Prevent Disease Recurrence Research Articles

The Effect of Colesevelam on the Microbiome in Postoperative Crohn's Disease.

While surgery plays a pivotal role in the management of ileal Crohn's disease, the risk of endoscopic recurrence following an ileocaecal resection can be greater than 65% within 12 months of surgery. More than 90% of patients with Crohn's disease have a concomitant diagnosis of bile acid diarrhea following an ileal resection. This pilot study aimed to assess whether the use of bile acid sequestrants in patients with Crohn's disease who have undergone a primary terminal ileal resection with concomitant bile acid diarrhea can alter the microbiome and prevent disease recurrence. Patients with Crohn's disease who underwent a primary terminal ileal resection and had symptoms of diarrhea within 1-3 months of surgery underwent 75SeHCAT testing for bile acid diarrhea. If positive (75SeHCAT ≤ 15%), patients were treated with colesevelam and stool samples were collected at 4 weeks, 8 weeks, and 6-12 months posttreatment. If negative (75SeHCAT > 15%), treatment was not given and were reviewed in the clinic as per local guidelines. All patients underwent a 6-12 month postoperative colonoscopy where further stool samples and mucosal biopsies were taken. Disease activity was established using the endoscopic Rutgeert's score, with disease remission defined as Rutgeert's score <i2 and disease recurrence ≥i2. 16S ribosomal RNA gene analysis was undertaken for the collected fecal and mucosal samples to assess α/β-diversity and microbial composition. A total of 14 patients who completed the study, 10 of whom had a 75SeHCAT positive diagnosis of bile acid diarrhea and were started on treatment with colesevelam. Four patients did not require treatment as 3 were asymptomatic and 1 had a negative 75SeHCAT scan. Three of the fourteen patients had disease recurrence at their 6-12 month postoperative colonoscopy assessment, of which 1 patient was taking colesevelam and 2 patients were not taking colesevelam. A total of 44 fecal samples and 44 mucosal biopsies underwent 16S ribosomal RNA gene analysis to assess α/β-diversity and microbial composition. In the colesevelam treated patients there was no significant difference in α/β-diversity pre- and posttreatment. Pretreatment, the 3 most abundant bacterial classes in all patients were Bacteroidia, Clostridia, and Gammaproteobacteria. Following 6-12 months of treatment, out of the 9 patients on colesevelam, 5/9 (55.6%) had a reduction in Bacteroidia, 9/9 (100%) had an increase in Clostridia, and 7/9 (77.8%) had a reduction in Gammaproteobacteria. Of the 2 patients not given colesevelam, one showed a reduction in Bacteroidia, increase in Clostridia and a reduction in Gammaproteobacteria. This small pilot study demonstrated that patients who were given colesevelam, were more likely to be in disease remission at their 6-12 months colonoscopy review compared with those not treated. Furthermore, treatment with colesevelam may have a role in altering the microbiome to help maintain remission states in postoperative Crohn's disease. Larger mechanistic studies are now needed to confirm these findings and demonstrate statistical significance as well as investigate whether this benefit may be present even in those patients with 75SeHCAT negative disease.

Low-magnitude high-frequency vibration reduces prostate cancer growth and extravasation in vitro

Prostate cancer (PCa) continues to rank among the most common malignancies in Europe and North America with significant mortality rates despite advancements in detection and treatment. Physical activity is often recommended to PCa patients due to its benefits in preventing disease recurrence and managing treatment-related side effects. However, physical activity may be challenging for elderly or bedridden patients. As such, vibration therapy has been proposed as a safe, effective, and easy to perform alternative treatment that may confer similar effects as physical exercise. Specifically, low-magnitude high frequency (LMHF) vibration has been shown to decrease breast cancer extravasation into the bone and reduce other types of cancer proliferation by impacting cell viability. Here, we investigated the effects of daily application of LMHF vibration (0.3 ​g, 60 ​Hz, 1 ​hour/day for 3 days) on prostate cancer growth and bone metastasis in vitro. Our findings suggest that LMHF vibration significantly reduces colony formation through a decrease in cell growth and proliferation. Moreover, using a 3D cell culture model, LMHF vibration significantly reduces PC3 spheroid size. Additionally, LMHF vibration reduces PCa cell extravasation into the bone microenvironment through the stimulation of osteocytes and subsequent osteocyte-endothelial cell cross talk. These findings highlight the potential of LMHF vibration for managing PCa growth and metastasis.

Diagnosis and surgical tactics in recurrent extrasphincteric fistulas of the rectum

Aim. To increase the effectiveness of surgical treatment in patients with recurrent forms of extrasphincteric rectal fistula.Material and Methods. Clinical data of 108 patients with recurrent extrasphincteric rectal fistulas were analysed. The patients were divided into two groups. The first, the main group, included 58 (53.7%) patients who underwent improved and developed surgical procedures. The second, control group, included 50 (46.3%) patients who were treated with traditional, well-known methods.In 6 (5.6%) cases grade I complexity of extrasphincteric recurrent rectal fistula was observed, in 23 (21.3%) cases grade II, in 62 (57.4%) cases grade III and in 17 (15.7%) cases grade IV complexity of fistula was observed.Results. In 13 (26.0%) cases, patients in the control group underwent surgery using the ligature method, and in 37 (74.0%) patients various known plastic surgery methods were used to close the internal hole. In patients with recurrent complex horseshoe-shaped extrasphincteric fistulas from the main group, a three-stage surgical procedure was performed, developed and improved in our clinic (n=18) to prevent disease recurrence and reduce the incidence of postoperative complications. In 21 (36.2%) patients, the method we developed for surgical correction of recurrent rectal fistulas of grade III-IV complexity with an extrasphincteric course was used.Conclusion. The developed and improved methods of surgical correction of recurrent extrasphincteric fistulas of the rectum allow radical excision of scar-inflammatory altered parafistula tissue, especially in fistulas of III-IV degree of complexity. These methods help to minimise both early and late postoperative complications, in particular they reduce the frequency of disease recurrence.

Navigating uncharted waters: assessing the impact of the COVID-19 pandemic on hematopoietic stem cell transplantation: challenges and innovations.

The COVID-19 pandemic has significantly impacted hematopoietic stem cell transplantation (HSCT), necessitating adaptations across pre-transplant, transplantation, and post-transplant phases. HSCT recipients with compromised immune systems face heightened risks of severe COVID-19 outcomes, including increased mortality. The pandemic prompted significant changes in treatment strategies, with many patients experiencing delays or deferrals in autologous stem cell transplantation (ASCT), alongside adjustments to chemotherapy regimens to prevent disease recurrence. Clinical practices have evolved to address pandemic-related challenges, including a decrease in allo-HSCT procedures, a shift towards using domestic donors and peripheral blood stem cells over bone marrow grafts, and integration of telemedicine to reduce patient burden. These adaptations aim to balance COVID-19 exposure risks with the need for lifesaving HSCT. Innovations in response to the pandemic include stringent infection control measures, modified conditioning regimens, and revised post-transplant care protocols to mitigate infection risks. The importance of optimizing antiviral treatments, exploring new immunomodulatory interventions, and researching broadly neutralizing antibodies for HSCT recipients has been underscored. Despite the difficulties, the pandemic has catalyzed significant learning and innovation in HSCT practices, emphasizing the need for ongoing adaptation and research to protect this vulnerable patient population.

Investigation of Cancer Stem Cell Surface Markers In The Tumor Tissues of Patients Who Had Live Transplantation Due To Hepatocellular Cancer And Evaluation of The Effect of These Markers on Prognosis

Background and purpose: To investigate the relevance between cancer stem cell(CSC) markers and tumor progression in hepatocellular carcinoma(HCC). Methods: Data of patients who underwent liver transplantation(LT) for HCC between February 1998 and September 2018 were collected. Patients over 18 years of age were included. Immunohistochemical staining were performed in paraffin blocks of liver explants containing HCC in terms of CSC markers, CD13, CD44, CD47, CD90 and EpCAM. Follow-up period, cancer recurrence, disease-free and overall survival were investigated. Results: There were 71 patients who met the inclusion criteria. Optimal evaluation conditions were not met for CD13 and CD90 staining. Disease recurrence was found to be more frequent in CD 44+ cases (p=0.008). Disease-free survival was significantly longer in CD44- group(160.2 vs 103.0 months, p=0.043). Overall survival was significantly shorter in CD44+ cases(171.7 vs 107.8 months, p=0.018). No statistically difference was found between CD47+/- or EpCAM+/- groups in terms of recurrence (p=0.27, p=0.24). There was no significant difference in disease-free and overall survival in CD47+/- or EpCAM+/- cases, respectively (CD47+/-; p=0.82, p=0.90, EpCAM; p=0.76, p=0.69). Conclusıon: Positive CD44markers in HCC is associated with a more aggressive course of disease. Targeted therapies for CD44antigens of CSCs may prevent disease recurrence and increase survival.

Chronic cutaneous chromoblastomycosis: A rare case

Background: Chromoblastomycosis (CBM) is a rare, chronic granulomatous and suppurative skin infection classified as a subcutaneous mycosis. CBM has a poor prognosis with a low cure rate and a high recurrence rate. The lack of scientific data regarding the diagnosis and treatment of CBM also presents a challenge for clinicians in treating this disease. Appropriate therapy can increase the cure rate and prevent disease recurrence. Case Illustration: A 66-year-old woman presented with swelling in her left arm since the last 18 years due to wood-related injuries. There were multiple well-defined hyperkeratotic verrucous plaques, papules, and nodules, measuring 6-10 cm in diameter on the left antebrachial and hand regions. Some lesions were covered with erosion and crusts. The patient also had bone malformation. Histopathological examination showed typical characteristics of CBM. The patient was treated with 100 mg Itraconazole b.i.d. for 8 months. Discussion: Clinical manifestations and histopathological examination showed typical characteristics of CBM. Bone malformation occurred due to complications in chronic cases. Facility limitations led to the inability to perform direct microscopic examination using potassium hydroxide (KOH) and fungal culture on Sabouraud's dextrose agar. After 8 weeks of treatment, the patient's lesions were improved. The patient will be evaluated every month until treatment is complete to monitor the side effects of therapy. Conclusion: CBM lesions were improved after 8 weeks of treatment. Bone malformation could occur in chronic cases. It is important to diagnose CBM correctly and provide adequate therapy for a good outcome.

Response to Antibiotic Treatment of Bacterial Vaginosis Predicts the Effectiveness of LACTIN-V (Lactobacillus crispatus CTV-05) in the Prevention of Recurrent Disease.

Live biotherapeutic products (LBPs) containing vaginal Lactobacillus crispatus are promising adjuvant treatments to prevent recurrent bacterial vaginosis (BV) but may depend on the success of initial antibiotic treatment. A post hoc analysis of data collected during the phase 2b LACTIN-V randomized control trial (L. crispatus CTV-05) explored the impact of clinical BV cure defined as Amsel criteria 0 of 3 (excluding pH, per 2019 Food and Drug Administration guidance) 2 days after completion of treatment with vaginal metronidazole gel on the effectiveness of an 11-week LACTIN-V dosing regimen to prevent BV recurrence by 12 and 24 weeks. At enrollment, 88% of participants had achieved postantibiotic clinical BV cure. The effect of LACTIN-V on BV recurrence compared with placebo differed by initial clinical BV cure status. The LACTIN-V to placebo risk ratio of BV recurrence by 12 weeks was 0.56 (95% confidence interval, 0.35-0.77) among participants with initial clinical BV cure after metronidazole treatment and 1.34 (95% confidence interval, 0.47-2.23) among participants without postantibiotic clinical BV cure. Among women receiving LACTIN-V, those who had achieved postantibiotic clinical BV cure at enrollment reached higher levels of detectable L. crispatus CTV-05 compared with women failing to achieve postantibiotic clinical BV cure. LACTIN-V seems to only decrease BV recurrence in women with clinical cure of BV after initial antibiotic treatment. Future trials of LBPs should consider limiting enrollment to these women.

A phase 1/2 study of vusolimogene oderparepvec (RP1) in primary melanoma (mel) to reduce the risk of sentinel lymph node (SLN) metastasis.

TPS9614 Background: The majority of the 80,000 newly diagnosed mel patients in the US have localized early-stage disease and undergo wide local excision (WLE) with or without SLN biopsy. The SLN is a critical prognostic marker and pivotal to immune response initiation, and fosters tumor-mediated immune suppression and pre-metastatic niches. Thus, SLN is a key target for local immune intervention. Vusolimogene oderparepvec (RP1), a locally administered oncolytic immunotherapy, provides a unique opportunity for intervention following mel diagnosis, prior to definitive surgical management. Derived from the HSV1 strain RH018A, RP1 exhibits superior killing on human tumor cell lines, designed with deletions in neurovirulence factors (ICP34.5 and ICP47) and immune-stimulating elements (increased US11 expression, GM-CSF and GALV-GP R-) to maximize oncolytic potency and induce cell death. Preclinical and clinical data demonstrate RP1's robust antitumor efficacy in advanced mel. This trial addresses a crucial gap in understanding RP1's impact on SLN dynamics, holding promise for preventing disease recurrence in this high-risk population. We hypothesize that in mel patients with high risk, clinically node negative disease (pT3b-T4b), administration of RP1 will reduce rates of SLN positivity compared to a historic control by favorably reshaping the immune landscape of the primary tumor, SLN and peripheral blood. Methods: This investigator-initiated, single site, open label, non-randomized phase 1/2 pilot study (NCT06216938) will enroll 25 patients with high-risk, clinically node-negative mel (pT3b-T4b). Major eligibility criteria include diagnosis of pT3b, T4a, or T4b non-uveal mel with visible residual tumor or positive initial biopsy margins, ECOG 0 or 1 and adequate organ function on screening labs. Patients will receive 3 doses (1ml/dose) of RP1, locally injected at the primary tumor site before standard WLE and SLN biopsy (SLNB). The first dose on day 1 will be 10e6 pfu/ml, followed by 10e7 pfu/ml for the next two doses on days 15 and 21, administered over 4-5 weeks before WLE and SLNB. Surgery occurs within 35 days of the 1st RP1 injection to avoid delays in definitive treatment. Biopsies and blood samples are obtained pre- and post-treatment. Patients will be followed for up to 3 years. Safety assessments include physical exams, labs, and adverse events (AE) monitoring. The primary endpoint is the rate of SLN positivity in the overall cohort, calculated by comparing the observed rates to the expected number of positive SLNs for that cohort using the Melanoma Institute of Australia's Prediction Tool. Secondary endpoints include safety and tolerability of RP1, RFS and OS. Exploratory correlative assays will compare the immunophenotype in primary tumor and the SLN (IHC) and in peripheral blood (flow cytometry) between baseline and on treatment. Clinical trial information: NCT06216938 .

The disease recurrence perception scale for patients with inflammatory bowel disease: Instrument development and cross-sectional validation study.

Disease recurrence perception plays a key role in disease management and subsequent disease recurrence prevention. However, there are no specific tools for assessing disease recurrence perception in patients with inflammatory bowel disease (IBD) characterized by alternating remission and recurrence. To develop and validate an instrument for measuring disease recurrence perception of patients with IBD, the study was conducted in two steps: (1) instrument development and (2) psychometric tests. A total of 623 patients with IBD participated in the study. The common sense model of illness self-regulation (CSM) was used as a framework for instrument development. The administered version contained 48 items intended to be relevant to at least one of the six dimensions of the model. Based on preliminary analyzes, 12 items were deleted leaving 36 items for more detailed psychometric and factor analyzes. The Cronbach's alpha coefficient of the total 36-item instrument was 0.915. The content validity indexes at item and scale levels were satisfactory. The test-retest reliability of the total instrument was 0.870. Exploratory principal components analysis (n = 278) was used to identify six components congruent with intended CSM constructs that accounted for 62.6% of total item variance. Confirmatory factor analysis (n = 345) found acceptable fit for the six factor measurement model (χ2/df = 1.999, GFI = 0.846, NFI = 0.855, IFI = 0.922, TLI = 0.910, CFI = 0.921, RMSEA = 0.054). Overall, the DRPSIBD demonstrated satisfactory reliability and validity to warrant further development as a measure of disease recurrence perception of patients with IBD.

Disease recurrence during supportive therapy following peri-implantitis treatment: A retrospective study.

Supportive therapy is key to prevent disease recurrence after peri-implantitis treatment. The primary objective was to quantify disease recurrence during supportive peri-implant therapy (SPIT) after peri-implantitis treatment. A secondary objective was to assess the success/failure of cumulative interceptive supportive therapy (CIST) after peri-implantitis treatment. Compliers (whether regular or erratic) with SPIT after peri-implantitis treatment during ≥12 months were retrospectively evaluated. CIST was prescribed whenever residual pockets ≥6 mm concomitant with profuse bleeding on probing (disease recurrence) were identified. Patient- and implant-related factors were analyzed to explore their associations with disease recurrence and the need for CIST. Disease recurrence was considered in 28 patients (40 implants). Of these, 14 patients (23 implants) further demonstrated radiographic evidence of progressive bone loss (≥1 mm). This represented an overall disease recurrence following peri-implantitis treatment of ~20% and ~ 10% at patient and implant levels, respectively. Smokers, patients diagnosed at baseline with periodontitis grade C, and males were significantly more prone to exhibit recurrence. Patients undergoing CIST due to instability were not likely to respond favorably (~70% continued to exhibit residual pockets). Disease recurrence during SPIT following peri-implantitis treatment on selected cases is ~20%. Patients undergoing CIST due to instability are not likely to respond favorably.

Oncology: What You May Have Missed in 2023.

Advances in oncology treatment methods have improved outcomes and quality of life for patients with cancer. However, care of these patients can be complex, and the contribution of physicians from different specialties is crucial. This article highlights important publications from 2023 on topics across a wide spectrum relating to the management of oncology patients. The literature was screened for significant new evidence that is relevant to internal medicine specialists and subspecialists whose focus is not oncology. Two articles address the importance of social interventions targeting end-of-life care for low-income and minority patients and the well-being of caregivers. Two additional articles address screening considerations in patients at risk for colorectal and lung cancer. Two more articles address safe use of hormone-related therapies to treat symptoms of menopause and prevent disease recurrence or progression in patients diagnosed with noninvasive breast neoplasia. Finally, several articles were included on topics related to COVID-19 vaccination in patients with cancer, use of cannabinoids for cancer pain control, chronic autoimmune adverse effects related to use of immune checkpoint inhibitors, and the incidence of second primary neoplasms.

Surgical rehabilitation of patients with Crohn’s disease

Objective — to enhance the outcomes of surgical rehabilitation for patients with Crohn’s disease through the improvement and implementation of organisational measures as well as general and specialised surgical strategies.&#x0D; Materials and methods. The study focused on the development of organisational measures as well as general and specialised surgical rehabilitation procedures for Crohn’s disease. The research was conducted to determine the scope of radical surgical interventions for complications resulting from segmental lesions with extensive damage to the intestinal tract. The study also aimed to develop methods of restorative, reconstructive and restorative operations that would reduce the frequency of postoperative complications, disease recurrence, digestive disorders in the intestinal tract, malabsorption, and anal incontinence. Additionally, the study aimed to improve the functional outcomes and quality of life for operated patients.&#x0D; Results. A total of 53 patients with Crohn’s disease — 28 (52.8%) men and 25 (47.2%) women — were operated on using specially designed surgical rehabilitation techniques. The patients undergoing surgery ranged in age from 19 to 45. 32 (60.4%) patients had segmental resections, while 21 (39.6%) had extensive resections. 8 (15.1%) patients underwent restorative operations, while 40 (75.4%) had reconstructive operations. A lifelong ileostomy was formed in 5 (9.4%) patients. Postoperative complications were observed in 12 (22.6%) patients, and disease relapses in 5 (9.4%) patients. One (1.8%) patient died after surgery. Positive functional outcomes, including improved digestion in the intestinal tract, normal absorption, and preservation of anal retention, were noted following restorative and reconstructive‑restorative operations.&#x0D; Conclusions. Organisational measures as well as general and specialised surgical rehabilitation strategies for Crohn’s disease allowed for more effective diagnosis and treatment of postoperative complications, better prevention of disease recurrence, improved digestion in the intestinal tract, normalised absorption processes, and preservation of anal retention. Following the implementation of specially designed surgical rehabilitation techniques, 20.7% and 1.8% of patients experienced early and late postoperative complications, respectively. Additionally, there were occurrences of postoperative mortality in 1.8% of patients and relapses in 9.4%. Severe forms of reflux ileitis, postcolectomy syndrome, and secondary anal incontinence syndrome were not observed.&#x0D;

Abstract 5656: Longitudinal spatial profiling reveals chemoresistance mechanisms and characteristics of minimal residual disease in high-grade serous ovarian cancer

Abstract High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy globally. Despite an initial response to upfront surgery and platinum-based chemotherapy in most cases, over 70% will relapse. A critical source of recurrence is minimal residual disease (MRD), which persists after upfront treatment yet is clinically undetectable. In this study, we performed second look laparoscopy (SLL) on advanced stage HGSOC patients who had received neoadjuvant chemotherapy (NACT) followed by interval debulking surgery and adjuvant chemotherapy and were in complete clinical remission by imaging and CA-125 tumor marker. Surgical MRD status was determined by pathological review of SLL biopsies. Matched samples from pre-treatment biopsy, interval debulking surgery and SLL in 4 MRD+ and 3 MRD- cases were analyzed using GeoMx Digital Spatial Profiling. Among them, samples from 1 MRD+ and 1 MRD- case were also profiled with Visium. The tumor cells of MRD+ cases exhibited stronger signaling related to hypoxia, angiogenesis, and epithelial-mesenchymal transition at baseline as well as diminished apoptosis signaling after NACT. In addition, progressively upregulated expressions of ATP binding cassette transporters were also observed over time in the tumor compartment of MRD+ cases, potentially contributing to chemoresistance. In the tumor microenvironment, MRD- cases displayed increased abundance of plasma cells, conventional dendritic cells and lymphocytes in both pre-treatment and interval debulking samples compared to MRD+ cases. Notably, Visium data of the MRD- case revealed tertiary lymphoid structures (TLS) in the pre-treatment sample, which became better organized following NACT, with plasma cells disseminating into adjacent tumor areas. Conversely, TLS were fewer and poorly organized in the MRD+ case. Longitudinal comparison of the 3 timepoints in MRD+ cases revealed more regulatory T cells in the stromal compartments of the MRD lesions. Furthermore, from Visium data, exclusion of CD8 T and plasma cells from the tumor core was evident in the MRD lesion. In line with this, strong TGF-β, IL-1β, IL6 and FGF2 signaling surrounding the tumor were noted, likely contributing to immune exclusion. The spatial distribution of multiple immune checkpoint molecules highly overlapped with that of CD8 T cells, indicating T cell exhaustion in the MRD lesion. In summary, these data suggested distinct cancer phenotypic states and immune features in surgically detected MRD+ HGSOC, shedding light on potential chemoresistance and immune evasion mechanisms that contribute to the MRD phase of disease. This study represents the first systemic characterization of ovarian cancer MRD by leveraging SLL, providing insights for designing personalized therapies aimed at eradicating these chemoresistant lesions and ultimately preventing disease recurrence. Citation Format: Yibo Dai, Anne Knisely, Barrett Craig Lawson, Sanghoon Lee, Khalida M. Wani, Rossana N. Lazcano Segura, Brenda Melendez, Jianfeng Chen, Yunhe Liu, Manoj Chelvanambi, Laura A. Gibson, Sarah B. Johnson, Chih-Chen Yeh, Davis R. Ingram, Courtney W. Hudgens, Kyung Serk Cho, Guangsheng Pei, Jiahui Jiang, Yanshuo Chu, Alexander J. Lazar, Jianjun Gao, Jennifer Wargo, Linghua Wang, Amir A. Jazaeri. Longitudinal spatial profiling reveals chemoresistance mechanisms and characteristics of minimal residual disease in high-grade serous ovarian cancer [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 5656.

ERBB3 Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature.

Despite successful clinical management of castration-sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer is only 32%. Combination treatment strategies to prevent disease recurrence are increasing, albeit in biomarker-unselected patients. Identifying a biomarker in CSPC to stratify patients who will progress on standard-of-care therapy could guide therapeutic strategies. Targeted deep sequencing was performed for the University of Illinois (UI) cohort (n = 30), and immunostaining was performed on a patient tissue microarray (n = 149). Bioinformatic analyses identified pathways associated with biomarker overexpression (OE) in the UI cohort, consolidated RNA sequencing samples accessed from Database of Genotypes and Phenotypes (n = 664), and GSE209954 (n = 68). Neutralizing antibody patritumab and ectopic HER3 OE were utilized for functional mechanistic experiments. We identified ERBB3 OE in diverse patient populations with CSPC, where it was associated with advanced disease at diagnosis. Bioinformatic analyses showed a positive correlation between ERBB3 expression and the androgen response pathway despite low dihydrotestosterone and stable expression of androgen receptor (AR) transcript in Black/African American men. At the protein level, HER3 expression was negatively correlated with intraprostatic androgen in Black/African American men. Mechanistically, HER3 promoted enzalutamide resistance in prostate cancer cell line models and HER3-targeted therapy resensitized therapy-resistant prostate cancer cell lines to enzalutamide. In diverse patient populations with CSPC, ERBB3 OE was associated with high AR signaling despite low intraprostatic androgen. Mechanistic studies demonstrated a direct link between HER3 and enzalutamide resistance. ERBB3 OE as a biomarker could thus stratify patients for intensification of therapy in castration-sensitive disease, including targeting HER3 directly to improve sensitivity to AR-targeted therapies.

Comparing the Efficacy of Different Maintenance Intervals on Preventing Disease Recurrence in Patients with A History of Periodontal Treatment

ABSTRACT Background: Scheduled maintenance appointments after periodontal treatment are very much critical for the success of the treatment. This is necessary for patients seeking to prevent disease recurrence and maintain oral health Materials and Methods: In this study, we conducted a comprehensive analysis to assess the efficacy of various maintenance intervals in preventing disease recurrence among patients with a history of periodontal treatment. We gathered data from a diverse group of patients who had undergone periodontal treatment and tracked their oral health over an extended period. Results: Our findings reveal compelling insights into the optimal maintenance intervals. Patients who attended maintenance appointments at three-month intervals showed a significant reduction in disease recurrence by 40%, compared to those at six-month intervals. Moreover, those on annual intervals experienced a disease recurrence rate of 60% Conclusion: In conclusion, our study underscores the importance of regular maintenance appointments after periodontal treatment. Patients who attend appointments every three months have a significantly lower risk of disease recurrence. These findings emphasize the need for tailored maintenance schedules to ensure long-term oral health.

Targeting CD20-expressing malignant melanoma cells augments BRAF inhibitor killing.

Mutant BRAF targeted therapies remain a standard of care for the treatment of metastatic malignant melanoma (MM); however, high initial response rates are tempered by the persistence of residual MM cells that eventually lead to disease recurrence and mortality. As MM recurrence during targeted therapy can present with the simultaneous occurrence of multiple tumour nodules at the original body sites, we hypothesized the presence of an intrinsically resistant MM cell subpopulation. To identify an MM cell subpopulation that is intrinsically resistant to targeted therapy and possibly responsible for MM recurrence. Using melanoma cell lines, we defined culture conditions for the reproducible three-dimensional growth of melanospheres to investigate putative cancer stem cell populations. We undertook RNA sequencing and bioinformatic analysis to characterize cell populations between adherent and nonadherent culture, and cells expressing or not expressing CD20. Furthermore, we defined an in vitro assay to evaluate the killing of melanoma cancer stem cells as a therapeutic test using combination therapies targeting driver mutation and CD20. We described the culture conditions that promote MM cells to form melanospheres with a reproducible colony-forming efficiency rate of 0.3-1.3%. RNA sequencing of melanosphere vs. conventional MM cell cultures (n = 6), irrespective of the BRAF mutation status, showed that melanosphere formation was associated with growth and differentiation transcriptional signatures resembling MM tumours. Importantly, melanosphere formation also led to the emergence of a CD20+ MM cell subpopulation, similar to that observed in primary human MM tumours. CD20+ MM cells were resistant to BRAF inhibitor therapy and, consistent with this finding, demonstrated a Forkhead box protein M1 transcriptomic profile (n = 6). Combining BRAF inhibitor and anti-CD20 antibody treatment led to the additional killing of previously resistant CD20+ BRAF mutant MM cells. In patients with MM that harbour a CD20+ subpopulation, combined therapy with BRAF inhibitor and anti-CD20 antibody could potentially kill residual MM cells and prevent disease recurrence.

Comprehensive review and update of stricturing Crohn's disease.

Up to 50% of patients with Crohn's disease develop a stricture within 10years of diagnosis. Crohn's strictures can compose of inflammation, fibrosis or smooth muscle expansion and usually a combination of these. There have been numerous new developments in imaging modalities in determining the composition of Crohn's strictures. Magnetic resonance imaging remains the best upfront imaging modality to characterize Crohn's strictures. Gastrointestinal ultrasound (GIUS) has an increasing role in clinical practice, particularly for monitoring stricture response as a treat-to-target tool. Novel imaging techniques to differentiate between fibrosis and inflammatory strictures have been developed including contrast-enhanced GIUS, strain or shear wave elastography with GIUS and multiple new magnetic resonance imaging (MRI) protocols, including diffusion weighted, delayed contrast enhancement and magnetization transfer MR protocols. However, these techniques require further validation and standardization. Regarding therapeutics, anti-tumor necrosis agents with a treat-to-target strategy have the highest quality evidence in treating strictures and can lead to stricture regression in some cases. Endoscopic balloon dilatation remains a mainstay in the treatment algorithm of treating predominantly fibrostenotic Crohn's strictures, particularly those which are symptomatic, < 5cm in length and not causing prestenotic dilatation. Endoscopic balloon dilatation has greater effectiveness in anastomotic strictures. Surgery remains an important treatment option in Crohn's strictures, with segmental resection and stricturoplasty having their own advantages and disadvantages.Kono-S anastomosis may be superior to conventional anastomosis for endoscopic recurrence; however, further high-quality studies are required to confirm this. Using risk stratification models such as the BACARDI risk model is important to guide management decisions between a medical and surgical approach. Early post-operative medical prophylaxis with an advanced therapy is an important consideration to prevent disease recurrence. This review expands on the above topics, highlights research gaps and provides a suggested investigation and management pathway in stricturing Crohn's disease.

Abstract A021: Adjuvant iC9.B7-H3 CAR T cell-based immunotherapy effectively eradicates local and distant metastases in pancreatic ductal adenocarcinoma

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Despite negative margin resections of the cancer and systemic therapy, PDAC often recurs. Pancreatic cancer-associated fibroblasts (CAFs) contribute to a highly desmoplastic tumor microenvironment (TME), preventing T cell infiltration. Moreover, CAF-secreted factors suppress the anti-tumor activity of T cells and shift tumor cells toward invasive proliferative and mesenchymal phenotypes. Therefore, targeting CAFs can enhance T-cell infiltration and improve treatment outcomes. In this study, we investigate using Chimeric Antigen Receptor (CAR) T cells targeting B7-H3 to eliminate PDAC metastatic disease in a preclinical mouse model. B7-H3, an immune checkpoint molecule, is highly expressed on PDAC cells and CAFs. Our CART-B7-H3 construct includes an inducible caspase 9 (iC9) suicide gene, which allows for the controlled elimination of the CAR T cells in the event of overwhelming cytokine release syndrome. Methods: The efficacy of iC9.B7-H3 CAR T cells was tested in vitro against human PDAC and fibroblast cell lines at various ratios. The antitumor activity of iC9.B7-H3 CAR T cells was assessed in PDAC cells after exposure to CAF-conditioned media, simulating TME with immunosuppressive cytokines. To validate the therapeutic potential of iC9.B7-H3 CAR T cells in vivo, NSG mice were orthotopically engrafted with patient-derived PDAC6 cells and hCAF1 cells at a ratio of 1:9, reflecting a clinically relevant model. After three weeks, the mice underwent surgical resection of the primary tumor (distal pancreatectomy and splenectomy) and were subsequently treated systemically with iC9.B7-H3 CAR T cells. Results: In vitro, at a high effector-to-target (E:T) ratio, iC9.B7-H3 CAR T cells effectively eliminated PDAC cells and CAFs. However, their anti-tumor activity was diminished when the E:T ratio was lowered (PDAC6 tumor cell killing (TCK): 92±5% at 1:1, hCAF1 TCK: 81.67±5% at 1:1, compared to PDAC6 TCK: 26±5% at 1:10, hCAF1 TCK: 0% at 1:10, P&amp;lt;0.0001). PDAC cells co-cultured with CAF cells demonstrated reduced susceptibility to elimination by iC9.B7-H3 CAR T cells compared to PDAC cells alone (PDAC3 TCK: 92±5% at 1:1, PDAC3+hCAF1 (1:9 ratio) TCK: 81±5% at 1:1, P=0.002). However, incubation with CAF-conditioned media did not significantly affect the elimination of PDAC cells by iC9.B7-H3 CAR T cells, which may suggest that CAFs may require direct cell-cell contact to exert their effects. In vivo, iC9.B7-H3 CAR T cells effectively eradicated both local and distant PDAC metastases for the length of the experiment (160 days), indicating long-term efficacy in the treatment of PDAC metastases with no adverse side effects. Conclusion: These data suggest that iC9.B7-H3 CAR T cells may be an effective adjuvant treatment for the eradication of micro-metastases and the prevention of disease recurrence in PDAC patients. Citation Format: Shahrzad Arya, Seyed Amir Sanatkar, Cristina Martin, Marco Ventin, Jingyu Jia, Giulia Cattaneo, Gabriella Lionetto, David T. Ting, Xinhui Wang, Sandra Ryeom, Cristina R. Ferrone, Soldano Ferrone. Adjuvant iC9.B7-H3 CAR T cell-based immunotherapy effectively eradicates local and distant metastases in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A021.

The Effect of Three Forms of Local Corticosteroids on Sinonasal Polyposis.

Since sinonasal polyposis (SNP) has a high recurrence rate after surgery, various studies have investigated the effect of corticosteroid medications to prevent disease recurrence. The present study was designed to compare the effect of three forms of local corticosteroids on preventing SNP recurrence post-operatively. This double-blind, randomized clinical trial study was conducted on 108 patients with SNP who underwent functional endoscopic sinus surgery (FESS). Permuted Block Randomization randomly assigned patients into three groups of 36 people: budesonide spray, betamethasone drop, and budesonide nebulizing suspension groups. One and six months after surgery, the patients were evaluated for recurrence of SNP by nasal endoscopy. SNOT 22 questionnaire was used to assess patients' subjective improvement rate pre- and post-operatively. According to the scores obtained in the Modified Lund-Kennedy Scoring, budesonide nebulizing suspension showed better effects on preventing the recurrence of sino-nasal polyps after FESS compared with betamethasone nasal drops. The score was significantly lower in the budesonide nebulizing suspension group compared to the betamethasone drop group (P=0.043). There was no statistically significant difference in the scores between the budesonide nebulizing suspension group and the betamethasone spray group (P=0.178). Also, we observed significant improvement in facial fullness in patients who received Budesonide nebulizing suspension. Budesonide nebulizing suspension, compared to betamethasone nasal drops, showed better effects on preventing the recurrence of SNP after FESS.

Cuproptosis gene-related, neural network-based prognosis prediction and drug-target prediction for KIRC.

Kidney renal clear cell carcinoma (KIRC), as a common case in renal cell carcinoma (RCC), has the risk of postoperative recurrence, thus its prognosis is poor and its prognostic markers are usually based on imaging methods, which have the problem of low specificity. In addition, cuproptosis, as a novel mode of cell death, has been used as a biomarker to predict disease in many cancers in recent years, which also provides an important basis for prognostic prediction in KIRC. For postoperative patients with KIRC, an important means of preventing disease recurrence is pharmacological treatment, and thus matching the appropriate drug to the specific patient's target is also particularly important. With the development of neural networks, their predictive performance in the field of medical big data has surpassed that of traditional methods, and this also applies to the field of prognosis prediction and drug-target prediction. The purpose of this study is to screen for cuproptosis genes related to the prognosis of KIRC and to establish a deep neural network (DNN) model for patient risk prediction, while also developing a personalized nomogram model for predicting patient survival. In addition, sensitivity drugs for KIRC were screened, and a graph neural network (GNN) model was established to predict the targets of the drugs, in order to discover potential drug action sites and provide new treatment ideas for KIRC. We used the Cancer Genome Atlas (TCGA) database, International Cancer Genome Consortium (ICGC) database, and DrugBank database for our study. Differentially expressed genes (DEGs) were screened using TCGA data, and then a DNN-based risk prediction model was built and validated using ICGC data. Subsequently, the differences between high- and low-risk groups were analyzed and KIRC-sensitive drugs were screened, and finally a GNN model was trained using DrugBank data to predict the relevant targets of these drugs. A prognostic model was built by screening 10 significantly different cuproptosis-related genes, the model had an AUC of 0.739 on the training set (TCGA data) and an AUC of 0.707 on the validation set (ICGC data), which demonstrated a good predictive performance. Based on the prognostic model in this paper, patients were also classified into high- and low-risk groups, and functional analyses were performed. In addition, 251 drugs were screened for sensitivity, and four drugs were ultimately found to have high sensitivity, with 5-Fluorouracil having the best inhibitory effect, and subsequently their corresponding targets were also predicted by GraphSAGE, with the most prominent targets including Cytochrome P450 2D6, UDP-glucuronosyltransferase 1A, and Proto-oncogene tyrosine-protein kinase receptor Ret. Notably, the average accuracy of GraphSAGE was 0.817 ± 0.013, which was higher than that of GAT and GTN. Our KIRC risk prediction model, constructed using 10 cuproptosis-related genes, had good independent prognostic ability. In addition, we screened four highly sensitive drugs and predicted relevant targets for these four drugs that might treat KIRC. Finally, literature research revealed that four drug-target interactions have been demonstrated in previous studies and the remaining targets are potential sites of drug action for future research.