Therapeutic Decisions Research Articles

Comparison between diffuse and partial involvement of thoracic lymph nodes on the outcome of sarcoidosis patients.

Sarcoidosis is a systemic disease of unknown etiology with diverse clinical manifestations. Disease may resolve spontaneously or require immunosuppression to control progression. Currently, there is no predictive model to direct treatment, and management is guided by symptoms and functional impairment. This study examines the association between biopsy features and prognosis. This is a retrospective population-based cohort study. New cases of biopsy-proven sarcoidosis were divided into two groups: those with diffuse thoracic lymph nodes (TLN) involvement, versus partial TLN involvement (Defined as Non-necrotizing granuloma (NNG) found in some but not all sampled TLN). We compared outcomes one year after diagnosis. We assessed the need for immunosuppression, the number of hospitalizations, and lung function deterioration. 77 cases were included in the final analysis. 48.1% demonstrated extensive TLN involvement, and 51.9% demonstrated partial or non-involvement of sampled TLN. The partial positive group had a more aggressive disease, reflected by a significantly higher need for steroid therapy in the first year after diagnosis (45.0% vs. 18.9% p=0.015). The number of hospitalizations and lung functions were not significantly different between groups. Our findings demonstrate a significantly increased need for steroidal therapy among sarcoidosis patients with a partial positivity of TLN. These findings suggest that the degree of TLN involvement can help predict worse outcome and guide therapeutic decisions.

Gaps and Controversies in Catatonia as a Movement Disorder.

The term "catatonia" was introduced by German psychiatrist Karl Kahlbaum in 1874. Although historically tied to schizophrenia, catatonia exhibits a diverse range of phenotypes and has been observed in various medical and neuropsychiatric conditions. Its intrinsic movement characteristics and association with hypokinetic and hyperkinetic phenomenologies place catatonia within the purview of movement disorders. Despite the presence of catatonia in psychiatry literature for over 150 years, many gaps and controversies persist regarding its etiopathogenesis, phenomenology, diagnostic criteria, and treatment. The current versions of the International Classification of Diseases (ICD-11) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) require clinicians to identify any three signs of 15 (ICD-11) or 12 (DSM-5) for the diagnosis of catatonia. Catalepsy and waxy flexibility are the only motor features with high specificity for the diagnosis. We highlight the gaps and controversies in catatonia as a movement disorder, emphasize the lack of a clear definition, and discuss the inconsistencies in the description of various catatonic signs. We propose the exploration of a bi-axial classification framework similar to that used for dystonia and tremor to encourage the evaluation of underlying etiologies and to guide therapeutic decisions to improve the outcome of these patients. © 2024 International Parkinson and Movement Disorder Society.

Lipopolysaccharide-binding protein in Crohn's disease patients: a promising noninvasive biomarker monitoring disease activity.

Following STRIDE-II recommendations, the discovery of novel noninvasive biomarkers, beyond the use of C-reactive protein (CRP) and fecal calprotectin, remains a medical need to further improve the monitoring of patients with inflammatory bowel disease (IBD). This study aims to evaluate the potential of serum lipopolysaccharide-binding protein (LBP) in monitoring IBD activity. This retrospective cross-sectional study included 69 IBD patients (43 Crohn's disease and 26 ulcerative colitis) and 82 controls. Serum LBP levels were measured by ELISA. Clinical, biological and endoscopic parameters were analyzed for IBD patients with no reports of missing data. Statistical tests, including nonparametric tests and receiver operating characteristic (ROC) curve analysis, were used to evaluate the diagnostic accuracy of LBP. IBD patients displayed a significantly higher LBP median [29.6 μg/ml (19.8-38.8) in Crohn's disease and 22.8 (13.7-38.8) in ulcerative colitis] than controls [5.8 (4.7-7.3), P < 0.001] with little overlapping distributions. In Crohn's disease patients, LBP levels gradually increased with endoscopic activity scores demonstrating a 1.7-fold rise in active patients compared to remitter patients ( P = 0.02). LBP level exhibited a positive correlation with CRP ( ρ = 0.75, P < 0.001) as well as fecal calprotectin ( ρ = 0.42, P < 0.01), both of which further increased when excluding cases that did not match endoscopic activity. LBP might be a promising noninvasive biomarker for monitoring disease activity, especially in Crohn's disease patients. In clinical situations where current biomarkers lack sensitivity, LBP could be discriminative and help filling the gap for reliable therapeutic decisions.

Early improvement with cariprazine as a predictor of antidepressant, anxiolytic, and antimanic response in bipolar I mania and depression: A pooled post hoc analysis of randomized cariprazine trials

BackgroundEarly symptomatic improvement may predict treatment response in bipolar I disorder. Cariprazine has demonstrated early treatment effects in bipolar I depression and mania studies; therefore, we assessed whether early improvement with cariprazine predicts eventual treatment response. MethodsPost hoc analyses used pooled data from randomized, double-blind, placebo-controlled bipolar I depression (NCT02670538, NCT02670551) and mania (NCT00488618, NCT01058096, NCT01058668) trials. In depression studies (cariprazine 1.5 mg/d, 3 mg/d, or placebo), early improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Anxiety Rating Scale (HAM-A) total scores (≥25 % improvement at day 15) and subsequent depressive/anxiety symptom response status (≥50 % improvement at week 6) were assessed. In mania studies (cariprazine 3–12 mg/d or placebo), early improvement in Young Mania Rating Scale (YMRS) total scores (≥25 % improvement at day 7) and manic symptom response status (≥50 % improvement at week 3) were assessed. ResultsPatients with bipolar I depression and early MADRS improvement were approximately 4- to 6-times as likely to achieve MADRS or HAM-A response than those without early improvement; patients with early HAM-A improvement were approximately 3- to 4-times as likely to achieve MADRS or HAM-A response. A subset of patients without early improvement with cariprazine 1.5 mg/d (20 %–31 %) subsequently responded following up-titration. Patients with mania and early YMRS improvement were approximately 5 times more likely to have manic symptom response than those without early improvement. LimitationsPost hoc analysis; relatively short study durations; flexible-dosing (mania studies). ConclusionsEarly symptom improvement with cariprazine may inform therapeutic decisions for patients with bipolar I disorder.

Multiparametric MRI-based radiomic model for predicting lymph node metastasis after neoadjuvant chemoradiotherapy in locally advanced rectal cancer

ObjectivesTo construct and validate multiparametric MR-based radiomic models based on primary tumors for predicting lymph node metastasis (LNM) following neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC) patients.MethodsA total of 150 LARC patients from two independent centers were enrolled. The training cohort comprised 100 patients from center A. Fifty patients from center B were included in the external validation cohort. Radiomic features were extracted from the manually segmented volume of interests of the primary tumor before and after nCRT. Feature selection was performed using multivariate logistic regression analysis. The clinical risk factors were selected via the least absolute shrinkage and selection operator method. The radiologist’s assessment of LNM was performed. Eight models were constructed using random forest classifiers, including four single-sequence models, three combined-sequence models, and a clinical model. The models’ discriminative performance was assessed via receiver operating characteristic curve analysis quantified by the area under the curve (AUC).ResultsThe AUCs of the radiologist’s assessment, the clinical model, and the single-sequence models ranged from 0.556 to 0.756 in the external validation cohort. Among the single-sequence models, modelpost_DWI exhibited superior predictive power, with an AUC of 0.756 in the external validation set. In combined-sequence models, modelpre_T2_DWI_post had the best diagnostic performance in predicting LNM after nCRT, with a significantly higher AUC (0.831) than those of the clinical model, modelpre_T2_DWI, and the single-sequence models (all p < 0.05).ConclusionsA multiparametric model that incorporates MR radiomic features before and after nCRT is optimal for predicting LNM after nCRT in LARC.Critical relevance statementThis study enrolled 150 LARC patients from two independent centers and constructed multiparametric MR-based radiomic models based on primary tumors for predicting LNM following nCRT, which aims to guide therapeutic decisions and predict prognosis for LARC patients.Key PointsThe biological characteristics of primary tumors and metastatic LNs are similar in rectal cancer.Radiomics features and clinical data before and after nCRT provide complementary tumor information.Preoperative prediction of LN status after nCRT contributes to clinical decision-making.Graphical

Non-specific markers of inflammation in bare-nosed wombats (Vombatus ursinus) with sarcoptic mange.

Sarcoptic mange, caused by epidermal infection with Sarcoptes scabiei, negatively impacts the health, welfare, and local abundance of bare-nosed wombats (Vombatus ursinus) in Australia. Improved understanding of the host immune response to disease and its contribution to pathophysiology could be used to inform management actions for this species in and ex situ. To evaluate the immune response of bare-nosed wombats to sarcoptic mange, we validated three assays (haptoglobin, agarose gel electrophoresis, and micro-erythrocyte sedimentation rate) measuring non-specific markers of inflammation using serum samples from free-living wombats from Tasmania (n = 33). We then analysed correlations between the assay results for each non-specific marker of inflammation and wombat's sarcoptic mange scores, and performed histopathological examinations to investigate association of the acute phase response with systemic amyloidosis. We present evidence that haptoglobin and erythrocyte sedimentation rate increased, and albumin decreased, in association with sarcoptic mange scores. This research demonstrates links between the acute phase response and sarcoptic mange severity in bare-nosed wombats, highlighting the utility of non-specific markers of inflammation for aiding assessment of the systemic effects of mange. Showing the value of agarose gel electrophoresis, we also identified specific acute phase proteins warranting future evaluation and found evidence of an immunoglobulin response in mange-affected wombats, revealed by increasing γ-globulins in association with apparent disease severity. Meanwhile, owing to its relatively low resource requirements and rapidity, the erythrocyte sedimentation rate assay may be useful as a point-of-care test to support therapeutic decisions in the field. Our methods and findings are likely to be applicable to a range of other clinical and population health scenarios in captive and free-living wombats, and species impacted by sarcoptic mange globally.

The incidence of TP53 mutations in patients with chronic lymphocytic leukemia in Iran

Objectives Chronic lymphocytic leukemia (CLL) is linked to a highly variable disease course regarding responses to chemoimmunotherapy and clinical outcomes. Mutations in TP53 and/or deletions in chromosome 17p locus [del(17p)] may lead to loss of a TP53 allele. We investigated TP53 mutations in patients with CLL. Material and Methods Thirty patients with CLL, aged 40–84 years, were included. Immunophenotyping of B cells was done using flow cytometry by CD5, CD10, CD19, CD20, CD23, CD49d, CD38, FMC7, and CD200 markers. Bone marrow aspiration and peripheral blood smear examination were also performed. DNA was extracted and sequencing was done using the Sanger method. Structural aberrations were investigated using the FISH method. Results TP53 mutations had a frequency of eight cases (23.3%), three of which were missense mutations (37.5%), three were intronic mutations (37.5%), and two were silent mutations (25%). Peripheral B lymphocytes had a mean of 82% with 4.59% prolymphocytes. Conclusion Accurate testing for TP53 mutations [TP53 and del(17p) mutations] before every treatment line enables us to make proper therapeutic decisions to improve patient outcomes.

IGF-I assay methods and biologic variability: evaluation of acromegaly treatment response.

Serum insulin-like growth factor (IGF-I) is the primary biochemical measure of disease activity in patients with acromegaly, and the 2014 Endocrine Society guidelines recommended normal age-adjusted serum IGF-I as the biochemical target of treatment. However, quantification and interpretation of IGF-I levels are subject to limitations that may affect therapeutic decisions. Techniques for measuring IGF-I have evolved greatly over the past 40 years and continue to do so. Results can vary substantially for different assays, procedures, and laboratories. For any assay, the interpretation of IGF-I values requires robust reference ranges. Using currently available large normative databases, the upper limit of normal (ULN) for IGF-I in middle-aged and elderly individuals is lower than historical reference ranges. Thus, the goal of achieving IGF-I < 1× ULN is more demanding than in the past, and some patients with acromegaly who were classified as "normal" (IGF-I < 1× ULN) in previous studies would be reclassified as above the ULN based on newer normative data. In addition, substantial intra-individual, week-to-week variation in serum IGF-I levels (unrelated to assay performance) has been observed. With changes over time in the measurement of IGF-I and the advent of updated reference ranges derived from large normative databases, it is difficult to justify rigid adherence to the goal of maintaining IGF-I below the ULN for all patients with acromegaly. Instead, symptoms, comorbidities, and quality of life should be considered, along with growth hormone and IGF-I levels, when evaluating the need for further treatment.

A prognostic nomogram to predict the cancer-specific survival of patients with initially diagnosed metastatic gastric cancer: a validation study in a Chinese cohort.

Few studies have been designed to predict the survival of Chinese patients initially diagnosed with metastatic gastric cancer (mGC). Therefore, the objective of this study was to construct and validate a new nomogram model to predict cancer-specific survival (CSS) in Chinese patients. We collected 328 patients with mGC from Northern Jiangsu People's Hospital as the training cohort and 60 patients from Xinyuan County People's Hospital as the external validation cohort. Multivariate Cox regression was used to identify risk factors, and a nomogram was created to predict CSS. The predictive performance of the nomogram was evaluated using the consistency index (C-index), the calibration curve, and the decision curve analysis (DCA) in the training cohort and the validation cohort. Multivariate Cox regression identified differentiation grade (P < 0.001), T-stage (P < 0.05), N-stage (P < 0.001), surgery (P < 0.05), and chemotherapy (P < 0.001) as independent predictors of CSS. Nomogram of chemotherapy regimens and cycles was also designed by us for the prediction of mGC. Thus, these factors are integrated into the nomogram model: the C-index value was 0.72 (95% CI 0.70-0.85) for the nomogram model and 0.82 (95% CI 0.79-0.89) and 0.73 (95% CI 0.70-0.86) for the internal and external validation cohorts, respectively. Calibration curves and DCA also demonstrated adequate fit and ideal net benefit in prediction and clinical applications. We established a practical nomogram to predict CSS in Chinese patients initially diagnosed with mGC. Nomograms can be used to individualize survival predictions and guide clinicians in making therapeutic decisions.

A novel signature constructed by mitochondrial function and cell death-related gene for the prediction of prognosis in bladder cancer

Bladder urothelial carcinoma (BLCA) presents a persistent challenge in clinical management. Despite recent advancements demonstrating the BLCA efficacy of immune checkpoint inhibitors (ICI) in BLCA patients, there remains a critical need to identify and expand the subset of individuals who benefit from this treatment. Mitochondria, as pivotal regulators of various cell death pathways in eukaryotic cells, exert significant influence over tumor cell fate and survival. In this study, our objective was to investigate biomarkers centered around mitochondrial function and cell death mechanisms to facilitate prognostic prediction and guide therapeutic decision-making in BLCA. Utilizing ssGSEA and LASSO regression, we developed a prognostic signature termed mitochondrial function and cell death (mtPCD). Subsequently, we evaluated the associations between mtPCD score and diverse clinical outcomes, including prognosis, functional pathway enrichment, immune cell infiltration, immunotherapy response analysis and drug sensitivity, within high- and low-risk subgroups. Additionally, we employed single-cell level functional assays, RT-qPCR, and immunohistochemistry to validate the differential expression of genes comprising the mtPCD signature. The mtPCD signature comprises a panel of 10 highly influential genes, strongly correlated with survival outcomes in BLCA patients and exhibiting robust predictive capabilities. Importantly, individuals classified as high-risk according to mtPCD score displayed a subdued overall immune response, characterized by diminished immunotherapeutic efficacy. In summary, our findings highlight the development of a novel prognostic signature, which not only holds promise as a biomarker for BLCA prognosis but also offers insights into the immune landscape of BLCA. This paradigm may pave the way for personalized treatment strategies in BLCA management.

Poly (adenosine diphosphate-ribose) polymerase inhibitors in the treatment of triple-negative breast cancer with homologous repair deficiency.

Breast cancer (BC) is a highly heterogeneous disease, and the presence of germline breast cancer gene mutation (gBRCAm) is associated with a poor prognosis. Triple-negative breast cancer (TNBC) is a BC subtype, characterized by the absence of hormone and growth factor receptor expression, making therapeutic decisions difficult. Defects in the DNA damage response pathway due to mutation in breast cancer genes (BRCA 1/2) lead to homologous recombination deficiency (HRD). However, in HRD conditions, poly (adenosine diphosphate-ribose) polymerase (PARP) proteins repair DNA damage and lead to tumor cell survival. Biological understanding of HRD leads to the development of PARP inhibitors (PARPi), which trap PARP proteins and cause genomic instability and tumor cell lysis. HRD assessment can be an important biomarker in identifying gBRCAm patients with BC who could benefit from PARPi therapy. HRD can be identified by homologous recombination repair (HRR) gene-based assays, genomic-scarring assays and mutational signatures, transcription and protein expression profiles, and functional assays. However, gold standard methodologies that are robust and reliable to assess HRD are not available currently. Hence, there is a pressing need to develop accurate biomarkers identifying HRD tumors to guide targeted therapies such as PARPi in patients with BC. HRD assessment has shown fruitful outcomes in chemotherapy studies and preliminary evidence on PARPi intervention as monotherapy and combination therapy in HRD-stratified patients. Furthermore, ongoing trials are exploring the potential of PARPi in BC and clinically complex TNBC settings, where HRD testing is used as an adjunct to stratify patients based on BRCA mutations.

Cancer therapy in patients with reduced kidney function.

Chronic Kidney Disease (CKD) and cancer constitute two major public health burdens and are on the rise. Moreover, the number of patients affected simultaneously by both conditions is growing. Potential nephrotoxic effect of cancer therapies is particularly important for patients with CKD, as they are also affected by several comorbidities. Therefore, administering the right therapy at the right dose for patients with decreased kidney function can represent a daunting challenge. We review in detail the renal toxicities of anti-cancer therapies i.e. conventional chemotherapy, targeted therapy, immune checkpoint inhibitors, and radioligand therapies, issue recommendations for patient monitoring along with guidance on when to withdraw treatment and suggest dosage guidelines for select agents in advanced stage CKD. Various electrolytes disturbances can occur as the result of the administration of anti-cancer agents in the patient with decreased kidney function. These patients are prone to developing hyponatremia, hyperkalemia, and other metabolic abnormalities because of a decreased GFR. Therefore, all electrolytes, minerals and acid base status should be checked at baseline and before each administration of chemotherapeutic agents. Moreover, studies on patients on kidney replacement therapy (KRT) are very limited and only single cases or small case series are published. Therefore, clinical therapeutical decisions in cancer patients with decreased function should be made by multidisciplinary teams constituted of medical oncologists, nephrologists, and other specialists. Onconephrology is an evolving and expanding subspecialty. It is crucial to consider anticancer drug treatment in these patients and offer them a chance to be treated effectively.

Safe immunosuppression. New tool for personalized immunosuppressant treatment in renal transplantation. A case report

Background: The adjustment of immunosuppressive therapy after kidney transplantation (KT) to avoid graft rejection remains an important challenge for clinicians. It is difficult to achieve a good balance between under-immunosuppression (with an increased risk of graft rejection) and over-immunosuppression (with an increased risk of side effects) by only relying on the available information about immunosuppressive drugs (IMS). Immunobiogram® (IMBG) is a novel in vitro diagnostic test that provides clinicians with information about the patient’s sensitivity to individual IMS. Objective: To present a case report of a patient with renal transplant in the maintenance phase who presented several complications probably related to the immunosuppression during the follow-up, where the use of IMBG as complementary information helped clinicians to guide the therapeutical decision. Methods: IMBG is a first-in-class in vitro immunoassay that involves the culture of the patient peripheral blood mononuclear cells (PBMCs) in a semi-solid 3D matrix, then submitted to immune stimulation. It reveals the capacity of an IMS over a gradient to inhibit the activation of immune cells. The read-out allows the building of a dose-response curve per IMS tested, which is mathematically analyzed by a software using the key curve parameters and finally to be translated into a sensitivity map to IMS. Findings: We present a case report of a 72-year-old patient with a cadaveric donor kidney transplant receiving standard immunosuppressive treatment with mycophenolate, tacrolimus, and corticosteroids. The patient presented several episodes of infections during the follow-up (SARS-CoV2, Cytomegalovirus, spondylodisquitis by Staphylococcus aureus, and emphysematous cystitis) which were managed with different treatment adjustments such as de-escalation of mycophenolate and switching to mTOR. The information provided by the IMBG showed a lack of sensitivity to mTOR which allowed to confirm the final adjustment to a treatment with tacrolimus and corticosteroids, remaining the patient stable since then. Discussion: Despite various adjustments to the immunosuppressive therapy during the follow-up, the patient continued experiencing adverse effects that could be related to an over-immunosuppression state. The IMBG provided pharmacodynamic information that complemented the clinical and pharmacokinetic data available, facilitating the individualization of the treatment. Conclusion: The case highlights the potential of the IMBG as a complementary clinical tool for personalized treatment of kidney transplant patient management.

Deep learning models for predicting the survival of patients with medulloblastoma based on a surveillance, epidemiology, and end results analysis

Medulloblastoma is a malignant neuroepithelial tumor of the central nervous system. Accurate prediction of prognosis is essential for therapeutic decisions in medulloblastoma patients. We analyzed data from 2,322 medulloblastoma patients using the SEER database and randomly divided the dataset into training and testing datasets in a 7:3 ratio. We chose three models to build, one based on neural networks (DeepSurv), one based on ensemble learning that Random Survival Forest (RSF), and a typical Cox Proportional-hazards (CoxPH) model. The DeepSurv model outperformed the RSF and classic CoxPH models with C-indexes of 0.751 and 0.763 for the training and test datasets. Additionally, the DeepSurv model showed better accuracy in predicting 1-, 3-, and 5-year survival rates (AUC: 0.767–0.793). Therefore, our prediction model based on deep learning algorithms can more accurately predict the survival rate and survival period of medulloblastoma compared to other models.

MULTIDISCIPLINARY APPROACHES TO THE DIAGNOSIS AND TREATMENT OF CENTRAL NERVOUS SYSTEM TUMORS

The symptoms of CNS tumors vary according to the location and tumor neurobiology, the mass effect of the neoplasm increases intracranial pressure (ICP), favoring seizures, headaches, projectile vomiting, optic nerve edema, compression of cranial nerves pairs, among other manifestations, which can be confused with numerous differential diagnoses. The objective of this article is to review therapeutic, multidisciplinary approaches performed with patients diagnosed with CNS tumors on different continents over the last decades, contributing to more precise therapeutic decisions on the subject, whether through clinical or surgical approaches. This study is an integrative literature review, which searched through the DeCS/MeSH descriptors “Neurology,” “Neurosurgery,” “Central Nervous System Tumors,” “Treatment,” and “Diagnosis” on PubMed, ScienceDirect, and BVS databases. Multidisciplinary involvement is essential to improve surveillance and decision-making for patients with CNS tumors. Interactions between different healthcare areas are crucial for enhancing the diagnostic process and the treatment of patients with these tumors. Imaging technology proved to be extremely useful for the diagnosis and assessment of the patient’s preoperative course. In terms of tumor incidence analyzed, it is predominantly female, and the main age group ranges from 41 to 50 years, varying according to each patient’s individual situation. Meningioma was the most frequently observed diagnosis, encompassing neurosurgery as one of the widely used treatments for various types of CNS tumors. The average hospitalization period for patients varied from 8 to 25 days, depending on the needs and personal issues of each patient.

II Brazilian Society of Rheumatology consensus for lupus nephritis diagnosis and treatment

ObjectiveTo develop the second evidence-based Brazilian Society of Rheumatology consensus for diagnosis and treatment of lupus nephritis (LN).MethodsTwo methodologists and 20 rheumatologists from Lupus Comittee of Brazilian Society of Rheumatology participate in the development of this guideline. Fourteen PICO questions were defined and a systematic review was performed. Eligible randomized controlled trials were analyzed regarding complete renal remission, partial renal remission, serum creatinine, proteinuria, serum creatinine doubling, progression to end-stage renal disease, renal relapse, and severe adverse events (infections and mortality). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to develop these recommendations. Recommendations required ≥82% of agreement among the voting members and were classified as strongly in favor, weakly in favor, conditional, weakly against or strongly against a particular intervention. Other aspects of LN management (diagnosis, general principles of treatment, treatment of comorbidities and refractory cases) were evaluated through literature review and expert opinion.ResultsAll SLE patients should undergo creatinine and urinalysis tests to assess renal involvement. Kidney biopsy is considered the gold standard for diagnosing LN but, if it is not available or there is a contraindication to the procedure, therapeutic decisions should be based on clinical and laboratory parameters. Fourteen recommendations were developed. Target Renal response (TRR) was defined as improvement or maintenance of renal function (±10% at baseline of treatment) combined with a decrease in 24-h proteinuria or 24-h UPCR of 25% at 3 months, a decrease of 50% at 6 months, and proteinuria < 0.8 g/24 h at 12 months. Hydroxychloroquine should be prescribed to all SLE patients, except in cases of contraindication. Glucocorticoids should be used at the lowest dose and for the minimal necessary period. In class III or IV (±V), mycophenolate (MMF), cyclophosphamide, MMF plus tacrolimus (TAC), MMF plus belimumab or TAC can be used as induction therapy. For maintenance therapy, MMF or azathioprine (AZA) are the first choice and TAC or cyclosporin or leflunomide can be used in patients who cannot use MMF or AZA. Rituximab can be prescribed in cases of refractory disease. In cases of failure in achieving TRR, it is important to assess adherence, immunosuppressant dosage, adjuvant therapy, comorbidities, and consider biopsy/rebiopsy.ConclusionThis consensus provides evidence-based data to guide LN diagnosis and treatment, supporting the development of public and supplementary health policies in Brazil.

HGG-08. DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT: A MULTI-INSTITUTIONAL EXPERIENCE

Abstract BACKGROUND Diffuse hemispheric glioma (DHG), H3 G34-mutant, is a rare, aggressive brain tumor molecularly defined by mutations in the H3-3A gene. Our study explored the association between patient outcomes and key molecular findings, resection extent, and temozolomide (TMZ) use. METHODS Multi-institutional chart and molecular analysis of 32 patients with H3 G34-mutant DHG. RESULTS The median patient age was 14 (10-28 years), with a M/F ratio of 1.4. The 1-year, 2-year, and 5-year PFS were 40.4% (23.7%, 57.1%), 22.1% (9.0%, 38.7%), and 11.0% (1.9%, 33.7%), respectively. The 1-year, 2-year, and 5-year OS were 82.5% (63.2%, 92.3%), 49.3% (28.7%, 66.3%), and 29.6% (9.1%, 50.6%), respectively. Patients who underwent a gross total resection (GTR) had improved PFS (p=0.0105) and OS (p=0.0184) compared to non-GTR patients. 22 patients (68.8%) received concurrent and/or adjuvant TMZ and had improved PFS (p=0.0278) compared to patients who did not receive front-line TMZ. Disease recurrence in relation to the radiation therapy (RT) field was analyzed in 17 patients; 5 recurred locally within the high-dose RT field, 5 recurred distantly, and 7 had both local and distant recurrences. There was no significant association between MGMT promoter methylation status (18 evaluable cases), PDGFRA amplification (N=6), and CDKN2A homozygous deletion (N=10) and survival outcomes. MGMT promoter methylation was not associated with increased TMZ efficacy (N=8 with MGMT silencing, N=4 without). CONCLUSIONS In our cohort, MGMT promoter methylation was not a favorable prognostic factor, in distinction from prior reports in adult and pediatric high-grade gliomas. Resection extent and the use of TMZ were associated with improved survival outcomes. As most treatment failures occurred within the high-dose RT field, extended fields do not appear warranted. Our findings may guide prognostic and therapeutic decisions in patients with H3 G34-mutant DHG and support the need for prospective efforts to improve outcomes in this patient population.

Ultrasound assessment of diaphragmatic dysfunction in non-critically ill patients: relevant indicators and update.

Diaphragm dysfunction (DD) can be classified as mild, resulting in diaphragmatic weakness, or severe, resulting in diaphragmatic paralysis. Various factors such as prolonged mechanical ventilation, surgical trauma, and inflammation can cause diaphragmatic injury, leading to negative outcomes for patients, including extended bed rest and increased risk of pulmonary complications. Therefore, it is crucial to protect and monitor diaphragmatic function. Impaired diaphragmatic function directly impacts ventilation, as the diaphragm is the primary muscle involved in inhalation. Even unilateral DD can cause ventilation abnormalities, which in turn lead to impaired gas exchange, this makes weaning from mechanical ventilation challenging and contributes to a higher incidence of ventilator-induced diaphragm dysfunction and prolonged ICU stays. However, there is insufficient research on DD in non-ICU patients, and DD can occur in all phases of the perioperative period. Furthermore, the current literature lacks standardized ultrasound indicators and diagnostic criteria for assessing diaphragmatic dysfunction. As a result, the full potential of diaphragmatic ultrasound parameters in quickly and accurately assessing diaphragmatic function and guiding diagnostic and therapeutic decisions has not been realized.

Challenges associated with managing treatment complications in an older patient with cardiac amyloidosis

BackgroundAmyloidosis, particularly wild-type transthyretin amyloidosis (ATTRwt), is an increasingly recognized cause of heart failure with preserved ejection fraction in the aging population. The complexity of managing ATTRwt in older patients underscores the necessity for individualized treatment approaches, yet clinical guidelines are lacking. This case report contributes to the understanding of ATTRwt management in the elderly, emphasizing the intricacies of medication tolerance and therapeutic decision-making.Case presentationAn 83-year-old Korean man with a history of hypertension presented with dyspnea and peripheral edema. Investigations including electrocardiography, transthoracic echocardiography, cardiac magnetic resonance, and Technetium pyrophosphate scintigraphy led to a diagnosis of ATTRwt cardiac amyloidosis. Initial management with heart failure medications, including an angiotensin-converting enzyme inhibitor, diuretic, and mineralocorticoid receptor antagonist, was modified due to evolving clinical presentations, such as hypotension and onset of atrial fibrillation. Challenges included intolerance to beta-blockers and bleeding complications from direct oral anticoagulant therapy. The patient’s treatment journey highlighted the need for personalized management strategies in older ATTRwt patients.ConclusionsThis case illustrates the challenges in diagnosing and managing ATTRwt amyloidosis in the elderly, particularly the complexities in medication management due to the patient’s age, comorbid conditions, and side effects. It underscores the importance of a tailored approach in managing ATTRwt in older populations and highlights the need for ongoing research and development of treatment strategies tailored to this demographic.

BIOM-12. LIQUID BIOPSIES IN CNS TUMORS: A COMBINED APPROACH TO PROFILING CSF

Abstract In precision medicine, molecular profiling of pediatric tumors is crucial for diagnosis, prognosis, and therapeutic decision-making. Traditional biopsy methods, often invasive, have inherent risks and may not capture a tumor’s heterogeneity. Liquid biopsy, however, offers a minimally invasive and comprehensive alternative. We demonstrate its utility in diagnosing and monitoring brain tumors using cell-free DNA (cfDNA) from cerebrospinal fluid (CSF), where conventional cfDNA plasma analysis has shown low sensitivity. Through digital droplet PCR, we analyzed 23 plasma samples from patients with BRAFV600E or H3K27M gliomas, detecting H3K27M in a single case. Conversely, CSF samples revealed 8 positives out of 9 for these mutations, underscoring CSF’s diagnostic value. We advanced our methodology by developing a 21-gene hybrid-capture panel paired with low-pass whole-genome sequencing to pinpoint copy number variations. In our reference sample set, the panel achieved a detection limit with variant allele frequencies as low as 0.5%. With 10ng of cfDNA, we reached 83% sensitivity and 100% specificity, which increased to 100% sensitivity with a 30ng input. Using this assay, we profiled 141 CSF samples from 119 patients, achieving 70% positivity rate in active disease cases in a validation cohort—ranging from 50% in low-grade gliomas to 84% in high-grade gliomas and 75% in medulloblastomas. Intriguingly, of 14 queried tumor samples lacking biopsy confirmation, half showed positive ctDNA results using the panel and/or low-pass whole-genome sequencing. This approach allowed for differential diagnoses in suspected medulloblastoma relapses, tailored therapeutic interventions based on CSF profiles, and effective treatment response monitoring. In summary, our integrated liquid biopsy strategy showcases a powerful, clinically applicable tool that significantly enhances patient care in pediatric neuro-oncology.