Search Results (547)

Background and Aim: Long-term treatment with biologic therapy alongside immunomAfodulators in patients with inflammatory bowel disease (IBD) can be associated with severe side effects. The objective of this study was to determine whether discontinuing anti-TNF treatment after two years in patients who have achieved mucosal healing is associated with lower relapse rates. Materials and Methods: A total of 67 patients with IBD from a single tertiary IBD Center who had achieved mucosal healing were enrolled in this retrospective study. In this single-center retrospective study (January 2014–December 2022), we screened 67 IBD patients in deep remission (endoscopic mucosal healing after ≥2 years of anti-TNF therapy). After excluding three patients without histologic data, 64 patients (25 ulcerative colitis, 39 Crohn’s disease) were analyzed. Mayo endoscopic sub-score and SES-CD were used to evaluate endoscopic activity after two years of anti-TNF therapy. Histological activity was assessed using the GHAS (for CD) and Nancy index (for UC). Results: A total of 67 patients were screened, of whom 3 were excluded due to a lack of biopsies. Of the 64 included patients, 39.06% (25/64) had UC and 60.9% (39/64) had CD, with a mean disease duration of 11.6 ± 8.0 years. All patients were in endoscopic remission at the time of therapy de-escalation, and 60.9% (39/64) also achieved histological remission (“deep remission”). In the follow-up of 38.6 months (IQR 30–48) after biologic therapy was stopped, 57.8% (37/64) relapsed with a median time to relapse of 13.5 months (IQR 8–24) off anti-TNF—a total of 34 patients required a restarting of biologic therapy. Using Spearman’s correlation, a moderate connection was observed between histological activity at withdrawal and subsequent relapse (rho = 0.467, p < 0.001). The probability of relapsing within 4 years after anti-TNF cessation was significantly higher (OR 2.72) in patients with histologically active disease at the time of de-escalation. Conclusions: Achieving ‘deep remission’ (clinical, endoscopic, and histological healing) may be a suitable parameter for making decisions on when to de-escalate therapy; however, given that over half of patients in endoscopic remission relapse after discontinuation, any de-escalation should be approached with caution and individualized patient assessment. Full article

Background: Radiation dose escalation for locally advanced pancreatic cancer (LAPC) using stereotactic magnetic resonance (MR)-guided online adaptive radiation therapy (SMART) or computed tomography (CT)-guided moderately hypofractionated ablative radiation therapy (HART) can achieve favorable outcomes although have not previously been compared. Methods: We performed a multi-center retrospective analysis of SMART (50 Gy/5 fractions) vs. HART (75 Gy/25 fractions or 67.5 Gy/15 fractions with concurrent capecitabine) for LAPC. Gray’s test and Cox proportional regression analyses were performed to identify factors associated with local failure (LF) and overall survival (OS). Results: A total of 211 patients (SMART, n = 91; HART, n = 120) were evaluated, and none had surgery. Median follow-up after SMART and HART was 27.0 and 40.0 months, respectively (p < 0.0002). SMART achieved higher gross tumor volume (GTV) coverage and greater hotspots. Two-year LF after SMART and HART was 6.5% and 32.9% (p < 0.001), while two-year OS was 31.0% vs. 35.3% (p = 0.056), respectively. LF was associated with SMART vs. HART (HR 5.389, 95% CI: 1.298–21.975; p = 0.021) and induction mFOLFIRINOX vs. non-mFOLFIRINOX (HR 2.067, 95% CI 1.038–4.052; p = 0.047), while OS was associated with CA19-9 decrease > 40% (HR 0.725, 95% CI 0.515–0.996; p = 0.046) and GTV V120% (HR 1.022, 95% CI 1.006–1.037; p = 0.015). Acute grade > 3 toxicity was similar (3.3% vs. 5.8%; p = 0.390), while late grade > 3 toxicity was less common after SMART (2.2% vs. 9.2%; p = 0.037). Conclusions: Ablative SMART and HART both achieve favorable oncologic outcomes for LAPC with minimal toxicity. We did not observe an OS difference, although technical advantages of SMART might improve target coverage and reduce LF. Full article

Background/Objectives: Patients with breast cancer who do not achieve a complete response to neoadjuvant chemotherapy (NAC) may benefit from intensified adjuvant systemic therapy. However, such treatment escalation is typically delayed until after tumour resection, which occurs several months into the treatment course. Quantitative ultrasound (QUS) can detect early microstructural changes in tumours and may enable timely identification of non-responders during NAC, allowing for earlier treatment intensification. In our previous prospective observational study, 100 breast cancer patients underwent QUS imaging before and four times during NAC. Machine learning algorithms based on QUS texture features acquired in the first week of treatment were developed and achieved 78% accuracy in predicting treatment response. In the current study, we aimed to validate these algorithms in an independent prospective cohort to assess reproducibility and confirm their clinical utility. Methods: We included breast cancer patients eligible for NAC per standard of care, with tumours larger than 1.5 cm. QUS imaging was acquired at baseline and during the first week of treatment. Tumour response was defined as a ≥30% reduction in target lesion size on the resection specimen compared to baseline imaging. Results: A total of 51 patients treated between 2018 and 2021 were included (median age 49 years; median tumour size 3.6 cm). Most were estrogen receptor–positive (65%) or HER2-positive (33%), and the majority received dose-dense AC-T (n = 34, 67%) or FEC-D (n = 15, 29%) chemotherapy, with or without trastuzumab. The support vector machine algorithm achieved an area under the curve of 0.71, with 86% accuracy, 91% specificity, 50% sensitivity, 93% negative predictive value, and 43% positive predictive value for predicting treatment response. Misclassifications were primarily associated with poorly defined tumours and difficulties in accurately identifying the region of interest. Conclusions: Our findings validate QUS-based machine learning models for early prediction of chemotherapy response and support their potential as non-invasive tools for treatment personalization and clinical trial development focused on early treatment intensification. Full article

Elevated levels of atherogenic lipoproteins are known to be associated with an increased risk of incident and recurrent cardiovascular events. Knowing that the immediate post-acute coronary syndrome (ACS) period is associated with the maximum risk of recurrent events, the gradual escalation of therapy allows the patient to remain above the targets during the most vulnerable period. In addition, the percentage of lipid-lowering levels for each class of drugs is predictable and has a ceiling. Hence, it is prudent to immediately start with a combination of lipid-lowering drugs following ACS according to the baseline lipid levels. Multiple studies with injectable lipid-lowering agents (PCSK9 inhibitors) such as EVOPACS, PACMAN MI, and HUYGENS MI have shown the feasibility of achieving LDL-C goals by day 28 and beneficial plaque modification in non-infarct-related coronary arteries. Recently, a study from India demonstrated that an upfront triple combination of oral lipid-lowering agents was able to achieve LDL-C goals in a majority of patients in the early post-ACS period. This notion is also supported by a few recent lipid-lowering guidelines advocating for an upfront dual combination of a high-intensity statin and ezetimibe following ACS. Henceforth, the goal should not only be the achievement of lipid targets but also their early achievement. However, the impact of this strategy on long-term cardiovascular outcomes is yet to be ascertained. Full article

Background/Objectives: Neurodegenerative proteinopathies, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB), are increasingly prevalent worldwide mainly due to population aging. These conditions are marked by complex etiologies, overlapping pathologies, and progressive clinical decline, with significant consequences for patients, caregivers, and healthcare systems. This review aims to synthesize evidence on the healthcare complexities of major neurodegenerative proteinopathies to highlight current knowledge gaps, and to inform future care models, policies, and research directions. Methods: We conducted a comprehensive literature search in PubMed/MEDLINE using combinations of MeSH terms and keywords related to neurodegenerative diseases, proteinopathies, diagnosis, sex, management, treatment, caregiver burden, and healthcare delivery. Studies were included if they addressed the clinical, pathophysiological, economic, or care-related complexities of aging-related neurodegenerative proteinopathies. Results: Key themes identified include the following: (1) multifactorial and unclear etiologies with frequent co-pathologies; (2) long prodromal phases with emerging biomarkers; (3) lack of effective disease-modifying therapies; (4) progressive nature requiring ongoing and individualized care; (5) high caregiver burden; (6) escalating healthcare and societal costs; and (7) the critical role of multidisciplinary and multi-domain care models involving specialists, primary care, and allied health professionals. Conclusions: The complexity and cost of neurodegenerative proteinopathies highlight the urgent need for prevention-focused strategies, innovative care models, early interventions, and integrated policies that support patients and caregivers. Prevention through the early identification of risk factors and prodromal signs is critical. Investing in research to develop effective disease-modifying therapies and improve early detection will be essential to reducing the long-term burden of these disorders. Full article

Background/Objectives: In the era of treat-to-target strategies in inflammatory bowel disease (IBD), transmural healing (TH) is gaining recognition as a promising therapeutic goal. TH has been associated with significantly better long-term outcomes, including reduced rates of hospitalization, surgery, and the need for therapy escalation. Cross-sectional imaging techniques, such as intestinal ultrasound (IUS), magnetic resonance imaging (MRI), and computed tomography enterography (CTE), offer a comprehensive, non-invasive means to assess this deeper level of healing. This review explores how TH is currently defined across various imaging modalities and evaluates the feasibility and cost-effectiveness of achieving TH with available therapies. Methods: A literature search was conducted across PubMed, Scopus, and Embase using keywords, including “transmural healing”, “intestinal ultrasonography”, “magnetic resonance imaging”, “computed tomography enterography”, “Crohn’s disease”, “ulcerative colitis”, and “inflammatory bowel disease”. Only English-language studies were considered. Results: Despite growing interest, there is no standardized definition of TH across imaging platforms. Among the modalities, IUS emerges as the most feasible and cost-effective tool, owing to its accessibility, accuracy (sensitivity 62–95.2%, specificity 61.5–100%), and real-time capabilities, though it does have limitations. Current advanced therapies induce TH in roughly 20–40% of patients, with no consistent differences observed between biologics and small molecules. However, TH has only been evaluated as a formal endpoint in a single randomized controlled trial to date. Conclusions: A unified and validated definition of transmural healing is critically needed to harmonize research and guide clinical decision-making. While TH holds promise as a meaningful treatment target linked to improved outcomes, existing therapies often fall short of achieving complete transmural resolution. Further studies are essential to clarify its role and optimize strategies for deep healing in IBD. Full article

The escalating global crisis of antimicrobial resistance, responsible for approximately 1.27 million deaths in 2019, has catalyzed renewed interest in bacteriophage therapy as a viable therapeutic alternative. With projections indicating that drug-resistant bacteria could cause over 39 million deaths worldwide by 2050, developing alternative antimicrobial strategies has become critically urgent. This comprehensive review examines the scientific foundation of bacteriophage therapy, traces its historical development from early Soviet applications through contemporary regulatory frameworks, and provides strategic guidance for developers seeking FDA approval for bacteriophage-based therapeutics. We analyze the current regulatory landscape across major jurisdictions, including manufacturing requirements and clinical development pathways essential for successful market authorization. Approximately 90 clinical trials involving bacteriophages are ongoing worldwide, with 41 studies in the United States demonstrating significant momentum in this field. Full article

The concept of “more is better” has long dominated cancer treatment, emphasizing aggressive therapies despite their toxicity. However, the rise of personalized medicine has fostered treatment de-escalation strategies aimed at minimizing toxicity, improving quality of life, and reducing costs. This position paper highlights key applications of de-escalation in medical oncology, with a primary focus on breast cancer and notable examples in colorectal, head and neck, ovarian, lung, and prostate cancers. Various approaches, including dose reduction, treatment duration shortening, and regimen optimization, have demonstrated efficacy without compromising clinical outcomes. Advances in molecular diagnostics, such as Oncotype Dx in breast cancer and circulating tumor DNA (ctDNA) analysis in colorectal cancer, have facilitated patient selection for de-escalation. While these strategies present promising results, challenges remain, particularly in balancing treatment intensity with oncologic control. The review underscores the need for further prospective trials to refine de-escalation approaches and ensure their safe integration into standard oncologic care. Full article

When non-functioning pituitary adenomas (NFPAs) behave aggressively or recur after first-line surgical treatment, it can be challenging to decide whether and how to escalate therapy. Up to 47% of patients with residual tumor after transsphenoidal surgery will show disease recurrence or progression and may require an intervention. Repeat surgical resection can be attempted in select cases if the tumor is accessible; for the remainder of patients, non-surgical treatment options may need to be considered. Radiotherapy can control tumor growth in 75% of NFPAs, but confers increased risk of hypopituitarism and other disorders. Currently, there are no medical therapies approved for patients with recurrent or aggressive NFPA. However, several have been investigated, including temozolomide, somatostatin receptor ligands, dopamine agonists, immune checkpoint inhibitors, vascular endothelial growth factor inhibitors, and peptide receptor radionuclide therapy. We present a review of the available evidence to provide guidance for pituitary endocrinologists and neuro-oncologists when treating patients with recurrent or aggressive NFPA. Full article

Conventional chemotherapy continues to form the backbone of treatment for many pediatric central nervous system (CNS) tumors. Advances have been made especially in the molecular underpinning of certain pediatric CNS tumors, allowing for advancement and consideration in incorporating this molecular information in molecular targeted therapy or appropriate de-escalation or escalation of therapy. In very young children with embryonal CNS tumors, intensive high-dose chemotherapy approaches have been used with varied increased survival in medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and rare embryonal subtypes, but there are certain molecular risk groups that require new therapies, such as the ATRT MYC subtype. Some CNS tumors remain resistant or refractory to conventional chemotherapy, especially in relapsed disease. Strategies to explore combination therapies with chemotherapy, novel agents, and novel approaches are needed to improve survival in this population in the future. Full article

Background: Kawasaki disease (KD) is a systemic vasculitis and the leading cause of acquired heart disease in children. Early identification of coronary artery abnormalities (CAAs) is crucial to guide treatment and improve outcomes. While transthoracic 2D echocardiography (TTE) remains the first-line imaging modality, it has limitations, particularly in visualizing distal coronary artery segments and detecting thrombi. Computed tomography coronary angiography (CTCA) offers enhanced visualization, but its role at initial presentation of KD remains underexplored. Methods: We reviewed the records of 71 children with KD who underwent CTCA at their initial presentation at a tertiary center between November 2013 and December 2024. The CTCA findings were compared with those of TTE. CTCA was performed after stabilization using radiation-minimized protocols. Results: Of 71 patients, 62 had CAAs on baseline TTE. CTCA confirmed CAAs in 39 patients, identified additional lesions in 23, and detected distal aneurysms and coronary branch involvement missed by TTE. In 20 patients with initially abnormal TTE, CTCA demonstrated normal coronaries, facilitating treatment de-escalation. CTCA identified coronary thrombi missed on TTE in two patients and congenital coronary anomalies in three patients. CTCA findings led to modification of therapy in multiple cases. Conclusions: CTCA is a valuable adjunct to TTE in evaluating coronary artery involvement at the time of initial presentation of children with KD. Given its superior visualization of the entire length of coronary arteries, CTCA has a vital role in therapeutic decision-making in KD. Full article

Objective: This study aimed to assess the effect of antibiotic de-escalation on 30-day mortality, duration of intravenous (IV) antibiotic therapy and length of hospital stay (LOS) in severe community-acquired pneumonia (sCAP). Methods: We performed a retrospective analysis of prospectively collected data from a cohort of adults diagnosed with sCAP and microbiologically confirmed etiology between 1995 to 2022. Two distinct time points of the de-escalation were analyzed: 3 and 6 days post-admission, corresponding, respectively, to the availability of microbiological results and the median time to clinical stability. Inverse propensity score-weighted binary logistic regression was used to adjust for potential confounders. Results: A total of 398 consecutive cases of sCAP were analyzed. No significant differences were observed between the de-escalation and non-de-escalation groups in terms of age, sex, comorbidities, or severity-related variables (such as impaired consciousness, shock, respiratory failure, or multilobar pneumonia). Patients in the de-escalation group had lower rates of leukopenia, bacteremia and empyema, and less need for mechanical ventilation, with variations depending on the timing of de-escalation. After adjusting for confounding factors in an inverse propensity score-weighted analysis, de-escalation within 3 or 6 days after admission was not associated with increased mortality risk (adjusted odds ratio [aOR] 1.48, 95% confidence interval [CI] 0.29–7.4; p = 0.63, and aOR 0.57, 95% CI 0.14–2.31, p = 0.43, respectively). Similar findings were observed for prolonged LOS. However, antibiotic de-escalation was related to a lower risk of prolonged IV antibiotic. Conclusions: Antibiotic de-escalation in microbiologically confirmed sCAP did not negatively impact clinical outcomes, supporting the safety of this strategy for optimizing antibiotic use in this serious infection. Full article

Molecular methods allow for a rapid identification of the main causative agents of pneumonia along with the most frequent resistance genes. Prolonged broad-spectrum antibiotic therapy without microbiological evidence of infection drives antimicrobial resistance. We evaluated if the result provided by the molecular method is helpful for antimicrobial de-escalation. All respiratory samples collected and directly processed via Real-Time PCR from patients with suspected pneumonia, of whom clinical data were available, were included in this study. In 82 patients out of a total of 174 (47.1%), antimicrobial therapy was modified after the molecular test, and in 28/82 (34.1%), antimicrobial de-escalation was carried out. Among the 92 patients in whom therapy was not modified, 33 (35.9%) were did not receive any antimicrobial therapy before the molecular test and no antibiotics were prescribed after the test. Therefore, in 61 (28 + 33) out of the 174 (35%) patients, unnecessary antimicrobials were discontinued or avoided. The syndromic panel used at our institution can be of help in better choosing when empiric antibiotic de-escalation therapy could be feasible. Full article

Background: Immune checkpoint inhibitors (ICIs) transformed cancer treatment, producing significant survival benefits. However, ICIs can trigger toxicities called immune-related adverse events (irAEs), including inflammatory arthritis (IA) and polymyalgia rheumatica (PMR)-like syndromes. Our study aimed to systematically further characterize musculoskeletal ultrasound (MSKUS) findings in patients with ICI-IA and ICI-PMR, collectively referred to as “MSK-irAEs”, and explore the role of US in guiding treatment. Methods: The authors conducted a comprehensive chart review for patients receiving ICIs undergoing MSKUS at our center’s rheumatology clinics. US examinations were performed and reviewed by two MSKUS-certified rheumatologists. Descriptive statistics were performed to summarize demographic, clinical, and treatment-related variables. US findings were categorized with a novel scoring system: 0—no signs of inflammatory arthropathy or tendinopathy, 1—potential signs of inflammation (grayscale ≥ 2, effusion without power Doppler, synovial hypertrophy in the joint), and 2—active inflammation in joints and/or tendons (characterized by power Doppler) and signs of inflammation. Results: Twenty-three patients were included. The median age was 63 years, 52% were male, and 87% were White. Melanoma was the most common cancer (48%). MSK-irAEs were diagnosed in nineteen (83%), with MSKUS showing inflammation in seventeen (74%). Sixteen (70%) received escalation in MSK-irAE treatment after MSKUS. Four (17%) had erosive disease due to MSK-irAEs, while one had erosive osteoarthritis. Individuals with inflammatory erosive changes experienced prolonged intervals between symptom onset and MSKUS, ranging from 17 to 82 months, suggesting that erosions may reflect chronic, under-recognized inflammation. On MSK-irAE therapy, nine (47%) experienced symptomatic improvement, five (26%) achieved resolution, and in four (21%) cases, it was too early to assess the response. MSKUS detected other causes of MSK symptoms besides MSK-irAEs in several patients, allowing ICI resumption in one. Conclusions: Our study highlights the clinical utility of MSKUS not only as a diagnostic tool but also to guide therapeutic decision-making. Full article

Background and Objectives: This study aimed to assess the prevalence of colistin prescriptions among patients with multidrug-resistant (MDR) Pseudomonas aeruginosa (P. aeruginosa) infections admitted to a tertiary teaching hospital in Jordan. Additionally, the study evaluated the appropriateness of colistin prescriptions and assessed resistance levels of this strain. Materials and Methods: In this retrospective study, adult patients who were infected with MDR P. aeruginosa and were admitted to Jordan University Hospital between January 2018 and March 2024 were included. Data on demographics, clinical characteristics, sources of infection, antibiotic therapy, and clinical outcomes were collected. Results: Out of the 85 patients who met the inclusion criteria for having MDR P. aeruginosa, colistin was administered to 16 patients (18.8%). Notably, approximately two-thirds (68.7%) of the isolates from patients who received colistin were classified as extensively drug-resistant (XDR). Among the isolates, 15 out of 16 (93.8%) were resistant to both ciprofloxacin and imipenem. Among the patients requiring colistin, five (31.3%) discontinued therapy, while two (12.5%) remained on colistin despite the availability of safer alternatives. No significant difference was observed in 30-day all-cause mortality between patients treated with colistin (0%) and those who were not (4.3%, p = 1.00). Similarly, the incidence of acute kidney injury did not differ significantly between the colistin group (0%) and the non-colistin group (p = 1.00). No significant difference was found in the hospital stay between colistin-treated patients (median 10.5 days, IQR [5.0–14.0]) and those not treated with colistin (median 13.0 days, IQR [7.0–21.0]), (p = 0.22). Conclusions: This study demonstrated that colistin was selectively initiated in high-risk patients, particularly those with XDR P. aeruginosa. However, its inappropriate continuation despite safer alternatives, as well as its discontinuation when no other options existed, raise concerns about antibiotic de-escalation practices. Interestingly, no significant differences in mortality or acute kidney injury were observed between patients who were treated with colistin and those who were not. These findings emphasize the need for antimicrobial stewardship programs and highlight the importance of large-scale trials to evaluate colistin’s efficacy and safety in MDR infections. Full article