Immunological Therapy Research Articles

Immunotherapeutic approaches for systemic lupus erythematosus: early overview and future potential.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Current SLE therapies include immunosuppressants, antimalarial drugs, non-steroidal anti-inflammatory drugs (NSAIDs), and corticosteroids, but these treatments can cause substantial toxicities to organs and may not be effective for all patients. In recent years, significant progress has been made in the treatment of SLE using immunotherapy, including Benlysta and Saphnelo. These advances in immunotherapy hold promise for SLE patients, providing new therapeutic options that may offer better clinical benefit and effectiveness. Simultaneously, several new biological therapies focusing on cytokines, peptides, targeted antibodies, and cell-based approaches are under clinical evaluation and have shown immense potential for the treatment of SLE. However, the complexity of SLE immunopathogenesis and disease heterogeneity present significant challenges in the development of effective immunological therapies. This review aims to discuss past experiences and understanding of diverse immunological targeting therapies for SLE and highlight future perspectives for the development of novel immunological therapies.

Abstract PO-070: New patient-derived head and neck cancer xenograft (PDX) panel for drug development, immuno-oncology and translational research

Abstract Head and neck squamous cell carcinomas (HNSCC) represent a heterogeneous group of epithelial cell malignancies arising from the upper aerodigestive tract. Despite of improved therapies, HNSCC remain a devastating disease. Oropharynx cancers are mainly attributed to infection with human papillomavirus (HPV). Since 2017, HNSCC are classified into HPV-negative and HPV-positive HNSCC. Therapies in the clinic are surgery and/or radiotherapy (RT)/radiochemotherapy (RCT) with a recurrence of about 50%. Therefore, new approaches are needed to improve long-term remission and patient survival. Recent advances in high-throughput molecular profiling have helped to identify genetic dispositions (TP53, FAT1, CDKNA2, NOTCH1 etc.) for HNSCC. We have generated and characterized a diverse panel (n = 85) of patient-derived xenografts (PDX) of HNSCC for preclinical research and immuno-oncological approaches. We successfully established 85 HNSCC PDX from fresh surgery tissue of primary and recurrent carcinomas by direct subcutaneous transplantation into immune-deficient mice. 14 HNSCC PDX were derived from HPV-positive tumors. We treated 28 HNSCC PDX with radiotherapy alone or radiochemotherapy. Heterogeneous individual responses to treatments resemble the clinical situation. For characterization, the established HNSCC PDX were treated with standard of cares (SoC) such as docetaxel, platinum compounds, cetuximab, 5-fluorouracil and investigational drugs. No correlation was observed to mutations and drug response. Molecular subtypes were determined based on gene expression data. Cetuximab response was associated with basal subtype and inflamed/mesenchymal subtype was negative predictive for cetuximab response. Further, 30 HNSCC PDX were analyzed for PD-L1 expression as suitable candidates for the evaluation of checkpoints inhibitors such as nivolumab and pembrolizumab and other novel immunotherapy approaches on humanized mice. To gain a deeper insight into the molecular biology, RNA sequencing was performed for 46 HNSCC models. Based on RNASeq data, an individual Human Leucocyte Antigen (HLA) profile of each PDX was determined and a comprehensive HLA matching analysis of the HNSCC models and 9 peripheral blood mononuclear cell (PBMC) donors was performed to enable personalized, preclinical immuno-oncology studies. Our newly and comprehensively characterized HNSCC PDX panel enables the evaluation of new targeted and immunological therapies in preclinical phase II studies. It provides an exceptional platform for the identification and validation of new targets and enables the preclinical screening of new combinations in translational research. Citation Format: Bernadette Brzezicha, Theresia Conrad, Maria Stecklum, Michael Becker, Konrad Klinghammer, Jens Hoffmann. New patient-derived head and neck cancer xenograft (PDX) panel for drug development, immuno-oncology and translational research [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-070.

Management of the Rectal Stump after Subtotal Colectomy Operations for Inflammatory Bowel Disease in the Era of Immunologic Therapy: A Two-Centre Cohort Study

Introduction: Inflammatory bowel disease (IBD) often requires surgical resection, such as subtotal colectomy operations to alleviate symptoms. However, IBD also has an inherently increased risk of colorectal dysplasia and cancer. Despite the well-accepted surveillance guidelines for IBD patients with an intact colon, contemporaneous decision-making models on rectal stump surveillance is sparse. This study looks at the fate of rectal stumps in IBD patients following subtotal colectomy. Methods: This is a two-centre retrospective observational cohort study. Patients were identified from NHS Grampian and NHS Highland surgical IBD databases. Patients that had subtotal colectomy between January 01, 2010 and December 31, 2017 were included with the follow-up end date on April 1, 2021. Socio-demographics, diagnosis, medical and surgical management data were collected from electronic records. Results: Of 250 patients who had subtotal colectomy procedures, only one developed a cancer in their rectal stump (0.4%) over a median follow-up of 80 months. A higher than expected 72% of patients had ongoing symptoms from their rectal stumps. Surveillance was varied and inconsistent. However, no surveillance, flexible sigmoidoscopy, or MRI identified dysplastic or neoplastic disease. Conclusion: Based on our results, we estimate that the prevalence of rectal cancer is lower than previously reported. Surveillance strategy of rectal stump varied as no current guidelines exist and hence is an important area for future study. Given the relatively low frequency of rectal cancer in these patients, and the low level of evidence available in this field, we would propose a registry-based approach to answering this important clinical question.

43703 Effects of Immunological Therapy on Demographics, Clinical Variables, and Survival in Merkel Cell Carcinoma Patients

43703 Effects of Immunological Therapy on Demographics, Clinical Variables, and Survival in Merkel Cell Carcinoma Patients

A novel signature of the ligand and receptor genes associated with disulfidoptosis for prediction of prognosis, immunologic therapy responses in hepatocellular carcinoma

BackgroudWe aimed to explore the prognostic features of ligand and receptor genes associated with disulfidoptosis in hepatocellular carcinoma (HCC) and establish a risk signature utilizing these genes to predict the prognosis of HCC patients. MethodsWe used scRNA-seq data from GSE166635 to differentiate malignant cells from normal cells using “copykat”.The study thoroughly examined the disparities in disulfidoptosis scores and the associated gene expressions between malignant and normal cells.We identified key ligand and receptor genes that are specific to HCC cells.Subsequently, Correlation analysis was conducted to ascertain the ligand and receptor genes associated with disulfidoptosis.We performed univariate Cox regression analysis to identify prognostic ligand and receptor genes associated with disulfidoptosis.We employed LASSO to construct a risk signature using prognostic ligand and receptor genes associated with disulfidoptosis.Lastly, we developed a nomogram model that integrates the risk signature with clinicopathological characteristics. ResultsMalignant cells displayed a marked increase in disulfidoptosis scores and the expression of associated genes compared to normal cells.We identified 110 receptor and ligand genes significantly associated with disulfidoptosis, and narrowed them down to create a risk signature comprising eight genes.Multivariate analysis confirmed the risk signature as an independent prognostic factor for HCC and validated its predictive value for immunotherapy outcomes.A novel nomogram was developed, incorporating stage information and the risk signature derived from disulfidoptosis-related receptor and ligand genes, demonstrating excellent predictive accuracy and reliability in HCC prognosis prediction. ConclusionRisk signatures based on disulfidoptosis-associated ligand and receptor genes can effectively predict HCC prognosis and may inform immunotherapy strategies.

Analysis of the clinical characteristics of 25 cases with parenchymal neuro-Behcet's disease

Objective: To retrospectively investigate the clinical data, radiological characteristics, treatment, and outcome of patients with parenchymal neuro-Behcet's disease (P-NBD) with particular emphasis on dizziness. Methods: This was a cross-sectional study of clinical data from 25 patients with a confirmed diagnosis of P-NBD who were admitted to the Department of Neurology of the First Medical Center of Chinese People's Liberation Army General Hospital between 2010 and 2022. The median age of the population was 37 years (range: 17-85 years). Clinical data were retrospectively analyzed, including gender, age of onset, disease duration, clinical manifestations, serum immune indicators, cerebrospinal fluid (CSF) routine biochemical and cytokine levels, cranial and spinal magnetic resonance imaging (MRI) findings, treatment, and outcome. Results: The majority of patients were male (16 cases; 64.0%), the mean age of onset was (28±14) (range: 4-58 years), and the disease course was acute or subacute. Fever was the most common clinical presentation, and the complaint of dizziness was not uncommon (8/25 patients). Analysis of serum immune indices, including complement (C3 and C4), erythrocyte sedimentation rate, interleukin-1 (IL-1), IL-6, IL-8 and tumor necrotic factor-alpha were abnormal in 80.0% of patients (20/25). Most of the 16/25 patients who underwent lumbar puncture tests had normal intracranial pressure and increased CSF white cell count and protein [median values were 44 (15-380) ×106/L and 0.73 (0.49-2.81) g/L, respectively]. Of the five patients who underwent CSF cytokine tests, four patients had abnormal results; of these, an elevated level of IL-6 was most common, followed by IL-1 and IL-8. The most common site of involvement in cranial MRI was the brainstem and basal ganglia (60.0% respectively), followed by white matter (48.0%) and the cortex (44.0%). Nine cases (36.0%) showed lesions with enhancement and six cases (24.0%) showed mass-like lesions. Three patients (12.0%) patients had lesions in the spinal cord, most frequently in the thoracic cord. All patients received immunological intervention therapy; during follow up, the majority had a favorable outcome. Conclusions: P-NBD is an autoimmune disease with multiple system involvement and diverse clinical manifestations. The symptom of dizziness is not uncommon and can be easily ignored. Early treatment with immunotherapy is important and can improve the outcome of these patients.

Deep-penetration functionalized cuttlefish ink nanoparticles for combating wound infections with synergetic photothermal-immunologic therapy

The challenge of wound infections post-surgery and open trauma caused by multidrug-resistant bacteria poses a constant threat to clinical treatment. As a promising antimicrobial treatment, photothermal therapy can effectively resolve the problem of drug resistance in conventional antibiotic antimicrobial therapy. Here, we report a deep-penetration functionalized cuttlefish ink nanoparticle (CINP) for photothermal and immunological therapy of wound infections. CINP is decorated with zwitterionic polymer (ZP, namely sulfobetaine methacrylate-methacrylate copolymer) to form CINP@ZP nanoparticles. Natural CINP is found to not only exhibit photothermal destruction of methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli), but also trigger macrophages-related innate immunity and enhance their antibacterial functions. The ZP coating on the surface of CINP enables nanoparticles to penetrate into deeply infected wound environment. In addition, CINP@ZP is further integrated into the thermosensitive Pluronic F127 gel (CINP@ZP-F127). After in situ spraying gel, CINP@ZP-F127 is also documented notable antibacterial effects in mice wound models infected with MRSA and E. coli. Collectively, this approach combining of photothermal therapy with immunotherapy can promote delivery efficiency of nanoparticles to the deep foci of infective wounds, and effectively eliminate wound infections.

P-503 Immunological therapies in women undergoing assisted conception: a systematic review and meta-analysis

Abstract Study question What is the effectiveness and safety of immunological therapies in women undergoing assisted conception? Summary answer The evidence on the overall effectiveness and safety of immunomodulators was scarce and uncertain, although some drugs may lead to improved outcomes in selected women. What is known already Embryo implantation is a pre-requisite for pregnancy success. It requires a state of immune tolerance within the maternal endometrium permitting the attachment and subsequent invasion into the decidua of the semi-allogenic blastocyst. Mechanistic data suggesting that heightened immune responses may impair implantation have led to the widespread use of immunomodulatory therapies in clinical practice. These include drugs such as aspirin, heparin, corticosteroids, intralipid and intravenous immunoglobulin (IVIG). However, despite the common use of immunomodulatory drugs in women having in vitro fertilisation (IVF), there is no consensus on their effectiveness and safety, owing to a paucity of well-designed interventional studies. Study design, size, duration We searched MEDLINE, EMBASE, PubMed and CENTRAL until September 2022. We selected randomised controlled trials (RCTs) investigating immunological therapies in women undergoing IVF, including aspirin, heparin, corticosteroids, granulocyte-colony stimulating factor (G-CSF), intralipid, intravenous immunoglobulin (IVIG), tumour necrosis factor-alpha inhibitors and peripheral blood mononuclear cells (PBMCs), evaluated alone or in combination, versus no intervention, placebo or any other immunomodulator(s). The primary outcomes were the rates of live birth or ongoing pregnancy (LBR/OPR) and miscarriage per participant. Participants/materials, setting, methods Two reviewers independently selected studies and extracted data. We conducted pairwise meta-analyses according to participants’ phenotypes as reported by the trialists, including: good prognosis, previous implantation failure, autoimmunity, high inflammation, thin endometrium, and low ovarian reserve. Using the Cochrane-RoB-1 tool, we restricted our primary analyses to RCTs at low risk of selection and other biases. We presented effect estimates as risk ratio (RR) with 95% confidence interval (CI) and considered I2>50% as representing substantial heterogeneity. Main results and the role of chance Our searches identified 14,893 records. We included a total of 84 studies in the qualitative synthesis, of which 43 contributed to the meta-analyses, evaluating in total 7,301 participants and 12 treatment comparisons. The primary analysis showed that aspirin resulted in little to no difference in LBR (RR 0.97, 95% CI 0.94-1.23; n = 688 women; moderate-certainty evidence) and MR (RR 1.20, 95% CI 0.73-1.99; n = 988 women; low-certainty evidence) compared with placebo. The data did not identify a difference in LBR/OPR in women using subcutaneous heparin (RR 1.30, 95% CI 0.80-2.12; n = 150 women; very low-certainty evidence) or IVIG (RR 1.28, 95% CI 0.32-5.16; n = 51 women; very low-certainty evidence) versus placebo. For the remaining interventions, the primary analysis was uncertain of an effect or insufficient for quantitative synthesis. However, the sensitivity analysis including all studies, irrespective of risk of bias, showed that corticosteroids may improve LBR in women with thyroid autoimmunity (RR 2.33, 95% CI 1.04-5.25; n = 60 women; very low-certainty evidence); intrauterine G-CSF may improve LBR in women with a thin endometrium (RR 2.57, 95% CI 1.24-5.29; n = 304 women; very low-certainty evidence); and intrauterine PBMCs may improve LBR in women with previous implantation failure (RR 2.03, 95% CI 1.33-3.10; n = 312 women; very low-certainty evidence). Limitations, reasons for caution For most of the interventions under study, the evidence was of low or very-low certainty, owing to limitations in study design, imprecision, indirectness and inconsistency. Further, very few studies reported on adverse events, highlighting a worrying lack of data on the safety of immunological therapies for women undergoing assisted conception. Wider implications of the findings A scarcity of well-designed RCTs limits the evidence on immunomodulators in women undergoing IVF. However, we identified positive signals for some therapies in specific conditions (e.g. corticosteroids for thyroid autoimmunity, intrauterine G-CSF for thin endometrium, and PBMCs in women with previous implantation failure). This merits further investigation in high-quality trials. Trial registration number PROSPERO registration number CRD42021294031

Neuroimaging of complications arising after CD19 chimeric antigen receptor T-cell therapy: A review.

Chimeric antigen receptor (CAR) T cells targeting the CD19 (cluster of differentiation 19) cell surface glycoprotein have emerged as a highly effective immunologic therapy in patients with relapsed or refractory B-cell malignancies. The engagement of CAR T cells with CD19 on the surface of neoplastic B cells causes a systemic cytokine release, which can compromise the blood-brain barrier and cause an immune effector cell-associated neurotoxicity syndrome (ICANS). In a small proportion of ICANS patients who demonstrate neuroimaging abnormalities, certain distinct patterns have been recognized, including signal changes in the thalami, external capsule, and brainstem, the subcortical and/or periventricular white matter, the splenium of the corpus callosum, and the cerebellum. On careful review of the underlying pathophysiology of ICANS, we noticed that these changes closely mirror the underlying blood-brain barrier disruption and neuroinflammatory and excitotoxic effects of the offending cytokines released during ICANS. Furthermore, other uncommon complications of CD19 CAR T-cell therapy such as posterior reversible encephalopathy syndrome, ocular complications, and opportunistic fungal infections can be catastrophic if not diagnosed in a timely manner, with neuroimaging playing a significant role in management. In this narrative review, we will summarize the current literature on the spectrum of neuroimaging findings in ICANS, list appropriate differential diagnoses, and explore the imaging features of other uncommon central nervous system complications of CD19 CAR T-cell therapy using illustrative cases from two tertiary care institutions.

Construction of a prognostic model for triple-negative breast cancer based on immune-related genes, and associations between the tumor immune microenvironment and immunological therapy.

Triple-negative breast cancer (TNBC) is the subtype of breast cancer with the worst prognosis, and it is highly heterogeneous. There is growing evidence that the tumor immune microenvironment (TIME) plays a crucial role in tumor development, maintenance, and treatment responses. Notably however, the full effects of the TIME on prognosis, TIME characteristics, and immunotherapy responses in TNBC patients have not been fully elucidated. Gene Expression Omnibus and The Cancer Genome Atlas data were used to data analysis. Single-cell sequencing and tissue microarray analysis were used to investigate gene expression. The concentrations and distributions of immune cell types were determined and analyzed using the CIBERSORT strategy. Tumor immune dysfunction and exclusion score and the IMvigor210 cohort were used to estimate the sensitivity of TNBC patients with different prognostic statuses to immune checkpoint treatment. Five immune-related genes associated with TNBC prognosis (IL6ST, NR2F1, CKLF, TCF7L2, and HSPA2) was identified and a prognostic evaluation model was constructed based on those genes. The respective areas under the curve of the prognostic nomogram model at 3 and 5 years were 0.791 and 0.859. The group with a lower nomogram score, with a better prognosis survival status and clinical treatment benefit rate. A prognostic model for TNBC that was closely related to the immune landscape and therapeutic responses was constructed. This model may help clinicians to make more precise and personalized treatment decisions pertaining to TNBC patients.

The role of B lymphocytes in selected rheumatological and neurological diseases

Introduction: B lymphocytes are responsible for humoral immune response. They play a crucial role in the development of the immune response and are essential in preventing infections as well as autoimmune and neoplastic diseases. They also constitute an important therapeutic target and are used in genetic and immunological therapies. In some cases, B cells can contribute to the pathogenesis of various diseases. Aim of study: The aim of this study is to summarize the current knowledge on the diverse role of B lymphocytes in selected rheumatic and neurological diseases using available scientific literature. Materials and Methods: This review was conducted using Pubmed and Google Scholar databases from 2009-2023. The research strategy was based on the following terms: B lymphocytes, monoclonal antibodies, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, systemic sclerosis, central nervous system damage, optic neuritis, Devic's syndrome. Conclusion: B lymphocytes play a significant role in the pathogenesis of many rheumatic and neurological diseases, therefore they represent a target for modern therapies. Their role and potential use are complex and differ depending on the specific disease entity. Further research will allow for the development of new targeted therapies, giving hope for improving the effectiveness of patient treatment.

Evolution of cancer treatment costs in the last 36 months in a self-funded health care in Brazil.

e18838 Background: In Brazil, cancer, in addition to being one of the main causes of illness and death, represents one of the highest public and private healthcare expenses. Regardless of the population profile, the direct costs of cancer pose as a real threat to the health system's sustainability. The objective of this study is to analyze the evolution of the use and costs of chemotherapy, targeted therapy, hormone therapy and immunotherapy. Methods: Retrospective cohort consisted of all health plan beneficiaries diagnosed with cancer and who received pharmacological treatment in the last 36 months (September/2019 to August/2022). Based on Period 1 (P1, Sep/2019 to Aug/2020), we analyzed the evolution in the other periods (P2 and P3, Sep/2020 to Aug/2021 and Sep/2021 to Aug/2022, respectively) of the use of chemotherapy and the costs involved (per capita and per patient treated). We also analyzed the evolution of expenses with oral antineoplastic agents and their proportion in relation to other routes of administration. The most prescribed therapies were analyzed. Microsoft Excel and Qlik Sense were used for relative and absolute frequencies, means and standard deviation (95% confidence intervals, significance when p < 0.05). Results: During the study period, 982 beneficiaries (683, 601 and 572, respectively in P1, P2 and P3) underwent treatment with antineoplastic agents (mean age 68 years, 50.7% women). In P1, 1.6% of the total exposed received some type of chemotherapy. In the following intervals, the percentage increased to 1.7% and 2.1%, P2 and P3, respectively. Although the cost per patient treated increased by 4.7% in 36 months, the annual expense per patient, that is, the entire portfolio of the plan and not just those diagnosed with cancer, increased by 40.5%. Should be noted that the variation that occurred in P2 in relation to P1 was 7.8%, however, in P3 compared to P2, 30.3%. The proportion of patients receiving oral antineoplastics in relation to those treated remained stable (53.6%, 54.7% and 52.3%, P1, P2 and P3, respectively). Ten active principles with the highest financial consumption and corresponding to more than half of the total expenses: nivolumab, daratumumab, bevacizumab, trastuzumab, pembrolizumab, pertuzumab, enzalutamide, atezolizumab, paclitaxel and brentuximab vedotin. Conclusions: Molecular and immunological therapies have revolutionized cancer treatment and improved patient outcomes and survival, however, new treatment options represent an additional challenge. In this study, the cost of cancer treatment has increased 40.5%, especially in the last period, which coincides with the expansion of the list of mandatory coverages and due to the resumption of procedures after COVID-19. Minimizing the financial impact of the new technologies, through responsible management focused on the patient and based on the best scientific evidence, is fundamental for maintaining the sustainability.

Tissue-specific heterogeneity of Human T follicular helper cells marked by unique transcriptomes and regulatory architecture

Abstract T follicular helper (T FH) cells represent a distinct lineage of CD4 T cells that engage with cognate B cells, facilitating the production of high affinity vaccine- and pathogen-specific antibodies. In humans, T FHcells can be detected in several tissues throughout the body, each representing a unique cellular environment complete with distinct signaling molecules. Despite T FHcell importance to human health, it remains unclear if and how anatomical location results in diversity among T FHcells. Here, we detail tissue-specific heterogeneity of human T FHcells reflected in both transcriptome and chromatin architecture. T FHcells sourced from circulating peripheral blood (cT FH), lung lymph nodes (lnT FH), tonsils (tT FH), and an in vitro differentiation model (exT FH), were subjected to RNA-sequencing and ATAC-sequencing. When comparing expression of conical T FHgenes, including BCL6 and PDCD1, a spectrum in magnitude emerged: cT FH< exT FH< lnT FH< tT FH. Increased chromatin accessibility at proximal cis-regulatory elements occurred within the loci of T FHgenes in a similar tissue-dependent fashion and correlated with transcript levels. Additionally, unique gene signatures were detected in each T FHpopulation, including the presence of distinct transcription factor networks, implying tissue specific T FHfunctionality. Integrating PageRank and scRNA-seq of tT FHcells revealed BCL-6, ASCL2, TOX, TOX2, and AIOLOS as potential regulators of the T FHgene program. Collectively, these findings detail tissue specific diversity amongst human T FHcells, while highlighting key developmental networks which could influence the design of future immunological therapies targeting T FHcells. Supported by grants from NIH: (RO1 AI113021, F32 AI161857)

Construction of an Excellent 7 mRNAsi-Related Gene Model Based on Cancer Stem Cells for Predicting Survival Outcome of Cervical Cancer

Background. Cervical cancer (CC) is one of the most frequent female malignancy. Cancer stem cells (CSCs) positively affect survival outcomes in cancer patients, but in cervical cancer, the mechanism of tumor stem cells is still uncertain. Methods. RNA-seq data and related clinical follow-up of patients suffering from CC were from TCGA. Consensus clustering screened prognostic mRNAsi-related genes and identified molecular subtypes for CC. Based on the overlapping differentially expressed genes (DEGs) in subtypes, we employed LASSO and multivariate Cox regression to screen prognostic-related genes and established the RiskScore system. The patients were grouped by RiskScore, the prognosis was analyzed by the Kaplan-Meier (K-M) curve among the various groups, and the precision of the RiskScore was assessed by the ROC curve. Finally, the potential worth of RiskScore in immunotherapy/chemotherapy response was assessed by evaluating TIDE scores and chemotherapy drug IC 50 values. Results. We noticed that patients with low mRNAsi had a shorter survival and then identified three molecular subtypes (C1-3), with the C1 having the worst prognosis and the lowest mRNAsi. Finally, we identified 7 prognostic-related genes (SPRY4, PPP1R14A, MT1A, DES, SEZ6L2, SLC22A3, and CXCL8) via LASSO and Cox regression analysis. We established a 7-gene model defined RiskScore to predict the prognosis of CC patients. K-M curve indicated that low RiskScore patients had improved prognosis, and ROC curves indicated that RiskScore could precisely direct the prognostic evaluation for those suffering from the cancer. This was also confirmed in the GSE44001 and GSE52903 external cohorts. Patients were more sensitive to immunotherapy if with low RiskScore, and RiskScore exhibited precise assessment ability in predicting response to immunological therapy in CC patients. Conclusion. CC stemness is associated with patient prognosis, and the RiskScore constructed based on stemness characteristics is an independent prognostic index, which is expected to be a guide for immunotherapy, providing a new idea for CC clinical practice.

Paraneoplastic Neurological Syndromes: A Single-Center Retrospective Study in Argentina (P9-13.005)

<h3>Objective:</h3> To describe the clinical features, diagnostic approach and treatments in patients diagnosed with paraneoplastic neurological syndromes (PNS). <h3>Background:</h3> PNS are due to an abnormal response of the immune system against the nervous system. In many cases, their identification allows early diagnosis of hidden tumors. Argentina ranks fifth in cancer frequency in Latin America, however data about PNS is lacking. <h3>Design/Methods:</h3> We performed a retrospective study including 42 adult patients with PNS treated between 2010 and 2021 in a referral center of Argentina. <h3>Results:</h3> Mean age at symptom onset was 59.6 years (range 20 to 82). The onset of symptoms was acute in 11 cases (26%), subacute in 25 (59.5%) and chronic in 6 (14.3%). The median time between the onset of symptoms and suspicion of PNS was 16.25 months (SD 16.7). The most frequent symptoms were paresthesias (23.8%) and limb weakness (19%). Classic PNS was found in 6 patients (14.3%) and non-classic PNS were identified in 26 cases (61.9%). An onconeural antibody was identified in 36 patients (85.7%). Primary tumors were found in 14 patients (33.3%). Lung cancer was the most frequent tumor (28.57%). The latency between suspected PNS and tumor diagnosis was 1.89 years (range 0.31 to 4.79). Twenty eight patients (66.7%) received immunological therapy. Nine patients received onco-specific treatment (chemotherapy or radiotherapy) and two patients were treated with tumor resections. Symptoms improved in 21.4% of patients, 57.1% remained stable and 21.4% worsened. Four patients died (9.5%). <h3>Conclusions:</h3> The clinical manifestations were under a non-classical syndrome, had a subacute course and were associated with lung cancer in the majority of cases. The latency between PNS onset and tumor identification was also variable despite the use of appropriate imaging techniques. The absence of antibodies does not rule out an occult tumor, which should not delay immunomodulatory treatment in the suspected cases. <b>Disclosure:</b> Mr. Caiza Zambrano has nothing to disclose. Fabio Gonzalez has nothing to disclose. Dr. Galarza Menoscal has nothing to disclose. Dr. Benetti has nothing to disclose. The institution of Marcela Uribe Roca has received research support from Roche. Dr. Bonardo has nothing to disclose. Manuel Fernandez Pardal has nothing to disclose. Dr. Leon Cejas has nothing to disclose. Dr. Reisin has nothing to disclose.

A Tale of Two Cases: When to Use PLEX That is The Question (P10-5.025)

<h3>Objective:</h3> NA <h3>Background:</h3> The diagnosis New Onset Status Epilepticus (NORSE) is rare. Autoimmune encephalitis (AIE) is one of the most common causes. Data on timely administration of Plasmapheresis (PLEX) vs IVIG/Solumedrol therapy is lacking. Seizure control can be used as a marker for response to therapy. <h3>Design/Methods:</h3> NA <h3>Results:</h3> In these two cases, we describe NORSE with newly diagnosed Autoimmune encephalitis. The clinical courses for each were different. Case 1, a 30 yo M with no pmh was admitted to Epilepsy Monitoring Unit (EMU). Patient was in focal status with LP CSF findings consistent with AIE. Patient had conventional treatment for AIE: steroids and IVIG. Patient was discharged upon clinical improvement. He was admitted a week later for worsening seizures. Patient’s seizures were treated with 5 PLEX sessions followed by chemotherapy (Actemra and Rituxan) administration in addition to high doses of antiseizure medication. Case 2, 32 yo M with no pmh presents with 11 days of generalized weakness, cognitive slowing/confusion. Patient had 6 generalized tonic clonic seizures. Patient was in the ICU and intubated. Various agents were used for seizure control such as Vimpat, Keppra, Depakote and Ketamine. Day 4, was started on steroids and IVIG. Day 11, started on 5 sessions of PLEX followed by chemotherapy (Actemra and Rituxan) with significant improvement. <h3>Conclusions:</h3> NORSE is a diagnosis with high rate of refractoriness to treatment and severe outcome. Early initiation of immunological therapy provide the most benefit. First line therapy is based on clinical presentation and expert opinion. These two cases illustrate better outcome with early initiation of plasmapheresis in rapidly progressing refractory focal status epilepticus of autoimmune etiology. Its been shown PLEX is better economically and less potential side effects as compared to IVIG. Rapid seizure control with combination of high dose new anti-seizure and immunological treatment in a timely manner are key for better outcomes. <b>Disclosure:</b> Dr. Dalal has nothing to disclose. Dr. Grunstein has nothing to disclose. Dr. Schneider has nothing to disclose. Dr. Proteasa has nothing to disclose.

Symptomatic Copper Deficiency Masquerading as Paraneoplastic Syndrome (P9-4.005)

<h3>Objective:</h3> To describe an unusual case of symptomatic copper deficiency initially suspected to be paraneoplastic syndrome. <h3>Background:</h3> Copper deficiency is exceedingly rare, especially in developed nations, and is usually the result of genetic deficit. It often presents with neuropathy, weakness and encephalopathy. In this case, we describe a case of copper deficiency presenting with weakness, hallucinations and encephalopathy initially mistaken for paraneoplastic syndrome in a patient recently diagnosed with breast cancer. <h3>Design/Methods:</h3> NA <h3>Results:</h3> Our patient is a 58 year old female with a history of recently diagnosed breast cancer who presented with new-onset lower extremity weakness and confusion. She was initially admitted to the medical-oncology service for management of her malignancy. During her hospitalization, she developed frank hallucinations and worsening encephalopathy. Neurologic workup including MRI brain, C and T-Spine, EEG, lumbar puncture with basic studies and autoimmune panel were negative. She got 3 days of IVIG and 5 days of PLEX with no improvement. The patient’s sister revealed for 8 weeks she had only been eating vegetables grown in her own garden. EMG revealed axonal sensorimotor neuropathy. Serum vitamins were checked and revealed a copper level of 30 ug/dL (80–120 ug/dL). She was started on IV copper replacement and slowly improved; she was seen in the clinic six months later with marked improvement of her mentation, but persistent lower extremity paraparesis. <h3>Conclusions:</h3> While vitamin deficiency—especially copper deficiency—is rare, it should be considered in cases where patients with weakness and neuropsychiatric symptoms have a benign neurologic workup and fail to respond to conventional immunologic therapies. <b>Disclosure:</b> Dr. Welsh has nothing to disclose. Dr. Hoskin has nothing to disclose.

Current understanding on pathogenesis and effective treatment of glycogen storage disease type Ib with empagliflozin: new insights coming from diabetes for its potential implications in other metabolic disorders.

Glycogen storage type Ib (GSDIb) is a rare inborn error of metabolism caused by glucose-6-phosphate transporter (G6PT, SLC37A4) deficiency. G6PT defect results in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa and into both glycogenolysis and gluconeogenesis impairment. Clinical features include hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia, hyperlipidemia, and growth retardation. Long-term complications are liver adenoma, hepatocarcinoma, nephropathy and osteoporosis. The hallmark of GSDIb is neutropenia, with impaired neutrophil function, recurrent infections and inflammatory bowel disease. Alongside classical nutritional therapy with carbohydrates supplementation and immunological therapy with granulocyte colony-stimulating factor, the emerging role of 1,5-anhydroglucitol in the pathogenesis of neutrophil dysfunction led to repurpose empagliflozin, an inhibitor of the renal glucose transporter SGLT2: the current literature of its off-label use in GSDIb patients reports beneficial effects on neutrophil dysfunction and its clinical consequences. Surprisingly, this glucose-lowering drug ameliorated the glycemic and metabolic control in GSDIb patients. Furthermore, numerous studies from big cohorts of type 2 diabetes patients showed the efficacy of empagliflozin in reducing the cardiovascular risk, the progression of kidney disease, the NAFLD and the metabolic syndrome. Beneficial effects have also been described on peripheral neuropathy in a prediabetic rat model. Increasing evidences highlight the role of empagliflozin in regulating the cellular energy sensors SIRT1/AMPK and Akt/mTOR, which leads to improvement of mitochondrial structure and function, stimulation of autophagy, decrease of oxidative stress and suppression of inflammation. Modulation of these pathways shift the oxidative metabolism from carbohydrates to lipids oxidation and results crucial in reducing insulin levels, insulin resistance, glucotoxicity and lipotoxicity. For its pleiotropic effects, empagliflozin appears to be a good candidate for drug repurposing also in other metabolic diseases presenting with hypoglycemia, organ damage, mitochondrial dysfunction and defective autophagy.

Prostate Cancer: From Molecular Imaging to Immunological and Target Therapies

Prostate cancer (PCa) is one of the most common malignancies and a leading cause of cancer-related deaths, affecting a million people worldwide with a particularly high burden in countries with a low human development index [...].

Application and progress of photodynamic therapy in combination therapy of lung cancer

Lung cancer is one of the most common malignant tumors with high morbidity and mortality. At present, the traditional treatments of lung cancer include surgical resection, radiotherapy, chemotherapy, targeted therapy and immunological therapy. The modern model of diagnosis and treatment tends to be multidisciplinary, individual, focusing on systemic therapy combined with local therapy. Recently, PDT(photodynamic therapy) becomes an emerging cancer treatment due to its advantages of low trauma, high selectivity, hypotoxicity, good reutilization. PDT has a good effect in the radical treatment of early airway cancer and palliative treatment of advanced airway tumor by using its photochemical reactions. Nevertheless, more attention is focused on combination therapy of PDT Combination with surgery can reduce tumor burden and eliminate potential lesions; Combination with radiotherapy can reduce the amount of radiation and improve therapeutic effect; Combination with chemotherapy achieves the combination of local and systemic therapy; Combination with targeted therapy can enhance anti-cancer targeting; combination with immunotherapy can improve anti-cancer immunity, etc. This article focused on PDT as a part of a combination therapy in the treatment of lung cancer, to provide a new treatment method for patients with poor therapeutic effect with traditional treatment.