Subsequent Treatment Strategies Research Articles

The effectiveness of sequential afatinib and furmonertinib in an advanced lung adenocarcinoma with rare compound EGFR mutation (L833V/H835L).

Uncommon atypical mutations account for 10-15% of all epidermal growth factor receptor (EGFR) activating mutations in nonsmall-cell lung cancer (NSCLC). Tumors harboring rare EGFR mutations show highly heterogeneous responses to EGFR tyrosine kinase inhibitors (TKIs). There is insufficient clinical evidence for uncommon types of EGFR mutations, especially those with compound EGFR mutations. In addition, for those with uncommon compound EGFR mutations, few studies have focused on acquired resistance mechanisms and subsequent treatment strategies after disease progression on EGFR-TKIs. Here, a 66-year-old smoking male was diagnosed with lung adenocarcinoma accompanied by pleural metastasis. A rare L833V/H835L compound mutation in exon 21 of EGFR was detected in tumor biopsy by next-generation sequencing. Afatinib was used as first-line therapy and showed favorable efficacy. The patient continued afatinib treatment for a duration of 24 months. A new T790M mutation was detected with a rebiopsy after progression on afatinib. Then the patient received cryoablation therapy and a third-generation EGFR-TKI, furmonertinib. Our case suggests that a comprehensive screening for EGFR mutations should be conducted before and during treatment in clinical practice, and afatinib and furmonertinib could be first- and second-line treatment options in NSCLC patients harboring EGFR L833V/H835L mutations.

Evaluation of Inflammatory Activity of Extraocular Muscles in Thyroid Associated Orbitopathy by [68Ga]DOTATATE PET/CT.

The accurate assessment of inflammatory activity of the extraocular muscles (EOMs) in thyroid associated ophthalmopathy (TAO) is crucial for formulating subsequent treatment strategies and prognostic judgments. This study aims to explore the efficacy of using [68Ga]DOTATATE PET/CT to assess the inflammatory activity of EOMs in TAO patients. This study enrolled 22 TAO patients and 6 healthy volunteers, all of whom underwent orbital [68Ga]DOTATATE PET/CT. Among these, 18 patients underwent orbital [99mTc]DTPA SPECT/CT within one week, and the other 4 patients received orbital MRI. All imaging data were independently assessed, followed by comparative data analysis. The patients then received different treatment schemes, and their prognosis was followed up. [68Ga]DOTATATE PET/CT could effectively evaluate the inflammatory activity of the EOMs in TAO patients and demonstrate good consistency with [99mTc]DTPA SPECT/CT and orbital MRI, but show a better resolution to distinguish EOMs and surrounding structure. The receiver operating characteristic (ROC) curves for each EOM, treated as individual research units, exhibited an area under the curve (AUC) exceeding 0.9. The medial rectus demonstrated the highest involvement and diagnostic accuracy(AUC = 0.976, P < 0.001). Patients treated with glucocorticoids showed significantly higher SUVmax in EOMs compared to those receiving symptomatic treatment (P < 0.01). [68Ga]DOTATATE PET/CT is a reliable method for assessing the inflammatory activity of EOMs in TAO patients, providing strong objective evidence for the precise diagnosis and treatment.

Biomarkers for the Molecular Diagnosis of IgE-Mediated Hymenoptera Venom Allergy in Clinical Practice.

Hymenoptera venom allergy (HVA) is a potentially life-threatening condition, making accurate diagnosis crucial for identifying significant IgE sensitizations and enabling effective venom immunotherapy. In this review, we provide a detailed overview of biomarkers for the molecular diagnosis of IgE-mediated hypersensitivity to Hymenoptera insect venoms in clinical practice, and we present, in a structured manner, their importance in differentiating genuine sensitizations versus cross-sensitizations using different diagnostic procedures. Updated algorithms are provided, along with the advantages and limitations of molecular diagnosis approaches. Geographical variations and rare species may pose further challenges in diagnosing and treating HVA, adding complexity to HVA management. This review informs readers about performing tailored diagnostics based on molecular allergen biomarkers and subsequent treatment strategies.

Development and validation of a radiomics-based nomogram for predicting pathological grade of upper urinary tract urothelial carcinoma

BackgroundUpper urinary tract urothelial carcinoma (UTUC) is a rare and highly aggressive malignancy characterized by poor prognosis, making the accurate identification of high-grade (HG) UTUC essential for subsequent treatment strategies. This study aims to develop and validate a nomogram model using computed tomography urography (CTU) images to predict HG UTUC.MethodsA retrospective cohort study was conducted to include patients with UTUC who underwent radical nephroureterectomy and received a CTU examination prior to surgery. In the CTU images, tumor lesions located in the renal calyces, renal pelvis and ureter were segmented, and radiomics features from the unenhanced, medullary, and excretory phases were extracted. The maximum relevance minimum redundancy algorithm, least absolute shrinkage and selection operator, and various machine learning (ML) algorithms—including random forest, support vector machine, and eXtreme gradient boosting—were employed to select radiomics features and calculate radiomics scores. Logistic regression (LR) analysis was performed to identify the independent influencing factors of clinical baseline characteristics. Multiple datasets of radiomics features were constructed by integrating single-phase radiomics features with the most significant independent factor. Both LR and ML algorithms were utilized to develop predictive models. The area under the receiver operating characteristic curve (AUC values), accuracy, sensitivity, and specificity were assessed for model performance evaluation. Decision curve analysis was conducted to evaluate the clinical net benefits.ResultsA total of 167 patients were enrolled in this study. Among them, 56 were diagnosed with low-grade UTUC (including papillary urothelial neoplasms with low malignant potential and low-grade urothelial carcinoma) as confirmed by postoperative pathological examination results, and 111 were of HG. These patients were randomly allocated to the training set and the validation set at a ratio of 7:3. The training set comprised 116 patients with a mean age of 63.5 ± 9.38 years and 38 males. The validation set comprised 51 patients with a mean age of 65.6 ± 11.1 years and 18 males. Hydronephrosis was identified as the most significant independent factor in the clinical baseline features. Models that include mixed-phase development achieve better performance compared to models that rely simply on single-phase development. The nomogram model had excellent predictive ability for HG UTUC, with AUC values of 0.844 and an accuracy of 0.793 in the validation sets. The nomogram model can enhance accuracy by 14.1% (79.3% vs. 65.2%) and sensitivity by 32.8% (93.2% vs. 60.4%) compared to urinary cytology.ConclusionsThis study developed a nomogram model, which significantly improved the diagnostic ability for HG UTUC compared to urinary cytology. Furthermore, the results of the decision curve analysis showed that the model had a net benefit and could provide a non-invasive and potentially diagnostic reference tool for HG UTUC.

Fast intraoperative detection of primary CNS lymphoma and differentiation from common CNS tumors using stimulated Raman histology and deep learning.

Accurate intraoperative diagnosis is crucial for differentiating between primary CNS lymphoma (PCNSL) and other CNS entities, guiding surgical decision-making, but represents significant challenges due to overlapping histomorphological features, time constraints, and differing treatment strategies. We combined stimulated Raman histology (SRH) with deep learning to address this challenge. We imaged unprocessed, label-free tissue samples intraoperatively using a portable Raman scattering microscope, generating virtual H&E-like images within less than three minutes. We developed a deep learning pipeline called RapidLymphoma based on a self-supervised learning strategy to (1) detect PCNSL, (2) differentiate from other CNS entities, and (3) test the diagnostic performance in a prospective international multicenter cohort and two additional independent test cohorts. We trained on 54,000 SRH patch images sourced from surgical resections and stereotactic-guided biopsies, including various CNS neoplastic/non-neoplastic lesions. Training and test data were collected from four tertiary international medical centers. The final histopathological diagnosis served as ground-truth. In the prospective test cohort of PCNSL and non-PCNSL entities (n=160), RapidLymphoma achieved an overall balanced accuracy of 97.81% ±0.91, non-inferior to frozen section analysis in detecting PCNSL (100% vs. 77.77%). The additional test cohorts (n=420, n=59) reached balanced accuracy rates of 95.44% ±0.74 and 95.57% ±2.47 in differentiating IDH-wildtype diffuse gliomas and various brain metastasis from PCNSL. Visual heatmaps revealed RapidLymphoma's capabilities to detect class-specific histomorphological key features. RapidLymphoma proves reliable and valid for intraoperative PCNSL detection and differentiation from other CNS entities. It provides visual feedback within three minutes, enabling fast clinical decision-making and subsequent treatment strategy planning.

Survival outcomes, multidimensional prediction and subsequent therapy in patients with hormone receptor-positive advanced breast cancer receiving palbociclib: a real-world analysis.

To date, the overall survival (OS) of hormone receptor-positive advanced breast cancer (ABC) treated with palbociclib has not been reported in Chinese patients. It still remains unclear what kind of patients may benefit in OS from palbociclib treatment and what the optimal sequential antineoplastic regimen is for those progressing on palbociclib. Therefore, we aimed to investigate the OS outcome of ABC patients receiving palbociclib, establish a predictive model to identify the potential candidates who may benefit from palbociclib and explore the ideal subsequent treatment strategy after palbociclib. This is a single-center ambispective real-world analysis of palbociclib in hormone receptor-positive ABC from April 2018 to August 2021. The patients were followed up via telephone or clinic visit. Progression-free survival (PFS), OS, overall response rate and time to second disease progression (PFS2) were evaluated as prognosis outcomes. Cyclin-dependent kinases 4/6 inhibitor (CDKI) score was established to predict OS benefit on the basis of tumor burden, line of palbociclib treatment and tumor marker. Fifty patients were included with the median PFS of 9.57 months and the median OS of 33.60 months. Age <65 years [hazard ratio (HR) 0.33, P=0.008], lung or liver involvement (HR 3.01, P=0.005) and > first line palbociclib therapy (HR 2.13, P=0.03) were independent unfavorable prognosticators for PFS. Positive estrogen receptor (ER) (HR 0.22, P=0.004), metastatic sites <3 (HR 3.59, P=0.02), absence of lung or liver involvement (HR 3.77, P=0.058) and PFS ≥12 months during palbociclib regimen (HR 0.14, P<0.001) could predict longer OS. CDKI score discriminated OS significantly (HR 4.41, P=0.009) and the CDKI score-based models were multidimensionally verified with satisfying performance, among which the area under the curve of receiver operating characteristic reached 0.835 and the C-index was 0.72. Moreover, chemo-free regimens saw improvement in time to second disease progression (HR 0.32, P=0.006) and OS (HR 0.32, P=0.049) for patients progressing on palbociclib compared with chemotherapy-based regimens. CDKI score is a practical and comprehensive tool in predicting OS benefit for ABC patients treated with palbociclib, which deserves further validation. Patients who progressed on palbociclib seem to keep benefiting from chemo-free antineoplastic treatments. These findings may help identify the candidates for CDK4/6 inhibitor and optimize the strategies for hormone receptor-positive ABC.

Application of Drug-Eluting Stent With Drug-Coated Balloon Strategy for the Endovascular Treatment of Long-Segment Femoropopliteal Artery Disease.

Endovascular therapy (EVT) has emerged as a primary approach for managing femoropopliteal artery (FPA) lesions, leveraging drug-eluting stents (DESs), and drug-coated balloons (DCBs), to enhance clinical outcomes. Although a full DES coverage strategy is effective in treating complex lesions, concerns over long-term complications prompt the exploration of alternative strategies. The aim of this study was to investigate clinical result of combination therapy of DES with DCB and compare them with full DES implantation. This retrospective, single-center study analyzed 131 patients with occlusive FPA lesions treated at our institution between 2019 and 2022. Patients with Rutherford classification stages 2 to 5 who underwent successful EVT were included. The study compared the outcomes of the drug-within-drug (DWD) strategy, ie, combining DES for failed vessel preparation segments and DCB for successful ones, with those of full DES implantation. The primary outcomes were the primary patency rates, and the secondary outcomes included clinically-driven target lesion revascularization (CD-TLR) rates, restenosis patterns, and survival outcomes. Of the 131 patients initially considered, 118 met the inclusion criteria, with 45 in the DWD group and 73 in the full metal jacket (FMJ) stent group. The DWD group demonstrated equivalent 1-year primary patency rates (85.3%) to the FMJ group (87.9%, p=0.239). Similarly, no significant differences in CD-TLR rates were found between the 2 groups. The restenosis patterns and subsequent treatment strategies were not significantly different. The DWD strategy offers a viable alternative to full DES coverage in treating long-segment FPA lesions, with comparable restenosis and target lesion revascularization (TLR) rates. This approach may mitigate risks associated with full-length stenting, such as thrombosis, and challenges in repeat revascularizations by tailoring treatment to lesion characteristics. The DWD strategy represents a promising approach for complex FPA lesions, providing a balanced solution that potentially reduces long-term complications while maintaining effective patency and revascularization rates. The efficacy of drug-eluting stents (DES) in treating femoropopliteal artery (FPA) lesions has been well demonstrated. However, concerns remain regarding complications such as thrombotic occlusion and aneurysmal degeneration, especially when full stemt coverage of whole lesions is performed. The "Drug-with-Drug" (DWD) strategy, which involves implanting DES only at sites with severe dissection or residual stenosis after pre-balloon dilation and using drug coated balloons (DCB) for segments successfully prepared without stenting, has shown comparable outcomes to full stent coverage. Unlike traditional bailout stenting or spot stenting, the DWD approach maximizes the benefits of drug technology and presents a valuable option for treating long-segment FPA lesions.

Different stimulation targets of rTMS modulate specific triple-network and hippocampal-cortex functional connectivity

BackgroundRepetitive transcranial magnetic stimulation (rTMS) is widely applied to treat Alzheimer's disease (AD). Various treatment targets are currently being explored in clinical research. However, target diversity can result in considerable heterogeneity. ObjectiveThis study aimed to investigate whether different rTMS targets can enhance cognitive domains by modulating functional connectivity (FC) of the hippocampus (HIP) and triple network, which comprises the salience network (SN), central executive network (CEN), and default mode network (DMN). MethodsWe enrolled 63 patients with AD, of whom 48 and 15 underwent rTMS targeting the left dorsolateral prefrontal cortex (dlPFC) and the bilateral angular gyrus (ANG), respectively. We examined the network-level FC differences within the triple-network before and after treatment. Additionally, we utilized HIP as a seed for voxel-level analysis. We compared the similarities and differences in the effects of dlPFC and ANG rTMS. ResultsrTMS targeting the dlPFC primarily influenced the FC of the CEN, whereas rTMS targeting the ANG primarily influenced the SN and DMN. Moreover, the right temporal lobe within the DMN exhibited reduced FC with the left HIP following both therapies. The results of least absolute shrinkage and selection operator (LASSO) analysis indicated that hippocampal-cortex FC played a dominant role in the therapeutic effect. The observed FC changes significantly correlated with improvements in multiple cognitive scales. ConclusionrTMS targeting different regions affected the FC of specific networks. Both stimulation targets modulate the FC of hippocampal-cortex to influence therapeutic outcomes. Classification of patients based on damaged networks can further inform subsequent treatment strategies.

Different treatments in chronic thromboembolic pulmonary hypertension: comparison of strategies in the Italian centre real-world experience

Abstract Rationale Pulmonary endarterectomy (PEA) has been the most effective therapy for chronic thromboembolic pulmonary hypertension (CTEPH). However, there is a substantial proportion of patients declared not operable in whom other treatment strategies are available: medical therapy and balloon pulmonary angioplasty (BPA). We aimed to compare different CTEPH treatment strategies effect in real-world setting. Methods All CTEPH referred to our Centre were included. We compare the short-term clinical, functional, exercise and haemodynamic effect of medical therapy (irrespective of subsequent treatment strategies), PEA and BPA (irrespective of previous/subsequent treatment strategies); we also describe the long-term outcome of the different patient groups. Results We included 467 patients (39% were treated only with medical therapy, 43% underwent PEA, 13% underwent BPA and 5% were not treated with any therapy). Patients treated only with medical therapy were the oldest; compared to patients undergoing PEA, they had a lower exercise capacity, a higher risk profile and gained a lower haemodynamic, functional and survival benefit from the treatment. Patients undergoing BPA had a lower haemodynamic improvement but a comparable functional, exercise and risk improvement and a similar survival compared to patients undergoing PEA; their survival is anyway better than patients undergoing only medical treatment. Untreated historical control patients had the worst survival. Conclusions We confirm the superiority of PEA compared to any alternative treatment in CTEPH and we observe that BPA, in patients declared not operable or with persistent/recurrent PH after PEA, leads to a better outcome than medical therapy alone.

ULTRASOUND IMAGING OF COMLICATIONS IN COMBAT CHEST TRAUMA

Abstract. Objective. The aim is to evaluate the effectiveness of ultrasound diagnostics in combat chest trauma at the stage of specialized surgical care. Materials and Methods: 53 cases of complications from combat chest trauma were analyzed during patient evacuation at the stage of specialized surgical care to assess the specificity, accuracy, and sensitivity of the ultrasound method for early detection of complications and to guide further treatment tactics. Results. The ultrasound diagnostic method has advantages in detecting complications of gunshot wounds to the chest, not only during the qualified medical care stages but also where continuous monitoring of these complications is required during further medical evacuation and treatment strategy selection. Conclusions.Therefore, the monitoring of chest trauma complications should be informative at all stages of medical care, accessible, and effective in determining the subsequent treatment strategy.

Prediction and validation of pathologic complete response for locally advanced rectal cancer under neoadjuvant chemoradiotherapy based on a novel predictor using interpretable machine learning

BackgroundPrecise evaluation of pathological complete response (pCR) is essential for determining the prognosis of patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy (NCRT) and can offer clues for the selection of subsequent treatment strategies. Most current predictive models for pCR focus primarily on pre-treatment factors, neglecting the dynamic systemic changes that occur during neoadjuvant chemoradiotherapy, and are constrained by low accuracy and lack of integrity. PurposeThis study devised a novel predictor of pCR using dynamic alterations in systemic inflammation-nutritional marker indexes (SINI) during neoadjuvant therapy and developed a machine-learning model to predict pCR. MethodsTwo cohorts of patients with LARC from center one from 2012 to 2017 and from center two from 2020 to 2023 were integrated for analysis. This study compared dynamic changes in blood indexes before and after neoadjuvant therapy and surgical operation. A least absolute shrinkage and selection operator (LASSO) regression analysis was conducted to mitigate collinearity and identify key indexes, constructing the SINI. Univariate and multiple logistic regression analyses were used to identify the independent risk factors associated with pCR. Additionally, 10 machine learning algorithms were employed to develop predictive models to assess risk. The hyperparameters of the machine learning models were optimized using a random search and 10-fold cross-validation. The models were assessed by examining various metrics, including the area under the receiver operating characteristic curves (AUC), the area under the precision-recall curve (AUPRC), decision curve analysis, calibration curves, and the precision and accuracy of the internal and external validation cohorts. Additionally, Shapley's additive explanations (SHAP) were employed to interpret the machine learning models. ResultsThe study cohort comprised 677 patients from the center one and 224 patients from the center two. Six key indexes were identified, and a predictive index, SINI, was constructed. Univariate and multiple logistic regression analyses revealed that SINI, clinical T-stage, clinical N-stage, tumor size, and the distance from the anal verge were independent risk factors for pCR in patients with LARC following NCRT. The mean AUC value of the extreme gradient boosting (XGB) model in the 10-fold cross-validation of the training set was 0.877. The XGB model demonstrated superior performance in the internal and external validation sets. Specifically, in the internal test set, the XGB model achieved an AUC of 0.86, AUPRC of 0.707, accuracy of 0.82, and precision of 0.80. In the external validation set, the XGB model exhibited an AUC of 0.83, AUPRC of 0.702, accuracy of 0.81, and precision of 0.81. Additionally, the predictions generated by the XGB model were analyzed using SHAP. ConclusionThis study involved developing and validating an XGB model using SINI to predict pCR in patients with LARC. Besides, a SINI-based machine learning model shows promise in accurately predicting pCR following NCRT in patients with resectable LARC, offering valuable insights for personalized treatment approaches.

A real world analysis of secondary BRAF variations after targeted therapy resistance in driver gene positive NSCLC

Secondary BRAF variations have been identified as a mechanism of resistance to tyrosine kinase inhibitors (TKIs) in patients with driver gene-positive NSCLC. Nevertheless, there is still a lack of consensus regarding the characteristics and subsequent treatment strategies for these patients. We retrospectively reviewed the medical records of patients with driver gene-positive NSCLC who received TKIs therapy at Zhejiang Cancer Hospital between May 2016 and December 2023. The clinical and genetic characteristics of these patients were assessed, along with the impact of various treatment strategies on survival. This study enrolled 27 patients with advanced NSCLC, in whom BRAF variations occurred at a median time of 28 months after the initiation of targeted therapy. The multivariate accelerated failure time (AFT) model revealed that, compared to chemotherapy-based regimens group, the combined targeted therapy group (p < 0.001) and the combined local treatment group for oligo-progression (p < 0.001) significantly extended patient survival. In contrast, continuing the original signaling pathway's targeted monotherapy was associated with shorter survival (p = 0.034). The median global OS for each treatment group was as follows: chemotherapy-based regimens group, 45 months; combined targeted therapy group, 59 months; combined local treatment group for patients with oligo-progression, 46 months; and targeted monotherapy group, 36 months. Study results indicate that the combination targeted therapy group (including TKIs, BRAF inhibitors, and/or MEK inhibitors) and the localized treatment group are more effective than traditional chemotherapy-based regimens in improving survival. Additionally, continuing targeted monotherapy along the original signaling pathway proves less effective than chemotherapy-based regimens.

Real-World Outcomes of Subsequent Chemotherapy after Progression Following Chemoradiation and Consolidative Durvalumab Therapy in Locally Advanced Non-small Cell Lung Cancer: An Exploratory Analysis from the CRIMSON Study (HOPE-005)

BackgroundThe optimal subsequent treatment strategy for locally advanced non-small cell lung cancer (LA-NSCLC) after chemoradiotherapy (CRT) and consolidative durvalumab therapy remains unknown. We aimed to determine the optimal subsequent treatment strategy for this clinical population. Materials and MethodsWe retrospectively enrolled 523 consecutive patients with LA-NSCLC treated with CRT and analyzed the treatment outcomes of subsequent therapy after progression following CRT and consolidative durvalumab therapy. Patients who received tyrosine kinase inhibitors as subsequent therapy were excluded. ResultsOut of 122 patients who received subsequent chemotherapy, 55% underwent platinum-based, 25% non-platinum-based, and 20% immune checkpoint inhibitor (ICI)-containing therapies. In the platinum-based group, patients with a durvalumab-progression-free survival (Dur-PFS) ≥ 1 year had a significantly longer median subsequent therapy-PFS (SubTx-PFS) than those with Dur-PFS < 1 year (13.2 months vs. 4.7 months; hazard ratio, 0.45; 95% confidence interval, 0.21–0.97; P = .04). Furthermore, among patients receiving non-platinum-based chemotherapy, the median SubTx-PFS was longer in the combined with angiogenesis inhibitor group than in the without group, although the difference was not statistically significant. No significant difference of SubTx-PFS was observed between the reason for durvalumab discontinuation and the outcomes of ICI-containing therapy. ConclusionIn clinical practice, platinum-based chemotherapy rechallenge is frequently employed following progression subsequent to CRT and consolidative durvalumab therapy for LA-NSCLC. Optimal treatment strategies may consider Dur-PFS and angiogenesis inhibitor feasibility. Further research is warranted to identify clinical biomarkers that can help identify patients who would benefit from ICI rechallenge.

Applications of Nanopore sequencing in precision cancer medicine.

Oxford Nanopore Technologies sequencing, also referred to as Nanopore sequencing, stands at the forefront of a revolution in clinical genetics, offering the potential for rapid, long read, and real-time DNA and RNA sequencing. This technology is currently making sequencing more accessible and affordable. In this comprehensive review, we explore its potential regarding precision cancer diagnostics and treatment. We encompass a critical analysis of clinical cases where Nanopore sequencing was successfully applied to identify point mutations, splice variants, gene fusions, epigenetic modifications, non-coding RNAs, and other pivotal biomarkers that defined subsequent treatment strategies. Additionally, we address the challenges of clinical applications of Nanopore sequencing and discuss the current efforts to overcome them.

Elemental Diet as a Therapeutic Modality: A Comprehensive Review

Elemental diets have been employed for the management of various diseases for over 50 years, with several mechanisms mediating their beneficial effects. Yet, they are underutilized due to poor palatability, access, cost, and lack of awareness regarding their clinical efficacy. Therefore, in this review, we aimed to systematically search and review the literature to summarize the formulation variability, mechanisms of action, clinical applications, and tolerability of the elemental diets in gastrointestinal diseases. While large prospective trials are lacking, elemental diets appear to exhibit objective and subjective clinical benefit in several diseases, including eosinophilic esophagitis, eosinophilic gastroenteritis, inflammatory bowel diseases, small intestinal bacterial overgrowth, intestinal methanogen overgrowth, chemoradiotherapy-associated mucositis, and celiac disease. Although some data support the long-term use of elemental diets as an add-on supplement for chronic pancreatitis and Crohn’s disease, most of the literature on exclusive elemental diets focuses on inducing remission. Therefore, subsequent treatment strategies for maintaining remission need to be adopted in chronic/relapsing diseases. Several mechanistic pathways were identified to mediate the effects of elemental diets, including food additive and allergen-free content, high passive absorption rate, and anti-inflammatory properties. High rates of intolerance up to 40% are seen in the trials where exclusive elemental diets were administered orally due to poor organoleptic acceptability; however, when tolerated, adverse events were rare. Other limitations of elemental diets are cost, access, and lifestyle/social restrictions. Moreover, judicious use is advised in presence of a concomitant restrictive food intake disorders. Elemental diets offer a potentially highly efficacious dietary intervention with minor side effects. Palatability, cost, access, and social restrictions are common barriers of use. Prospective clinical trials are needed to elucidate the role of elemental formulas in the management of individual diseases.

What are the benefits of therapeutic drug monitoring in the optimization of adalimumab therapy? a systematic review and meta-analysis up to 2022.

Persistent uncertainties exist surrounding the therapeutic drug monitoring (TDM) of adalimumab in clinical settings. To address these issues, we conducted a systematic review to assess the current evidence regarding the benefits of TDM for adalimumab. PubMed, EMBASE, and Cochrane Databases were searched from inception to October 2022. The trials regarding to the list three key questions were considered: 1) Could routine proactive TDM assist in improving outcomes in patients receiving adalimumab? 2) Could reactive TDM assist in guiding subsequent treatment strategies for patients with treatment failure to adalimumab? 3) Could TDM assist in informing dose reduction or discontinuation in patients with low disease activity or in remission treated with adalimumab? Two reviewers independently selected the studies and extracted the data. Meta-analysis was performed to calculate the relative risk (RR) and 95% confidence interval (CI). A total of 9 studies was included in this review. For proactive TDM, meta-analysis indicated that proactive TDM (n = 163/257, 63.42%) showed no significant superiority over reactive TDM and/or conventional management (n = 336/606, 55.44%) in achieving and/or maintaining clinical remission by random effects model (RR: 1.24, 95% CI 0.98-1.58, I 2 = 73%). There were three studies that supporting the reactive TDM, low drug levels in the absence of anti-drug antibodies (ADA) strongly indicate the need for dose intensification, and infliximab is a feasible choice for patients with low drug levels and ADA positivity. While swapping to another class should be considered in patients with adequate drug levels. In addition, TDM can help clinicians optimize dosing schedules and prevent overtreatment in patients who have achieved low disease activity and sufficient drug concentrations, with no predictive value for successful adalimumab discontinuation. Current evidence suggests that proactive TDM is numerically but not statistically significant superiority over reactive TDM and/or conventional management. Reactive TDM can aid in understanding treatment failure and developing subsequent therapy. For patients reaching low disease activity and remission, TDM can help successful dose reduction, while it cannot inform the successful drug discontinuation. However, existing trials are limited, and more well-designed trials are necessary to clarify the role of TDM in adalimumab treatment.

Mechanisms of resistance to trastuzumab in HER2-positive gastric cancer.

Gastric cancer is one of the most prevalent cancers worldwide, and human epidermal growth factor receptor 2 (HER2)-positive cases account for approximately 20% of the total cases. Currently, trastuzumab + chemotherapy is the recommended first-line treatment for patients with HER2-positive advanced gastric cancer, and the combination has exhibited definite efficacy in HER2-targeted therapy. However, the emergence of drug resistance during treatment considerably reduces its effectiveness; thus, it is imperative to investigate the potential mechanisms underlying resistance. In the present review article, we comprehensively introduce multiple mechanisms underlying resistance to trastuzumab in HER2-positive gastric cancer cases, aiming to provide insights for rectifying issues associated with resistance to trastuzumab and devising subsequent treatment strategies.

Tailoring advanced breast cancer treatment after cyclin-dependent kinase 4/6 inhibitors progression - real-world data analysis.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represent the gold standard of the hormone receptor positive human epidermal growth factor receptor 2 (HER-2) negative advanced breast cancer. However, optimal treatment after disease progression is a matter of debate. We aimed to assess predictive and prognostic factors associated with the treatment outcome following CDK4/6i progression. We retrospectively analyzed patients who progressed on CDK4/6i treatment between 2018 and 2024. Treatment based on molecular findings (PIK3CA mutation), genetic findings (BRCA1/2 germline mutation), or adapted to the change in the tumor phenotype in rebiopsy (anti-HER2 therapy in the transformation to HER-2-positive disease) was grouped into tailored treatment and compared to the endocrine-based therapy and chemotherapy alone. Five hundred twelve patients were treated with CDK4/6i. Two hundred patients with disease progression were enrolled in the study. Duration of response to CDK4/6i was not predictive of the response to subsequent treatment, whereas the progression in the central nervous system was the worst prognostic factor. Thirty patients were ineligible for subsequent treatment. Survival after CDK4/6i progression was significantly longer in patients eligible for tailored treatment. The median PFS in patients with tailored treatment (n=19) was 13.5 months vs. 4.9 months in patients with non-tailored therapy (n=151; p=0.045). 12-month PFS was 54.1% with tailored treatment [95% CI 24.1-76.7%] compared to 18.5% with non-tailored therapy [95% CI 11.6-26.6%]. The median OS for patients treated with a tailored approach was not reached compared to 11.5 months with non-tailored treatment (p=0.016). The 24-month OS for patients treated with a tailored approach was 80.2% [95% CI 40.3-94.8%] compared to 21.1% [95% CI 12.2-31.7%] for patients with non-tailored treatment. Tailoring of subsequent treatment strategy seems to be essential for achieving long-term benefit. Further studies are required, as the prognosis after CDK4/6i progression remains dismal, especially in cases affecting the central nervous system.

The treatment outcomes of patients who failed to be randomly assigned after atezo/bev induction therapy in the Chinese TALENTop study.

e16183 Background: Hepatocellular carcinoma (HCC) patients with macrovascular invasion (MVI) are considered to be at an advanced stage of disease with limited treatment options. The combination therapy of atezolizumab (atezo) plus bevacizumab (bev) has become a global standard of care for those patients and made conversion resection possible. The Chinese TALENTop study (NCT04649489) is aiming to clarify whether hepatic resection may provide additional benefit in HCC patients with MVI responding to atezo/bev. For patients without opportunity to receive hepatic resection, subsequent treatment outcomes will be reported. Methods: Potentially resectable HCC patients with MVI and without extrahepatic metastasis are eligible for this study. Eligible patients receive 3 cycles of atezo/bev and 1 cycle of atezo as primary systemic therapy (induction phase). Patients assessed as partial response (PR) or stable disease (SD) per RECIST v1.1 and considered suitable for R0 hepatic resection are randomized in a 1:1 ratio to either Arm A, hepatic resection followed by atezo/bev for 1 year, or Arm B, continuing atezo/bev therapy. The primary endpoint is the time to treatment failure. Patients failed to be randomized will enter the survival follow-up phase. After 296 patients entered induction phase, the patient profile, subsequent treatments per local standard of care and survival of patients who failed to be randomized were analyzed. Results: From Apr 2021 to Jun 2023, 296 patients were enrolled and entered induction phase and 175 patients failed to be randomized and were followed up until Sept 2023. The main reasons for failure to be randomized were disease progression (64.6%), investigator assessment of unsuitability for R0 hepatic resection (14.3%), and others. The 175 patients were characterized with a median age of 52 (26-76), and 166 (95%) had HBV infection. Among them, 165 (94%) had combined PVTT, 24 (14%) had combined HVTT and 5 (3%) had combined IVCTT. At a median follow-up time of 10.9 months (9.7-13.1), the median overall survival (mOS) is 13.8 months (8.9-15.8), 6- and 12-month survival rate were 71% and 53%, respectively. As the result of best response during induction phase, 3 patients (1.7%) achieved PR, 92 patients (52.6%) achieved SD and 65 patients (37.1%) were PD. 123 patients (70%) received subsequent therapy. The mOS of patients received different subsequent therapies was showed below. Conclusions: This study provides data on HCC patients with MVI after receiving atezo/bev. The result shows favorable survival even in patients failed to randomization to receive conversion resection, and subsequent treatment strategy may differ survival outcomes. Clinical trial information: NCT04649489 . [Table: see text]

Severe Hyperhidrosis Secondary to Bupropion Use and Treatment. A case report.

IntroductionHyperhidrosis, the excessive and uncontrollable sweating, is a well-documented side effect of various medications. Among these, bupropion, a commonly prescribed antidepressant and smoking cessation aid, has been associated with the development of severe hyperhidrosis in a subset of patients. This clinical report aims to shed light on a compelling case of severe hyperhidrosis induced by bupropion use and the subsequent treatment strategies employedThe patient under discussion is a 42-year-old female with a history of recurrent major depressive disorder and a previous favorable response to selective serotonin reuptake inhibitors (SSRIs). Due to side effect concerns and a desire to quit smoking, she was transitioned to bupropion, a norepinephrine-dopamine reuptake inhibitor (NDRI), at a standard therapeutic dose of 150 mg daily.Approximately four weeks after initiating bupropion therapy, the patient began experiencing debilitating symptoms of excessive sweating, particularly affecting her palms, soles, and axillae. The profuse sweating episodes occurred throughout the day and night, significantly impairing her quality of life, social interactions, and occupational functioning. No previous history of hyperhidrosis was reported, and physical examinations revealed no underlying medical conditions or dermatological issues.ObjectivesTo aknowledge the importance of recognizing and addressing medication-induced side effects within the realm of psychiatry and an early implementation of patient-centered treatment.MethodsClinical case report and a brief literature review.ResultsThe treatment of hyperhidrosis secondary to bupropion use presents a challenging clinical scenario that requires a delicate balance between managing the distressing side effect and ensuring the continued efficacy of psychiatric therapy. Given the rarity of severe hyperhidrosis as a side effect of bupropion, there is a limited body of evidence guiding treatment strategies. Gradual withdrawal in the dose of bupropion was initiated, with careful monitoring of depressive symptoms to prevent relapse, switching to Duloxetine 90mg daily, with adecuate efectiveness.In this particular case, the combination of medication adjustment and psychological support led to a significant reduction in hyperhidrosis symptoms. The patient reported improved social interactions, enhanced self-esteem, and restored occupational functioning. Importantly, her depressive symptoms remained well-managed, underscoring the success of the treatment strategy.ConclusionsThis clinical report highlights the importance of a patient-centered approach when addressing rare medication-induced side effects within the field of psychiatry. Bupropion withdrawal and regular follow-up showed effective in the treatment of the simptoms. Future research may provide additional insights and treatment options for cases like this, further enhancing patient care and outcomes.Disclosure of InterestNone Declared