High Risk Of Treatment Failure Research Articles

Enhancing the Social Network: Multimodal Treatment for Comorbid Borderline Personality Disorder and Alcohol Use Disorder.

More than half of all people with borderline personality disorder will develop alcohol use disorder in their lifetime. These disorders mutually reinforce each other, with a higher risk for treatment failure and poor outcomes, including suicide, yet no widely available treatments have been found to be effective for both diagnoses concurrently, leaving patients and clinicians alike stranded between two clinical domains that rarely overlap despite shared features. In the absence of alternatives, good psychiatric management (GPM) capitalizes on standard-of-care interventions using generic clinical tools that do not require specialization. In an effort to broaden and stabilize the social networks of connections for patients with interpersonal hypersensitivity, GPM relies on a multimodal approach that combines the indicated pharmacological and psychosocial interventions for the treatment of alcohol use disorder with a common-factors approach for borderline personality disorder. This multimodal approach emphasizes psychoeducation, social rehabilitation, management of suicidality, and active management of these frequently comorbid conditions. In this article, the authors describe GPM's strategy of stabilizing and broadening the patient's social network to target the core interpersonal and stress hypersensitivity. To do this, clinicians can use interventions for significant others combined with empirically supported and widely available mutual-help groups, such as Alcoholics Anonymous, that structure and regulate relational instabilities with community norms, standards, roles, and procedures. GPM also promotes family interventions for both conditions to reduce conflict and increase support within existing relationships, thereby strengthening patients' capacity to work on their sobriety and borderline personality disorder by mitigating aloneness and its effects.

Gender-specific outcomes in pilonidal sinus disease: Female outcomes after cleft lift surgery in a large prospective Danish cohort.

Pilonidal sinus disease (PSD) is a common condition particularly affecting young men. Females affected by the condition account for about 20% of patients and are rarely mentioned, much less studied specifically. In this study we evaluate the surgical outcomes in a female population following Bascom's cleft lift (BCL) surgery in primary extensive disease, non-healing wounds after previous surgery and recurrent disease in a large Danish cohort from a high-volume centre. The study is based on a prospective database established at Randers Regional Hospital in 2016. All patients undergoing BCL surgery from June 2016 until October 2022 were included in this study. In all, 560 patients underwent BCL surgery at our centre during this period. Eighty-eight (15.7%) were women. Only 10 (11.3%) were operated due to primary extensive manifestations. The rest presented with either non-healing wounds after previous surgery (47.7%) or recurrent PSD (41%). Risk of recurrence in female patients was 30% higher than in male patients (risk ratio 1.30, 95% CI 0.79-2.09) and the risk of prolonged healing after BCL surgery was 46% higher in women compared to men (risk ratio 1.46, 95% CI 1.02-2.14). Female PSD patients may represent a subcategory of patients at higher risk of treatment failure and should be dealt with as such. Initially, few present with the need for extensive surgery. However, given the common occurrence of prolonged healing and recurrence, we recommend a minimal invasive approach when possible.

P-1550. Systematic Literature Review of Acute Cystitis or Afebrile Urinary Tract Infection in Men

Abstract Background Acute cystitis in men is classified as complicated urinary tract infection (UTI), despite the absence of functional and/or structural anatomical abnormalities of the urinary tract, associated with a higher risk of treatment failure. We conducted a systematic literature review (SLR) to identify and summarize evidence on the epidemiology (incidence, etiology, antimicrobial resistance [AMR], recurrence) and treatment patterns of acute cystitis or afebrile UTI among men with no signs of systemic infection. Methods Systematic searches for English language articles were conducted Jan 1, 2011–May 12, 2023 in the MEDLINE, MEDLINE In-Process, and Embase databases via OvidSP. Gray literature sources (Table 1) were reviewed. Publications were evaluated by 2 independent reviewers (Table 2). Results Database searches yielded 1025 records with 6 studies eligible for inclusion (Figure 1). Studies were primarily excluded if the population of interest was not included or if outcomes were inseparable for the population of interest. The 6 studies were conducted 2012–2020 in 6 geographic regions (1 US). Sample sizes ranged from 18 to 4876 patients. Four studies reported age (median 44–71 years; Table 3). Population of interest was defined as “uncomplicated” (3 studies) or “acute cystitis”/“afebrile UTI” (3 studies). The incidence of uncomplicated UTI was 6.5/1000 person-years in a retrospective cohort (Netherlands) and increased with age. Relapse, defined as continuation of UTI symptoms ≤ 28 days of stopping treatment, after initial symptom resolution, ranged from 9.9% to 16.9% (referred to as recurrence rates in this study). Escherichia coli (E. coli) were the etiologic bacteria in 39–94% of patients. Nitrofurantoin (56.0%) and fluoroquinolones (62.8%) were the most commonly prescribed antibiotics in the Netherlands and Japan, respectively. AMR among E. coli ranged from 11.8% to 47.1% in 1 study. Conclusion AMR in males with acute cystitis/afebrile UTI may be higher than females in some geographic regions. The SLR identified 6 studies with heterogenous designs, inclusion criteria, and UTI definitions, highlighting the need for research using standard definitions to characterize acute cystitis/afebrile UTI in men, including recurrence rates and the burden of AMR. Funding: GSK study 220916 Disclosures Fanny S. Mitrani-Gold, MPH, GSK: Employee|GSK: Stocks/Bonds (Public Company) Amber Martin, BS, PPD Evidera: Employee of PPD Evidera, which received funding from GSK for this study. Priscilla Wittkopf, PhD, GSK: Grant/Research Support|PPD Evidera: Employee of PPD Evidera, which received funding from GSK for this study.|ThermoFisher Scientific: Stocks/Bonds (Private Company) Joanna Kamar, MPH, PPD Evidera: Employee of PPD Evidera, which received funding from GSK for this study. Madison T. Preib, MPH, GSK: Employee|GSK: Stocks/Bonds (Public Company) Ashish V. Joshi, PhD, GSK: Employee|GSK: Stocks/Bonds (Public Company) Aruni Mulgirigama, MBBS, GSK: Employee|GSK: Stocks/Bonds (Public Company)

Abstract B030: Novel strategy to improve response of high risk HPV+ HNSCC to radiation therapy

Abstract Background: Improving understanding of head and neck squamous cell carcinoma (HNSCC) has led to the discovery of novel molecular markers to stratify risk and guide treatment decisions. Recently, we have identified two subtypes of HPV+ OPSCC – one with good prognosis and one with poor prognosis. The subtypes are distinct in many ways – somatic genes mutated, HPV viral oncogenes expression, the physical state of the viral genome (integrated vs episomal), as well as global mutation and methylation profiles. Intriguingly, all differences converge on intrinsic tumor NF-κB activity with constitutively active NF-κB (usually arising from genetic defects in NF-κB regulators, including TRAF3 and CYLD) driving significantly elevated radiation sensitivity and improved patient survival. NF-κB-based groups define an important clinically actionable prognostic biomarker in HPV+ HNSCC: one important goal is to de-escalate therapy for patients with molecularly low-risk tumors to improve quality of life amongst survivors, while another goal is to improve the cure for of patients with a high risk of treatment failure. Material and methods: We utilized HPV+ head and neck cancer cells, HPV+ HNSCC xenografted mouse model, patient-derived xenografts (PDX), as well as our novel fully immunocompetent mouse model of high risk HPV+ HNSCC; we applied targeted fractionated radiation. To activate NF-κB, we used two clinically applicable drugs with different mechanisms of action: Toll-like receptor 5 (TLR5) agonist and mitochondria-derived activator of caspases (SMAC) mimetic. Custom NF-κB NanoString panel contains our recently developed NF-κB gene signature along with HPV genes and housekeeping genes that are used to normalize the gene expression data. Results: Both drugs activated NF-κB in HPV+ HNSCC and significantly improved response of HPV+ head and neck cancer cells and tumors to radiation. Interestingly, TLR5 agonist alone had a strong tumor suppressing effect in low NF-κB HPV+ HNSCC; this effect was significantly better than 32 Gy focused radiation given in fractions of 4 Gy. Custom NF-κB NanoString panel is robustly prognostic with NF-κB active tumors having improved outcomes after chemoradiation. Conclusions: Because of the average relatively favorable prognosis of HPV+ HNSCC, urgent need for improved therapy for patients with aggressive high risk tumors is greatly undervalued. Here, we present a clinical assay to risk stratify patients with HPV+ HNSCC and begin to explore pharmacological activation of NF-κB as a strategy to sensitize high risk HPV+ HNSCC to radiation therapy. TLR5 agonist is well known for the remarkable normal tissue protective effects against radiation and other damaging conditions; the dual effect of entolimod – sensitization of HPV+ HNSCC to radiation, while simultaneously protecting normal tissues from severe side effects - may be useful for patients with high-risk HPV+ head and neck cancer in combination with radiotherapy. Citation Format: Sri Vemulamanda, Natalia Issaeva1, Aditi Kothari, Travis Schrank, Wendell G. Yarbrough. Novel strategy to improve response of high risk HPV+ HNSCC to radiation therapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B030.

Efficacy of treatment options for complicated urinary tract infections including acute pyelonephritis: a systematic literature review and network meta-analysis.

Aim: Compared with uncomplicated urinary tract infections (UTIs), complicated UTIs (cUTIs) including acute pyelonephritis (AP) present with significant morbidity, a higher risk of treatment failure and typically require longer courses of treatment, or alternative antibiotics. The emergence of drug-resistant organisms represents a considerable challenge in the treatment of patients with cUTIs/AP and has limited antibiotic options. Carbapenems are considered the current last line of therapy, however, carbapenem resistance represents a growing problem. Although several established and novel treatment options are available, direct comparative evidence is lacking. Methods: Randomized controlled trials (RCTs) were identified by systematic literature review of Embase®, MEDLINE® and Cochrane databases (database inception to 15th June 2022). Relevant conference proceedings (2020-2022) were also reviewed. Following feasibility assessment to verify network connectivity at an overall level, outcome specific networks were prepared. Bayesian network meta-analysis (NMA) was performed (using R version 4.2.1) to determine the relative efficacy of various treatments for cUTI/AP, including cefepime+enmetazobactam. Convergence was assessed by visual inspection of trace plots. The accuracy of the posterior estimates was assessed using the Monte Carlo error for each parameter. Published study results were included in the synthesis of the relative risk (RR) of efficacy end points, using a logit link with binomial likelihood distribution. Results: Feasibility assessment was conducted for 40 RCTs identified, to assess the viability of constructing a network of interlinked RCTs. Of those, 28 studies were included in the master NMA network. A fixed effects model (FEM) was selected due to low statistical heterogeneity, according to I2 values. For composite outcome at test of cure (TOC), ceftolozane+tazobactam, cefepime+enmetazobactam, cefiderocol, levofloxacin and plazomicin demonstrated significantly higher RRs versus carbapenems. For microbiological eradication at TOC, cefepime+enmetazobactam, plazomicin, cefiderocol, fosfomycin, meropenem+vaborbactam and ceftazidime+avibactam demonstrated significantly higher RRs versus carbapenems. RRs for cefepime+enmetazobactam were also significantly higher versus several established and novel treatment options for composite outcome, microbiological eradication and clinical cure. Conclusion: Against the backdrop of increasing bacterial resistance, these findings suggest that cefepime+enmetazobactam may represent an effective carbapenem-sparing treatment option in patients with cUTI including AP.

Vertebral osteomyelitis in patients with an underlying malignancy or chronic kidney disease - who is at higher risk for adverse outcome?

Patients with vertebral osteomyelitis (VO) and comorbidities, notably chronic kidney disease (CKD), are at risk of early mortality. The aim of this study was to compare characteristics and outcomes of VO patients with an underlying malignancy (ONCO) to VO patients with CKD and VO patients without comorbidities (CONTROL). We performed a retrospective analysis of data which was prospectively collected between 2008 and 2020. Primary outcome was treatment failure defined as death and/or recurrence of VO within one year. 241 VO patients (ONCO = 56; CKD = 47; CONTROL = 138) were analysed. Treatment failure occurred in 26% of ONCO and 45% of CKD patients. Staphylococcus aureus was the most common causative pathogen in the CKD (57%) and CONTROL group (43%). ONCO patients showed a broader distribution of common VO-causing pathogens, with coagulase-negative staphylococci (CoNS) accounting for the highest proportion of causative bacteria (27%). Nevertheless, S.aureus was associated with a significantly higher risk of treatment failure in VO ONCO patients. Treatment failure in VO CKD patients was twice as high as in VO ONCO patients. However, both groups showed high treatment failure rates. CoNS should be considered when starting empirical antibiotic treatment in VO ONCO patients. Moreover, oncological patients with VO caused by S.aureus should be monitored closely.

Differences in microorganism profile in periprosthetic joint infections of the hip in patients affected by chronic kidney disease

BackgroundPatients affected by chronic kidney disease (CKD) are at increased risk of periprosthetic joint infection (PJI) after total hip arthroplasty (THA). This patient population has a higher risk of recurrent infections and hospitalization. The aim of this study is to compare the profile of microorganisms in patients with CKD and PJI of the hip versus controls and to individuate potentially unusual and drug-resistant microorganisms among the causative bacteria.Materials and methodsA total of 4261 patients affected by PJI of the hip were retrospectively studied. Patients affected by CKD in this population were identified and compared with a control group of patients with PJI but without CKD. Data on patient characteristics and comorbidities were collected. The microorganisms responsible for PJI were identified and compared between both groups.ResultsThe CKD group included 409 patients, 54.3% male, mean age of 73.8 ± 8.9 years, a higher body mass index (BMI) than the general population (29.88 ± 5.90 kg/m2), and higher age-adjusted CCI of 6.15 ± 2.35. Overall, 70 different isolates of microorganisms were identified, including 52 Gram-positive spp., 28 Gram-negative spp., 3 fungi, and 1 mycobacterium. Polymicrobial infections were more common in CKD group than controls (47.9% versus 30.9%; p < 0.0001). Staphylococcus spp. were the most common bacteria in both groups, followed by Gram-negative Enterobacteriaceae and Streptococcus spp. CKD group showed a higher risk of developing infections caused by Staphylococcus aureus (p = 0.003), Gram-negative bacteria, and Candida (p = 0.035).ConclusionsRenal failure exposes patients who undergo THA to PJI caused by microorganisms that are potentially more drug resistant, leading to a higher risk of treatment failure. Knowing in advance the different microorganism profiles could help to plan a different surgical strategy.Level of Evidence III.

Neoadjuvant chemotherapy vs upfront surgery for resectable locally advanced oral squamous cell carcinoma: A retrospective single center study.

Oral squamous cell carcinoma (OSCC) is one of the most common cancers in humans. The role of neoadjuvant chemotherapy (NAC) in OSCC remains controversial. The study aimed to investigate the effect of NAC on locally advanced OSCC and identify prognostic factors varying is different therapies to ultimately guide the optimal selection of future treatment. A total of 156 patients with locally advanced OSCC were enrolled. The clinical characteristics and survival outcomes of patients with and without NAC were compared. The primary endpoint was overall survival (OS), and the secondary endpoint was disease-free survival (DFS). Among the 156 patients enrolled in this study, 81 patients received NAC followed by surgery and 75 patients received surgery alone. No significant difference in OS at 3 years was detected (78.3% vs 79.8%, p = 0.76). However, a significantly worse DFS was observed in the NAC group (42.4% vs 59.2%, p = 0.048). Within the NAC group, 50 patients (61.7%) had a favorable clinical response, and 12 patients (14.8%) had a complete pathological response. Better survival outcomes were observed in patients with favorable clinical responses. In stratified analysis, patients of pT3/4 OSCC after NAC showed worse DFS than those of the same stage who underwent surgery alone (40.2% vs 58%, p = 0.033). In Cox regression, clinical response and pathological stage were predictors of survival in the NAC group, while pathological stage was the only predictor of OS in the surgery group. Patients with advanced pathological stages after NAC may be at a higher risk of treatment failure, and upfront surgery is recommended for locally advanced OSCC patients in current clinical practice.

Factors for Treatment Failure After Fecal Microbiota Transplantation in Clostridioides difficile Infection.

Recently, fecal microbiota transplantation (FMT) has been introduced as an effective treatment option for Clostridioides difficile infection (CDI). However, the risk factors associated with FMT treatment failure have not been well demonstrated. Therefore, we aimed to investigate the risk factors of treatment failure or recurrence after FMT for CDI. This retrospective study included 124 patients with CDI who underwent FMT at Inha University Hospital between November 2017 and August 2021 and were followed up for 8 weeks after FMT for symptoms of CDI. FMT failure was defined as diarrhea recurrence or a positive stool test. We assessed the risk factors for treatment failure, including comorbidities, antibiotic use pre- and post-FMT, and the number of CDI episodes before FMT. Ninety-three patients (75%) experienced symptom improvement <7 days after FMT, while treatment failure occurred in 40 patients (32.3%). Multivariate analysis revealed that males had a lower symptom improvement rate <7 days after FMT (p = 0.049). Patients using antibiotics after FMT showed a higher rate of recurrence or treatment failure in <8 weeks (p = 0.032). Patients requiring antibiotics after FMT should be considered at higher risk of treatment failure. Careful antibiotic stewardship, particularly minimizing non-essential antibiotic use before and after FMT, may significantly enhance treatment outcomes. Further large-scale prospective studies are warranted to confirm these findings and develop targeted antibiotic management protocols for improving the efficacy of FMT in CDI treatment.

Treatment of Early Pregnancy Loss With Mifepristone and Misoprostol Compared With Misoprostol Only.

To compare the rates of treatment failure in cases of early pregnancy loss between mifepristone-misoprostol and misoprostol only. This retrospective cohort study included patients who received medical treatment for early pregnancy loss between 2016 and 2023 at a single medical center. Patients returned for a follow-up ultrasonogram after 1 week and were treated again with misoprostol if needed. Finally, they were instructed to obtain an ultrasonogram after menstruation and to return for evaluation in case retained product of conception was suspected. We defined treatment failure as needing any surgical intervention because of retained product of conception, including cases when retained product of conception was diagnosed and treated after menstruation. In May 2022, we changed our protocol for treating early pregnancy loss from misoprostol to mifepristone and misoprostol. We compared the failure rate between patients who received mifepristone-misoprostol and those treated with misoprostol only. A total of 999 patients were included: 224 in the mifepristone-misoprostol group and 775 in the misoprostol-only group. The rate of treatment failure was significantly lower in the mifepristone-misoprostol group compared with the misoprostol-only group (17.8% vs 25.1%, P=.002). After multivariant analysis was performed, the use of mifepristone and misoprostol was associated with a reduction of 34% in the odds ratio for treatment failure compared with misoprostol alone (adjusted odds ratio 0.661, 95% CI, 0.44-0.97, P=.038). In addition, prior vaginal delivery was associated with a lower risk for treatment failure, and increasing gestational age (according to ultrasonogram) was correlated with a higher risk for treatment failure. The addition of mifepristone to misoprostol was associated with a significantly lower rate of treatment failure, including late surgical intervention for early pregnancy loss, compared with misoprostol alone.

A Possible Tool for Guiding Therapeutic Approaches to Urinary Infections with Klebsiella pneumoniae: Analyzing a Dataset from a Romanian Tertiary Hospital.

Introduction: The emergence of carbapenem-resistant pathogenic bacteria is a growing global public health concern. Carbapenem-resistant uropathogenic strains of Klebsiella pneumoniae can cause uncomplicated or complicated urinary tract infections, leading to a high risk of treatment failure and the spread of resistance determinants. The objectives of this 24-month study were to identify the prognostic characteristics of patients who were infected with carbapenem-resistant Klebsiella pneumoniae (CRKpn) and to create a tool to estimate the probability of a CRKpn infection before having the complete results of a patient's antibiogram. Results: We found that 41.6% of all urinary infections with Kpn were caused by CRKpn. Factors such as male gender, the presence of upper urinary tract infections, invasive urinary maneuvers, recent infection with or carriage of the germ, and the nosocomial occurrence of UTIs with Kpn were predictive for CRKpn infection. Based on these factors, we proposed a model to estimate the presence of CRKpn. Methods: A retrospective case-control study including all hospitalized patients with urinary tract infections (UTIs) caused by Klebsiella pneumoniae was carried out. We reported data as percentages, identified independent predictors of the presence of CRKpn, and proposed a tool to evaluate the probability through multivariate analysis. Conclusions: Through this study, we aim to provide clinicians with a tool to support decision making regarding first-line antibiotic treatment.

Embolization of the Middle Meningeal Artery for Chronic Subdural Hematoma.

Patients receiving standard treatment for chronic subdural hematoma have a high risk of treatment failure. The effect of adjunctive middle meningeal artery embolization on the risk of treatment failure in this population remains unknown. We randomly assigned patients with symptomatic chronic subdural hematoma to undergo middle meningeal artery embolization as an adjunct to standard treatment (embolization group) or to receive standard treatment alone (control group). Either surgical or nonsurgical standard treatment had been chosen for each patient before randomization. The primary efficacy outcome was a composite of the following events: recurrent or residual chronic subdural hematoma (measuring >10 mm) at 180 days; reoperation or surgical rescue within 180 days; or major disabling stroke, myocardial infarction, or death from neurologic causes within 180 days. The primary safety outcome was a composite of major disabling stroke or death from any cause within 30 days. Among 310 enrolled patients, 149 were randomly assigned to the embolization group and 161 to the control group; 189 patients were to receive surgical standard treatment and 121 nonsurgical standard treatment. The mean age of the patients was 73 years, and 70% were men. In the primary efficacy analysis, a primary-outcome event occurred in 19 of 120 patients (16%) in the embolization group, as compared with 47 of 129 patients (36%) in the control group (odds ratio, 0.36; 95% confidence interval, 0.20 to 0.66; P = 0.001). In the primary safety analysis, 4 of 144 patients (3%) in the embolization group and 5 of 166 patients (3%) in the control group either had a major disabling stroke or died within 30 days. Through 180 days, 12 patients (8%) in the embolization group and 9 patients (5%) in the control group had died, with death from neurologic causes occurring in 1 patient (1%) in the embolization group and in 3 patients (2%) in the control group. Among patients with symptomatic chronic subdural hematoma, adjunctive middle meningeal artery embolization resulted in a lower risk of treatment failure than standard treatment alone, without resulting in an increased incidence of disabling stroke or death in the short term. Further study of longer-term safety outcomes is warranted. (Funded by Balt USA; STEM ClinicalTrials.gov number, NCT04410146.).

The Prognostic and Risk Factors for Children With High-Risk Mature B-Cell Non-Hodgkin's Lymphoma: A Retrospective Multicenter Study.

Our previous study (CCCG-BNHL-2015) reported the treatment strategies and outcomes of pediatric B-cell non-Hodgkin's lymphoma (B-NHL) in China which showed that children in low-risk groups already have a dramatically favorable prognosis. However, for high-risk groups, the prognosis still needs to be improved. In this study, we aimed to identify the factors influencing prognosis in high-risk groups (stage III and stage IV). Our results revealed that gender, lactate dehydrogenase (LDH) level, stage at the time of diagnosis, and early complete remission (CR) achievement were significant factors influencing prognosis (p < 0.05). The 3-year EFS rate for R4 group patients without rituximab treatment was only 25.0% ± 20.4%. Among all patients in stage IV, the 5-year EFS rates for those with involvement of only bone marrow (BM) or central nervous system (CNS) were 83.0% ± 4.5%, 81.8% ± 8.2%, but the 5-year EFS rates for those with both BM and CNS involved were only 37.5% ± 15.3% (p = 0.002). For stage III patients with LDH ≥ 4N, the 5-year EFS rates for those achieving CR and those not achieving CR after 2 treatment cycle were 88.9% ± 5.2% and 67.9% ± 7.3%(p = 0.036). Therefore, R4 group patients benefited from rituximab treatment. However, children at stage III, LDH ≥ 4N not achieving CR after the 2nd treatment cycle, and those with both BM and CNS involved are still at a very high risk of treatment failure. This study serves as a crucial reference for optimizing risk stratification, refining treatment categorizations, and optimizing treatment protocols.

Tumor Response and Its Impact on Treatment Failure in Rectal Cancer: Does Intensity of Neoadjuvant Treatment Matter?

Objectives: Additional adjuvant treatment in patients with rectal cancer with limited response to neoadjuvant treatment to mitigate their higher risk of treatment failure remains controversial. Methods: This is a post hoc analysis of a cohort study of 3 randomized phase 2 or 3 trials (CAO/ARO/AIO-94, -04, and -12 trial) that included 1948 patients with locally advanced rectal adenocarcinoma. After excluding patients with missing information, 1788 patients (1254 men and 524 women; median age: 62.6 years, age range: 19-84 years) were eligible. We analyzed the extent of tumor response and its association with the incidence of treatment failure after different neoadjuvant treatment approaches. Results: Tumor response was significantly enhanced with more intensive neoadjuvant treatment. After a median follow-up of 55 months for the entire cohort (IQR: 37 months-62 months), the incidence of treatment failure (TF) stratified by tumor response or post-neoadjuvant pathological outcome was not significantly affected by the intensity of neoadjuvant treatment, whereas the ypTNM stage was significantly associated with the risk of treatment failure. Conclusions: In this cohort study, we provide evidence that limited or no response to intensified neoadjuvant treatment protocols is not likely to be more strongly associated with an extensive risk of TF after 5-FU CRT+/- adjuvant chemotherapy.

Respiratory rate-oxygenation index on the 3rd day is the best predictor of treatment failure in COVID-19 patients.

Predictors of outcomes are essential to identifying severe COVID-19 cases and optimizing treatment and care settings. The respiratory rate-oxygenation (ROX) index, originally introduced for predicting the failure of non-invasive support in acute hypoxemic respiratory failure (AHRF), has not been extensively studied over time during hospitalization. This multicenter prospective observational study analyzed COVID-19-related AHRF patients admitted to eight Italian hospitals during the second pandemic wave. The study assessed the ROX index using receiver operator characteristic curves and areas under the curve with 95% confidence intervals to predict treatment failure, defined as endotracheal intubation (ETI) or death. A total of 227 patients (69.2% males) were enrolled, with a median arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio at admission of 248 (interquartile range: 170-295). Nearly one-third (29.5%) required ETI or died during hospitalization. Those who experienced treatment failure were older (median age 70 versus 61 years, p<0.001), more likely to be current or former smokers (8.5% versus 6.4% and 42.4% versus 25.5%, p=0.039), had a higher prevalence of cardiovascular diseases (74.6% versus 46.3%, p<0.001), and had a lower PaO2/FiO2 ratio at presentation (median 229 versus 254, p=0.014). Gender, body mass index, and other comorbidities showed no significant differences. In patients who failed treatment, the ROX index was higher at presentation and worsened sharply by days 3 and 4. Conversely, in patients who survived without requiring ETI, the ROX index remained stable and reduced after 5-6 days. The ROX index's predictive ability improved notably by the third day of hospitalization, with the best cut-off value identified at 8.53 (sensitivity 75%, specificity 68%). Kaplan-Meier curves indicated that a ROX index of 8.53 or lower on days 1, 2, or 3 was associated with a higher risk of treatment failure. Thus, a single ROX index assessment on day 3 is more informative than its variability over time, with values of 8.53 or lower predicting non-invasive respiratory support failure in hospitalized COVID-19 patients.

Impact of select actionable genomic alterations on efficacy of neoadjuvant immunotherapy in resectable non-small cell lung cancer

BackgroundNeoadjuvant immune checkpoint inhibitors (ICIs) have improved survival outcomes compared with chemotherapy in resectable non-small cell lung cancer (NSCLC). However, the impact of actionable genomic alterations (AGAs) on the efficacy...

Abstract A014: Protein-informed gene methylation signatures to predict treatment response and outcomes in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer with dismal outcomes. We need new biomarkers to optimize the limited treatment combinations used in current clinical practice. Many machine-learning models have been presented based on mutational or transcriptome data claiming to predict outcomes. Still, they do not provide actionable targets (genes) that could improve treatment response. Moreover, DNA-methylation changes that influence gene/protein expression have been explored for this purpose. From the literature, we curated a 122-gene panel (January 1970 to April 2024) constructed on the proteins with preclinical (on cell lines or mouse models) or clinical (tissue-based studies) evidence suggesting their individual roles in influencing response to drugs often used in managing PDA such as gemcitabine (Gem), nab-paclitaxel, oxaliplatin, 5-fluorouracil, irinotecan, and cisplatin. We hypothesized that methylation changes in these genes are surrogates for gene/protein expression and tested their clinical significance in The Cancer Genome Atlas (TCGA) PDA population (n=184). The goal was to develop methylation signatures composed of specific cytosines followed by guanine residue (CpG) sites that aid in identifying patients at high risk of treatment failure and poor outcomes. We used elastic net multivariate analysis to calculate survival and plot Kaplan Meier plots based on our gene panel. The alpha (α) used for this script was calculated based on the lowest mean error and the minimum lambda (λ) value accordingly for each iteration (100 iterations to calculate the best values for α and λ). Our analysis yielded 28 methylation signatures that could identify high-risk PDA patients with poor overall survival (OS). The number of CpG sites in these signatures ranged from 1 to 1933. The differences in OS for these signatures were better than those available in the literature. The best signature had 18 CpG sites (17 months (m) vs. not evaluable) followed by a 53-CpG site signature (16 m vs. 67m) and a 6-CpG site signature (17m vs. 67m). A signature with the highest CpG sites (1933) was not better than those with smaller ones (16m vs. 21m). Multiple signatures had &amp;gt;1 CpG sites from one gene. Early growth response 1 (EGR1) coding the KCNH2 gene has featured in most signatures. One CpG site in this gene had a clinically significant prognostic value (15m vs. 30m). Other frequently featured genes were CCDC85A, EGFR, SST, and HMGA1. The main drawbacks for this study were that Gem-related genes (&amp;gt; 60) dominated the panel, and those with Gem treatment dominated the patient population. This panel should be further refined to make it more relevant to current clinical practice. We provide preliminary evidence suggesting the clinical significance of our panel and lay the foundation for future studies that would enable us to personalize prognostication and treatment selection in PDA patients. Our work can provide novel therapeutic targets that, alone or in combination with chemotherapy, can improve the outcomes for PDA. Citation Format: Ashish Manne, Harshitha Puram, Deepak Sherpally, Sravan Jeepalyam, Upender Manne. Protein-informed gene methylation signatures to predict treatment response and outcomes in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A014.

Persistent Lymph Node Metastases After Neoadjuvant Chemoradiotherapy for Rectal Cancer

Patients with locally advanced rectal cancer and persistent lymph node metastases (PLNM) after neoadjuvant treatment are at high risk of developing locoregional and distant metastasis, yet optimal postsurgical treatment of these patients is limited. To analyze the association of PLNM with pretreatment clinical parameters, intensity of neoadjuvant treatment, and long-term oncological outcomes. This cohort study is a post-hoc analysis of 3 randomized clinical trials (Surgical Oncology Working Group of Germany [CAO], Radiological Oncology Working Group of Germany [ARO], and Working Group for Internal Oncology in the German Cancer Society [AIO]) conducted in Germany in 1994, 2004, and 2012 that included 1948 patients with locally advanced rectal cancer recruited between February 1995 and January 2018. Statistical analysis was conducted between September 2023 and February 2024. Receiving preoperative fluorouracil-based chemoradiotherapy (CRT, comprising the preoperative group of CAO/ARO/AIO-94 and the control group of CAO/ARO/AIO-04), fluorouracil-based CRT plus oxaliplatin (experimental group of CAO/ARO/AIO-04), or total neoadjuvant treatment (TNT) with fluorouracil-based CRT plus oxaliplatin with induction or consolidation leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin chemotherapy within the CAO/ARO/AIO-12 trial. The associations of PLNM with clinical parameters, intensity of neoadjuvant treatment, and cumulative incidences of LR, DM, and overall survival were assessed. A total of 1888 patients (1333 male participants [70.6%]; median [range] age, 62 [19-84] years) with locally advanced rectal adenocarcinoma (clinical tumor stage 3 to 4 and/or clinically node-positive) treated within 3 consecutive clinical trials were analyzed. A total of 522 (29%) experienced PLNM; 378 had lymph node stage (ypN) 1 (20%) after neoadjuvant treatment (ypN) 1 (20%), and 174 had ypN2 (9%). Age, clinical T-stage, N-stage, grading, carcinoembryonic antigen levels, and time interval from completion of CRT to surgery were significantly associated with PLNM, whereas sex and tumor location were not. The percentage of patients with ypN2 stage was almost halved after TNT (18 of 293 patients [6%]) compared with patients treated with fluorouracil-based CRT (114 of 1009 patients [11.3%]; χ26 = 16.693; P = .01). After a median (IQR) follow-up of 54 (37-62) months, 5-year overall survival was 86.1% (95% CI, 83.9%-88.4%) for ypN0, 74.0% (95% CI, 83.9%-88.4%) for ypN1, and 43% for ypN2 (95% CI, 35.4%-52.2%) (P < .001). The 5-year cumulative incidences of locoregional and distant metastases were, respectively, 3% (95% CI, 2.1%-4.2%) and 20% (95% CI, 18%-23%) for ypN0, 6% (95% CI, 3.4%-8.8%) and 40% (95% CI, 34%-46%) for ypN1, and 19% (95% CI, 13%-26%) and 72% (95% CI, 63%-79%) for ypN2 (both P < .001). In this cohort study, PLNM unmasked an unfavorable phenotype of rectal cancer at high risk for treatment failure. More aggressive adjuvant treatment might be considered; however, risk-adapted surveillance strategies and early recurrence-directed surgery, if feasible, are important strategies in this group of patients with CRT- and/or chemotherapy-resistant disease.

Prospective Assessment of Outcomes After Femoral Condyle Osteochondral Allograft Transplantation With Concurrent Meniscus Allograft Transplantation.

Osteochondral allograft transplantation (OCAT) and meniscus allograft transplantation (MAT) have each become more commonly implemented for the treatment of young to middle-aged patients with complex knee pathology. Evidence regarding tibiofemoral OCAT in the setting of concurrent MAT is limited. The purpose of this study was to characterize outcomes for femoral condyle OCAT with concurrent MAT (OCAT+MAT) in the ipsilateral compartment of patients after evidence-based shifts in practice. It was hypothesized that OCAT+MAT would be associated with successful outcomes characterized by statistically significant and clinically meaningful improvements in patient-reported outcome measures (PROMs) of knee pain and function in >80% of patients for at least 2 years after transplantation. Case series; Level of evidence, 4. With institutional review board approval and documented informed consent, patients who underwent primary OCAT+MAT between 2016 and 2020 and enrolled in a lifelong registry for prospective collection of outcomes after OCAT were included. Patients with minimum 2-year follow-up data regarding complications, failures, adherence, and PROMs were analyzed. Patients who required OCAT and/or MAT revision or conversion to arthroplasty were defined as experiencing treatment failures. A total of 23 consecutive patients (mean age, 37.1 years; mean body mass index, 28 kg/m2; 14 men) met the inclusion criteria, with a mean follow-up of 51 months (range, 24-86 months). The initial treatment success rate was 78% based on 5 initial treatment failures, and the overall success rate was 83% based on a successful revision OCAT. All failures occurred in the medial compartment. Older patient age (42.2 vs 32.1 years; P = .046) and nonadherence to postoperative restriction and rehabilitation protocols (P = .033; odds ratio, 14) were significant risk factors for treatment failure. All measured PROMs achieved significant improvements (P < .001) and minimum clinically important differences at a minimum of 2 years postoperatively. OCAT+MAT was associated with successful short- to mid-term outcomes in 83% of cases. Evidence-based shifts in practice were implemented before the enrollment of this patient cohort. Older patients and those who were not adherent to postoperative restriction and rehabilitation protocols had a significantly higher risk for treatment failure and subsequent conversion to arthroplasty.

A systematic review and meta-analysis of comparative clinical studies on antibiotic treatment of brucellosis

Brucellosis is a difficult to treat infection that requires antibiotic combinations administered over several weeks for clearance of infection and relapse prevention. This systematic review summarizes current evidence for antibiotic treatment of human brucellosis. PubMed, EMBASE, Scopus, CINAHL, Web of Science, and China Academic Journal databases were searched for prospective studies that had compared different antibiotic regimens for treating human brucellosis in the last 25 years. Thirty-four studies recruiting 4182 participants were eligible. Standard dual therapy with doxycycline + rifampicin had a higher risk of treatment failure compared to triple therapy which added streptomycin (RR: 1.98, 95% CI 1.17–3.35, p = 0.01) or levofloxacin (RR: 2.98, 95% CI 1.67–5.32, p = 0.0002), but a similar or lower risk compared to alternative dual antibiotic combinations (p > 0.05). The same combination had a higher risk of relapses compared to triple therapy which added streptomycin (RR: 22.12, 95% CI 3.48–140.52, p = 0.001), or levofloxacin (RR: 4.61, 95% CI 2.20–9.66, p < 0.0001), but a similar or lower risk compared to other dual antibiotic combinations (p > 0.05). Triple antibiotic therapy is more effective than standard dual therapy with rifampicin and doxycycline. However, the latter is also efficacious and suitable for uncomplicated disease.