. Citation Format: Maria Teresa Herrera Abreu, Uzma Khalid, Jian Ning, Rosalind Cutts, Gemma Wilson, Christopher Lord, Amanda Swain, Nicholas Turner. Inhibition of GPX4 enhances CDK4/6 inhibitor activity in 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 PS12-04.

Abstract PO4-19-07: Tailored Axillary Surgery (TAS) in Patients with Clinically Node-Positive Breast Cancer in the Upfront Surgery Setting: A Prospective, Single-Arm, Multicenter Trial

Abstract A brief background discussion: Axillary lymph node dissection (ALND), which can induce lymphedema, has been omitted in clinically node-negative(cN0) patients with positive sentinel lymph nodes (SLNs) if they meet the eligibility criteria of ACOSOG Z0011. Furthermore, the omission of ALND has been attempted through targeted axillary dissection (TAD) in patients whose clinically node-positive(cN+) status converts to ycN0 after neoadjuvant chemotherapy. However, ALND remains the standard of care in patients with cN+ who undergo upfront surgery. Trial design: This is a prospective, single-arm, multicenter phase II feasibility trial with the participation of 41 hospitals belonging to the breast cancer study group of Japan Clinical Oncology Group (JCOG). Tailored axillary surgery (TAS) removes labeled lymph node (LN) with clip, wire, or tattoo, palpable LNs, and SLNs. ALND is performed after TAS. These LNs removed by ALND other than TAS are defined as non-TAS LNs. Eligibility criteria: The eligibility criteria are as follows: 1) histologically-proven invasive breast cancer, 2) upfront surgery is planned, 3) pathologically diagnosed metastatic LN (cytology or core needle biopsy), 4) 1-3 LN metastases in level I by imaging, 5) cT1-3, and 6) females aged ≥18 and ≤74 years on the enrollment date. Specific aims: This trial aims to establish a surgical method of tailored axillary surgery (TAS) among patients with cN+ who undergo upfront surgery and to determine the appropriate criteria for the next phase III TAS trial, which omits ALND by TAS safely. The primary endpoint is the non-TAS LNs positive rate. Clinicopathological factors (the number of suspected metastases by imaging, the number of metastases in LNs resected by TAS, tumor size, and invasive ductal/lobular carcinoma) are analyzed to predict the non-TAS LN metastasis rate (e.g., < 10%). The secondary endpoints are the TAS LNs identification rate, marked LN resection rate, arm edema incidence rate, and QOL (FACT-B, QuickDASH). Statistical methods: In this trial, among the combinations of factors involved in treatment selection, the objective is to narrow down the combinations that will result in a non-TAS metastasis-positive rate of less than 10% when TAS is performed. For a single combination, 167 cases need to be considered to reject a non-TAS metastasis-positive rate of 10% or more (5% one-sided alpha error, 70% power, and 5% expected value). However, performing these studies for all combinations lacks feasibility. Therefore, we decided to improve the estimation accuracy by using a regression model with the non-TAS metastasis-positive rate as the outcome variable and the factors involved in treatment selection as explanatory variables and to search for combinations of factors with a non-TAS metastasis-positive rate less than 10%. Based on the rule of thumb that a sample size of at least ten times the number of factors is required when using regression methods, a regression model is used when 60 cases are accumulated. The combinations with a 90% confidence upper limit of less than 10% of non-TAS metastasis positivity as the predictive value of the regression model will be selected as candidate combinations that fulfill the conditions. If the accuracy of the predictive value is considered insufficient, 60 cases will be added sequentially up to a maximum of 300 cases. Present accrual and target accrual: The patient recruitment was started in April 2023. Up to 300 patients will be enrolled over a 2-year recruitment period. Twenty-one patients were already enrolled until July 2023. Citation Format: Kaori Terata, Yasuaki Sagara, Tadahiko Shien, Takehiko Sakai, Shin Takayama, Dai Kitagawa, Tsuguo Iwatani, Takahiro Tsukioki, Mami Ogita, Naoko Sanuki, Masayuki Yoshida, Hitoshi Tsuda, Seiichiro Yamamoto, Hiroji Iwata. Tailored Axillary Surgery (TAS) in Patients with Clinically Node-Positive Breast Cancer in the Upfront Surgery Setting: A Prospective, Single-Arm, Multicenter 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 PO4-19-07.

Abstract PO1-05-09: ASCENT-07: A phase 3, randomized, open-label study of sacituzumab govitecan versus treatment of physician’s choice in patients with HR+/HER2– inoperable, locally advanced, or metastatic breast cancer post-endocrine therapy

Abstract Background: Approximately 70% of all breast cancer (BC) cases are hormone receptor positive/human epidermal growth factor receptor 2-negative (HR+/HER2–), with ~65% of these being HR+/HER2-low (immunohistochemistry [IHC]1+, IHC2+/in situ hybridization [ISH]–). Despite an increasing number of available endocrine and targeted treatments for metastatic disease, tumors eventually develop resistance to endocrine therapy (ET). Chemotherapy, the standard of care for patients (pts) whose cancers no longer respond to ET, is associated with poor outcomes, representing a high unmet need in the first-line endocrine-resistant setting. Sacituzumab govitecan (SG) is a Trop-2–directed antibody-drug conjugate (ADC) that delivers SN-38 (the active metabolite of the topoisomerase inhibitor irinotecan) to tumor cells via internalization, and to the surrounding tumor microenvironment via the bystander effect. SG demonstrated a significant and clinically meaningful survival benefit in the phase 3, randomized TROPiCS-02 trial, and is approved in the US for inoperable, locally advanced, or metastatic HR+/HER2– BC after ET and ≥ 2 systemic therapies in the metastatic setting. ASCENT-07 will examine the efficacy and safety of SG in the first-line chemotherapy setting, ie, in patients with inoperable, locally advanced, or metastatic ET resistant HR+/HER2– BC. Study design: ASCENT-07 (NCT05840211) is a randomized, open-label, global study evaluating SG versus treatment of physician’s choice (TPC) chemotherapy in pts with HR+/HER2– inoperable, locally advanced, or metastatic BC who have received ET and are eligible for their first chemotherapy for advanced/metastatic disease. Pts aged ≥ 18 years with histologically confirmed HR+/HER2– (HER2 IHC0 or HER2-low [IHC1+, IHC2+/ISH–]) according to ASCO/CAP criteria, measurable disease per RECIST v1.1, and ECOG performance status of 0 or 1 will be included. Pts are eligible if they meet ≥ 1 of the following criteria: progressive disease (PD) in the metastatic setting on ≥ 2 lines of ET (± targeted therapy) (disease recurrence within the first 24 months of starting adjuvant ET is considered a line of therapy), PD within 6 months of first-line ET (± CDK 4/6 inhibitor) in the metastatic setting, or disease recurrence within 24 months of adjuvant ET with CDK 4/6 inhibitor initiation and no longer a candidate for additional ET. PD on the most recent therapy will be documented by CT or MRI per RECIST v1.1. Key exclusion criteria include prior treatment targeting topoisomerase I. Pts will be randomized to SG 10 mg/kg IV on days 1 and 8 of a 21-day cycle or TPC (capecitabine, paclitaxel, nab-paclitaxel). The primary endpoint is progression-free survival (PFS) assessed by blinded independent central review (BICR) per RECIST v1.1 criteria or death from any cause, whichever comes first. Secondary endpoints include PFS (assessed by the investigator), overall survival, objective response rate and duration of response per BICR and investigator, and quality of life (QoL) assessed using the EORTC QLQ-C30 cancer questionnaire (primarily change in the Physical Functioning domain at week 16 and time to deterioration in the Global Health Status/QoL domain). Pharmacokinetics and immunogenicity analyses will be undertaken in pts receiving SG. Incidence of adverse events and serious adverse events, including relationship to study drug(s), will be reported. Laboratory and vital signs will be monitored. ASCENT-07 is currently open for recruitment and requires ~654 eligible pts to provide adequate power for assessment of the primary and key secondary endpoints. Citation Format: Hope Rugo, Javier Cortés, Giuseppe Curigliano, Carlos Barrios, Kevin Punie, Yeon Park, Hiroji Iwata, Alex Young, Xuehan Ren, Pelin Cinar, Komal Jhaveri. ASCENT-07: A phase 3, randomized, open-label study of sacituzumab govitecan versus treatment of physician’s choice in patients with HR+/HER2– inoperable, locally advanced, or metastatic breast cancer post-endocrine therapy [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 PO1-05-09.

Abstract PO1-20-13: TROPION-Breast04: A phase 3 study of neoadjuvant datopotamab deruxtecan (Dato-DXd) + durvalumab followed by adjuvant durvalumab vs the standard of care in treatment-naive early-stage triple negative or HR-low/HER2– breast cancer

Abstract Background: The current standard of care for patients (pts) with treatment-naive Stage II–III triple-negative breast cancer (TNBC) is neoadjuvant pembrolizumab + anthracycline/taxane/platinum-based chemotherapy followed by surgery and adjuvant pembrolizumab monotherapy. However, among pts who received the combination of pembrolizumab and chemotherapy in the KEYNOTE-522 trial (NCT03036488), 28% ultimately discontinued therapy due to treatment-related adverse events, and 37% had residual disease at the time of surgery, which was associated with poor outcomes. Consequently, there remains an unmet need to develop a treatment approach that improves pathologic complete response (pCR) rates and long-term survival while reducing chemotherapy-associated toxicity in pts with early-stage TNBC. Dato-DXd is a TROP2-directed antibody-drug conjugate that consists of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to a potent topoisomerase I (Topo-I) inhibitor via a plasma stable tetrapeptide-based tumor-selective cleavable linker. Dato-DXd monotherapy has demonstrated a manageable safety profile and encouraging preliminary efficacy in pts with metastatic TNBC in the Phase 1 TROPION-PanTumor01 study (NCT03401385), with a confirmed objective response rate (ORR) of 32% in all pts and 44% in Topo-I inhibitor-naive pts with measurable disease at baseline. The combination of Dato-DXd with durvalumab has demonstrated durable responses in unresectable locally advanced or metastatic TNBC in the Phase 1b/2 BEGONIA study (NCT03742102), with an ORR of 79%, median duration of response of 15.5 months and median progression-free survival of 13.8 months. The ongoing Phase 3 TROPION-Breast03 trial (NCT05629585) is evaluating Dato-DXd ± durvalumab versus standard-of-care therapy as adjuvant treatment in pts with Stage I–III TNBC with residual invasive disease at the time of surgery after neoadjuvant treatment. The TROPION-Breast04 trial aims to determine if improved efficacy and safety can be achieved with neoadjuvant Dato-DXd + durvalumab followed by adjuvant durvalumab, compared with the pembrolizumab-based standard of care regimen in pts with previously untreated TNBC or hormone receptor-low (estrogen and/or progesterone receptor 1% to <10%; neither hormone receptor may be ≥10%)/HER2-negative (HR-low/HER2–) breast cancer. Trial design: TROPION-Breast04 (NCT06112379) is an ongoing Phase 3, 2-arm, parallel-group, randomized, open-label, multicenter, global trial. Approximately 1728 adults (aged ≥18 years) with previously untreated histologically confirmed Stage II–III unilateral or bilateral primary invasive TNBC or HR-low/HER2– breast cancer per AJCC edition 8 as assessed by the investigator, and an ECOG PS of 0 or 1, will be randomized 1:1 into one of two arms: neoadjuvant Dato-DXd + durvalumab followed by adjuvant durvalumab-based therapy, or neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab-based therapy (full treatment details are provided in the Table). Randomization will be stratified by lymph node status, tumor stage, HR status, and geographic region. Pts with distant disease and any prior surgery, radiotherapy, or systemic anticancer therapy will be excluded from the study. The primary endpoints are pCR and event-free survival. The key secondary endpoint is overall survival; others are distant disease-free survival, patient reported outcomes, pharmacokinetics, immunogenicity, and safety/tolerability. TROPION-Breast04 opened for enrolment in November 2023. Citation Format: Heather McArthur, Sara Tolaney, Sibylle Loibl, Rebecca Dent, Peter Schmid, Jamil Asselah, Erwei Song, Naoki Niikura. TROPION-Breast04: A phase 3 study of neoadjuvant datopotamab deruxtecan (Dato-DXd) + durvalumab followed by adjuvant durvalumab vs the standard of care in treatment-naive early-stage triple negative or HR-low/HER2– 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 PO1-20-13.

Abstract PO4-03-06: Body mass index and response to neoadjuvant chemo-immunotherapy among women with primary triple negative breast cancer

Abstract Background: Elevated body mass index (BMI) is associated with lower rates of pathologic complete response (pCR) after neoadjuvant chemotherapy in patients with breast cancer. The addition of PD-1 receptor inhibition with pembrolizumab to neoadjuvant chemotherapy is now considered the standard of care for patients with stage II or III triple negative breast cancer (TNBC) based on results from the KEYNOTE-522 (KN-522) trial. In other cancer types such as melanoma and lung cancer, patients with overweight/obesity have better survival outcomes following treatment with immunotherapy compared to patients with normal weight, despite a higher incidence of any-grade immune-related adverse events (irAEs). Whether BMI is associated with differential response and toxicity in patients with TNBC treated with neoadjuvant chemo-immunotherapy is unknown. Methods: Patients with stage II-III TNBC treated with neoadjuvant chemotherapy plus pembrolizumab per the KN-522 regimen from 8/2021 – 9/2022 at Memorial Sloan Kettering Cancer Center were included in this retrospective study. Patient characteristics, tumor characteristics, treatments, surgical pathology information, and irAEs were abstracted from medical records. pCR was defined as absence of invasive or in situ carcinoma in breast and axillary node tissue surgical specimens. BMI was categorized per standard definitions: underweight/normal weight < 25 kg/m2, overweight 25-29.9 kg/m2, and obese >=30 kg/m2. Wilcoxon rank sum tests, Pearson’s chi-squared tests, and Kendall rank correlation tests were used to test associations between variables. Results: 143 patients were included in this study. 57 patients (39.8%) were underweight/normal weight, 46 (32.2%) were overweight, and 40 (28.0%) were obese. Overall, 79/143 patients (55.2%) experienced a pCR. Among patients with a pCR, median BMI was 26.3 kg/m2 (interquartile range [IQR] 23.1-30.5 kg/m2); among patients without a pCR, median BMI was 26.1 kg/m2 (IQR 23.6-30.0 kg/m2; p >0.9). There was no significant association between BMI category and pCR (p=0.9). Overall, 63/143 (44%) of patients experienced an irAE; 42 (29.4%) required treatment for an irAE. There were no associations between BMI and the incidence (p=0.5) or frequency (p=0.7) of irAEs. Conclusions: In this TNBC cohort treated with neoadjuvant chemo-immunotherapy, BMI was not associated with rates of pCR or irAEs. These findings highlight the divergent impact of BMI on immunotherapy response across cancer types. Confirmatory studies in independent cohorts are needed. Citation Format: Sherry Shen, Sara Myers, Yuan Chen, Stephanie Downs-Canner, Nour Abuhadra, Tiffany Traina, Mark Robson, Neil Iyengar. Body mass index and response to neoadjuvant chemo-immunotherapy among women with primary triple negative 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 PO4-03-06.

Abstract PO3-01-04: Neoadjuvant compared to adjuvant chemotherapy combined with trastuzumab in patients with HER2-positive breast cancer: a register-based cohort study

Abstract Introduction Neoadjuvant therapy (NAT) is considered the standard of care in patients with HER2-positive breast cancer mainly due to the possibility to adjust the post-neoadjuvant treatment based on the tumor response to NAT. However, there is no convincing evidence on a survival benefit with NAT compared to adjuvant therapy (AT) for HER2-positive breast cancer. The aim of the present study was to compare the two therapeutic strategies in a register-based cohort of Swedish patients with primary operable HER2-positive breast cancer. Method The research database BCBaSe 3.0, which is based on the Swedish National Quality breast cancer register, was used to identify patients with primary operable HER2-positive breast cancer that diagnosed between 2008 and 2020 and received either NAT or AT including chemotherapy and trastuzumab. To mitigate confounding by indication bias, propensity score matching (PSM) with 1:1 matching was applied. The effectiveness of the two therapeutic strategies was investigated through analyzing distant disease-free survival (DDFS), breast-cancer specific survival (BCSS), and overall survival (OS). Multivariate Cox regression analyses were performed for the outcomes of interest to provide Hazard Ratios (HR) and corresponding 95% Confidence Intervals (CI). Results In total, 7258 patients with primary operable HER2-positive breast cancer treated with either NAT or AT were identified, 1789 (24.6%) received NAT and 5469 (75.4%) AT. After 1:1 PSM, 1258 patients in each therapeutic strategy were available for comparisons. After a median follow-up of 63 months, no statistically significant differences between NAT and AT were observed in either outcome (HR for DDFS: 0.97; 95% CI: 0.72 – 1.30; HR for BCSS: 0.69; 95% CI: 0.45 – 1.07; HR for OS: 0.72; 95% CI: 0.50 – 1.05). In subgroup analyses, estrogen-receptor status did not impact the results that remained statistically non-significant between NAT and AT whereas in patients with clinically positive lymph node status, NAT resulted in better BCSS (HR: 0.44; 95% CI: 0.22 – 0.89) and OS (HR: 0.49; 95% CI: 0.29 – 0.90). The latter trend was not evident in patients with clinically negative lymph node status. Conclusion Our study results confirm the equivalence of NAT and AT in terms of prognosis for patients with operable HER2-positive disease and imply a potential benefit of NAT compared to AT in patients with clinically positive lymph node status. Considering the emerging treatment strategies in HER2-positive breast cancer patients treated with NAT (pertuzumab as a part of NAT, T-DM1 as post-neoadjuvant therapy) that have been shown to improve survival but are not reflected in the study cohort, NAT should be considered as the strategy with the higher possibility to improve long-term prognosis for patients with HER2-positive disease. Citation Format: Servah Hosseini-Mellner, Åsa Wickberg, Antonis Valachis, Andreas Karakatsanis. Neoadjuvant compared to adjuvant chemotherapy combined with trastuzumab in patients with HER2-positive breast cancer: a register-based cohort study [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 PO3-01-04.

Abstract PO1-19-01: NRG-BR008: A Phase III Randomized Trial of Radiotherapy Optimization for Low-risk HER2-positive Breast Cancer (HERO)

Abstract Background: Breast radiotherapy (RT) is the standard of care for patients with early-stage breast cancer (BC) who undergo breast-conserving surgery (BCS). However, the magnitude of benefit of RT is less clear in BCS patients with low-risk disease who receive effective systemic therapy. Among patients with early-stage HER2-positive (HER2+) BC, 10-year locoregional recurrence has been reported as low as 1.5% following BCS, adjuvant chemotherapy and HER2-targeted therapy, and RT. Given these exceedingly favorable outcomes, with the addition of HER2-directed therapy, we seek to evaluate the feasibility of omitting RT among patients with early-stage HER2+ BC following BCS and appropriate systemic therapy. Methods: This is a phase III randomized trial for patients ≥40 years with early-stage, node-negative HER2+ (IHC/FISH) BC treated with BCS with negative margins and sentinel lymph node biopsy or axillary dissection. Patients undergoing primary surgery must have pathologic T1 (< 2 cm) N0 disease, while patients receiving neoadjuvant therapy must have clinical T1-2 (with radiographically T< 3.0 cm) N0 disease and exhibit a pathologic complete response (ypT0N0) at surgery. All patients must receive cytotoxic chemotherapy and HER2-targeted therapy, either in the adjuvant or neoadjuvant setting. Stratification is by age (< 60; ≥60), tumor size (≤1 cm; >1 cm), estrogen-receptor status (positive; negative), and systemic therapy sequencing (adjuvant vs neoadjuvant). Patients will be randomized to standard breast RT in addition to continuation of trastuzumab to complete a year of treatment (Arm 1), or trastuzumab alone (Arm 2). Endocrine therapy will be recommended for patients with hormone-receptor positive tumors. The primary endpoint is the recurrence-free interval (RFI). Secondary endpoints include the time to ipsilateral breast recurrence, locoregional recurrence, disease-free survival, and overall survival, in addition to the 7-year ipsilateral breast recurrence rate among those not receiving RT. A health-related quality of life sub-study will assess differences in patient-reported breast pain and worry. We estimate a 7-year RFI of 97.5% with RT and allow for a clinically acceptable decrement of 3.63% without RT (7-year RFI of 93.87%; HR 2.5) to establish omission of RT as non-inferior. NRG-BR008 aims to enroll 1,300 patients over 4.5 years, yielding 80% power to detect the non-inferiority of RT omission with a one-sided α=0.05. We expect to observe the required 38 RFI events within 6 years of additional follow-up. The NRG-BR008/HERO trial opened to accrual in March, 2023. NCT05705401. Support: U10CA180868, -180822, UG1CA189867, U24CA196067; Susan G. Komen Foundation (JR) Citation Format: Lior Braunstein, Melissa Mitchell, Hanna Bandos, William Sikov, Atif Khan, Peter Chen, Patricia Ganz, Reshma Jagsi, Julia White, Reena Cecchini, Hyejoo Kang, Shannon Puhalla, Kelly Bolton, Eileen Connolly, Erica Stringer-Reasor, Kimberly Gergelis, Thomas Julian, Eleftherios Mamounas, Norman Wolmark. NRG-BR008: A Phase III Randomized Trial of Radiotherapy Optimization for Low-risk HER2-positive Breast Cancer (HERO) [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 PO1-19-01.

Abstract PO5-05-08: LOSS OF SINGLEMINDED 2S RESULTS IN A PI3K SUBUNIT SWITCH WHICH DRIVES THERAPEUTIC RESISTANCE IN ESTROGEN RECEPTOR POSITIVE BREAST CANCER

Abstract Estrogen receptor (ER) + breast cancer (BC) comprises over 70% of BC cases and are targeted via ER modulated therapies. Despite this, ER+BC patients can experience recurrence within 20 years and the majority of BC related deaths can be attributed to metastatic ER+BC. These distant metastases are commonly diagnosed as endocrine therapy resistant. Thus, there is an unmet need to identify novel biomarkers for treating ER+ patients with metastases. We have identified a tumor suppressor gene, singleminded 2s (SIM2s), expressed in breast epithelial cells that inhibits epithelial to mesenchymal transition and metastasis, and is downregulated in the progression of breast disease. In ER+BC cell lines, loss of SIM2s results in upregulation of mesenchymal markers and increased PI3K/Akt signaling. Dysregulation of the PI3K/Akt signaling pathway in ER+BC is involved with tumor progression and acquired therapeutic resistance. Our study suggests loss of SIM2s confers resistance in ER+BC through a PI3K subunit switch resulting in upregulation of pro-survival signaling. MCF7 SIM2 knock out cells exhibit increased expression of mesenchymal markers and undergo a phenotypic change compared to wild type cells. Utilizing a migration/invasion assay, MCF7 SIM2 knock out cells exemplify an increase in invasion potential compared to wild type cells. Furthermore, changes in PI3K subunit expression were observed via western blot and real time qPCR analysis. Clonogenic assays revealed an acquired resistance to PI3Kα inhibition, but a susceptibility to PI3Kδ inhibition. This is a significant finding as a current standard of care for patients with ER+ breast cancer recurrence is PI3Kα inhibition. PI3Kδ is an already approved therapeutic target in chronic lymphocytic leukemia, thus PI3Kδ may present a new therapeutically targetable opportunity for ER+BC recurrence. Elucidating the mechanism for acquired therapeutic resistance is an integral avenue for understanding how breast cancer progresses and improving the prognosis of ER+BC patients. Citation Format: Garhett Wyatt, Rachel Steinmetz, Traci Lyons, Weston Porter. LOSS OF SINGLEMINDED 2S RESULTS IN A PI3K SUBUNIT SWITCH WHICH DRIVES THERAPEUTIC RESISTANCE IN ESTROGEN RECEPTOR 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 PO5-05-08.

Abstract PS11-07: High prevalence of HER2-Low and AR expression in breast cancer brain metastases provide novel therapeutic options

Abstract Background: Although survival rates for patients with advanced breast cancer (BC) have improved overall, rates of BC brain metastases (BCBM) have increased over the past two decades, occurring in up to 15% to 30% of patients. BCBM greatly reduce quality of life and overall survival (OS) and are now the leading cause of BC patient mortality. Patients with primary HER2+ and triple negative BC (TNBC) are at highest risk for BM. Locoregional therapy with surgery and radiation are currently standard of care (SOC), but these treatments have significant morbidity and BCBM progressing despite these interventions are hard to treat. Systemic therapies to reduce cognitive impairment and increase survival are desperately needed, particularly in HER2-negative patients. Currently, immune checkpoint inhibitors (ICIs) and small molecules such as PARP inhibitors are among the limited systemic options that have BCBM activity in HER2-negative BC. However, the benefit of these therapies is limited to a select group of patients. For example, androgen receptor (AR) is expressed in 60-80% of all BC and, in our recently completed clinical trial (NCT03206203), patients with AR+ metastatic TNBC treated with carboplatin +/- atezolizumab received no clinical benefit from the addition of atezolizumab. Alternatives to ICIs are needed for patients with AR+ TNBC. HER2-low (H2L) BC is a newly defined subset of HER2-negative BC with a HER2 immunohistochemical (IHC) score of 1+ ( >10%) or 2+/in situ hybridization (ISH) negative phenotype. Recent clinical trials have demonstrated significant clinical benefit from novel HER2 antibody-drug conjugates (ADCs) in treating H2L BC. Trastuzumab-deruxtecan (T-Dxd), a HER2-directing ADC (topoisomerase I inhibitor conjugated to a humanized HER2-targeted antibody) was recently FDA approved as the first targeted therapy to treat H2L BC and can penetrate the blood–brain barrier. DESTINY-Breast04 demonstrated notable PFS and OS benefit of T-DXd compared to SOC in patients with H2L metastatic BC and included 61 patients with BCBM (results anticipated shortly). The overall rates of AR and H2L expression in patients with BCBM is unknown. The goal of this study is to investigate the prevalence of AR and HER2-low expression in a large cohort of BCBM treated at our institution. Methods: We retrospectively assessed rates of H2L and AR positivity (AR+) among patients with BCBM whose treatment included surgery at our institution between 2005-2023. Results were correlated with clinical receptor status (HR+/HER2-, HER2+/HR+, HER2+/HR- and TNBC) and clinical characteristics. Results of ER, PR, and HER2 testing performed for clinical purposes on the brain metastases and primary tumors were obtained from pathology reports. We retrieved formalin-fixed paraffin-embedded tissue blocks of the brain metastases and performed IHC for AR (SP107) and prognostic markers for cases with missing data. Results: We identified 101 cases of BCBM. Based on clinical prognostic markers, BCBM subtypes were HR+/HER2- (22%), HR+/HER2+ (14%), HER2+/HR- (21%) and TNBC (43%). Forty-five percent of the BCBM (n=45) were AR+ ( >10%) and 24% (n=24) demonstrated > 50% AR+. Among tumors with >50% AR+, 42% (n=10) are H2L (7 HR+[30%] and 3 TNBC [13%]). Forty-two percent of BCBM were H2L. Among the HER2-negative BCBM (n= 66), 64% (n=42) were H2L, including 23 of 44 TNBC (52%) and 19 of 22 HR+ (86)%. Fifteen percent of BMBC changed clinical subtype from the primary, including conversion to TNBC and H2L. Conclusion: AR+ positive (24% > 50% expression) and HER2-Low expressing (42%) tumors represent a significant proportion of our BCBM cohort providing exciting new options for treatment. Trials re-evaluating AR antagonists in combination with SOC utilizing high AR+ thresholds may benefit patients with BCBM. At least 10% of BCBM are both H2L and demonstrate >50% AR positivity providing the rationale for the combination of ADCs such as T-DXd and AR-targeted therapies for BCBM. Citation Format: Guadalupe Garcia, Paula Gonzalez-Ericsson, Brian Lehmann, Bret Mobley, Jennifer Pietenpol, Laura Kennedy, Ben Park, Melinda Sanders. High prevalence of HER2-Low and AR expression in breast cancer brain metastases provide novel therapeutic options [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 PS11-07.

Analgesic Efficacy of Thoracolumbar Interfascial Plane Block versus Standard Care in Patients Undergoing Lumbar Spinal Surgeries—A Randomized Controlled Trial

Abstract Background Patients who undergo spine surgery often experience severe pain postoperatively. Multimodal analgesia inclusive of a regional block provides optimal pain relief. Thoracolumbar interfascial plane (TLIP) block may provide promising analgesia in these patients. Materials Fifty consenting adults aged between 18 and 60 years undergoing elective lumbar spinal surgeries under balanced general anesthesia were divided into two equal groups (group T: received bilateral TLIP block, and group C: received conventional opioid analgesia). All the patients were taken care of by an independent anesthesiologist unaware of the study protocol in the postanesthesia care unit. The postoperative pain was assessed by visual analog scale (VAS). Time to first rescue analgesia, total morphine consumption, complications, and patient satisfaction were also recorded. Results Postoperative mean VAS scores till 12 hours were significantly higher in the control group. The mean time to the first analgesic requirement among group T and group C patients was 404.4 ± 25.1 and 150.2 ± 12.4 minutes, respectively (p < 0.001). Morphine consumptions in 24 hours were also significantly higher in group C (3.36 ± 1.04 vs. 7.84 ± 1.43; p < 0.001). Mean intraoperative fentanyl consumption was significantly more in group C (122.4 ± 16.4 µg and 140.4 ± 21.7 µg; p = 0.001). Complications were similar in both groups. However, patient satisfaction was significantly higher in group T (p < 0.001). Conclusion TLIP block provided superior analgesia, decreased opioid consumption, and improved patient satisfaction as compared with patients receiving standard general anesthesia with opioid analgesics. Hence, TLIP block could be a component of multimodal analgesia in patients undergoing lumbar spine surgeries.CTRI No.: CTRI/2021/03/031682

Abstract PO2-25-01: Tumor Derived Chitinase-3 like 1 Induces Neutrophil Extracellular Traps that Promote T cell Exclusion and Resistance to Immunotherapies in Breast Cancer

Abstract Breast cancer remains the most prevalent cancer and a major cause of mortality affecting women worldwide. Chemotherapy along with radiation and surgery have long been the standard of care for breast cancer patients. However, devastating side effects, resistance to treatments and relapse are major concerns for patients and physicians. With the rise of immunotherapies as a treatment option for various cancers, there is a critical need to understand the mechanisms through which cancers evade the immune system. Targeting such mechanisms holds the key to improve patient response to immunotherapy, especially in breast cancer where efficacy rates remain low. In a subset of poor outcome Triple Negative Breast Cancers, cytotoxic T cells are excluded from the tumor nest and restricted to the surrounding stroma, a phenomenon known as stromal restriction. Our data from genetically engineered mouse models and human tumors identified that the secreted cytokine Chitinase-3 like 1 (Chi3l1) promotes stromal restriction of T cells in several tumor types including breast, lung and colon. Chi3l1 ablation in pre-clinical models of breast cancer results in increased T cell infiltration into the tumor nest which delayed mammary tumorigenesis and improved response to immunotherapy. We further demonstrate that Chi3l1 promotes T cell exclusion through the direct induction and deposition of neutrophil extracellular traps (NETs) which form a barrier that restricts T cell entry. Neutrophil depletion or pharmacological disruption of NET formation abrogates Chi3l1-induced T cell exclusion and histologically phenocopies Chi3l1 ablation. Thus, our results indicate that Chi3l1 is a major immunosuppressive cytokine that promotes breast cancer progression by inducing NET formation and inhibiting T cell infiltration. Given the importance of T cell infiltration in immune elimination of nascent tumors, the future targeting of Chi3l1 should improve immunotherapy efficacy and outcomes in patients with tumors characterized by a T cell excluded microenvironment. Citation Format: Tarek Taifour, Sherif Samer Attalla, Dongmei Zuo, Yu Gu, Virginie Sanguin-Gendreau, Hailey Dall-Proud, Emilie Solymoss, Tung Bui, Hellen Kuasne, Vasilios Papavasiliou, Chun Geun Lee, Suchitra Kamle, Peter Siegel, Jack Elias, Morag Park, William Muller. Tumor Derived Chitinase-3 like 1 Induces Neutrophil Extracellular Traps that Promote T cell Exclusion and Resistance to Immunotherapies in 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 PO2-25-01.

Imaging Characteristics and Clinical Utility of Half-Dose vs. Full-Dose Ultra-Widefield Fundus Fluorescein Angiography

PurposeIn early 2022, a fluorescein shortage occurred in the United States. To meet the standard of care for patients who required ultra-wide fundus fluorescein angiography (UWFFA), a regimen of half-dose (250mg) sodium fluorescein (10%) was adopted instead of the full-dose (500mg) at the Cole Eye Institute (CEI). In this paper, we compare the image quality, clinical utility, and the side effect profile of half-dose vs full-dose fluorescein in UWFFA for a cohort of stable patients. DesignRetrospective chart review. Subjects, Participants, and/or ControlsPatients with retinal vascular disease were included if they received half-dose and full-dose UWFFA (Optos California, Dunfermline, UK) within 6 months at the CEI. Eyes were excluded if they received intraocular injections, laser procedures, new immunosuppression, and worsened or improved inflammation on clinical examination. Methods, Intervention, or TestingQuantitative assessment of vascular leakage was performed using a machine-learning enhanced automated segmentation platform. Leakage from late-phase UWFFA images was compared between half-dose and full-dose images. Qualitative assessment of image quality and relative vascular leakage was performed by 2 masked independent reviewers. Side effects after fluorescein administration were recorded for each patient. Main Outcome MeasuresMasked leakage grading and automated leakage scores. ResultsThere were 52 eyes of 35 patients, 42 (81%) uveitic, 5 (9%) diabetic, and 4 (8%) normal controls. Patients had no change to their visual acuity (LogMAR mean 0.3±0.6), anterior chamber and vitreous cell between UFFWA’s. UWFFA images were deemed of equal quality and leakage by both masked reviewers (78-87% agreement, kappa 0.642). Automated leakage analysis showed mildly increased leakage in half-dose images overall (3.8% vs 2.8%, p=0.01), and in the macula (1.5% vs 0.6%, p=0.01). Side effects included nausea (half (n=3, 9%) vs full (n=2, 6%), p=0.69) and urticaria (n=0, 0% vs n=1, 2%, p=0.99) and were not different between doses. ConclusionsIn this cohort, half dose UWFFA produced images that were of similar quality, clinical utility and with a similar side effect profile compared to full dose. Half dose UWFFA can be used to accurately assess the retinal vasculature and could be used primarily as a method to save cost and prevent waste.

Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial.

Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059). There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis. Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

Focus on Pneumonia After Organ Transplantation: Is There a Need for Specific Medical Care in the Emergency Department?

Pneumonia is a major cause of hospitalization and has a substantial impact on health care costs. Diagnosis and treatment of pneumonia in solid organ transplant (SOT) patients remain a challenge for clinicians in the emergency department. This study aimed to evaluate demographic features, clinical patterns, history of hospitalization, and diagnosis of adult patients after organ(s) transplantation (liver, kidney, pancreas) with severe pneumonia requiring hospitalization. The aim is to determine whether patients undergoing SOT receive or require specific care and whether they need to be prioritized. This was a single-center observational study of adult patients after SOT with severe pneumonia requiring hospitalization. The data set for the analysis included only patients with pneumonia as the main reason for hospitalization. The diagnosis of pneumonia was suspected based on the American Thoracic Society criteria. The study revealed that the standard of care for patients with a history of SOT did not significantly differ from care provided to the non-SOT patients with pneumonia admitted to the same hospital during a 94-week period. There were notable differences, such as post-transplant patients being transferred more quickly to the hospital ward, having longer hospital stays, and receiving antibiotics earlier than the non-SOT group.

Impact of psychopathology on day-to-day living in patients with schizophrenia: A network analysis

Although the relationship between schizophrenia and disability is well established, the relationship between the symptoms of the disorder and functional domains remains unclear. The current study explored the nuances of the relationship between symptoms and domains of functioning in a sample of 1127 patients with schizophrenia. We assessed the symptoms of schizophrenia with the Positive and Negative Syndrome Scale (PANSS) and psychosocial functioning with the mini-ICF-APP (mini-International Classification of Functioning Rating for Limitations of Activities and Participation in Psychological Disorders). The mean PANSS score was 94.28 (27.20), and the mean mini-ICF-APP score was 25.25 (8.96), both of which are indicative of severe symptom load and impairment. We were able to show a strong relationship and overlap between symptoms and disability in patients with schizophrenia. We identified several symptoms related to functional impairment. Deficits in judgment and abstract thinking contribute to impairment through poor adherence (to routines and compliance with rules) and difficulties in planning and organizing. We believe that in schizophrenia, symptoms and their interactions constitute a disorder beyond any single manifestation. Furthermore, we suggest that cognitive testing and cognitive treatment should become part of the standard of care for patients with schizophrenia.

Vital Sign Monitoring for Cancer Patients Based on Dual-Path Sensor and Divided-Frequency-CNN Model.

Monitoring vital signs is a key part of standard medical care for cancer patients. However, the traditional methods have instability especially when big fluctuations of signals happen, while the deep-learning-based methods lack pertinence to the sensors. A dual-path micro-bend optical fiber sensor and a targeted model based on the Divided-Frequency-CNN (DFC) are developed in this paper to measure the heart rate (HR) and respiratory rate (RR). For each path, features of frequency division based on the mechanism of signal periodicity cooperate with the operation of stable phase extraction to reduce the interference of body movements for monitoring. Then, the DFC model is designed to learn the inner information from the features robustly. Lastly, a weighted strategy is used to estimate the HR and RR via dual paths to increase the anti-interference for errors from one source. The experiments were carried out on the actual clinical data of cancer patients by a hospital. The results show that the proposed method has good performance in error (3.51 (4.51 %) and 2.53 (3.28 %) beats per minute (bpm) for cancer patients with pain and without pain respectively), relevance, and consistency with the values from hospital equipment. Besides, the proposed method significantly improved the ability in the report time interval (30 to 9 min), and mean / confidential interval (3.60/[-22.61,29.81] to -0.64 / [-9.21,7.92] for patients with pain and 1.87 / [-5.49,9.23] to -0.16 / [-6.21,5.89] for patients without pain) compared with our previous work.

Transcriptome analysis reveals PRKCA as a potential therapeutic target for overcoming cisplatin resistance in lung cancer through ferroptosis

Cisplatin-based chemotherapy is the current standard care for lung cancer patients; however, drug resistance frequently develops during treatment, thereby limiting therapeutic efficacy.The molecular mechanisms underlying cisplatin resistance remain elusive. In this study, we conducted an analysis of microarray data from the Gene Expression Omnibus (GEO) database under the accession numbers GSE21656, which encompassed expression profiling of cisplatin-resistant H460 (DDP-H460)and the parental cells (H460). Subsequently, we calculated the differentially expressed genes (DEGs) between DDP-H460 and H460. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEGs demonstrated significant impact on the Rap1, PI3K/AKT and MAPK signaling pathways. Moreover, protein and protein interaction (PPI) network analysis identified PRKCA, DET1, and UBE2N as hub genes that potentially contribute predominantly to cisplatin resistance. Ultimately, PRKCA was selected for validation due to its significant prognostic effect, which predicts unfavorable overall survival and disease-free survival in patients with lung cancer. Network analysis conducted on The Cancer Genome Atlas (TCGA) database revealed a strong gene-level correlation between PRKCA and TP53, CDKN2A, BYR2, TTN, KRAS, and PIK3CA; whereas at the protein level, it exhibited a high correlation with EGFR, Lck, Bcl2, and Syk. The in vitro experiments revealed that PRKCA was upregulated in the cisplatin-resistant A549 cells (DDP-A549), while knockdown of PRKCA increased DDP-A549 apoptosis upon cisplatin treatment. Moreover, we observed that PRKCA knockdown attenuated DDP-A549 proliferation, migration and invasion ability. Western blot analysis demonstrated that PRKCA knockdown downregulated phosphorylation of PI3K expression while upregulated the genes involved in ferroptosis signaling. In summary, our results elucidate the role of PRKCA in acquiring resistance to cisplatin and underscore its potential as a therapeutic target for cisplatin-resistant lung cancer.