Poor Response Research Articles

Ayurvedic management of Vascular Parkinsonism: A Case Report

Introduction: Vascular parkinsonism (VP) is a distinct clinicopathological entity from idiopathic Parkinson’s disease, which is presumably caused by cerebrovascular disease. It is characterized by predominant lower body parkinsonism, postural instability, shuffling or freezing gait, absence of rest tremors, absence or poor response to dopamine, and the presence of corticospinal tract signs. Methodology: A 62-year-old male patient was admitted to the Panchakarma IPD of VAC, Ollur complaining of tremors in the hands (left > right), weakness in the left hand, slowness in activities and speech, memory loss, swaying while walking, and pain over the left shoulder joint for the past 10 months. On examination, extrapyramidal signs were positive. He underwent a treatment protocol for Vatavyadhi, including Udvarthanam, Dhanyamladhara, Sirodhara, Vasthi, and Shastika Sali Pinda Sweda, along with Samanoushadis, for a period of 26 days, which yielded better results in the condition. Result: patient assessment was conducted using the Modified Hoehn and Yahr scale, Schwab and England ADL scale, and PDQ-39 scale on the 1st and 26th days. After the treatment, there was a notable amelioration of symptoms, a reduction in disability, and an enhancement in overall quality of life.

Real-World Efficacy and Safety of Dupilumab Use in Japanese Adult Patients with Atopic Dermatitis: A Single-Center, Retrospective, 104-Week, Observational Study

Background/Objectives: Dupilumab is an interlekin-4 receptor antibody that exerts its efficacy by inhibiting the signaling pathway of interleukin-4/interleukin-13, and it is currently used clinically as a highly potent therapeutic for atopic dermatitis. However, there have been few reports on the therapeutic effect of dupilumab using long-term real-world data. To accumulate further real-world data through long-term use of dupilumab, we performed a retrospective study on the courses of patients with atopic dermatitis who were treated with dupilumab for at least 104 weeks in our university hospital. Methods: We examined the treatment courses of 30 adult patients. Results: Subjective (e.g., itch visual analog scale and Dermatology Life Quality Index) and objective (e.g., Eczema Area and Severity Index) indices and some biomarkers showed improvements over time with dupilumab treatment, even in cases with poor early response to dupilumab treatment. As for the therapeutic effect on anatomical regions, although the therapeutic effect on the head and neck region was weak in the early stages, it improved over time, and at 104 weeks, it showed a therapeutic effect that was comparable to other regions. Conclusions: Therefore, our study demonstrated the advantages of prolonged administration of dupilumab in atopic dermatitis.

RNA methylation of CD47 mediates tumor immunosuppression in EGFR-TKI resistant NSCLC.

Although immune checkpoint inhibitors (ICIs) have been successfully utilized in patients with non-small cell lung cancer (NSCLC), EGFR-mutated patients didn't benefit from ICIs. The underlying mechanisms for the poor efficacy of this subgroup remain unclear. CD8+T cells cytotoxicity, DCs phagocytosis and immunofluorescence assay were applied to examine the immunosuppressive microenvironment of NSCLC. m6A RNA immunoprecipitation, luciferase assay and immunohistochemistry were used to explore the relationship between CD47 and ALKBH5 in EGFR-TKI resistant NSCLC. Autochthonous EGFR-driven lung tumor mouse model and PDXs were performed to explore the therapeutic potential of CD47 antibody and EGFR-TKI combination. We found that EGFR-TKI resistance promoted a more immunosuppressive tumor microenvironment and inhibited anti-tumor functions of CD8+ T cells. Mechanistically, the m6A eraser ALKBH5 was inhibited in EGFR-TKI resistant NSCLC, which subsequently upregulates CD47 by catalyzing m6A demethylation and causes immunosuppression. Combined treatment with EGFR-TKI and inhibitors of CD47 enhances antitumor immunity and EGFR-TKI efficacy in vivo. Collectively, our findings reveal the possible underlying mechanism for poor immune response of ICIs in EGFR-TKI resistant NSCLC and provide preclinical evidence that targeted therapy combined with innate immune checkpoint blockade may provide synergistic effects in NSCLC treatment.

Mitochondria-targeting of oxidative phosphorylation inhibitors to alleviate hypoxia and enhance anticancer treatment efficacy.

Hypoxia is a common feature of solid tumors and is associated with a poor response to anticancer therapies. Hypoxia also induces metabolic changes, such as a switch to glycolysis. This glycolytic switch causes acidification of the tumor microenvironment (TME), thereby attenuating the anticancer immune response. A promising therapeutic strategy to reduce hypoxia and thereby sensitize tumors to irradiation and/or antitumor immune responses is pharmacological inhibition of oxidative phosphorylation (OXPHOS). Several OXPHOS inhibitors (OXPHOSi) have been tested in clinical trials. However, moderate responses and/or substantial toxicity has hampered clinical implementation. OXPHOSi tested in clinical trials inhibit the oxidative metabolism in tumor cells as well as healthy cells. Therefore, new strategies are needed to improve the efficacy of OXPHOSi while minimizing side effects. To enhance the therapeutic window, available OXPHOSi have, for instance, been conjugated to triphenylphosphonium (TPP+) to preferentially target the mitochondria of cancer cells, resulting in increased tumor uptake compared to healthy cells, as cancer cells have a higher mitochondrial membrane potential. However, OXPHOS inhibition also induces reactive oxygen species (ROS), and subsequent antioxidant responses, which may influence the efficacy of therapies, such as platinum-based chemotherapy and radiotherapy. Here, we review the limitations of the clinically tested OXPHOSi metformin, atovaquone, tamoxifen, BAY 87-2243 and IACS-010759 and the potential of mito-targeted OXPHOSi and their influence on ROS production. Furthermore, the effect of the mitochondria-targeting moiety TPP+ on mitochondria is discussed as this affects mitochondrial bioenergetics.

Comprehensive Breslow thickness (BT)-based analysis to identify biological mechanisms associated with melanoma pathogenesis.

Breslow thickness (BT), a parameter measuring the depth of invasion of abnormally proliferating melanocytes, is a key indicator of melanoma severity and prognosis. However, the mechanisms underlying the increase in BT remain elusive. Utilizing data from The Cancer Genome Atlas (TCGA) human skin cutaneous melanoma (SKCM), we identified a set of BT-related molecules and analyzed their expression and genomic heterogeneity across pan-cancerous and normal tissues. Through consensus clustering, we identified two distinct BT phenotypes in melanoma, which exhibited significant differences in clinical, genomic, and immune infiltration characteristics. High BT molecular expression was associated with reduced CD8+ T cell infiltration and poor immunotherapy response, potentially mediated by the Macrophage Migration Inhibitory Factor (MIF) signaling pathway. In vitro experiments confirmed that BT molecules, including TRIM29, SERPINB5, and RAB25, promoted melanoma development through distinct mechanisms. Notably, fibroblast-derived TRIM29 and B-cell-derived RAB25 interacted with SPP1+ monocytes/macrophages via different pathways. Our findings suggest that genomic variations leading to imbalanced expression of BT molecules across cancers contribute to increased BT, which is closely linked to an immunosuppressive microenvironment. The involvement of multiple cell types and complex intercellular interactions underscores the importance of evaluating dynamic cellular crosstalk in the tumor microenvironment to better understand BT increases and develop more effective immunotherapeutic strategies.

Genetic loss of Uchl1 leads to female infertility by affecting oocyte quality and follicular development.

Ubiquitin C-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme specifically highly expressed in the brain and gonads. Inhibition of UCHL1 hydrolase activity impairs oocyte maturation. Uchl1 knockout mice exhibit reproductive dysfunction, but the underlying pathogenesis remains unclear. Uchl1 knockout mice were used to explore the role of UCHL1 in oocyte maturation and follicle development. Oocyte development potential and mitochondrial membrane potential were also assessed to determine UCHL1 function on early embryo development. Transcriptome and proteomic analyses were conducted to elucidate molecular changes associated with Uchl1 knockout. Uchl1-/- mice exhibited ovarian dysfunction and infertility, with decreased serum estrogen, reduced antral follicle number, and diminished oocyte developmental potential compared to wild types. Histological examination revealed compromised follicle development and disrupted granulosa cell function in Uchl1-/- ovaries. In vitro, Uchl1-/- follicles had impaired preantral follicle development and poor FSH response. Loss of UCHL1 not only leads to mitochondrial dysfunction in oocytes, but also negatively affected estrogen biosynthesis with downregulation of steroidogenic acute regulatory protein (STAR) and estrogen receptor alpha (ER-α) in granulosa cells. Additionally, downregulated expression of connexin 37 (CX37), which is known to impair gap junction intercellular communication between oocyte and granulosa cells, transmitted the Uchl1 gene damage from oocyte to granulosa cells, which in turn affected functions of follicles and even the whole ovary. Loss of UCHL1 leads to significant disruptions in follicular development and oocyte quality, resulting in infertility. UCHL1 in oocytes influences not only the quality and quantity of the oocytes themselves, but also the follicles and the ovaries as a whole. This disruption ultimately manifests in symptoms similar to diminished ovarian reserve (DOR).

Patients outcomes in lung adenocarcinoma transforming to small-cell lung cancer after tyrosine kinase inhibitor therapy

BackgroundNon-small cell lung cancer (NSCLC) transforming to small cell lung cancer (SCLC) is one of the mechanisms of resistance to tyrosine kinase inhibitors (TKIs). Cases of NSCLC transforming into SCLC have been discovered. However, we lack concentrated data on the characteristics of this population and the transformed SCLC to aid our insight of the biology and clinical value of NSCLC transforming with positive.MethodsWe systematically reviewed the published literatures and summarized the pathological and clinical characteristics, and the prognosis, of published cases.Results140 patients with lung adenocarcinoma (LUAD) were included in this study, with a median age of 56.8 years. The median time from the first diagnosis of LUAD transforming to SCLC (ttSCLC) was 20.0 months. The median overall survival (mOS) after the diagnosis of SCLC was 11.0 months (95% CI, 7.41 to 14.59 months). In the univariate analysis, ever smoking (either former or current) was a promising predictor of a shorter ttSCLC (HR, 1.73; 95% CI, 1.14 to 2.62; P = 0.010). TKIs therapy administered as a second line and beyond treatment was related to a significant delay in SCLC onset compared to first-line therapy (HR, 0.62; 95% CI, 0.40 to 0.96; P = 0.031). The median progression-free survival (mPFS) on first-line platinum plus etoposide after the conversion to SCLC was 3.0 months. Female appeared to be related to worse outcomes after transformation of SCLC.ConclusionTransformed SCLC exhibited poor response to primary SCLC classic chemotherapy and immunotherapy. It carries a worse prognosis. Exploring novel therapeutic strategies for transformed SCLC is imperative.

TP53 Alterations Associate with Poor Response to Lenvatinib in Patients with Advanced Thyroid Cancer.

No data are available about the possible association of TP53 mutations and the response to multikinase inhibitors (MKIs) in thyroid cancer (TC). We evaluated the impact of TP53 mutations on the response to lenvatinib (LEN) in advanced TCs and in in vitro models. We investigated the molecular profile, including TP53 mutations, of 30 tumor tissues from patients treated with LEN, and tested p53 status by immunohistochemistry. These data were compared with clinical-pathological features, and tumor response to LEN. The response to LEN was also evaluated in TP53-defective and TP53-proficient TC cell lines. TP53 mutations significantly correlated with a poor response to LEN (p=0.005). TP53 mutated patients had a shorter progression-free survival (PFS) (p<0.0001) and overall survival (OS) rates (p=0.0007). Accordingly, patients harbouring altered nuclear p53 protein expression had shorter PFS and OS (p=0.0001 and p=0.0056, respectively). These data were confirmed in a validation cohort. In accordance with clinical data, TC cell lines with p53 alterations had low or null sensitivity, while those TP53 wild type showed different degrees of sensitivity, primarily due to the increased number of tumor cells in G1 phase, consistent with the cytostatic effect of LEN. We show for the first time in advanced TC that the presence of TP53 alterations is a predictor of poor response to LEN treatment and associates to worse PFS and OS rates. The evaluation of TP53 mutations/p53 expression might be included into the patient/tumor characterization to be done before starting an MKI treatment.

Neoadjuvant immunotherapy for locally advanced/metastatic mismatch repair deficient colorectal cancer: A two-year institutional experience.

179 Background: MMRd is a tumour agnostic biomarker predictive of response to immune checkpoint inhibitors (ICIs). Given the poor response to 5-FU based chemotherapy, ICIs are now being explored in early MSI-H CRC. The outcomes on this strategy are limited. Methods: We retrospectively evaluated early outcomes for patients receiving neoadjuvant ICIs for unresectable locally advanced/oligometastatic MMRd colorectal cancer (CRC), where intention of treatment was downstaging to permit curative resection. Following discussion at regional MDT, suitable patients were administered a PD-1 inhibitor 6-weekly until disease progression or improvement rendering suitability for surgical resection (to max of 2 years). Results: From October 2022-September 2024, ten patients with MMRd CRC were commenced on neoadjuvant ICIs. These comprised six right, one left sided colonic and three rectal tumours. Median age at diagnosis was 59 (IQR54–68). Four patients had family history of CRC. One patient had clinical stage II, seven stage III and two patients oligometastatic stage IV disease. All were patients with initially unresectable disease, with potential for curative resection pending response to ICI. Histologically, two tumours were poorly differentiated, two mucinous phenotype and six moderately differentiated adenocarcinomas. BRAF mutation was identified in three patients. None had KRAS mutation. Three rectal cancers received radiotherapy in addition to immunotherapy. Five required a defunctioning stoma either prior to or on ICI. Median follow-up was 12.5 months (IQR7-17). Objective response rate by RECIST 1.1 was 100%, with significant downstaging in 9 of 10 patients. The remaining patient is early in treatment course with no reimaging. To date, complete clinical response (cCR) has been observed in three patients (33%). All 10 patients are alive. Grade 3-4 treatment-related adverse events occurred in two patients (20%) who developed treatment-related strictures (one also had tumour perforation). This was successfully managed with defunctioning ileostomy and antibiotics, with subsequent cCR. Conclusions: We report impressive early outcomes of immunotherapy for locally advanced/metastatic MMRd CRC, with excellent downstaging and high predicted cCR. This highlights the importance of screening all CRC for MSI-H/MMRd. In the setting of initially unresectable CRC, an ICI-first approach can render patients eligible for surgery, however deep responses can result in local effects including strictures and/or perforation.

Molecular characteristics and prognostic impact of GNAS mutations in colorectal cancer: An international collaborative study between United States and Japan.

48 Background: GNAS (Guanine nucleotide-binding protein, alpha stimulating) encodes the alpha subunit of the stimulatory G protein, and gain of function mutations in this gene have been previously identified, especially those located at the R201 codon. Although GNAS R201C/H has been associated with mucinous histology and poor response to chemotherapy in appendiceal cancer, the impact of GNAS mutations in colorectal cancer (CRC) remains unclear. Methods: We conducted a comparative, integrative analysis of GNAS mutations in CRC using two cohorts: MD Anderson Cancer Center (MDA) across all stages (N=5,249) and the GALAXY study involving only resectable disease (UMIN000039205, N=2,599). We assessed the correlation between GNAS pathogenic mutations and microsatellite stability, CRC sidedness, co-mutations, and survival outcomes. The Chi-squared test was used for categorical variables, and the log-rank test for overall survival (OS) and disease-free survival (DFS). Results: In the MDA and GALAXY cohorts, GNAS mutations were identified in 107 (2.0%) and 61 (2.4%) patients, respectively. Prevalence of GNAS mutations was higher in right sided tumors (MDA: 3.8% vs. 1.3%, GALAXY: 6.2% vs 2.8%, p&lt;0.01 for both cohorts) and microsatellite instability-high (MSI-H) tumors (MDA: 6.5% vs. 1.8%, GALAXY: 16.5% vs. 1.4%, p&lt;0.01 for both cohorts). There was not an association of GNAS mutations with stage in either cohort. GNAS was significantly enriched for co-mutation with KRAS in the MDA cohort (OR=3.26, P&lt;0.01), similar to prior observations in appendix cancer, but was not significantly associated with KRAS mutations in the GALAXY cohort (OR=1.35, P=0.3). GNAS mutations were mutually exclusive with TP53 in both cohorts (MDA: OR=0.58, P=0.026; GALAXY: OR=0.21, P&lt;0.01). With regards to survival, in the MDA cohort, GNAS mutant tumors had a trend towards worse OS in the overall population (20 mo vs. 33 mo, HR=1.27, 95% CI=0.61-1, P=0.085). The survival impact of GNAS mutations was greatest in metastatic patients (Stage IV: 19 mo vs. 38 mo, HR=1.49, 95% CI=0.47-0.94, P=0.021 vs. Stage I-III: HR=1.35, 95% CI=0.46-1.2, P=0.22). The GALAXY cohort showed no significant association between GNAS mutations and DFS (HR=1.05, 95% CI=0.6-1.8, P=0.9). In both cohorts, GNAS mutations had a worse prognosis in left-sided CRC (MDA: HR for OS = 1.45, P = 0.091; GALAXY: HR for DFS=2.15, P=0.09) with no significant effect observed in right-sided CRC (MDA: HR for OS=0.91, P=0.68; GALAXY: HR for DFS=0.65, P=0.3). Conclusions: Our findings highlighted the intricate role of GNAS mutations in CRC, demonstrating its higher prevalence in MSI-H and right-sided colon, significant association with KRAS mutations, and divergent prognostic impacts based on tumor sidedness. Further research is needed to elucidate the mechanisms behind the worsened survival in left-sided GNAS- mutated CRC.

Analysis of Prognostic Factors for Internal Carotid Artery Invasion by Nasopharyngeal Carcinoma

Background: The prognostic impact of internal carotid artery (ICA) invasion in nasopharyngeal cancer (NPC) patients is not well established. Thus, we conducted a retrospective study to analyze the prognostic factors for ICA invasion by NPC. Methods: This retrospective study included consecutive biopsy-proven NPC patients who received CCRT from November 2015 to December 2022 at E-Da Hospital. Patients were then classified into two groups according to ICA invasion by tumor or not. Survival was estimated by the Kaplan–Meier method with a five-year overall survival (OS) rate and five-year disease specific survival (DSS) rate. Results: A total of 191 patients with pathologically confirmed NPC were included in this study, with 54 patients in the ICA invasion group and 137 patients in the no ICA invasion group. The ICA invasion group showed a worse prognosis compared to the no ICA invasion group (p &lt; 0.001 in OS and DSS). Patients were stratified into a poor response group and good response group. OS and DSS in the poor response group had a significant difference compared to the good response group (both p &lt; 0.001). In multivariate analysis, NLR was an independently prognostic factor for OS (HR 2.430, 95% CI 1.040–5.678, p = 0.040 and HR 0.412, 95% CI 0.176–0.962, p = 0.040, respectively) and for DSS (HR 2.430, 95% CI 1.040–5.678, p = 0.040 and HR 0.412, 95% CI 0.176–0.962, p = 0.040, respectively). Conclusions: Locally advanced NPC patients with ICA invasion have a miserable outcome and NLR represents a significant prognostic factor that impacts treatment decisions and survival.

Peritoneal dialysis-associated peritonitis caused by Coxiella Burnetii: A case report.

Peritoneal dialysis (PD)-associated peritonitis (PDAP) is the leading cause of PD failure and discontinuation of PD. Several zoonotic pathogens could lead to the development of PDAP. Coxiella burnetii (C. burnetii) was a zoonotic pathogen and the cause of Q fever. However, reports of PDAP caused by C. burnetii are rare. We herein report the first case of PDAP caused by C. burnetii in mainland China. A 45-year-old woman was admitted to our hospital with chief complaint of yellow and cloudy PD effluent for 2 days. She had undergone PD for 5 years due to end-stage renal disease. She was engaged in cattle and sheep breeding. The culture of PD effluent was negative, even for specific species, such as Mycobacteria and fungi. The culture from the PD effluent tested positive for C. burnetii by adopting metagenomic next-generation sequencing on day 37. We diagnosed her as PDAP caused by C. burnetii. Empirical treatment with multiple broad-spectrum antibiotics (including vancomycin, etimicin, piperacillin) was initially adopted. After identifying C. burnetii as the culprint as the PDAP, the regimen was changed to doxycycline (100 mg twice daily) and moxifloxacin (400 mg once daily) orally, leading to clinical improvement. The white blood cell count of the PD effluent decreased to within the normal range and the culture of PD effluent was negative for C. burnetii at the visit of 4 months after discharge. Also, there was no sign for recurrence. Vigilance should be heightened for PDAP cases with negative culture of PD fluid and poor response to standard broad-spectrum antibiotic treatment, along with a history of cattle and sheep breeding. In such conditions, PD effluent should be tested to detect possible peritonitis caused by C. burnetii, even in patients without symptoms of fever. Prompt pathogen identification and appropriate treatment are crucial for clinical improvement of such cases.

Sustained T cell-independent type 2 antibody response in a naturally MHC II-deficient teleost fish.

Atlantic cod (Gadus morhua) is well-known to show poor specific antibody responses after immunization, despite having high natural IgM levels. Unlike mammals and nearly all examined other vertebrates, cod lack the MHC II-CD4 axis required for T cell-dependent (TD) antibody responses. We evaluated the cod's antibody response to hapten carriers inducing T cell-independent (TI) and TD responses in mammals. Remarkably, cod generated strong hapten-specific IgM levels against hapten linked to TI-2 antigens ficoll or dextran. Specific IgM levels plateaued 6-9 weeks after a single immunization and remained stable for six months. The serum half-life of IgM was 4 days, indicating continuous IgM production during this period. These findings reveal unique immune mechanisms in Atlantic cod, enhancing our understanding of vertebrate immunology and aiding the development of novel vaccination strategies in aquaculture.

Prognostic Stratification of Epithelioid Pleural Mesothelioma Based on the Hippo-TEADs Network

Background. The Hippo pathway is the most frequently altered signaling in pleural mesothelioma (PM). Epithelioid PM (ePM) is associated with better outcome than non-epithelioid subtypes, but its prognosis can be heterogeneous. Here, we tried to stratify ePM using the expression levels of the Hippo-TEAD network. Methods. Thirty patients with ePM were included in this study. Tumors were stratified using the expression levels of 74 genes belonging to the Hippo-TEAD network and using the non-negative matrix factorization algorithm. Results were validated using ePM cases from the TCGA cohort. Alterations associated with the molecular subgroups were investigated using mutation and copy number alteration data from TCGA. Results. Two groups of ePM (i.e., HP1 and HP2) were identified and validated using TCGA data. HP2 comprises about one-third of tumors. These tumors are frequently high-grade (73% vs. 35%), have higher levels of downstream Hippo effectors (i.e., YAP1, WWTR1 and TEADs), lower levels of VSIR—which encodes for VISTA—and poorer PFS and OS. HP2 tumors commonly harbor homodeletions in Hippo core suppressors (25% vs. 3%), while no specific gene mutation or copy number alterations of Hippo genes was associated with the two groups. Conclusions. ePM can be stratified in prognostic subtypes based on the expression levels of the Hippo-TEAD network. Higher levels of downstream Hippo effectors are associated with poor response to platinum-pemetrexed doublet and worse OS. The stratification of ePM based on the activation of the YAP/TAZ-TEAD axis is an intriguing approach in the light of the inhibitors of this signaling that are currently under investigation.

Neoadjuvant pyrotinib and trastuzumab in HER2-positive breast cancer with no early response (NeoPaTHer): efficacy, safety and biomarker analysis of a prospective, multicentre, response-adapted study

The potential benefits of pyrotinib for patients with trastuzumab-insensitive, HER2-positive early-stage breast cancer remain unclear. This prospective, multicentre, response-adapted study evaluated the efficacy and safety of adding pyrotinib to the neoadjuvant treatment of HER2-positive breast cancer patients with a poor response to initial docetaxel plus carboplatin and trastuzumab (TCbH). Early response was assessed using magnetic resonance imaging (MRI) after two cycles of treatment. Patients showing poor response, as defined by RECIST 1.1, could opt to receive additional pyrotinib or continue standard therapy. The primary endpoint was the total pathological complete response (tpCR; ypT0/isN0) rate. Of the 129 patients enroled, 62 (48.1%) were identified as MRI-responders (cohort A), 26 non-responders continued with four more cycles of TCbH (cohort B), and 41 non-responders received additional pyrotinib (cohort C). The tpCR rate was 30.6% (95% CI: 20.6–43.0%) in cohort A, 15.4% (95% CI: 6.2–33.5%) in cohort B, and 29.3% (95% CI: 17.6–44.5%) in cohort C. Multivariable logistic regression analyses demonstrated comparable odds of achieving tpCR between cohorts A and C (odds ratio = 1.04, 95% CI: 0.40–2.70). No new adverse events were observed with the addition of pyrotinib. Patients with co-mutations of TP53 and PIK3CA exhibited lower rates of early partial response compared to those without or with a single gene mutation (36.0% vs. 60.0%, P = 0.08). These findings suggest that adding pyrotinib may benefit patients who do not respond to neoadjuvant trastuzumab plus chemotherapy. Further investigation is warranted to identify biomarkers predicting patients’ benefit from the addition of pyrotinib.

Comparing the Efficacy of Combined Intralesional Triamcinolone Acetonide With Topical Calcipotriol Versus Intralesional Triamcinolone Acetonide Monotherapy in Scalp and Beard Alopecia Areata: Results From a Randomized Single-Blinded Clinical Trial.

Intralesional (IL) steroids are the first-line treatment option for localized alopecia areata (AA). The present study aimed to compare the efficacy of topical calcipotriol with IL triamcinolone acetonide versus IL triamcinolone acetonide alone in AA. This randomized single-blinded clinical trial was conducted in a dermatology outpatient department. Both groups A and B received IL triamcinolone acetonide injections every 4 weeks for 12 weeks. Group A also received twice-daily topical calcipotriol. Follow-up was done every 4 weeks till 12 weeks. The primary outcome parameter was hair density assessment using a hair regrowth scale (RGS). Other parameters were the presence or absence of poor clinical response (less than 50% hair density), regrowth patterns, dermoscopy features, and adverse effects. Seventy-three (179 patches) patients completed the study. RGS and patches with more than 50% terminal hair regrowth significantly improved in both the groups beginning in the fourth week and going forward (P-value: .001, .001). The two treatment groups exhibited no statistically significant difference in terminal hair density (P values: .930, .616, .178). However, subgroup analysis showed a statistically significant difference in scalp patches of group A compared to group B in the 12th week of the study (P = .018) but not in beard patches (P-value: .527). Group A exhibited more irritation with a reduced incidence of atrophy. The addition of topical calcipotriol to IL steroid showed increased efficacy in scalp patches of AA but not in beard patches. Also, the incidence of atrophy was lower in the combination group.

P-44. Immunogenicity and Safety of High-dose versus Standard-dose Quadrivalent Inactivated Influenza Vaccine in Patients Living with HIV: A Randomized Controlled Trial

Abstract Background Influenza can lead to severe complications in patients living with HIV (PLWH). Annual standard-dose (SD) quadrivalent inactivated influenza vaccine (QIIV) is recommended for PLWH, although it is associated with poor vaccine response. We aimed to investigate the immunogenicity and safety of high-dose (HD) versus SD QIIV in PLWH, as well as safety. Methods We conducted a randomized, open-label, controlled trial to compare the immunogenicity of the 2023 southern hemisphere HD QIIV at 60 μg (Efluelda, Sanofi) versus SD QIIV at 15 μg (Fluarix tetra, Sanofi) in patients living with HIV (PLWH) during August and November 2023. Seroprotection (SP), defined as serum hemagglutination-inhibition antibody titers ≥1:40 at 1 month post-vaccination, was assessed. Adverse events (AEs) following vaccination were also evaluated. Results We enrolled 110 patients who received the study vaccine, and 103 (52 HD; 51 SD) were eligible for analysis. Among them, 65 (62.1%) were male, with a mean age (SD) of 49.6 (11.2) years and a median CD4 count (IQR) of 555 (418-680) cells/mm3. The integrase strand transfer-based regimen was the most common antiretroviral regimen (57.3%), and the majority had an undetectable HIV viral load (93.2%). Fifty-two (50.5%) achieved SP to all strains (A/H1N1, A/H3N2, B/Victoria and B/Yamagata) after vaccination. Those who received HD QIIV reached SP significantly more compared to SD QIIV (61.5% vs. 39.2%, p = 0.02). In particular, SP to the A/H3N2 strain was significantly greater in the HD QIIV group compared to the SD QIIV group (76.9% vs. 52.9%, p = 0.011). Use of HD QIIV were independent factors for SP to all strains (OR 2.7, 95%CI 1.9-6.1, p = 0.02) and SP to the A/H3N2 strain (OR 3.2, 95%CI 1.4-7.8, p = 0.01). Twenty-nine (57.3%) participants in the HD group reported AEs, including muscle ache (36.5%), pain at the injection site (21.2%), and fever (13.5%). Those were all non-severe and comparable to those receiving SD QIIV. Conclusion HD QIIV could offer significantly better immunogenicity across all strains, especially the A(H3N2) strain, compared to SD QIIV in PLWH and should be considered as the preferred influenza vaccine for this population, without safety concerns. TCTR20230501002. Disclosures All Authors: No reported disclosures

P-1503. Dual β-Lactam Approach for Treatment of Mycobacterium abscessus Infections in Adults – Results in 19 Patients

Abstract Background The prevalence of Mycobacterium abscessus (Mab) infection is rising, with immunocompromised individuals being especially susceptible. While treatment success for the subspecies abscessus has been as low as 33%, recent studies and case reports suggest potential efficacy of select dual β-lactam (Dβ). This study evaluated the efficacy and tolerability of select Dβ in treating MDR-Mab infections, guided by in-vitro susceptibility results. Methods We reviewed the treatment of 19 adults with Mab infection at the University of Florida Hospital, Gainesville, who underwent Dβ synergy testing between January 2019 and March 2023. Medical histories, laboratory results, and clinical outcomes were reviewed. We summarized patient and infection characteristics and compared the time from diagnosis to Dβs initiation across outcomes Results Of the 19 patients (mean age: 54 years; 68% females), 11 (58%) had undergone solid organ transplantation or had cancer, and 6 (32%) were on immunosuppressants for autoimmune diseases. Pulmonary infections predominated (68%), with 47% of isolates were macrolide resistant. 11 patients (58%) were due to subspecies abscessus. The Dβs most frequently used for treatment were imipenem combined with either amoxicillin (31%) or ceftaroline (26%). Successful clinical cure or stable culture conversion with ongoing treatment was observed in 9 (47%) cases. 4 patients died during treatment. We observed a trend towards shorter times before initiation of Dβ treatment among patients who were cured. Time to initiation of Dβ therapy exceeded 90 days in 3 of 4 patients who died. Eighteen of 19 patients tolerated dual β-lactams therapy well. Among the 5 who discontinued treatment, the multi-drug regimen, not specifically the dual β-lactams, was the likely cause Conclusion Treatment with Dβ-containing regimens was associated with higher cure rates in this cohort of severely ill, immunocompromised patients. Earlier treatment correlated with better outcomes. Given the poor response to current treatment regimens and the initial promising results of Dβ therapy, clinical trials are planned. Finally, the chosen Dβs may not fully represent the optimal selection due to patient-driven preferences, possibly underscoring a conservative rather than optimal treatment outcome. Disclosures All Authors: No reported disclosures

A Review and Comparison of Immune-Checkpoint Inhibitors in the Treatment of Metastatic Uveal Melanoma

Introduction: Metastatic uveal melanoma (mUM) is a rare and aggressive malignancy characterised by poor responsiveness to conventional chemotherapies, posing significant treatment challenges. Immune checkpoint inhibitor (ICI) therapies, including monotherapies with Ipilimumab, pembrolizumab, and nivolumab, as well as dual ICI therapy, have emerged as potential treatments. Whilst current research favours dual therapy over single therapy, comprehensive individualised comparisons of the efficacy and safety profiles of these therapies remain limited. This meta-analysis aims to evaluate the clinical outcomes of single ICI therapies individually and compare against combination therapy to guide optimal treatment strategies for mUM. Methods: A systematic literature review was conducted to identify studies reporting objective response rates (ORR), disease control rates (DCR), median progression-free survival (MPFS), and adverse event rates (AER) for Ipilimumab, pembrolizumab, nivolumab, and dual ICI therapy. Data were aggregated using forest plots and analysed to compare the efficacy and safety of each regimen. Results: Dual ICI therapy demonstrated the highest ORR and DCR but showed no statistically significant advantage over monotherapies. Dual therapy also had a lower MPFS than both pembrolizumab and nivolumab monotherapies. Furthermore, dual therapy was associated with a much greater AER compared to any single therapy, including pembrolizumab and nivolumab. Conclusions: While dual ICI therapy offers improved ORR and DCR on aggregate analyses, monotherapies like pembrolizumab provide comparable outcomes in specific metrics, particularly MPFS, with significantly reduced toxicity. These findings underscore the need for personalised ICI regimens tailored to individual patient profiles rather than defaulting to dual therapy. Further research is essential to refine treatment guidelines and optimise outcomes for mUM patients.

Tumor Lesion Uptake of [177Lu]Lu-DOTA-Rituximab in Skeletal and Splenic Disease in Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and a sizable fraction of the DLBCL patients presents with advanced, relapsed, and refractory disease, demonstrating poor response to standard chemotherapy regimens. Radioimmunotherapy (RIT) has shown to be clinically effective in refractory DLBCL. We present the case of a patient with DLBCL with [18F]FDG-avid widespread skeletal as well as splenic involvement as poor prognostic extranodal disease on FDG PET/CT. RIT based on [177Lu]Lu-DOTA-rituximab was explored to study the biodistribution and dosimetry of [177Lu]Lu-DOTA-rituximab in CD20-positive lymphoma. An exceptionally high tracer concentration in skeletal and splenic disease was observed, supporting its potential RIT application in relapsed and refractory DLBCL patients in the future.