Citations

Abstract Purpose: The aim of PREDICT was to confirm clinical validity and the potential for clinical utility of serial circulating tumor cell (CTC) enumeration in patients with metastatic breast cancer, focusing on its prognostic value in different breast cancer subtypes and clinical settings. Experimental Design: In total, 4,436 individual patient-level data with CTC results from both baseline and one follow-up (CellSearch; Menarini Silicon Biosystems) were analyzed to evaluate the association between CTC detection and overall survival (OS) in the full patient cohort and separately for tumor and treatment types. Results: Using the cutoff ≥1 CTC for CTC positivity, 913 (20.6%) patients had 0 CTCs at both time points (neg/neg) and 325 (7.3%) and 1,189 (26.8%) patients converted from CTC negative to CTC positive (neg/pos) or vice versa (pos/neg), whereas 2,009 (45.3%) patients had at least one CTC at both time points (pos/pos). The median OS for the neg/neg, neg/pos, pos/neg, and pos/pos group was 45.6, 26.1, 32.3, and 17.3 months, respectively (P < 0.0001, global log-rank test). CTC responders (pos/neg) showed a lower risk of death compared with CTC nonresponders (pos/pos; HR, 0.48; 95% confidence interval, 0.44–0.53). Similar results were obtained in subgroup analyses according to hormone receptor and HER2 subtype, treatment type, and with a ≥5 CTC cutoff for CTC positivity. Conclusions: Follow-up CTC assessments strongly predict OS independently from tumor subtype and treatment. New randomized trials to define the clinical utility of CTC monitoring for risk stratification and as an early response marker in metastatic breast cancer are urgently needed.

Background Intra-articular corticosteroid (IACS) injection and peri-articular corticosteroid injection are commonly used to treat musculoskeletal conditions. Results vary by musculoskeletal region, but most studies report short-term benefit with mixed results on long-term relief. Publications showed adverse events from single corticosteroid injections. Recommended effective doses were lower than those currently used by clinicians. Methods Development of the practice guideline for joint injections was approved by the Board of Directors of the American Society of Regional Anesthesia and Pain Medicine and the participating societies. A Corticosteroid Safety Work Group coordinated the development of three guidelines: peripheral nerve blocks and trigger points; joints; and neuraxial, facet, and sacroiliac joint injections. The topics included safety of the technique in relation to landmark-guided, ultrasound-guided, or radiology-aided injections; effect of the addition of the corticosteroid on the efficacy of the injectate; and adverse events related to the injection. Experts on the topics were assigned to extensively review the literature and initially develop consensus statements and recommendations. A modified version of the US Preventive Services Task Force grading of evidence and strength of recommendation was followed. A modified Delphi process was adhered to in arriving at a consensus. Results This guideline focuses on the safety and efficacy of corticosteroid joint injections for managing joint chronic pain in adults. The joints that were addressed included the shoulder, elbow, hand, wrist, hip, knee, and small joints of the hands and feet. All the statements and recommendations were approved by all participants and the Board of Directors of the participating societies after four rounds of discussion. There is little evidence to guide the selection of one corticosteroid over another. Ultrasound guidance increases the accuracy of injections and reduces procedural pain. A dose of 20 mg triamcinolone is as effective as 40 mg for both shoulder IACS and subacromial subdeltoid bursa corticosteroid injections. The commonly used dose for hip IACS is 40 mg triamcinolone or methylprednisolone. Triamcinolone 40 mg is as effective as 80 mg for knee IACS. Overall, IACS injections result in short-term pain relief from a few weeks to a few months. The adverse events include an increase in blood glucose, adrenal suppression, detrimental effect on cartilage lining the joint, reduction of bone mineral density, and postoperative joint infection. Conclusions In this practice guideline, we provided specific recommendations on the role of corticosteroids in joint, bursa, and peritendon injections for musculoskeletal pain.

Abstract Background Antibiograms are an important stewardship tool that can inform optimal empiric therapy; most antibiograms are hospital-wide. Unit-specific antibiogram data for unique patient populations including intensive care unit and pediatrics is robust; however, published experience with unit-specific antibiograms in the hematology-oncology (heme-onc) population is limited. These patients are unique because of the common use of antimicrobial prophylaxis, prolonged broad-spectrum antibiotics, and an immunocompromised state. We sought to examine the trends in antibiogram antimicrobial susceptibility over time. Methods This retrospective quality initiative included microbiology results (first isolates per patient per timeframe) from Mayo Clinic Rochester from 2012 to 2022. Eligible cultures were those identified as being obtained from one of 8 hematology, oncology, or bone marrow transplant inpatient units. Agar dilution susceptibility testing and Clinical and Laboratory Standards Institute (CLSI) breakpoints were used. Screening PCRs (eg, VRE PCR) were excluded. Culture and susceptibilities were identified by an EMR based report, compiled annually, and reported for two-year periods. Susceptibility rates were compared using the Chi-square test and Chi-square analysis for trends. Results There were 4 gram-negative and 5 gram-positive organism groups that met CLSI antibiogram criteria of ≥ 30 isolates and were included (tables 1-4). There were several significant differences in comparison to the hospital-wide antibiogram, with lower antibiotic susceptibility rates in the heme-onc units for multiple organisms, notably fluoroquinolones to E.coli and P. aeruginosa and several cephalosporins to Enterobacterales as well as penicillin and levofloxacin to Viridans group Streptococcus and vancomycin to E. faecium (tables 1&2). Over the period of 2012-2013 to 2021-2022, susceptibility rates remained stable among the heme-onc antibiogram, with few significant changes (tables 3&4). Conclusion Heme-onc antibiograms illustrated susceptibility rate differences compared to our hospital-wide antibiograms, particularly for antimicrobials used as prophylaxis. Through population-specific antibiograms, providers may be able to improve empiric antibiotic selection. Disclosures Christina G. Rivera (O'Connor), Pharm.D, Gilead Sciences: Board Member

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261

Abstract Nocardiosis is an uncommon yet potentially devastating infection. Nocardia tends to affect individuals with chronic lung disease or immunocompromising conditions, 2 groups increasing in number. Incidence of nocardiosis is likely to increase as well, and it is vital to have an approach to this complex disease. Here, we aim to review the presentation, diagnosis, and management of Nocardia in the modern era. We will also highlight areas of uncertainty in our understanding of nocardiosis and propose a general approach to nocardiosis therapy, accounting for response and tolerance of Nocardia treatment.

Abstract BACKGROUND Mouse double minute 2 (MDM2) inhibits the tumor suppressor protein 53 (p53). Brigimadlin, a potent oral MDM2-p53 antagonist, restores wild-type (wt) p53 function and has shown early efficacy in patients with solid tumors. Glioblastoma (GBM) is an area of unmet need with 5-year survival at <10%. In p53 wt GBM patient-derived xenograft models, brigimadlin promotes tumor cell apoptosis and extends survival in combination with radiotherapy (RT). METHODS NCT05376800 is a Phase 0/Ia non-randomized, open-label, single-arm trial that aims to measure brigimadlin concentration in brain tumor tissue in patients with histologically or radiologically newly diagnosed GBM eligible for resection (Phase 0), and determine the maximum tolerated dose of brigimadlin plus RT in patients with TP53 wt, IDH wt, MGMT promoter unmethylated GBM (Phase Ia). In Phase 0, patients received one brigimadlin dose (30 mg or 45 mg) ~12-24 hours before resection. Phase 0 primary endpoints are the measured total concentration and the calculated unbound concentration of brigimadlin in brain tissue homogenate from non-contrast enhancing (NCE) and contrast enhancing (CE) regions. The predefined threshold for trial continuation is 0.5 nmol/L (corresponding to IC50 in GBM cell lines) unbound brigimadlin in CE samples in ≥50% of patients. Brigimadlin concentration was measured using liquid chromatography-mass spectrometry and corrected for amount of brigimadlin in residual blood. Unbound concentration was calculated using an in vitro estimate of unbound fraction (fu): 0.654% (rat brain slice). fu in human plasma was 0.22%. Ratio of unbound concentration in brain versus plasma (Kp,uu) was calculated. Biomarker testing was performed. RESULTS Data are available for 11 patients (brigimadlin 30 mg: n=6; 45 mg: n=5). In the 30 mg group, median total brigimadlin concentration in NCE samples was 267 nmol/L (4 samples, range 86-316 nmol/L) and 332 nmol/L (6 samples, range 272-952 nmol/L) in CE samples. In the 45 mg group, median total brigimadlin concentration in NCE samples was 197 nmol/L (5 samples, range 140-347 nmol/L) and 603 nmol/L (5 samples, range 441-905 nmol/L) in CE samples. Unbound concentration exceeded the 0.5 nmol/L threshold in most cases. Post-brigimadlin, an increase in selected p53 target gene expression was observed in CE versus NCE tissue. CONCLUSION Unbound brigimadlin concentrations in CE regions in all patients receiving the low dose of 30 mg brigimadlin exceeded the 0.5 nmol/L threshold. Kp,uu in most patients was close to 1 in CE regions. Biomarker data support target engagement in brain tissue. Our findings support continued investigation of brigimadlin in GBM. Recruitment is ongoing. Updated data will be presented.The trial is funded by Boehringer Ingelheim.

AbstractBackgroundThe clinical relevance of cardiac troponin (cTn) elevation in takotsubo syndrome (TTS) remains uncertain. The present study sought to investigate the role of cardiac troponin (cTn) elevations in mortality prediction of patients with Takotsubo syndrome (TTS).MethodsPatients enrolled in the International Takotsubo (InterTAK) Registry from January 2011 to February 2020 with available data on peak cTn levels were included in the analysis. Peak cTn levels during the index hospitalization were used to define clinically relevant myocardial injury. The threshold at which clinically relevant myocardial injury drives mortality at 1 year was identified using restricted cubic spline analysis.ResultsOut of 2′938 patients, 222 (7.6%) patients died during 1‐year follow‐up. A more than 28.8‐fold increase of cTn above the upper reference limit was identified as threshold for clinically relevant myocardial injury. The presence of clinically relevant myocardial injury was significantly associated with an increased risk of mortality at 5 years (adjusted HR 1.58, 95% CI 1.18–2.12, p =.002). Clinically relevant myocardial injury was related to an increased 5‐year mortality risk in patients with apical TTS (adjusted HR 1.57, 95% CI 1.21–2.03, p =.001), in presence of physical stressors (adjusted HR 1.60, 95% CI 1.22–2.11, p =.001), and in absence of emotional stressors (adjusted HR 1.49, 95% CI, 1.17–1.89, p =.001).ConclusionThis study for the first time determined a troponin threshold for the identification of TTS patients at excess risk of mortality. These findings advance risk stratification in TTS and assist in identifying patients in need for close monitoring and follow‐up.