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1-year efficacy results after MR-guided risk-adapted stereotactic radiotherapy of infra-diaphragmatic oligometastases in a multicenter phase II trial
No full textBACKGROUND AND PURPOSE: The SOFT (Stereotactic ablative radiotherapy of infra-diaphragmatic sOFT tissue metastases) trial assesses the safety and efficacy of risk-adapted MR-guided stereotactic ablative radiotherapy (SABR) of infra-diaphragmatic soft tissue metastasis in patients with oligometastatic disease (OMD) (clinicaltrials.gov ID NCT04407897). This paper reports the one-year efficacy analysis and evaluates associations between local control (LC) and clinical and dosimetric parameters.
MATERIALS AND METHODS: This investigator-initiated, multicenter, single-arm, phase 2 study recruited patients from four MR-linac centers in Denmark and the US. Patients with De novo or recurrent OMD with ≤ 5 metastases in ≤ 3 organs and patients with induced OMD or oligoprogressive disease (OPD) with ≤ 3 metastases were eligible. Fractionation schemes were 45-75 Gy in 3-8 fractions.
RESULTS: The trial included 121 patients with 147 oligometastatic lesions, primarily in the liver (41 %), lymph nodes (35 %), or adrenal glands (14 %). The median follow-up time was 13.0 months, interquartile range (IQR) (11.7,13.7) months. The 1-year LC rate was 89 %, 95 % confidence interval (CI) (83,94 %). We did not observe any statistically significant associations between LC and clinical and dosimetric parameters. The median progression-free survival was 7.1 months, 95 % CI (6.0,9.4). One- and two-year overall survival was 82.6 %, 95 % CI (76.2 %,89.7 %), and 65.1 %, 95 % CI (56.4 %,75.3 %). Sixty-one patients (50 %) were kept off systemic therapy throughout the one-year follow-up.
CONCLUSION: In our study, treatment with risk-adapted, MR-guided SABR resulted in a high one-year local control and survival rate and could keep half of the patients off systemic therapy within the first year of follow-up
Treatment of Critical Bleeds in Patients With Immune Thrombocytopenia: A Systematic Review
No full textOBJECTIVES: Evidence-based protocols for managing bleeding emergencies in patients with immune thrombocytopenia (ITP) are lacking. We conducted a systematic review of treatments for critical bleeding in patients with ITP.
METHODS: We included all study designs and extracted data in aggregate or individually for patients who received one or more interventions and for whom any of the following outcomes were reported: platelet count response, bleeding, disability, or death.
RESULTS: We identified 49 eligible studies reporting 112 critical bleed patients with ITP, including 66 children (median age, 10 years), 36 adults (median age, 41.5 years), and 10 patients with unreported age. Patients received corticosteroids (n = 67), IVIG (n = 49), platelet transfusions (n = 41), TPO-RAs (n = 17), and splenectomy (n = 28) either alone or in combination. Studies reported 29 different treatment combinations, the 5 most common were corticosteroids, platelet transfusion and splenectomy (n = 13), corticosteroids and IVIG (n = 13), or splenectomy alone (n = 13); IVIG alone (n = 11); and corticosteroids, IVIG and TPO-RA (n = 8). Mortality among patients with critical bleeds in ITP was 30.6% for adults and 19.7% for children.
CONCLUSIONS: The effects of individual treatments on patient outcomes were uncertain due to very low-quality evidence. There is a need for a standardized approach to the treatment of ITP critical bleeds.
SYSTEMATIC REVIEW REGISTRATION: CRD42020161206
Abnormalities Of Mitochondrial Function In Renal Epithelial Cells Of Dogs With Chronic Heart Failure And Dogs With Cardiorenal Syndrome
No full textBackground: Chronic heart failure (HF) is often accompanied by abnormalities of kidney function that contribute to progressive worsening of the HF state. Cardiorenal syndrome (CRS) in humans with HF is sometimes attributed to kidney underperfusion secondary to low cardiac output and/or low renal perfusion pressure, but the cellular mechanism(s) is not fully understood. We previously showed that mitochondrial (MITO) function is abnormal in cardiomyocytes of the failing heart, and it is possible that similar energetic dysfunction in the kidneys contributes to renal dysfunction in HF. In the present study, we tested the hypothesis that MITO function is abnormal in kidneys of dogs with chronic HF and dogs with CRS compared to normal (NL) dogs. Methods: MITO functional studies were performed in fresh renal epithelial cells isolated from the left kidney of 6 NL dogs, 6 HF dogs (LV ejection fraction 34±1 %) and 6 CRS dogs (LV ejection fraction 33±2%), for a total n=18 animals. HF was produced using coronary microembolizations. CRS was produced in HF dogs by unilateral nephrectomy of the right kidney and creation of a stenosis of the left renal vein sufficient to result in renal venous congestion (increasing venous pressure by 20-30 mmHg). MITO function was assessed as follows: 1) Mitochondrial ADP-stimulated state-3 respiration (ADPresp) was measured using a Strathkelvin respirometer, 2) mitochondrial complex-IV (COX-IV) activity was measured polarographically, 3) mitochondrial membrane potential (Δψm) was measured using the fluorescent cationic JC-1 dye, and 4) mitochondrial maximum rate of ATP synthesis (ATPsyn) was measured using the bioluminescent ApoSENSOR assay kit. Results: The table summarizes all MITO function measurements. ADPresp, COV-IV activity, Δψm, and ATPsyn were significantly lower in renal epithelial cells from HF dogs compared to NL dogs. Moreover, all MITO parameters were significantly lower in cells from CRS dogs when compared to NL dogs as well as to HF dogs. Conclusions: MITO function of renal epithelial cells is abnormal in HF dogs and markedly compromised in CRS dogs. MITO abnormalities likely contribute to renal dysfunction that accompanies HF. Additional investigations are needed to test if interventions that improve MITO function in the setting of HF can protect renal function or treat CRS
American Radium Society Appropriate Use Criteria Systematic Review and Guidelines on Reirradiation for Non-Small Cell Lung Cancer Executive Summary
No full textDefinitive thoracic reirradiation can improve outcomes for select patients with non-small cell lung cancer (NSCLC) with locoregional recurrences. To date, there is a lack of systematic reviews on safety or efficacy of NSCLC reirradiation and dedicated guidelines. This American Radium Society Appropriate Use Criteria Systematic Review and Guidelines provide practical guidance on thoracic reirradiation safety and efficacy and recommends consensus of strategy, techniques, and composite dose constraints to minimize risks of high-grade/fatal toxicities. Preferred Reporting Items for Systematic Reviews and Meta-Analyses systematic review assessed all studies published through May 2020 evaluating toxicities, local control and/or survival for NSCLC thoracic reirradiation. Of 251 articles, 52 remained after exclusions (3 prospective) and formed the basis for recommendations on the role of concurrent chemotherapy, factors associated with toxicities, and optimal reirradiation modalities and dose-fractionation schemas. Stereotactic body radiation therapy improves conformality/dose escalation and is optimal for primary-alone failures, but caution is needed for central lesions. Concurrent chemotherapy with definitive reirradiation improves outcomes in nodal recurrences but adds toxicity and should be individualized. Hyperfractionated reirradiation may reduce long-term toxicities, although data are limited. Intensity modulated reirradiation is recommended over 3D conformal reirradiation. Particle therapy may further reduce toxicities and enable safer dose escalation. Acute esophagitis/pneumonitis and late pulmonary/cardiac/esophageal/brachial plexus toxicities are dose limiting for reirradiation. Recommended reirradiation composite dose constraints (2 Gy equivalents): esophagus V60 \u3c 40%, maximum point dose (Dmax) \u3c 100 Gy; lung V20 \u3c 40%; heart V40 \u3c 50%; aorta/great vessels Dmax \u3c 120 Gy; trachea/proximal bronchial tree Dmax \u3c 110 Gy; spinal cord Dmax \u3c 57 Gy; brachial plexus Dmax \u3c 85 Gy. Personalized thoracic reirradiation approaches and consensus dose constraints for thoracic reirradiation are recommended and serve as the basis for ongoing Reirradiation Collaborative Group and NRG Oncology initiatives. As very few prospective and small retrospective studies formed the basis for generating the dose constraint recommended in this report, further prospective studies are needed to strengthen and improve these guidelines
Plain language summary of first-line amivantamab-lazertinib in previously untreated high-risk EGFR-altered non-small-cell lung cancer in MARIPOSA
No full textWhat is this summary about? This plain language summary describes the efficacy results from high-risk subgroups in the phase 3 MARIPOSA study. The study evaluated the safety and efficacy of amivantamab plus lazertinib, a third-generation tyrosine kinase inhibitor (TKI), compared with osimertinib, another third-generation TKI, or lazertinib in patients with advanced non-small-cell lung cancer (NSCLC) with exon 19 deletions (Ex19del) or exon 21 L858R substitution alterations in the epidermal growth factor receptor (EGFR) gene who had not received treatment before. Among all patients, at a median follow-up of 22 months, the median progression-free survival (PFS) for amivantamab plus lazertinib was 23.7 months compared with 16.6 months for osimertinib, with a 30% lower risk of their disease getting worse or dying. Median duration of response was 9 months longer with amivantamab plus lazertinib compared with osimertinib. Here, we report the results from a secondary analysis of the MARIPOSA study in patients with high-risk cancer characteristics associated with poor disease outcomes, such as TP53 gene alterations, cancer DNA in the bloodstream, and liver or brain metastases. We will refer to patients with high-risk cancer traits as ‘high-risk subgroups’.
What were the results? 1074 adults with locally advanced or metastatic EGFR-altered NSCLC were randomly divided into 3 treatment groups (patients who received amivantamab plus lazertinib, osimertinib alone, or lazertinib alone) in a 2:2:1 ratio. Here, we report the results for the amivantamab plus lazertinib and osimertinib monotherapy groups. Among high-risk subgroups, the median PFS was 20.3 months for amivantamab plus lazertinib compared with 15.0 months for osimertinib. PFS benefits were seen for those without TP53 alterations, cancer DNA in the bloodstream, and liver or brain metastases. As with treatments for NSCLC and other cancers, side effects occurred in most patients, many of which are commonly seen with amivantamab and other EGFR-targeting therapies. Venous thromboembolic events (VTE), commonly associated with lung cancer, occurred more often in patients receiving amivantamab plus lazertinib compared with those receiving osimertinib.Severe VTEs were rare (less than 1%). However, few patients received anticoagulants to prevent VTEs (5%) or stopped taking amivantamab plus lazertinib due to these side effects (amivantamab plus lazertinib: 3%; osimertinib: less than 1%).
What do the results mean? Most patients with advanced NSCLC have at least one high-risk feature. Among high-risk subgroups, amivantamab plus lazertinib compared with osimertinib extended the time that their cancer did not worsen. These results could be relevant to a wide range of patients with amivantamab plus lazertinib as a potential treatment option
Clinical Characteristics and Outcomes of Patients with Cirrhosis Who Develop Infective Endocarditis
No full textBackground: Infective endocarditis (IE) is an increasingly common infection that results in significant morbidity and mortality. An important but under-analyzed subpopulation of patients with IE are those with concomitant cirrhosis. This study compared the characteristics and outcomes of patients with and without cirrhosis who were hospitalized with IE.
Methods: The authors conducted a retrospective cohort study in adult patients with IE admitted at a single center from 2010 to 2020, comparing outcomes between those with and without cirrhosis at the time of admission.
Results: A total of 22 patients with a history of cirrhosis and 356 patients without a history of cirrhosis were included. Over a quarter (27.3%) of those with cirrhosis experienced a decompensation event within two years of their admission for IE. Clinical features, microbiology, and direct complications from IE were largely similar between groups. There was no significant difference in IE-related mortality rates between groups, although, in an overall survival analysis, the group with cirrhosis did have a higher risk of all-cause mortality at 2 years (HR = 2.85; p = 0.012).
Conclusions: This study highlights that IE in patients with cirrhosis may contribute to or trigger decompensation events. Further research is warranted to better understand morbidity outcomes in patients with cirrhosis who develop IE
Profiling Blood-Based Neural Biomarkers and Cytokines in Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis Using Single-Molecule Array Technology
No full textExperimental autoimmune encephalomyelitis (EAE) is a preclinical animal model widely used to study multiple sclerosis (MS). Blood-based analytes, including cytokines and neural biomarkers are the predictors of neurodegeneration, disease activity, and disability in patients with MS. However, understudied confounding factors cause variation in reports on EAE across animal strains/studies, limiting the utility of these biomarkers for predicting disease activity. In this study, we investigated blood-based analyte profiles, including neural markers (NFL and GFAP) and cytokines (IL-6, IL-17, IL-12p70, IL-10, and TNF-α), in two clinically distinct EAE models: relapsing-remitting (RR)-EAE and chronic-EAE. Ultrasensitive single-molecule array technology (SIMOA, Quanterix) was used to profile the analytes in the blood plasma of mice at the acute, chronic, and progressive phases of disease. In both models, NFL was substantially increased during post-disease onset across all phases, with a pronounced increase observed in chronic-EAE. The leakage of GFAP into peripheral blood was also greater after disease onset in both EAE models, especially in the acute phase of chronic-EAE. Among all cytokines, only IL-10 had consistently lower levels in both EAE models throughout the course of disease. This study suggests NFL, GFAP, and IL-10 as potential translational predictors of disease activity in EAE, making them potential candidates as surrogate markers for the preclinical testing of therapeutic interventions in animal models of MS
Functional outcomes reporting using an adjusted outcomes index for mechanical thrombectomy in anterior cerebral artery occlusions – A case series
No full textIntroduction: The decision to intervene with mechanical thrombectomy (MT) for anterior cerebral artery (ACA) strokes is often made based on anticipated long-term functional outcomes using modified Rankin scores (mRS) which is primarily based on ambulatory status. Here, we review our single-center experience with ACA MT and evaluate the utility of various functional outcomes reporting.
Methods: A case series of 15 patients undergone MT for ACA stroke using the Solitaire or Trevo stent-retrievers was completed. The data retrieved included patient demographics, initial National Institute of Health Stroke Scale (NIHSS), thrombolysis in cerebral infarction (TICI) scores and number of passes, post-procedure 24-hour NIHSS, intra-operative or post-operative complications, discharge NIHSS and mRS, and 90-day mRS.
Results: There were 87 % favorable ACA TICI scores (i.e. 2B/C and 3) and 80 % first pass recanalization rate. The Solitaire 4 mm stent-retriever was employed in the majority of cases (60 %). No procedural complications were noted in 73 % of cases and no hemorrhagic conversion in 87 % of cases. 90-day mRS scores of 0–2 were noted in 26 % of patients. Using an adjusted outcomes index, 80 % of patients had favorable outcomes based on the 24-hour baseline-adjusted NIHSS score decrease of ≥ 41 %.
Conclusion: Our preliminary findings here highlight successful radiographic and favorable functional outcomes using the Solitaire and Trevo stent-retrievers (3–6 mm luminal diameter) for ACA MT when reporting with the adjusted outcomes index as compared to the 90-day mRS score. Further studies comparing these outcomes reporting metrics with a larger sample size will be needed to further elucidate this notable difference
Pain, Anger, and Aggression: A Complex Interplay of Symptoms, Social Factors, and Behaviors.
No full textWhat Characteristics of Orthopaedic Surgery Residency Programs Are Associated With Increased Percentage of Matched Women Residents?
No full textBACKGROUND: Women are underrepresented in the field of orthopaedics, and growth of the proportion of women is lagging behind all other medical specialties. Improvement begins with recruiting more women residents; however, few data exist regarding the factors that may attract women applicants to orthopaedic training programs.
QUESTIONS/PURPOSES: In the 2020 to 2023 match cycles: (1) Was there a relationship between the percentage of women who matched into orthopaedic residency programs and the percentage of women residents or the percentage of women faculty in a given program? (2) What other program attributes were associated with an increased percentage of matched women applicants? (3) How did these trends change prior to and after the COVID-19 pandemic?
METHODS: Internet searches were used to identify orthopaedic surgery residency programs and obtain program-specific information including match data, resident and faculty rosters, fellowship offerings, and parental leave policies. NIH research funding rank of the institution, United States News and World Report (USNWR) ranking of the orthopaedic department, and Doximity program rank were determined using public data. A total of 175 programs were included in the 2020 match cycle, 197 in 2021, 201 in 2022, and 202 in 2023. Pearson correlations and Wilcoxon rank sums were used to evaluate the association between various program attributes and matched women applicants. Mixed-effects logistic regression was performed to determine ORs for matching women residents based on independent variables of interest.
RESULTS: A positive relationship was found between women faculty and women residents matched, as an increasing percentage of women faculty were associated with a modestly increasing percentage of matched women residents (r = 0.19, p \u3c 0.001). The same relationship was found with current women residents, in that a greater percentage of women residents correlated modestly with a greater percentage of women matched (r = 0.22, p \u3c 0.001). Additionally, as independent variables, a higher percentage of women faculty and current women residents separately suggested increased odds of matching women residents (faculty OR 1.28 [95% confidence interval (CI) 1.14 to 1.44], residents OR 1.21 [95% CI 1.11 to 1.32]). Other program attributes associated with an increased percentage of matched women residents included number of fellowship offerings and ranking in Doximity, USNWR, and NIH funding. An increasing number of fellowship offerings was associated with an increasing percentage of women matched (r = 0.32, p \u3c 0.001), and as an independent variable, more fellowship offerings suggested slightly increased odds of matching women residents (OR 1.14 [95% CI 1.08 to 1.19]). There was a higher percentage of matched women residents in programs with a top-40 ranking in Doximity (top-40 median 25%, not top-40 median 17%; p = 0.004), USNWR (top-40 median 29%, not top-40 median 20%; p = 0.02), or NIH funding (top-40 median 33%, not top-40 median 17%; p \u3c 0.001) in 2023. The percentage of matched women residents changed from pre- to post-COVID-19 pandemic. Of the programs that had match data available, 24% (204 of 838) of matched applicants were women in 2023, an increase from 20% in 2020. In all, 34% (55 of 164) of these programs did not match a woman resident in the 2023 cycle, a decrease from 2020 (44%). The odds of matching women residents slightly increased with time while holding percentage of women faculty, percentage of women residents, and number of fellowship offerings constant (time effect in each respective model: faculty OR 1.13 [95% CI 1.04 to 1.22], resident OR 1.10 [95% CI 1.02 to 1.19], fellowship OR 1.11 [95% CI 1.03 to 1.19]).
CONCLUSION: Given that programs with greater presence of women faculty and women residents are associated with higher percentages of matched women applicants, training institutions should focus their efforts on recruiting women orthopaedic surgeons to their staff, with the goal of subsequently increasing their representation of women residents. Additionally, given our data on fellowship offerings and program rankings, programs can work to expand the resources available at their institution, including fellowships and research funding. Overall, our data suggest that women who apply to orthopaedic residencies are in a strong position, requiring programs to compete for them, with well-rounded, diverse, and highly ranked programs having greater success.
CLINICAL RELEVANCE: This is a new and positive shift for the field of orthopaedic surgery toward gender parity. Future studies should look further into the effect of different parental leave policies on matching women residents and factors that draw women to certain orthopaedic subspecialties