Initial Clinical Response Research Articles

Transfer learning approach in pre-treatment CT images to predict therapeutic response in advanced malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a poor-prognosis disease. Owing to the recent availability of new therapeutic options, there is a need to better assess prognosis. The initial clinical response could represent a useful parameter. We proposed a transfer learning approach to predict an initial treatment response starting from baseline CT scans of patients with advanced/unresectable MPM undergoing first-line systemic therapy. The therapeutic response has been assessed according to the mRECIST criteria by CT scan at baseline and after two to three treatment cycles. We used three slices of baseline CT scan as input to the pre-trained convolutional neural network as a radiomic feature extractor. We identified a feature subset through a double feature selection procedure to train a binary SVM classifier to discriminate responders (partial response) from non-responders (stable or disease progression). The performance of the prediction classifiers was evaluated with an 80:20 hold-out validation scheme. We have evaluated how the developed model was robust to variations in the slices selected by the radiologist. In our dataset, 25 patients showed an initial partial response, whereas 13 patients showed progressive or stable disease. On the independent test, the proposed model achieved a median AUC and accuracy of 86.67% and 87.50%, respectively. The proposed model has shown high performance even by varying the reference slices. Novel tools could help to improve the prognostic assessment of patients with MPM and to better identify subgroups of patients with different therapeutic responsiveness.

B - 105 ICANS, CAR-T, and Cognition: a Case Study

Abstract Objective Immune effector cell-associated neurotoxicity syndrome (ICANS), an autoimmune delirious condition, affects 37.5% to 77% of individuals during or after chimeric antigen receptor T-cell (CAR-T) treatment for hematologic cancers (Grant et al., 2022). Initial clinical response varies widely but may include apraxia, aphasia, disorientation, and hallucinations (Möhn et al., 2022). Recent research indicates complete symptom resolution in most patients a month post-ICANS onset (Sales et al., 2023). However, a self-report study suggested more than 1 in 3 report persisting cognitive sequelae 1–5 years post-ICANS onset (Rurak et al., 2020). This discrepancy may be due to subtle changes missed by the Montreal Cognitive Objective Assessment (Sales et al., 2023; Möhn et al., 2022). The current case report investigates neurobehavioral outcome post-ICANS via comprehensive neuropsychological assessment. Method Two weeks post-CAR-T therapy, a 53-year-old male exhibited abrupt onset facial palsy and cognitive slowing prompting hospitalization. His wife reported new-onset apathy, atypical behaviors exacerbation (e.g., licking plate), and cognitive lapses (e.g., short-term memory, slowing, repeating questions) with little insight. Neuroimaging revealed supratentorial white matter hyperintensities plus calvarium and R skull base enhancing lesion regression. Results Neuropsychological assessment 10-months post-ICANS revealed subtle executive inefficiencies with family reports of improved yet ongoing social disinhibition and apathy. Conclusions This is the first comprehensive neuropsychological assessment of a patient who developed ICANS post-CAR-T therapy. Neuropsychologists should be aware of delayed cognitive sequelae possibility of this advancing treatment option. Future studies will be useful for patient/family preparation.

Adding Evidence to an Evidence-Based Classification for Recurrent Weight Gain after Bariatric and Metabolic Surgery from a Norwegian National Registry.

In 2023, the first evidence-based classification for recurrent weight gain (RWG) after metabolic and bariatric surgery was introduced. It uses early and late follow-up weight loss benchmarks based on standard deviations (SD) of percentage total weight loss(%TWL) results from the large Dutch Audit for Treatment of Obesity (DATO) registry (n > 18,000). We aimed to validate this classification and confirm its clinical relevance with an external cohort. The DATO-based classification defines all RWG as grade 1, as long as weight-loss does not drop below DATO's late-follow-up minus one SD benchmark (20%TWL). Grade 3 represents clear outliers whose RWG evolves below DATO's late follow-up minus two SD benchmark (10%TWL), with grade 2 in-between. Grades 2a/3a represent initial suboptimal clinical response, with nadir %TWL never exceeding DATO's early-follow-up minus one SD benchmark (25%TWL). Grades 2b/3b represent late clinical deterioration from nadir weight loss ≥ 25%TWL. We compared baseline characteristics, SD based benchmarks, RWG and comorbidities from the Scandinavian Obesity Surgery Registry Norway (SOReg-N) with these DATO-derived grades. The SOReg-N population (n = 3064) was comparable at baseline, with more sleeve gastrectomies (54% versus DATO 22.5%). The SD benchmarks were at early follow-up minus one SD 25.8%TWL, at 5years minus one SD/minus two-SD 17.2%TWL/7.0%TWL (DATO 25%TWL/20%TWL/10%TWL). Percentage of patients and amount of RWG were similar to DATO. In line with DATO, comorbidities were predominant in grades 2a/3a, with least improvement in grade 3a. Also, grade 3b showed more favorable characteristics at baseline. The SOReg-N cohort confirmed the weight-loss benchmarks defining the DATO-derived grades, the distribution of patients and their RWG across the grades, and correlations between grades and comorbidities. Male gender, older age and comorbidities were predominant among patients with initial suboptimal clinical response (RWG grades 2a/3a), but not for late clinical deterioration (RWG grades 2b/3b). This classification can be used for populations with diverse weight loss trajectories and offers an evidence-based guide for clinical decision-making and standardization.

Contact X-ray Brachytherapy as a sole treatment in selected patients with early rectal cancer – Multi-centre study

Background and purposeRadical surgery is the standard of care for early rectal cancer. However, alternative organ-preserving approaches are attractive, especially in frail or elderly patients as these avoid surgical complications. We have assessed the efficacy of sole Contact X-ray Brachytherapy (CXB) treatment in stage-1 rectal cancer patients who were unsuitable for or declined surgery. Materials and methodsThis retrospective multi-centre study (2009–2021) evaluated 76 patients with T1/2-N0-M0 rectal adenocarcinomas who were treated with CXB alone. Outcomes were assessed for the entire cohort and sub-groups based on the T-stage and the criteria for receiving CXB alone; Group A: patients who were fit enough for surgery but declined, Group B: patients who were high-risk for surgery and Group C: patients who had received prior pelvic radiation for a different cancer. ResultsWith a median follow-up of 26(IQR:12–49) months, initial clinical Complete Response (cCR) was 82(70–93)% with rates of local regrowth 18(8–29)%, 3-year actuarial local control (LC) 84(75–95)%, distant relapse 3 %, and no nodal relapse. 5-year disease-free survival (DFS) and overall survival (OS) were 66(48–78)% and 58(44–75)%. Lower OS was observed in Groups B [HR:2.54(95 %CI:1.17, 5.59), p = 0.02] and C [HR:2.75(95 %CI:1.15, 6.58), p = 0.03]. Previous pelvic radiation predicted lower cCR and OS. The main toxicity was G1-2 rectal bleeding (26 %) and symptoms of impaired anal sphincter function were not reported in any patients. ConclusionCXB treatment alone achieved a high cCR rate with satisfactory LC and DFS. Inferior oncological outcomes were observed in patients who had received prior pelvic radiotherapy. CXB alone, with its favourable toxicity profile and avoidance of general anaesthesia and surgery risks, therefore, can be considered for patients who are unsuitable for or refuse surgery.

IL-1 receptor antagonism reveals a yin-yang relationship between NFκB and interferon signaling in chronic lymphocytic leukemia

Nuclear factor kappa B (NFκB) is a pathogenic factor in chronic lymphocytic leukemia (CLL) that is not addressed specifically by current therapies. NFκB is activated by inflammatory factors that stimulate toll-like receptors (TLRs) and receptors for interleukin-1 (IL-1) family members. IL-1 is considered a master regulator of inflammation, and IL-1 receptor signaling is inhibited by the IL-1 receptor antagonist anakinra. These considerations suggested that anakinra might have a role in the treatment of CLL. Consistent with this idea, anakinra inhibited spontaneous and TLR7-mediated activation of the canonical NFκB pathway in CLL cells in vitro. However, CLL cells exhibited only weak signaling responses to IL-1 itself, and anakinra was found to inhibit NFκB along with oxidative stress in an IL-1 receptor-independent manner. Anakinra was then administered with minimal toxicity to 11 previously untreated CLL patients in a phase I dose-escalation trial (NCT04691765). A stereotyped clinical response was observed in all patients. Anakinra lowered blood lymphocytes and lymph node sizes within the first month that were associated with downregulation of NFκB and oxidative stress in the leukemia cells. However, inhibition of NFκB was accompanied by upregulation of type 1 interferon (IFN) signaling, c-MYC-regulated genes and proteins, and loss of the initial clinical response. Anakinra increased IFN signaling and survival of CLL cells in vitro that were, respectively, phenocopied by mitochondrial antioxidants and reversed by IFN receptor blocking antibodies. These observations suggest that anakinra has activity in CLL and may be a useful adjunct for conventional therapies as long as compensatory IFN signaling is blocked at the same time.

HyperArcTM volumetric modulated arc therapy for hypopharyngeal cancer with solitary recurrence in the cervical vertebra: A case report and literature review.

It is difficult to reirradiate head and neck cancers because of the toxicity from previous radiation dose delivery. Conventional volumetric modulated arc therapy (VMAT) and intensity-modulated radiation therapy often have poor target coverage. The new HyperArcTM VMAT (HA-VMAT) planning approach reportedly has better target coverage, higher conformity, and can spare normal organs compared to conventional VMAT; however, research on recurrent head and neck cancers is limited. Here, we report the clinical outcomes of HA-VMAT for previously irradiated hypopharyngeal cancer with solitary recurrence in the first cervical vertebra (C1). A 52-year-old Asian male was diagnosed with a hypopharyngeal cancer. The patient received concurrent chemoradiotherapy with a radiation dose of 70 Gy in 33 fractions and achieved complete clinical response. Two years later, solitary recurrence was observed in the C1 vertebra. Solitary recurrence in the C1 vertebra. Owing to concerns regarding the toxicity to adjacent organs, we decided to use HA-VMAT to achieve better tumor coverage and critical organ sparing. Tumor regression was observed on the imaging. At 9 months follow-up, the patient was disease-free and had no late toxicities. This is the first report regarding the clinical outcomes of HA-VMAT for previously irradiated hypopharyngeal cancer with solitary recurrence over the C1 vertebra. HA-VMAT achieves highly conformal dose distribution and excellent sparing of critical organs. There was a favorable initial clinical response with no toxicity. Long-term follow-up is essential in such cases.

A pilot study comparing the initial clinical response to different proton pump inhibitors within first week in treating erosive esophagitis

AbstractGastroesophageal reflux disease (GERD) characterized by heartburn and/or acid regurgitation symptoms is one of the most common gastrointestinal disorders. The rapid onset of proton pump inhibitors (PPIs) to improve annoying symptom is an essential need in treating GERD. There was no report about the short‐term clinical effects comparing lansoprazole 30 mg to rabeprazole 20 mg. This pilot study was designed to compare the initial one‐week clinical response of the two drugs in GERD with erosive esophagitis. Total 44 patients with GERD were enrolled in this study and randomized into two groups. The patients had the symptoms of acid regurgitation, heartburn, or feeling of acidity in the stomach and erosive esophagitis proven by endoscopy. They respectively received once‐daily dose of lansoprazole 30 mg (n = 23) and rabeprazole 20 mg (n = 21) for treatment of GERD. The primary end point was complete symptom resolution (CSR). The CSR rate was evaluated by questionnaire including acid regurgitation, heartburn sensation and epigastric pain at day 1, 3 and 7. Two patients in the arm of rabeprazole had poor compliance of drugs and were excluded from analysis. The final patient numbers were 23 in the arm of lansoprazole and 19 in rabeprazole. The baseline characteristics of two groups were similar in age, gender, body mass index (BMI), Helicobacter pylori infection, GERD severity, smoking, alcohol, coffee, spicy, sweet food and laboratory data. The ingestion of tea was the only one variable with significant difference between the two groups (65.2% and 31.58%, p = .03). At day 1, 3 and 7, the CSR rate of lansoprazole and rabeprazole were 21.74% and 26.32% (p = 1.000), 34.78% and 31.58% (p = .827), 47.83% and 47.37% (p = .976), respectively. The other clinical factors, including age, gender, BMI, Helicobacter pylori infection, smoking, alcohol, coffee, tea, spicy, sweet food and laboratory data, have also no significant influence on CSR rates at day 1, 3, 7. However, the patients with GERD C and D had significantly higher CSR rate than patients with GERD A and B at day 1 and 7 (CSR rate at day 1: 50.00% vs. 15.63, p = .040; day 3: 60.00% vs. 25.00%, p = .059; day 7: 90.00% vs. 34.38%, p = .003). In multivariate regression analysis, the patients with GERD C and D still had significantly higher CSR rate than patients with GERD A and B at day 7 (Odds ratio: 28.27, 95% CI: 2.10–380.03, p = .012). The CSR rates between lansoprazole group and rabeprazole group at day 1, 3, 7 were not significantly different, so the difference of PPIs did not play the role on the initial clinical response within 1 week for the erosive GERD patients. However, the patients with more severe erosive GERD on endoscopy had higher CSR rate at day 7.

Blood Cell Count Ratios at Baseline are Associated with Initial Clinical Response to Clozapine in Treatment-Resistant, Clozapine-Naïve, Schizophrenia-Spectrum Disorder.

Clozapine is the recommended treatment for managing treatment-resistant schizophrenia (TRS), and immunological mechanisms may be involved in its unique antipsychotic efficacy. This study investigated whether baseline immune abnormalities measured with blood cell count ratios can predict the clinical response after initiating treatment with clozapine in patients with clozapine naïve TRS. A longitudinal design was developed, involving 32 patients diagnosed with treatment-resistant, clozapine-naïve schizophrenia-spectrum disorder. Patients were evaluated at baseline before clozapine starting and 8 weeks of follow-up. Psychopathological status and immune abnormalities (blood cell count ratios: neutrophil-lymphocyte ratio [NLR], monocyte-lymphocyte ratio [MLR], platelet-lymphocyte ratio [PLR] and basophil-lymphocyte ratio [BLR]) were evaluated in each visit. Baseline NLR (b=- 0.364; p=0.041) and MLR (b =- 0.400; p=0.023) predicted the change in positive symptoms over the 8-week period. Patients who exhibited a clinical response showed higher baseline NLR (2.38±0.96 vs. 1.75±0.83; p=0.040) and MLR (0.21±0.06 vs. 0.17±0.02; p=0.044) compared to non-responders. In the ROC analysis, the threshold points to distinguish between responders and non-responders were approximately 1.62 for NLR and 0.144 for MLR, yielding AUC values of 0.714 and 0.712, respectively. No statistically significant differences were observed in the blood cell count ratios from baseline to the 8-week follow-up. Our study emphasizes the potential clinical significance of baseline NLR and MLR levels as predictors of initial clozapine treatment response in patients with TRS. Future studies with larger sample sizes and longer follow-up periods should replicate our findings.

Abstract 6314: Potent inhibition of tumor relapse after anti-HER2 affibody tagged with cotinine (switch) plus anti-cotinine switchable CAR T cell therapy by repeated re-injection of the switch

Abstract Chimeric antigen receptor (CAR) T cells targeting CD19 or the B cell maturation antigen (BCMA) have demonstrated impressive initial clinical responses. However, on follow-up assessment, a notable fraction of the patients with significant initial clinical response eventually experienced relapse. CAR T cell therapies targeting solid tumors have shown an even lower rate of clinical response as well as shorter remission periods. A prior study has shown that re-injection of the anti-HER2 CAR T cells was effective in a rhabdomyosarcoma relapse patient (Cancer Res 79, LB147 (2019)), but the repeated production of CAR T cells is costly, thus raising questions about its feasibility in practice. Previously, we developed a cotinine-based CAR T cell system (zCART) comprised of a tumor antigen-specific affibody conjugated with cotinine and an anti-cotinine scFv CAR, and demonstrated the anti-tumor activity of an anti-HER2 zCART treatment in both in vitro and in vivo settings. In this study, we tested the efficacy of anti-HER2 zCART treatment in vivo using an intraperitoneal (IP) tumor model with a single infusion of zCART cells. The anti-HER2 switch was injected daily for 7 days. When the HER2 positive tumor relapsed, the mice were re-treated with the same dose of anti-HER2 switch treatment for an additional 7 days. We observed that re-injection of only the anti-HER2 switch and not combined with zCART cells effectively and potently inhibited relapse of HER2 positive tumors. Furthermore, the efficacy of the anti-HER2 switch re-injection treatment was maintained in one additional relapse. In summary, the zCART system has potential to treat cancer relapse following CAR T cell therapy without the need for an additional production round of CAR T cells. Citation Format: Ki Hyun Kim, Soohwan Kim, Eun-Hoe Lee, Soo-Yoon Lim, Sung Min Kim, E-Young Kim, Hyun-Jong Lee, Seong Yeol Kim, Min Yoon, Young-Ha Lee, In-Sik Hwang, Yoon Lee, Jong-Hoon Kim, Jong-Seo Lee, Junho Chung. Potent inhibition of tumor relapse after anti-HER2 affibody tagged with cotinine (switch) plus anti-cotinine switchable CAR T cell therapy by repeated re-injection of the switch [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6314.

Abstract 5869: Investigation of molecular alterations associated with double resistance to BRAF and MEK inhibition in melanoma

Abstract More than 50% of melanomas harbor activating BRAF kinase mutations, with BRAFV600E representing more than 90% of BRAF mutations. Inhibition of mutant BRAF by BRAF inhibitors (BRAFi) in patients with advanced melanoma yields a remarkable initial clinical response. Limited duration response and disease recurrence of inhibitors occurs due to acquired drug resistance. Recently identified mechanisms of MAPK hyperactivation in acquired resistance to BRAFi have encouraged clinicians to employ a combination of BRAF and MAPK inhibitors to block the MAPK signaling pathway more effectively. However, most patients treated with this combination therapy still relapse due to de novo drug resistance. Therefore, innovative strategies are still necessary to improve the precision and durability of anti-melanoma therapies. To investigate the mechanism of both BRAFi and MEKi resistance (double resistance, DR) in mutant BRAF melanomas, we have developed models from four human melanoma cell lines to explore the hypothesis that molecular alterations are related to double resistance to BRAFi and MEKi in melanoma. We have found that BRAFi-MEKi double-resistant models exhibit distinct differences in morphology and growth kinetics. Specifically, BRAFi-MEKi double-resistant human melanomas express a higher level of FGFb and PAI-1 expression. We confirmed that overexpression of FGFb and PAI-1 in parental cells could increase the ability to resist BRAF and MEK inhibition. Additionally, we discovered that decreased expression of FGFb and PAI-1, via knock-down, inhibition, or CRISPR in double resistant cells, can restore cell sensitivity to treatments of BRAFi and MEKi. To further elucidate the role of FGFb and PAI-1 on resistant melanoma, we have extended our scope to in vivo mouse xenograft models. Our findings uncovered the mechanism of how melanoma cells can escape BRAFi and MEKi attacks and offer a rational strategy to guide future clinical treatments. Citation Format: Armond J. Isaak, GeGe R. Clements, Lei Huang, Yifei Qin, Qiang Zho, Glenn Merlino, Yanlin Yu. Investigation of molecular alterations associated with double resistance to BRAF and MEK inhibition in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5869.

Abstract 177: Targeting murine or human KLRG1 exerts potent anti-tumor efficacy involving both CD8T cells and NK cells

Abstract Clinical response to anti-PD-1 immunotherapy is correlated with patients who have a T cell-inflamed tumor microenvironment. Some patients with immune cell infiltration fail to respond, and some patients experiencing an initial clinical response develop acquired resistance. It is likely that additional immune-regulatory pathways need to be targeted to expand the efficacy of immunotherapies. To identify a broader array of therapeutic relevant immunotherapy molecules in T cell-inflamed tumors, our lab utilized gene expression profiling to characterize tumor antigen-specific dysfunctional CD8+ T cells in the tumor microenvironment. One molecule that was found to be overexpressed on these CD8+ T cells was C-type lectin inhibitory receptor, KLRG1. KLRG1 is an ITIM domain-containing receptor mostly explored on NK cells, and the known ligands are N- and E- cadherins which are broadly expressed in solid cancers. Analysis of single cell RNA-Seq data from tumor biopsies of melanoma patients classified as responders or non-responders to anti-PD-1 therapy revealed significantly higher expression of KLRG1 expression on tumor-infiltrating T cell subsets in non-responders, suggesting a possible salvage immune suppressive role. To determine the potential functional relevance of KLRG1 on tumor control, we generated KLRG1 knockout (KO) mice, then implanted tumors and assessed tumor growth rate in vivo. KLRG1 KO mice showed markedly slowed B16 melanoma tumor growth compared to WT mice, arguing it is a critical negative regulator of anti-tumor immunity. Both antigen-specific CD8+ T cells and NK cells were expanded in these tumors, and depletion of CD8+ T cells or NK cells eliminated this tumor control. Genetic deletion of N-cadherin from B16 cells also resulted in slowed tumor growth, suggesting that tumor cells are providing the functionally relevant ligand. To assess the degree of inhibitory function of human KLRG1, we generated a humanized KLRG1 knock-in mouse model. We confirmed that human KLRG1 can biochemically interact with murine cadherins. Knock-in mice with the humanized KLRG1 protein had significantly increased tumor growth compared to both WT and KLRG1 KO mice, indicating a stronger immunosuppressive effect of human KLRG1 compared to murine KLRG1. An antagonistic antibody blocking interaction of human KLRG1 with its ligands was generated, which potentiated human T cell activation in vitro. Administration of anti-human KLRG1 Ab to tumor-bearing humanized KLRG1 mice led to markedly reduced tumor growth. In summary, our data support KLRG1 as a functionally critical negative regulator of the anti-tumor immune response and that blocking KLRG1-cadherin interactions has potential as a therapeutic candidate. Citation Format: Tyler A. Jones, Stephen Sinicrope, Kei Yasuda, Jan Pinkas, Thomas F. Gajewski. Targeting murine or human KLRG1 exerts potent anti-tumor efficacy involving both CD8T cells and NK cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 177.

Third-party fecal microbiota transplantation for high-risk treatment-naïve acute GVHD of the lower GI tract

AbstractDisruption of the intestinal microbiome is observed with acute graft-versus-host disease (GVHD) of the lower gastrointestinal (LGI) tract, and fecal microbiota transplantation (FMT) has successfully cured steroid-refractory cases. In this open-label, single-arm, pilot study, third-party, single-donor FMT was administered in combination with systemic corticosteroids to participants with high-risk acute LGI GVHD, with a focus on treatment-naïve cases. Participants were scheduled to receive 1 induction dose (15 capsules per day for 2 consecutive days), followed by 3 weekly maintenance doses, consisting of 15 capsules per dose. The primary end point of the study was feasibility, which would be achieved if ≥80% of participants able to swallow ≥40 of the 75 scheduled capsules. Ten participants (9 treatment-naïve; 1 steroid-refractory) were enrolled and treated. The study met the primary end point, with 9 of 10 participants completing all eligible doses. Organ-specific LGI complete response rate at day 28 was 70%. Initial clinical response was observed within 1 week for all responders, and clinical responses were durable without recurrent LGI GVHD in complete responders. Exploratory analyses suggest that alpha diversity increased after FMT. Although recipient microbiome composition never achieved a high degree of donor similarity, expansion of donor-derived species and increases in tryptophan metabolites and short-chain fatty acids were observed within the first 7 days after FMT. Investigation into the use of microbiome-targeted interventions earlier in the treatment paradigm for acute LGI GVHD is warranted. This trial was registered at www.ClinicalTrials.gov as #NCT04139577.

Incidence and predictors of complications in Gram-negative bloodstream infection.

The incidence of metastatic complications in Gram-negative bloodstream infection (GN-BSI) remains undefined. This retrospective cohort study examines the incidence and predictors of complications within 90days of GN-BSI. Patients with GN-BSIs hospitalized at two Prisma Health-Midlands hospitals in Columbia, South Carolina, USA from 1 January 2012 through 30 June 2015 were included. Complications of GN-BSI included endocarditis, septic arthritis, osteomyelitis, spinal infections, deep-seated abscesses, and recurrent GN-BSI. Kaplan-Meier analysis and multivariate Cox proportional hazards regression were used to examine incidence and risk factors of complications, respectively. Among 752 patients with GN-BSI, median age was 66years and 380 (50.5%) were women. The urinary tract was the most common source of GN-BSI (378; 50.3%) and Escherichia coli was the most common bacteria (375; 49.9%). Overall, 13.9% of patients developed complications within 90days of GN-BSI. The median time to identification of these complications was 5.2days from initial GN-BSI. Independent risk factors for complications were presence of indwelling prosthetic material (hazards ratio [HR] 1.73, 95% confidence intervals [CI] 1.08-2.78), injection drug use (HR 6.84, 95% CI 1.63-28.74), non-urinary source (HR 1.98, 95% CI 1.18-3.23), BSI due to S. marcescens, P. mirabilis or P. aeruginosa (HR 1.78, 95% CI 1.05-3.03), early clinical failure criteria (HR 1.19 per point, 95% CI 1.03-1.36), and persistent GN-BSI (HR 2.97, 95% CI 1.26-6.99). Complications of GN-BSI are relatively common and may be predicted based on initial clinical response to antimicrobial therapy, follow-up blood culture results, and other host and microbiological factors.

The Association Between Preoperative Insulin-Like Growth Factor 1 Levels and the Total Body Weight Loss in Women Post Laparoscopic Sleeve Gastrectomy.

Despite the well-described optimal initial clinical response of sleeve gastrectomy (SG) in the treatment of obesity, some patients do not achieve optimal initial clinical response. Insulin-like growth factor-1 (IGF-1) has currently shown an association with post-bariatric surgery weight loss. This study aimed to assess the IGF-1 levels in female patients with obesity, the change after surgery, and their association with the metabolic profile and weight loss after surgery. This was a prospective study that was conducted on adult female patients who were recruited for SG. The patients underwent clinical and laboratory investigations that included the IGF-1 measurement. At the 1-year follow-up, the same clinical and laboratory measures were repeated. This study included 100 female patients. At the 1-year follow-up, there was a statistically significant reduction in body mass index (BMI) (p < 0.001), fasting HbA1C levels (p < 0.001), and triglycerides (p < 0.001), as well as a statistically significant increase in HDL (p < 0.001) and IGF-1 (p < 0.001). Multiple regression analysis revealed that, among the patients baseline characteristics, the significant predictors for the percentage of total weight loss (%TWL) were the patients' BMI (p < 0.001) and IGF-1 levels (p < 0.001). The ROC curve showed that an IGF1 cutoff value of ≤ 23ng/ml detected suboptimal initial clinical response, with a sensitivity of 95.35% and a specificity of 100%. This study underscores the significant impact of SG on weight loss and metabolic improvements in female patients. Baseline IGF-1 levels emerged as a crucial predictor of optimal initial clinical response.

P677 The Oxford Anti-TNF Study of Immunogenicity and Sustained Response (OASIS-IBD): Analysis of 40,000 Patient Years of Anti-TNF Use

Abstract Background Anti-TNF therapy is established as a mainstay in IBD management. Recent data raise controversies regarding efficacy of these agents, sustainability of response, and identification of factors that may influence outcomes, including dose escalation and need for long-term concurrent immunosuppression (Lancet Gastro.Hep.2019;4:341). Methods We report a retrospective cohort study of 699 IBD patients on anti-TNF at our centre between 2005-2022. Clinical data were obtained from patient records and pharmacy database (TABLE 1). Primary outcomes were overall loss of response (LOR) at any timepoint; and secondary LOR (after an initial clinical response to therapy). Cox regression analysis was performed to identify variables independently affecting outcome. Kaplan-Meyer survival curves were constructed to demonstrate overall response rates (persistence on drug) and secondary LOR (Figure 1a-d). Dose adjustments were made proactively in a Virtual Clinic. Results 204 patients had a diagnosis of ulcerative colitis (UC), 481 Crohn’s Disease (CD) and 14 IBD-unclassified. 126 patients received both infliximab (IFX) and adalimumab (ADA). Median duration on IFX was 42 months (range 0-204); median duration on ADA was 48.5 months (range 0-180). 48% of patients on IFX underwent dose escalation, as did 40% on ADA. Overall, 58 patients (7.6%) remained on treatment at 120 months. Overall survival rates for IFX at 12 months were 83% (82%CD vs. 82%UC); and at 36 months were 71% (69%CD vs. 74%UC). Overall survival rates for ADA at 12 months were 84% (89%CD vs. 59%UC); and at 36 months were 72% (78% CD vs. 42% UC) (Figure 1a-b). Secondary LOR rates for IFX at 12 months were 6% (5%CD vs. 9%UC); and at 36 months were 16% (15%CD vs.19%UC). Secondary LOR rates for ADA at 12 months were 7% (5%CD vs. 19%UC); and at 36 months were 16% (12% CD vs. 42% UC) (Figure 1c-d). There was no difference in survival analysis for IFX between CD and UC. On Cox regression analysis, for IFX, immunomodulation was associated with reduction in overall LOR (HR=0.48, p=1.07e-05) but not secondary LOR (HR=0.78, p=0.31) (Figure 1e-f). For ADA, outcomes were better for CD vs. UC for both overall LOR (HR=0.35, p=3.29e-07) and secondary LOR (HR=0.35, p=9.99e-05). Conclusion We demonstrate encouraging response rates in the first three years of therapy, with a small proportion remaining on therapy beyond 120 months. Survival rates on IFX were similar for UC and CD, but for ADA were significantly lower in UC. Secondary LOR was not affected by immunomodulation. Further analysis of relation to drug levels, dose escalation and genotyping is underway. This work was supported by The Leona M &amp; Harry B Helmsley Charitable Trust.

P034 Peripheral immune cell activity and biopsy gene expression in chronic pouchitis patients treated with tofacitinib: early induction results from the STOPit trial

Abstract Background The Study of TOfacitinib for the treatment of chronic PouchITis (STOPit) is an investigator-initiated, open-label induction, double-blind, placebo-controlled, maintenance withdrawal study to determine the effectiveness of tofacitinib at inducing and maintaining remission in patients with chronic pouchitis. In this interim assessment, we evaluated blood samples and biopsy gene expression collected during the open-label induction period to discover biomarkers of initial clinical response. Methods We collected blood (n = 10 pairs, n = 5 non-responders) and biopsies (n = 21 pairs, n = 9 non-responders) at baseline and after 8 weeks of tofacitinib induction therapy (all participants received 10 mg twice daily induction). We classified patients as responders if they achieved a decrease of ≥ 2 in their modified pouchitis disease activity index after 8 weeks. Bulk peripheral blood mononuclear cells (PBMCs) and memory CD4+ T cells (TMEMs) were isolated from whole blood samples. Cytokines induced by stimulation in the presence or absence of tofacitinib were assessed in culture supernatants by bead array (PBMCs stimulated with PMA/Io or LPS, TMEMs stimulated with CD3/CD28 tetramer). Gene expression was measured in biopsies by qPCR in the pouch and pre-pouch ileum at both time points. Results At baseline, non-responders produced more IL-17 from both their PBMCs stimulated with PMA/Io and TMEMs stimulated with tetramer than responders, but responders secreted more IL-12p70, MCP, IL-10 and IL-8. Tofacitinib inhibited stimulation-induced IL-10 and IL-6 secretion in PBMCs in both responders and non-responders but failed to reduce IFNγ and TNF secretion selectively in non-responders only. All cytokine responses investigated in TMEMs, including IFNγ and TNF, were inhibited by tofacitinib in both responders and non-responders, suggesting the PBMC cell type refractory to inhibition with tofacitinib in non-responders is not TMEMs. Baseline biopsy ileal gene expression of IL18, HES1 and CXCL10 was decreased in responders compared to non-responders, while MMP7 was increased. Clinical response to tofacitinib led to a reduction in pouch expression of GLIS3, G0S2 and WNT5a from baseline to week 8 whereas these genes were unchanged or increased in non-responders. Conclusion Baseline functional immune cell responses and biopsy gene expression may discriminate chronic pouchitis patients' response to tofacitinib therapy and point to a mechanism underlying non-responsiveness. Recruitment for this trial is ongoing, allowing us to bolster and expand our findings with increasing sample sizes.

P854 Tofacitinib demonstrates preliminary efficacy in induction of remission in chronic pouchitis

Abstract Background Pouchitis is common following total proctocolectomy for ulcerative colitis (UC) and ileal pouch-anal anastomosis (IPAA) and generally responds to antibiotics. However, up to 20% of patients develop either antibiotic-dependent or antibiotic-refractory pouchitis, collectively referred to as chronic pouchitis. Methods We report our preliminary induction results from a multi-center open label induction with randomized withdrawal trial to assess the efficacy of tofacitinib in chronic pouchitis. All eligible participants received 10mg tofacitinib twice daily for 8 weeks, with an additional 8 weeks of therapy given to patients with an inadequate initial clinical response. The primary endpoint was clinical response (a reduction of clinical PDAI≥2) at week 8. Secondary endpoints included endoscopic response (a reduction of endoscopic PDAI≥2), mPDAI remission (modified pouchitis disease activity index (mPDAI)≤ 4 and a reduction of mPDAI≥2), mPDAI response (a reduction of mPDAI≥2) and improvement in health-related quality of life (HRQoL) using the short inflammatory bowel disease questionnaire (SIBDQ). Serum cytokine levels was analyzed using LEGENDplex human inflammation panel 1. Univariate analysis was performed to identify clinical and biochemical predictors of response to tofacitinib. Results A total of 33 patients with chronic pouchitis (Table 1) were included in the preliminary analysis. The clinical and endoscopic response rates at week 8 were 55% and 58% respectively, with a median improvement of 1 (p&amp;lt;0.05) and 3 (p&amp;lt;0.05) respectively (Figure 1). The mPDAI remission rate was 49% at week 8 with an mPDAI response rate of 73%. Endoscopic responders exhibited significant improvements in endoscopic oedema, granularity, friability, and mucous exudate (p&amp;lt;0.05). There was significant improvement in HRQoL, with the median SIBDQ score increasing from 35 at baseline to 54 at week 8 (p&amp;lt;0.05). Eleven patients received a further 8 weeks of therapy with a clinical response rate of 36%, yielding an overall response rate including extended induction of 67%. Univariate analysis did not reveal significant differences in baseline characteristics, clinical, or biochemical markers between responders and non-responders. However, a history of corticosteroid use (p=0.08) and high baseline levels of faecal calprotectin (p=0.15) demonstrated a non-significant association with treatment response. Elevated baseline serum levels of IL-1b, IFN-a and IL-33 were associated with a treatment response at week 8 (p&amp;lt;0.05). Conclusion Tofacitinib demonstrated preliminary efficacy in inducing both clinical and endoscopic response in patients with chronic pouchitis who have undergone IPAA for UC.

Maintenance of antidepressant effect by dextromethorphan in patients with treatment-resistant depression who respond to ketamine intervention

Although conventional oral antidepressants are effective in patients with major depressive disorder (MDD), up to 30% of these patients do not achieve symptomatic remission, even after undergoing two trials of antidepressants. Such patients are classified as having treatment-resistant depression (TRD). The glutamate neurotransmitter system has attracted attention as a potential target for treatment that may serve as an alternative to antidepressant treatment. Ketamine is a prototypical N-methyl-d-aspartate receptor (NMDAR) antagonist that has demonstrated substantial promise as a rapid-acting antidepressant for patients with TRD. A single infusion of ketamine causes a noticeable antidepressant effect within 4 h, which peaks after 24 h and then gradually declines. Sustaining the initial clinical response to ketamine infusion in patients with TRD is a major clinical challenge. Dextromethorphan and ketamine share similar pharmacological properties, including their effects on NMDARs, mu-opioid receptors, and sigma-1 receptors. The pathogenesis of MDD, a complex and heterogeneous disorder, has been linked to multiple neurotransmitter systems. Patients with TRD who favorably respond to acute ketamine treatment are likely to respond well to subsequent dextromethorphan therapy. Therefore, we hypothesized that dextromethorphan could sustain the antidepressant effect of ketamine infusion. Because of the rapid and extensive metabolism of dextromethorphan by cytochrome P450 2D6 (CYP2D6), a high dose of dextromethorphan or a combination of dextromethorphan with CYP2D6 inhibitors is required to maintain the antidepressant effect of ketamine.

Safety and Efficacy of Anakinra in Haemophagocytic Lymphohistiocytosis Associated with Acute Leukaemia

Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition in which immune hyperactivation and dysregulation results in a cytokine storm. It may be primary or secondary to infection, autoimmune disorders or malignancies (HLH-M). Lymphoma is the most widely described association in HLH-M; there is very limited data linking acute leukaemia and HLH. Current recommended treatments for HLH-M include steroids, IVIG and etoposide-containing regimens. In contrast, the recommended treatment in HLH- Macrophage activation syndrome is anti-IL1 directed therapy such as anakinra. In 2021 NHS England approved the use of anakinra to treat HLH of any cause, but the safety and efficacy data of anakinra in HLH-M is limited. We report a retrospective review of all patients diagnosed with HLH and acute leukaemia (AML) or acute lymphoblastic leukaemia (ALL) in a single London tertiary referral centre (University College London Hospitals NHS Foundation Trust (UCLH)), between 1 January2019 and 31 December 2022. We analysed electronic health records (EHR) of all patients diagnosed with ALL or AML and cross-referenced this with records of all patients referred to the UCLH HLH MDT. This identified 468 patients with acute leukaemia, of whom 13 (2.8%) were diagnosed with HLH. For diagnostic purposes, we utilised H scores (comprising laboratory and clinical parameters providing an HLH probability for each patient) using clinical and laboratory data collected from the EHR. HLH was diagnosed in patients with a clinical suspicion of HLH and an H score of &amp;gt;169. Patients were treated with various types of immunosuppressive therapy (IST). Twelve (92%) received anakinra, three (17%) of whom had anakinra monotherapy whilst the remainder had anakinra with steroids (38%), steroids and IVIG (15%), or steroids, IVIG and etoposide (8%). Anakinra was given intravenously in eleven patients and subcutaneously in one, with a mean daily dose of 4.6mg/kg. All patients required critical care input during their HLH treatment. Eight (62%) were admitted to intensive care unit (ICU) on diagnosis with HLH and required ventilatory and vasopressor support; the remainder were reviewed by critical care outreach. 92% patients had an initial rapid clinicopathological response following IST, becoming afebrile, reduction in oxygen requirement and haemodynamic stability seen within 24-72 hours. One patient (8%) had an initial clinical response to anakinra, methylprednisolone and IVIG triple therapy, but displayed subsequent rapid deterioration in the context of pseudomonal infection and died of multiorgan failure. Nine patients (69%) had no clinicopathological recurrence of HLH following initial treatment. Three (23%) had an initial clinical response to IST but had subsequent biochemical and clinical relapse of HLH. These patients all had relapsed/refractory disease on HLH recurrence. Only one (8%) patient died from HLH. Eight (62%) remain in remission from leukaemia at the end of the study period. Three patients (23%) died of refractory leukaemia, whilst a fourth patient is receiving palliative care for refractory disease. Although the link between HLH and lymphoma is well characterised, there is limited data on HLH in the context of acute leukaemia. In this case series, 2.8% of the patients treated with acute leukaemia developed HLH, which is comparable to the 3% for lymphoma quoted elsewhere. Although 92% of patients had microbiological or radiological evidence of infection on HLH diagnosis, many infections involved organisms not classically associated with HLH e.g. rhinovirus, indicating that the underlying leukaemia may play a central role in HLH-M pathogenesis. This is highlighted by the relapse of HLH which occurred alongside leukaemia relapse in three patients. Treatment responses and outcomes were favourable compared to the existing literature. Tamamyan et al reported an overall survival rate of 15% in 13 patients with HLH-M. Delavigne et al reported a three-month mortality rate of 36% in AML patients presenting with HLH during induction, compared to our figure of 23% for this time period and our overall survival rate of 62%. We believe this is the first case series demonstrating the effectiveness and high overall survival of HLH-M patients with concurrent leukaemia diagnosis using anakinra. Early treatment with anakinra alongside other immunosuppression may explain the trend towards improved outcomes in our cohort.

IFSO Consensus on Definitions and Clinical Practice Guidelines for Obesity Management—an International Delphi Study

IntroductionThis survey of international experts in obesity management was conducted to achieve consensus on standardized definitions and to identify areas of consensus and non-consensus in metabolic bariatric surgery (MBS) to assist in an algorithm of clinical practice guidelines for the management of obesity.MethodsA three-round Delphi survey with 136 statements was conducted by 43 experts in obesity management comprising 26 bariatric surgeons, 4 endoscopists, 8 endocrinologists, 2 nutritionists, 2 counsellors, an internist, and a pediatrician spanning six continents over a 2-day meeting in Hamburg, Germany. To reduce bias, voting was unanimous, and the statements were neither favorable nor unfavorable to the issue voted or evenly balanced between favorable and unfavorable. Consensus was defined as ≥ 70% inter-voter agreement.ResultsConsensus was reached on all 15 essential definitional and reporting statements, including initial suboptimal clinical response, baseline weight, recurrent weight gain, conversion, and revision surgery. Consensus was reached on 95/121 statements on the type of surgical procedures favoring Roux-en-Y gastric bypass, sleeve gastrectomy, and endoscopic sleeve gastroplasty. Moderate consensus was reached for sleeve gastrectomy single-anastomosis duodenoileostomy and none on the role of intra-gastric balloons. Consensus was reached for MBS in patients > 65 and < 18 years old, with a BMI > 50 kg/m2, and with various obesity-related complications such as type 2 diabetes, liver, and kidney disease.ConclusionsIn this survey of 43 multi-disciplinary experts, consensus was reached on standardized definitions and reporting standards applicable to the whole medical community. An algorithm for treating patients with obesity was explored utilizing a thoughtful multimodal approach.Graphical