Citations

Background: Posthepatectomy liver failure (PHLF) represents a life-threatening complication with limited therapeutic options. Neutrophils play a critical and dynamic role during regeneratory processes, but their role in human liver regeneration is incompletely understood, especially as underlying liver disease, detectable in the majority of patients, critically affects hepatic regeneration. Here we explored intrahepatic neutrophil accumulation and neutrophil extracellular traps (NETs) in patients with PHLF and validated the functional relevance of NETs in a murine partial hepatectomy (PHx) model. Methods: We investigated the influx of neutrophils, macrophages, eosinophils, and mast cells and the presence of their respective extracellular traps in liver biopsies of 35 patients undergoing hepatectomy (10 patients with PHLF) before and after the initiation of liver regeneration by fluorescence microscopy. In addition, NET formation and neutrophil activation were confirmed by plasma analysis of 99 patients (24 patients with PHLF) before and up to 5 days after surgery. Furthermore, we inhibited NETs via DNase I in a murine PHx model of mice with metabolically induced liver disease. Results: We detected rapid intrahepatic neutrophil accumulation, elevated levels of myeloperoxidase release, and NET formation in regenerating human livers, with a significantly higher increase of infiltrating neutrophils and NETs in patients with PHLF. Circulating markers of neutrophil activation, including elastase, myeloperoxidase, and citrullinated histone H3, correlated with markers of liver injury. In a murine PHx model, we showed that the inhibition of NET accelerated hepatocyte proliferation and liver regeneration. Conclusions: Patients with PHLF showed accelerated intrahepatic neutrophil infiltration and NET formation, which were associated with liver damage. Further, we identified postsurgical myeloperoxidase levels as predictive markers for adverse outcomes and observed that blocking NETs in a murine PHx model accelerated tissue regeneration.

AbstractTo determine whether quantitative computed tomography (qCT)‐derived metrics of pulmonary vascular volume distribution could distinguish chronic obstructive pulmonary disease (COPD) subjects with associated pulmonary hypertension (PH) from those without and to characterize associations of these measurements with clinical and physiological characteristics and outcomes. We collected retrospective CT, pulmonary hemodynamic, clinical, and outcomes data from subjects with COPD and right‐heart catheterization‐confirmed PH (PH‐COPD) and control subjects with COPD but without PH. We measured the volumes of pulmonary vessels < 5 and >10 mm2 in cross‐sectional area as a percentage of total pulmonary vascular volume (qCT‐derived volume of pulmonary vessels < 5 mm2 in cross‐sectional area as a volume fraction of total pulmonary blood volume [BV5%] and qCT‐derived volume of pulmonary vessels > 10 mm2 in cross‐sectional area [BV10] as a volume fraction of total pulmonary blood volume [BV10%], respectively) using Functional Respiratory Imaging (FRI), an automated qCT platform, and compared them between PH and control arms and between subjects with mild‐moderate PH and those with severe disease. Correlations of hemodynamics with pulmonary function and associations with survival were tested. Forty‐five PH‐COPD and 42 control subjects were studied. BV5% was lower in PH subjects (32.2% vs. 37.7%, p = 0.003), and BV10% was higher (50.2% vs. 43.5, p = 0.001). Subjects with severe PH did not differ from those with mild‐moderate PH in qCT. Pulmonary vascular volumes were not associated with pulmonary function. BV10 was associated with mean pulmonary artery pressure (r = 0.3, p = 0.05). Associations with survival were observed for BV5% (hazard ratio 0.63, p = 0.02) and BV10% (hazard ratio 1.43, p = 0.03) in the PH‐COPD arm, but not for controls. qCT‐derived measures of pulmonary vascular volume may have diagnostic and prognostic significance in PH‐COPD and should be investigated further as screening and risk stratification tools

Background: Recently, the posterior horn lateral meniscal oblique radial tear (LMORT) was identified in 12% of acute anterior cruciate ligament (ACL) injuries. However, patient-reported outcomes for repair of this relatively common tear have not been reported. Purpose: To determine the minimum 2-year functional outcomes after LMORT repair at the time of ACL reconstruction (ACLR) compared to a matched cohort of patients who underwent isolated ACLR (iACLR). Study Design: Cohort study; Level of evidence, 3. Methods: Included were 100 patients (mean age at surgery, 21 years; range, 13-45 years) who underwent primary ACLR between 2010 and 2018. The mean follow-up period was 4.1 ± 2.0 years (range, 2.0-9.2 years). A total of 50 patients with surgically repaired LMORT type 3 or type 4 lesions, defined as partial or complete tears >10 mm from the root (LMORT group) were matched 1:1 based on age, date of surgery, and graft choice with 50 patients who underwent iACLR (iACLR group). The postoperative outcomes were compared between groups using the International Knee Documentation Committee subjective score (sIKDC) and the Tegner activity scale. An updated medical history was obtained via the electronic medical record to determine any subsequent complications and reoperations. Results: There was 1 ACL graft failure in each group as well as 5 (10%) reoperations per group. None of the patients in the LMORT group necessitated a lateral meniscal revision repair or partial meniscectomy. The LMORT and iACLR groups reported comparable sIKDC scores (92.5 ± 6.8 vs 91.9 ± 8.2, respectively; P = .712) as well as Tegner scores (6.7 ± 1.8 vs 6.6 ± 1.8, respectively; P = .910) at final follow-up. No failures of the LMORT repairs were reported. Conclusion: The study findings demonstrated that reoperations, graft failure rates, patient-reported outcomes, and patient activity levels at ≥2 years after type 3 and 4 LMORT repairs at the time of ACLR compared favorably with those of a matched cohort of patients who underwent iACLR with intact meniscus.

Background: Radiographic surveillance of colorectal cancer (CRC) after curative-intent therapy is costly and unreliable. Methylated DNA markers (MDMs) detected primary CRC and metastatic recurrence with high sensitivity and specificity in cross-sectional studies. This study evaluated using serial MDMs to detect recurrence and monitor the treatment response to anti-cancer therapies. Methods: A nested case-control study was drawn from a prospective cohort of patients with CRC who completed curative-intent therapy for CRC of all stages. Plasma MDMs were assayed vis target enrichment long-probe quantitative-amplified signal assays, normalized to B3GALT6, and analyzed in combination with serum carcinoembryonic antigen to yield an MDM score. Clinical information, including treatment and radiographic measurements of the tumor burden, were longitudinally collected. Results: Of the 35 patients, 18 had recurrence and 17 had no evidence of disease during the study period. The MDM score was positive in 16 out of 18 patients who recurred and only 2 of the 17 patients without recurrence. The MDM score detected recurrence in 12 patients preceding clinical or radiographic detection of recurrent CRC by a median of 106 days (range 90–232 days). Conclusions: Plasma MDMs can detect recurrent CRC prior to radiographic detection; this tumor-agnostic liquid biopsy approach may assist cancer surveillance and monitoring.

Abstract Despite major strides in cancer research and therapy, these advances have not been equitable across race and ethnicity. Historically marginalized groups (HMG) are more likely to have inadequate preventive screening, increased delays in diagnosis, and poor representation in clinical trials. Notably, Black, Hispanic, and Indigenous people represent 30% of the population but only 9% of oncology clinical trial participants. As a result, HMGs lack equitable access to novel therapies, contradicting the principle of distributive justice, as enshrined in the Belmont report, which demands the equitable selection of subjects in research involving human subjects. The lack of clinical trial diversity also leads to low generalizability and potentially harmful medical practices. Specifically, patients with brain cancer face unique barriers to clinical trial enrollment and completion due to disease-specific neurologic and treatment-induced conditions. Collectively, the intersection of these disease-specific conditions with social determinants of health fosters a lack of diversity in clinical trials. To ameliorate this disparity in neuro-oncology clinical trial participation, we present interventions focused on improving engagement of HMGs. Proposals range from inclusive trial design, decreasing barriers to care, expanding trial eligibility, access to tumor profiling for personalized medical trials, setting reasonable metrics and goals for accrual, working with patient community stakeholders, diversifying the neuro-oncology workforce, and development of tools to overcome biases with options to incentivize equity. The diversification of participation amongst neuro-oncology clinical trials is imperative. Equitable access and inclusion of HMG patients with brain tumors will not only enhance research discoveries but will also improve patient care.

ImportanceYoung women with breast cancer who have germline pathogenic variants in BRCA1 or BRCA2 face unique challenges regarding fertility. Previous studies demonstrating the feasibility and safety of pregnancy in breast cancer survivors included limited data regarding BRCA carriers.ObjectiveTo investigate cumulative incidence of pregnancy and disease-free survival in young women who are BRCA carriers.Design, Setting, and ParticipantsInternational, multicenter, hospital-based, retrospective cohort study conducted at 78 participating centers worldwide. The study included female participants diagnosed with invasive breast cancer at age 40 years or younger between January 2000 and December 2020 carrying germline pathogenic variants in BRCA1 and/or BRCA2. Last delivery was October 7, 2022; last follow-up was February 20, 2023.ExposurePregnancy after breast cancer.Main Outcomes and MeasuresPrimary end points were cumulative incidence of pregnancy after breast cancer and disease-free survival. Secondary end points were breast cancer–specific survival, overall survival, pregnancy, and fetal and obstetric outcomes.ResultsOf 4732 BRCA carriers included, 659 had at least 1 pregnancy after breast cancer and 4073 did not. Median age at diagnosis in the overall cohort was 35 years (IQR, 31-38 years). Cumulative incidence of pregnancy at 10 years was 22% (95% CI, 21%-24%), with a median time from breast cancer diagnosis to conception of 3.5 years (IQR, 2.2-5.3 years). Among the 659 patients who had a pregnancy, 45 (6.9%) and 63 (9.7%) had an induced abortion or a miscarriage, respectively. Of the 517 patients (79.7%) with a completed pregnancy, 406 (91.0%) delivered at term (≥37 weeks) and 54 (10.4%) had twins. Among the 470 infants born with known information on pregnancy complications, 4 (0.9%) had documented congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in disease-free survival was observed between patients with or without a pregnancy after breast cancer (adjusted hazard ratio, 0.99; 95% CI, 0.81-1.20). Patients who had a pregnancy had significantly better breast cancer–specific survival and overall survival.Conclusions and RelevanceIn this global study, 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. Pregnancy following breast cancer in BRCA carriers was not associated with decreased disease-free survival.Trial RegistrationClinicalTrials.gov Identifier: NCT03673306