Standard Of Care For Patients Research Articles

Neoadjuvant immunotherapy and nonoperative management of dMMR gastroesophageal adenocarcinoma (GEA): A retrospective case series.

451 Background: Perioperative chemotherapy with surgery is the standard of care for patients (pts) with resectable gastric or gastroesophageal junction adenocarcinoma (GEA). However, recent studies have shown more favorable responses after neoadjuvant immunotherapy (NIO) in patients with mismatch repair deficient (dMMR) cancers. Herein, we present the outcomes of 10 cases with dMMR GEA. Methods: We retrospectively reviewed patients with GEA at Mayo Clinic Arizona who met the following criteria: have dMMR disease by IHC, nonmetastatic operable disease, and received NIO +/- chemotherapy. Patient demographics, disease characteristics, and clinical outcomes were extracted. The primary endpoint was clinical complete response (cCR) in patients treated with non-operative management (NOM) defined as complete radiological response and no residual disease on endoscopic ultrasound (EUS) and biopsy. Results: 10 pts with dMMR GEA with a median age of 70 (43-85) were identified. 6 pts had T2N0, 1 had T4N0, 3 had N+ disease. 8 pts received NIO monotherapy upfront, 1 received NIO after progressing on chemotherapy, and 1 concurrently with chemotherapy. No grade 3/4 toxicities were reported, however, 2 pts discontinued therapy due to arthralgia and colitis. After NIO, 9/10 pts had significant or complete resolution of FGD avidity on PET/CT, while 1/10 had stable disease. 3/10 pts underwent surgical resection, with 2 achieving pathological complete response (pCR) and the third showing T1N0 disease with no recurrence 1 year after surgery. Notably, one of the pts with pCR passed away due to surgical complications. 7/10 patients had NOM, of whom, 4 had cCR and 3 had radiological response only, as no EUS data was available. 4/7 NOM pts had follow up data at 6 months with no evidence of progression, of whom one pt remained progression-free at 33 months. ctDNA testing was performed in 6/10 pts: 2 had undetectable ctDNA at baseline, while 3 became MRD-negative after NIO, consistent with radiological and/or pathological response, and 1 had persistent ctDNA both before and after NIO, despite cCR. Conclusions: This study demonstrates exceptional and prolonged response, along with good tolerability to NIO in pts with dMMR GEA, supporting the feasibility of non-operative management in such patients.

Phase 1b portion of the ACTION-1 phase 1b/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177 Lu somatostatin analogue (SSA) therapy: Safety and efficacy findings.

661 Background: RYZ101 ( 225 Ac-DOTATATE) is an alpha-emitting radiopharmaceutical in development for SSTR2+ solid tumors. Alpha-particles have a shorter path length/higher linear energy transfer than beta-particles, causing more frequent double-strand DNA breaks and potentially improving the therapeutic index. ACTION-1 (NCT05477576) is a two-part, global, randomized, controlled, open-label, phase 1b/3 trial of RYZ101 in advanced, well-differentiated SSTR+ GEP-NETs progressing after 177 Lu-SSA therapy. Herein, we report updated results from the phase 1b portion of the trial. Methods: The phase 1b portion of the ACTION-1 trial had a dose de-escalation/Bayesian optimal interval design with boundaries based on a dose-limiting toxicity (DLT) rate of 25%. Patients received RYZ101 IV every 8 weeks for 4 cycles. Planned dose levels (n=6/level): Level 0 (starting dose) 120 kBq/kg; Level 1 90 kBq/kg; Level 2 60 kBq/kg. DLTs were assessed for 56 days after the first RYZ101 dose. Treatment-emergent adverse events (TEAEs) were graded by NCI-CTCAE v5.0. A Data Review Committee oversaw dose de-escalation decisions/safety data. Tumor response was assessed locally by RECIST v1.1. Results: Seventeen patients received at least one dose of RYZ101 at 120 kBq/kg (4 doses: 15 patients; 2 doses: 2 patients; median 8.3 MBq). Baseline patient characteristics: median age 63 years; male (n=11); ECOG PS 0/1 (n=10/7); primary tumor site GI/pancreas (n=12/5). As of 14 December 2023, the most frequent TEAEs were anemia (58.8%), nausea (58.8%), and fatigue (52.9%). Serious adverse events (SAEs) were observed in 6 patients (35.3%, none were treatment-related); grade ≥3 TEAEs occurred in 9 patients (5 were treatment-related, 29.4%). No TEAEs led to treatment discontinuation. Four patients had TEAEs leading to dose modification, dose hold, and/or dose delays. There was one grade 5 TEAE of hepatic failure that was deemed unrelated to the study drug. The confirmed objective response rate was 29.4% (n=5; 1 complete response, 4 partial responses). One additional patient had an unconfirmed partial response at the time of data cutoff, which was subsequently confirmed. Seven patients (41.2%) had stable disease and 3 (17.6%) had progressive disease. The median duration of response was not estimable (95% CI 9.26 months, not estimable), and the median progression-free survival was not estimable (95% CI 12.16 months, not estimable). Conclusions: RYZ101 was well tolerated, and a fixed dose of 10.2 MBq was declared the recommended phase 3 dose. Initial data suggest promising efficacy and a manageable safety profile. Part 2 (phase 3) of the ACTION-1 trial is enrolling and will compare RYZ101 at 10.2 MBq every 8 weeks for 4 cycles with standard of care in patients with advanced SSTR2+ GEP-NETs progressing after 177 Lu-labeled SSAs. Clinical trial information: NCT05477576 .

Efficacy of PD-1 blockade plus chemotherapy in patients with oncogenic-driven non-small-cell lung cancer

BackgroundPD-1 blockade plus chemotherapy has become the first-line standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without oncogenic drivers. Oncogenic-driven advanced NSCLC showed limited response to PD-1 blockade monotherapy or chemotherapy alone. Whether NSCLC patients with oncogenic drivers could benefit from PD-1 blockade plus chemotherapy remains undetermined.MethodsThree hundred twelve NSCLC patients with at least one oncogenic driver alteration received PD-1 plus chemotherapy or each monotherapy were retrospectively identified. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared to evaluate the therapeutic outcomes differences among patients with different oncogenic drivers.ResultsOne hundred sixty-two patients received PD-1 blockade plus chemotherapy, 57 received PD-1 blockade monotherapy and 93 received chemotherapy alone were included. Oncogenic driver mutations including KRAS (31.4%), EGFR (28.8%), HER2 (14.7%), BRAF (10.6%), RET (7.4%), and other mutations (7.1%) were identified. Patients with oncogenic drivers who received PD-1 blockade plus chemotherapy had significantly better outcomes compared to those received PD-1 blockade or chemotherapy alone (ORR: 51% vs. 18% vs. 25%, P < 0.001; median PFS: 10.0 [95% CI: 8.9–12.6] vs. 3.7 [95% CI: 2.9–5.1] vs. 5.3 [95% CI: 4.5–6.2] months, P < 0.001; median OS: 26.0 [95% CI: 23.0–30.0] vs. 14.3 [95% CI: 9.6–19.8] vs. 16.1 [95% CI: 11.6–21.9] months, P < 0.001). The superior efficacy was consistently found in separate analyses for patients received first-line and second/third line treatments. Among individual gene alterations, patients with KRAS, EGFR, or BRAF mutations treated with PD-1 blockade plus chemotherapy achieved markedly improved PFS and OS than those received PD-1 blockade or chemotherapy alone. Multivariate Cox regression analysis revealed that PD-1 blockade plus chemotherapy was independently associated with better PFS and OS.ConclusionPD-1 blockade plus chemotherapy demonstrated superior efficacy than PD-1 blockade monotherapy or chemotherapy alone in patients with oncogenic-driven advanced NSCLC, particularly in KRAS, EGFR and BRAF subgroups. These findings suggest that PD-1 blockade plus chemotherapy may be considered as an optional treatment option for patients without available targeted therapies.

Chemoradiotherapy (CRT) followed by sequential tislelizumab (TIS) + CAPOX and TIS monotherapy for organ preservation in locally advanced low rectal cancer.

TPS315 Background: CRT followed by total mesorectal excision (TME) is the standard care for patients with locally advanced low rectal cancer (≤ 5cm from the anal margin). However, TME may lead to permanent colostomy and severely impact quality of life. Organ preservation is, therefore, a critical unmet need for these patients. The proportion of patients achieving clinical complete response (cCR) after CRT is relatively low, with the literature reporting around 20%. Total neoadjuvant therapy (TNT) has been investigated to increase cCR rate. Several clinical trials demonstrated that PD-1 inhibitor combined with TNT could result in significate improvement in pathological complete response rate (pCR rate, 39.8% vs 15.3%, p &lt; 0.001 in UNION study) or complete response rate (pCR+cCR rate, 44.8% vs 26.9%, p = 0.031 in a randomized phase 2 study) compared with TNT alone in rectal cancer patients. The RELIEVE-01 study (NCT06390982) was designed to evaluate the efficacy in organ preservation with CRT followed by sequential TIS + CAPOX and TIS monotherapy in patients with low rectal cancer. Methods: This multicenter, single-arm, phase 2 study will enroll 46 pts with histopathologically confirmed rectal adenocarcinoma (≤ 5cm from the anal margin), pMMR/MSI-L/MSS, cT1-3N1M0/T2-3N0M0, and ECOG PS ≤1. Pts will initially receive 6 weeks of CRT (50.4 Gy/28F, capecitabine 825 mg/m 2 , bid, d1-5 each week), followed by 4 cycles of TIS + CAPOX (TIS, 200 mg, IV, d1; capecitabine 1000 mg/m 2 , bid, d1-14; oxaliplatin 130 mg/m 2 , d1) in a 21-day cycle. Then, clinical response will be assessed to determine the subsequent treatment. Patients with cCR will receive TIS + CAPOX (4 cycles) and TIS (up to 9 cycles), and then be managed using the W&amp;W strategy. Patients with non-cCR will undergo TME. Patients with near-cCR will be given local excision, and those achieving pCR will receive the same treatment as cCR patients, and for those with non-pCR after local excision, TME will be performed. The primary endpoint is rate of CR (cCR plus pCR post local resection). Secondary endpoints include organ-preserving rate, event-free survival rate and OS rate at 1, 2 and 3 years, respectively. Recruitment is ongoing. Clinical trial information: NCT06390982 .

Association between adjuvant component of perioperative chemotherapy and survival outcomes in resected gastric cancer (GC).

378 Background: Perioperative chemotherapy is the standard of care for resectable GC but many patients do not proceed to or complete adjuvant chemotherapy (AC). It remains unclear whether AC following neoadjuvant chemotherapy (NAC) improves survival. Methods: Patients with GC who received NAC and underwent curative-intent gastrectomy from 2006-2022 were identified from an institutional database. Patients with mismatch repair-deficient/microsatellite instability-high tumors, GEJ tumors, M1 disease, neoadjuvant radiotherapy, total neoadjuvant intent treatment, incomplete NAC (&lt;66% of planned cycles), and incomplete data were excluded. A lymph node ratio (LNR) risk cutoff was determined using maximally selected rank statistics. Kaplan-Meier analysis with log-rank tests were used to compare overall survival (OS) and disease-free survival (DFS). Cox proportional hazards regression models were used to identify independent predictors of OS and DFS. All analyses were performed in R statistical software. Results: Of 340 patients included, 264 (78%) received AC. Most common reasons for incomplete AC were postoperative complications (20%), poor performance status (16%), minimal pathologic response to NAC (14%), patient choice (14%), and NAC toxicity (9%). Median follow-up was 6.4 years. In the overall cohort, there was no significant difference in OS (median 10 vs. 8.3 years; p=0.14) or DFS (7.0 vs. 7.5 years; p=0.12) between AC and non-AC groups. In node-negative (ypN-) patients (n=170), there was no association between receipt of AC and OS (12 vs. 10 years; p=0.6) or DFS (12 vs. 10 years; p=0.8). On univariable analysis, lack of AC receipt was not associated with shorter OS (p=0.3) or DFS (p=0.4). In the node-positive (ypN+) cohort (n=170), AC receipt was associated with significantly longer DFS (4.8 vs. 2.7 years; p=0.031) but not OS (5.5 vs. 2.8 years; p=0.071). However, on multivariate analysis, AC only showed a non-significant trend towards longer DFS (HR 0.77 [95% CI 0.49-1.19]; p=0.20). High-risk patients based on LNR (LNR&gt;0.0684; n=112) who received AC (n=87; 78%) had longer OS (p=0.033) and DFS (p=0.014). No such differences were observed in the low risk LNR subgroup (LNR&lt;0.0684; n=227). Conclusions: Following NAC, AC was not associated with improved survival in patients with ypN- GC. The association between AC and survival in ypN+ GC remains unclear but LNR may be used to identify patients with ypN+ disease who may benefit from AC. These observations require prospective validation but may have implications for clinical care and future trial design.

Association of tumor treating fields (TTFields) therapy with overall survival in newly diagnosed glioblastoma.

Glioblastoma (GBM) is a rare and aggressive primary central nervous system tumor with high morbidity and mortality. Standard treatments include surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy, but these options are often insufficient and cause severe side effects. Tumor Treating Fields (TTFields) have emerged as a fourth treatment, offering improved survival, better prognosis, and minimal side effects, significantly enhancing the quality of life for GBM patients. For newly diagnosed cases, TTFields combined with TMZ is the recommended standard of care for eligible patients. Current GBM therapy focuses on extending survival while reducing harm. Ongoing research seeks to explore TTFields in innovative radiological-based therapeutic paradigms.

Targets Selection for Precision Therapy of Relapsed/Refractory Multiple Myeloma: the Latest Advancements.

According to the guidelines, the primary treatment for multiple myeloma is still based on drugs such as carfilzomib, lenalidomide, or daratumumab. However, patients with relapsed/refractory multiple myeloma (RRMM) may be insensitive or develop resistance to the above therapeutic medications. Thus, formulating standardized and rational treatment regimens for such patients remains an area for consideration. Multidrug combinations are available for the therapy of patients with relapsed/refractory multiple myeloma to improve their clinical outcome and prevent the occurrence of multidrug resistance. For instance, combination therapy with immunomodulators, proteasome inhibitors, and CD38 monoclonal antibodies. With the development of genomics and molecular diagnostic technologies, RRMM has entered the era of precision therapy. Targeted immunotherapeutic drugs such as monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor-T (CAR-T) cells have shown promising clinical response rates and favorable safety profiles in several clinical and experimental studies. These cutting-edge medicinal treatments may provide new hope for a cure for RRMM. However, the choice of treatment regimen still needs to adhere to the principle of individualization. Generally, we recommend treatment with drugs of a new generation or novel mechanism of action for patients with RRMM who are first relapsed, such as next-generation proteasome inhibitors, next-generation immunomodulators, and CD38-based monoclonal antibody regimens.For multiple relapsed RRMM, we recommend choosing a combination regimen or participating in relevant clinical trials. Additionally, monoclonal antibodies have become the standard of care for patients with RRMM. With the introduction of CAR-T therapy, ADCs, and bispecific antibodies, RRMM patients are expected to achieve deep remissions and long-term survival again.

Relative Dose Intensity of Daratumumab, Lenalidomide, and Dexamethasone in Multiple Myeloma

Background: Daratumumab (DARA), lenalidomide (LEN), and dexamethasone (DEX, DRd) are one of standards of care for patients with multiple myeloma (MM); however, the clinical impact of relative dose intensity (RDI) remains unclear. In this retrospective study, the aim was to analyze the relationship between the RDI and clinical outcomes in patients with myeloma treated with DRd. Methods: The numbers of patients with newly diagnosed, relapsed, and/or refractory MM were 40 and 71, respectively. Results: The median patient age was 74 years, and the median RDIs for DARA, LEN, and DEX were 84.0%, 39.4%, and 14.6%, respectively. At a median 26.8 months follow-up interval, the 2-year time to the next treatment (TTNT) of the high RDI of DARA (cutoff, 90%) was greater than that of the low RDI of DARA (77.3% vs. 51.6%, p &lt; 0.001), and the 2-year overall survival (OS) of the low RDI of DEX (cutoff, 15%) was longer than that of the high RDI of DEX (87.7% vs. 61.0%, p = 0.027). Multivariate analysis showed that a high RDI for DARA and low RDI for DEX were associated with longer TTNT and OS (hazard ratio, 0.503, p = 0.044; hazard ratio 0.426, p = 0.022, respectively). The high RDI of DARA and low RDI of DEX reduced the incidence of severe infections (p = 0.040 and 0.049). Conclusion: The high RDI of DARA and low RDI of DEX predicted good clinical outcomes in this study’s cohort.

Discovery and Development of CFTR Modulators for the Treatment of Cystic Fibrosis.

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which regulates ion and fluid transport across epithelial cells. Mutations lead to complications, with life-limiting lung disease being the most severe manifestation. Traditional treatments focused on managing symptoms, but advances in understanding CF's molecular basis led to small-molecule CFTR modulators. Ivacaftor, which is a potentiator, was approved for gating mutations. Dual combinations like ivacaftor/lumacaftor and ivacaftor/tezacaftor brought together a potentiator and a class 1 corrector for F508del homozygous patients. Triple-combination CFTR modulators, including ivacaftor/tezacaftor/elexacaftor with an additional class 2 corrector, are now the standard of care for most CF patients, transforming the outlook for this disease. These drugs stabilize and potentiate the CFTR protein, improving lung function, sweat chloride levels, quality of life, and survival. This Perspective discusses CFTR structure and mutations, biological assays, medicinal chemistry research in identifying CFTR modulators, and clinical data of these agents.

Thrombolysis for Ischemic Stroke Beyond the 4.5-Hour Window: A Meta-Analysis of Randomized Clinical Trials.

A minority of patients with stroke qualify for intravenous thrombolysis (IVT) within 4.5-hour window. The safety and efficacy of IVT beyond this period have not been well studied. We systematically searched MEDLINE, Embase, Cochrane, and ClinicalTrials.gov for relevant randomized clinical trials. Randomized clinical trials comparing IVT versus standard medical care in patients with ischemic stroke beyond 4.5 hours of symptom onset or last known well without mechanical thrombectomy (MT) were included. Primary outcomes were excellent (modified Rankin Scale score of 0-1) and good (modified Rankin Scale score of 0-2) functional outcomes at 90 days, symptomatic intracerebral hemorrhage (sICH), and death at 90 days. Pooled odds ratios (ORs) with 95% CIs were calculated using a random-effects model. Heterogeneity was assessed by Q test and quantified by I² values. Eight randomized clinical trials (1742 patients; mean age, 69.8±9 years, 63.5% men) were included. Compared with standard medical care, IVT achieved higher rates of excellent (OR, 1.43 [95% CI, 1.17-1.75]; Q=2.30; P=0.94; I2=0%) and good functional outcomes (OR, 1.36 [95% CI, 1.12-1.66]; Q=2.07; P=0.96; I2=0%) at 90 days but also increased sICH rates (OR, 4.25 [95% CI, 1.67-10.84], Q=0.48; P=0.99; I2=0%). Mortality at 90 days did not significantly differ between treatment groups (OR, 1.28 [95% CI, 0.87-1.89]; Q=4.63; P=0.59; I2=0%). Subanalyses yielded numerically higher odds of excellent functional outcomes when patients were selected with perfusion imaging (3 studies, OR, 1.45 [95% CI, 1.08-1.94]) compared with diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch (3 studies, OR, 1.34 [95% CI, 0.94-1.91]) and when treated with tenecteplase (3 studies, OR, 1.47 [95% CI, 1.06-2.04]) compared with alteplase (5 studies, OR, 1.38 [95% CI, 1.08-1.78]). IVT for ischemic stroke beyond 4.5 hours, without MT, led to increased odds of excellent and good functional outcomes compared with standard medical care, despite higher odds of sICH, and a nonsignificant numerical increase in mortality.

A systematic review on the influence of coagulopathy and immune activation on New Onset Atrial Fibrillation in patients with sepsis.

New Onset Atrial Fibrillation (NOAF) is the most common arrhythmia in intensive care. Complications of NOAF include thromboembolic events such as myocardial infarction and stroke, which contribute to a greater risk of mortality. Inflammatory and coagulation biomarkers in sepsis are thought to be associated with NOAF development. The aim of this systematic review and narrative synthesis is to identify inflammatory and coagulation biomarkers as predisposing risk factors for NOAF in sepsis. Three databases (Medline, Cochrane Library, and Scopus) were searched using a predefined search strategy. Inclusion / exclusion criteria were applied, and quality assessments were performed using the Newcastle Ottawa Scale (NOS). We identified 1776 articles; and 12 articles were included in this review. 8 articles were retrospective observational studies and 4 were prospective observational studies. There was considerable heterogeneity between studies regarding outcomes, methodological design, quality, definitions and reported biomarkers of interest. There is evidence that C-reactive protein (CRP) is associated with NOAF, with hazard ratios 3.33 (3.32-3.35) p = 0.001 and odds ratios of 1.011 (1.008-1.014) p<0.001. International Normalised Ratio (INR) and fibrinogen may be associated with NOAF with odds ratios reported as 1.837 (1.270-2.656) p = 0.001 and 1.535(1.232-1.914) p<0.001 respectively. Further research is required to confirm the association between inflammatory and coagulation biomarkers and the development of NOAF in sepsis. A broader evidence base will guide treatment strategies, improving the standard of care for patients who develop NOAF in sepsis. Furthermore, given the heterogeneity between studies consideration should be given to inclusion of immune biomarkers in future core outcome sets for trials investigating NOAF.

P-1892. Dabbling with Dalbavancin: Implementation and Cost-savings of an Inpatient-to-Outpatient Dalbavancin Pathway

Abstract Background Dalbavancin is a lipoglycopeptide antibiotic with in vitro activity against gram-positive organisms and a terminal half-life of 14.4 days. One dose provides 7 days of therapy whereas a novel 2-dose regimen provides up to 4-6 weeks. These strategies are attractive alternatives to standard of care for patients in whom daily IV antibiotics are not feasible. There also may be a financial benefit as the dosing schedule allows for completion of therapy in the outpatient setting and can reduce hospitalization costs. Methods This study is a retrospective chart review of all patients who received dalbavancin at Tampa General Hospital. Our institution approved the use of dalbavancin at no cost to patients for vancomycin-susceptible gram-positive infections who remain hospitalized only to receive IV antibiotics. All patients received at least one 1500mg dose inpatient to save 7 days of hospitalization; some patients planned to follow up a week later in an outpatient clinic for a second 1500mg dose to save at least 4 weeks of hospitalization. Cost estimates are based on the patient’s hospitalization cost prior to receiving dalbavancin and do not include avoided implicit costs. Results From 12/13/22 to 3/31/24, 28 patients received dalbavancin; 14 (50%) planned to receive a second dose and 11 (78.6%) successfully received their dose in clinic. The majority of patients (60.7%) reported a history of injection drug use. Most infections were monomicrobial (85.7%) with S. aureus being the most common pathogen. An estimated 527 days of hospitalization were avoided, representing a cost savings of $684,712.44. The institutional drug cost for dalbavancin was $104,772, leading to an estimated net hospital cost savings of $579,940.44. The all-cause 30-day readmission or revisit rate was 28.6%, similar to reported readmission rates in this population, however the 30-day infection-related readmission or revisit rate was favorable (10.7%). Conclusion The use of dalbavancin to facilitate discharge resulted in significant cost savings without increasing infection-related readmissions. Further cost-benefit analysis on true economic impact including the reduction in nosocomial infections and avoidance of toxicities is warranted. Disclosures All Authors: No reported disclosures

Low-dose Systemic Tissue-type-plasminogen-activator Compared to Conventional Anti-coagulation for the Treatment of Intermediate-high Risk Pulmonary Embolism.

Pulmonary embolism (PE) is a frequent cause of death. Acute PE may be treated either with full anticoagulation (AC) alone or thrombolytic therapy with systemic tissue-- type-plasminogen-activator (tPA) based on risk assessment. Currently, AC is the standard of care for most patients with intermediate-high-risk PE, with low-dose tPA emerging as an effective alternative. However, studies directly comparing the efficacy and safety of low-dose tPA to AC are lacking in this patient population. The aim of this study was to retrospectively compare the efficacy and safety of low-- dose tPA, compared to AC alone in right ventricular function and in-hospital mortality and bleeding complications in patients presenting with intermediate-high risk PE. This is a single-center, retrospective cohort trial conducted at a university hospital. A total of 148 patients were screened, and 88 patients qualified for this study. The primary endpoints were changes in right ventricular function on echocardiogram in 24 hours, in-hospital mortality, and major bleeding complications. Eighty-eight consecutive patients with intermediate high-risk PE were included. Twenty- six patients (29.5%) received low-dose systemic tPA administered via intravenous infusion, and 62 patients (70.4%) received standard full-dose anticoagulation. There were no significant differences in baseline vital signs or PESI scores between the low-dose tPA and the AC group. Patients in the low-dose tPA group had worse RV function and higher troponin levels at baseline but showed significant improvement in all RV parameters assessed during the 24-hour follow-up. In comparison, there was no significant improvement in RV function in the AC group. There were more bleeding events in the AC group. LOS was shorter in the low-dose tPA group. Treatment with low-dose prolonged infusion of tPA may be an effective and safe therapy in patients with intermediate-risk PE. Compared to AC, low-dose tPA was effective in decreasing PASP and restoration of RV function.

Combining Colchicine and Antiplatelet Therapy to Tackle Atherothrombosis: A Paradigm in Transition?

Atherothrombosis, the primary driver of acute cardiovascular (CV) events, is characterized by the activation of three key pathophysiological pathways: platelets, coagulation, and inflammation. Dual antiplatelet therapy (DAPT) is the current standard of care for patients with acute coronary syndrome, providing significant reductions in cardiovascular (CV) events, albeit with an associated increased risk of bleeding. However, the high residual risk of recurrent events among these patients highlights the need for alternative strategies to treat and prevent atherothrombosis. To this extent, several approaches aimed at targeting atherothrombosis have been proposed. Among these, a strategy of dual-pathway inhibition simultaneously targeting platelets, using single or DAPT, and coagulation, using a low-dose anticoagulant such as rivaroxaban 2.5 mg twice daily, has shown to reduce CV events but at the expense of increased bleeding. Targeting inflammatory pathways has the potential to be a highly effective strategy to tackle atherothrombosis without increasing bleeding risk. Several anti-inflammatory agents have been tested in patients with coronary artery disease, but to date only colchicine is approved for secondary prevention on top of standard care, including antiplatelet therapy. However, many aspects of colchicine’s mechanism of action, including its antiplatelet effects and how it synergizes with antiplatelet therapy, remain unclear. In this review, we summarize the available clinical and pre-clinical evidence on the antiplatelet effects of colchicine and its synergistic interactions with antiplatelet therapy, highlighting their potential role in addressing atherothrombosis.

Enhancing paediatric and congenital cardiology e-learning postgraduate education: insights from the Association for European Paediatric and Congenital Cardiology directed webinar series.

A series of webinars covering widespread knowledge on paediatric cardiology and cardiac surgery topics was initiated by Association for European Paediatric and Congenital Cardiology, serving towards preparation for the Association for European Paediatric and Congenital Cardiology certification in paediatric and congenital cardiology. This study investigated the impact of webinars as educational tools for junior paediatric cardiologists in the post-COVID-19 pandemic era. A cross-sectional survey design study using an online survey as a tool for the assessment of trainees. An open and closed-ended SurveyMonkey questionnaire was used to document the learners' opinions on webinars. Results were reported using descriptive statistical analyses. Twenty-seven Association for European Paediatric and Congenital Cardiology junior members participated in the online survey from twelve different countries. Most of the participants were trainees in paediatric cardiology (56%), and the remainder were junior consultants in paediatric cardiology. Approximately 70% found no difficulties in participating in the webinars. The webinars were appreciated by participants, who found the webinars interactive and highly educational with contents highly applicable to everyday clinical practice. Significant heterogeneity emerged in training programmes across Europe and worldwide in terms of programme duration, number of fellows, teaching approach, and assessments. Training opportunities such as courses, grants, and more webinars were suggested as tools to support continuous learning by the Association for European Paediatric and Congenital Cardiology. The Association for European Paediatric and Congenital Cardiology webinar series has confirmed the crucial role of online-based learning resources in the new generation of junior paediatric cardiologists. Association for European Paediatric and Congenital Cardiology webinars and the examination in paediatric cardiology may help standardise training across Europe, promoting the highest standards in patient care.

Case report: Musculoskeletal metastastic inflammatory myofibroblastic tumor (IMT) treated by sequential ALK-TKI with longterm response

Inflammatory myofibroblastic tumors (IMTs) are known to be associated with rearrangements of the anaplastic lymphoma kinase (ALK) gene. The treatment of this type of tumor includes systemic therapies such as chemotherapies or anti-inflammatories; in recent years, targeted anti-ALK therapies have emerged and became the standard of care in ALK rearranged patients. We aimed to present a rare case of musculoskeletal IMT with ALK rearrangement, characterized by metastatic evolution and enhanced responses to sequential treatment with all ALK-TKI. We have outlined a potential treatment pathway involving sequential ALK-TKI targeted therapies and successive local interventions to control the cancer.

Effectiveness of a New Device for Hand, Wrist, and Forearm Rehabilitation: Feasibility Randomized Controlled Trial.

Forearm, wrist, and hand impairments affect many individuals and impose a significant economic burden on health care systems. The FEPSim (flexion, extension, pronation, and supination) is designed for hand and wrist rehabilitation. It could become part of the standard care for upper extremity rehabilitation, aiming to improve range of motion, dexterity, and strength during therapeutic activities. However, the FEPSim has not yet been tested in a health care setting, highlighting the need for a trial to assess its effectiveness in upper extremity rehabilitation. We aim to assess the feasibility of conducting a definitive trial investigating the effectiveness of adding a new device for hand therapy exercises, the FEPSim, to standard care for patients with impairments of the hand, wrist, and forearm. Thirty-eight patients with impairments of distal upper extremities were randomly assigned either to the intervention group (FEPSim and standard care, n=19) or to the control group (standard care, n=19). Therapeutic activities to increase strength, range of motion, resistance, and dexterity were delivered by treating hand therapists using the FEPSim device for the intervention group. Outcome measures included wrist passive and active range of motion, grip strength, pinch grip force, and the Patient-Rated Wrist Evaluation. The trial retention rate (36/38, 95%) and compliance (control group: 100%; intervention group: 89%) were high. The comparisons of the change-from-baseline between groups revealed that in 63.2% (12/19) of the outcome variables, the change was in favor of the FEPSim, with statistically significant improvements in passive wrist flexion (t34=-0.335, P=.008) and grip strength (t34=-1.841, P=.04). The FEPSim was accepted as part of standard care by therapists and patients at 2 hospitals. The trial design was feasible for hand intervention using the FEPSim device. The FEPSim positively affected grip strength, an objective measure of hand functioning.

Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial.

Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study. Historically, first-line treatment of BRAF V600E-mutant mCRC with chemotherapy regimens has had limited efficacy. The phase 3 BREAKWATER study investigated EC+mFOLFOX6 versus standard of care (SOC) in patients with previously untreated BRAF V600E mCRC. The dual primary endpoint of progression-free survival is event driven; data were not mature at data cutoff. BREAKWATER met the other dual primary endpoint of objective response rate, demonstrating significant and clinically relevant improvement in objective response rate (EC+mFOLFOX6: 60.9%; SOC: 40.0%; odds ratio, 2.443; 95% confidence interval (CI): 1.403-4.253; 99.8% CI: 1.019-5.855; one-sided P = 0.0008). Median duration of response was 13.9 versus 11.1 months. At this first interim analysis of overall survival, the hazard ratio was 0.47 (95% CI: 0.318-0.691; repeated CI: 0.166-1.322). Serious adverse event rates were 37.7% versus 34.6%. The safety profiles were consistent with those known for each agent. BREAKWATER demonstrated a significantly improved response rate that was durable for first-line EC+mFOLFOX6 versus SOC in patients with BRAF V600E mCRC. ClinicalTrials.gov identifier: NCT04607421 .

Prognostic and clinical heterogeneity of PD1 and PD-L1- immunohistochemical scores in endometrial cancers.

PD1/PD-L1 inhibition (ICi) has recently become a new standard of care for patients with advanced MMR-deficient (MMRd) endometrial cancers. Nevertheless, response to immunotherapy is more complex than the presence of a single biomarker and therefore it remains challenging to predict patients response to ICi beyond MMRd tumors. Elevated PD-L1 expression (CPS ≥ 1) is often used as a prognostic marker as well as a predictive biomarker of response to ICi in different tumor types. In a retrospective, patient derived study, we analyzed PD1- and PD-L1 staining and correlated the results of different scores to clinical data to evaluate the prognostic impact of these scores. Immunohistochemical analysis of the receptor PD1 and the receptor ligand PD-L1 were performed on TMAs of primary paraffin‑embedded tumor samples. All patients were treated for primary endometrial cancer in the Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Campus-Lübeck, Germany between the years 2006-2018. The evaluation and determination of the tumor proportion scoring (TPS), the combined positive score (CPS) and the immune cell scoring (IC) was automatically assessed semi-quantitatively, and results were correlated with clinicopathological characteristics and survival. 130 samples were evaluable and 64% showed a positivity (IC > 0) for the receptor PD1 and 56% for the receptor ligand PD-L1. Patients with a PD1 IC Score ≥ 1 showed a significant longer disease-free survival of 140months (95% confidence interval (CI): 124-158) compared to patients with a lower IC < 1 for PD1 of 89months (95% confidence interval (CI): 69-110); p = 0.017). Furthermore, the disease-free survival for patients with a CPS ≥ 5 for PD1 was longer (153.7months (95% confidence interval (CI): 134-173.6) vs. 98.6months (95% confidence interval (CI): 83-114); p = 0.036). Additionally, a PD1 CPS ≥ 5 showed a better overall survival but the result was not statistically significant. No difference in survival was found between patients with PD-L1 higher or lower than CPS 5. In this study we pointed out that there are significant clinical differences among several immunohistochemical scoring systems. In our trial, a PD1-positivity with CPS ≥ 5 and IC ≥ 1 were significantly associated to a better disease-free survival while there was no association with TPS. The PD1-IC scoring was associated with MMRd while the TPS scoring was not. Therefore, PD1-IC could be more appropriate for endometrial carcinomas compared to TPS and could also add prognostic information beside the more established PD-L1-staining. Further prospective studies are needed for a validation of these scores in combination with other biomarkers.

Comparison of the two treatment methods in primary hyperparathyroidism due to solitary parathyroid adenoma, Ultrasound-guided percutaneous alcohol ablation vs. parathyroidectomy: a randomized controlled trial

BackgroundPrimary hyperparathyroidism (pHPT) is the third most common endocrine system disorder. Parathyroidectomy (PTx) is the gold standard of care in symptomatic patients. Patients who are not surgical candidates may benefit from percutaneous ethanol ablation, which is a minimally invasive procedure. This study aims to evaluate the effectiveness and safety of PTx vs. PEA.MethodA single-centered randomized, not-blinded parallel clinical trial in consecutive patients with pHPT treated with percutaneous alcohol ablation (PEA) between January 2020 and November 2021. Patients with a confirmed solitary parathyroid adenoma and a biochemically verified pHPT were randomly enrolled in the PTx or PEA groups. Complications and lab data were evaluated 24 h, 2 weeks, 3 months, and 6 months following interventions. Effectiveness was defined as complete response (normal calcium and PTH), partial response (reduced but not normalized PTH with normal serum calcium), or disease persistence (elevated calcium and PTH). SPSS 22.0 was used for statistical analysis.ResultThe final sample comprised 68 patients in each group which 113 of whom were female (83.0%). Complete response was observed in 91.1% (n = 62) of the PEA group and 98.5% (n = 67) of the PTx group. According to repeated-measures analysis, Calcium, PTH, Phosphorus, and Alkaline phosphatase fell significantly and continuously in each intervention group, except for the persistent patients. According to ROC analysis, a cutoff of > 425.5 mm3 for the adenoma volume and > 13.5 mm for its largest diameter showed a sensitivity = 75% and specificity = 69% for partial response in the PEA group (AUC = 0.81 and 0.84, respectively). PTx group experienced statistically significant higher pain according to the Visual Analogue Scale (VAS score) (p < 0.001).ConclusionPTH, serum-adjusted Calcium, and adenoma size and volume were all significantly reduced by PTx and PEA, with no significant difference between them. PEA is an effective alternative to PTx, particularly in adenomas with a volume of less than 425.5 mm3 and a maximum diameter of 13.5 mm.Trial registration numberIRCT20210204050241N1 (04/26/2021).