Advanced hepatic fibrosis, driven by the activation of hepatic stellate cells (HSCs), affects millions worldwide and is the strongest predictor of mortality in nonalcoholic steatohepatitis (NASH); however, there are no approved antifibrotic therapies. To identify antifibrotic drug targets, we integrated progressive transcriptomic and morphological responses that accompany HSC activation in advanced disease using single-nucleus RNA sequencing and tissue clearing in a robust murine NASH model. In advanced fibrosis, we found that an autocrine HSC signaling circuit emerged that was composed of 68 receptor-ligand interactions conserved between murine and human NASH. These predicted interactions were supported by the parallel appearance of markedly increased direct stellate cell-cell contacts in murine NASH. As proof of principle, pharmacological inhibition of one such autocrine interaction, neurotrophic receptor tyrosine kinase 3–neurotrophin 3, inhibited human HSC activation in culture and reversed advanced murine NASH fibrosis. In summary, we uncovered a repertoire of antifibrotic drug targets underlying advanced fibrosis in vivo. The findings suggest a therapeutic paradigm in which stage-specific therapies could yield enhanced antifibrotic efficacy in patients with advanced hepatic fibrosis.

Improved imaging and neoadjuvant chemotherapy (NAT) have led to higher pathologic complete response rates (pCR) in patients with invasive breast cancer. This has questioned the necessity of surgery and axillary lymph node (ALN) dissection in these patients. Prospective clinical trials are implementing extensive core biopsies of the tumor bed of patients with clinical complete response as a means to identify and spare them breast surgery. In addition, it is anticipated that patients with pCR are most likely going to have no or minimal disease in ALN as well. To verify the feasibility of these trials, we performed a pathologic analysis of all our patients who have undergone NAT from 2009 to present. Using pathology data base, we identified 362 patients treated with neoadjuvant chemotherapy followed by surgery. Clinical and pathologic information including gross and microscopic descriptions as well as biomarker status was collected. pCR was 50% for patients with negative ALN pretreatment but only 28% for patients with positive ALN at diagnosis. Despite achieving pCR in the breast, up to 10% of patients with positive ALN and 1% with negative ALN had persistent disease. Eight percent of patients that were presumed to have no ALN disease either clinically and or by imaging were found to have metastatic carcinoma in ALN. The metastases were predominantly (80%) <5 mm, and not palpable on physical examination and or due to biopsy sampling error. pCR in breast and ALN directly correlated with tumor size, ALN disease, and Her2 positive and triple negative receptor phenotype. In breast cancer patients who are node positive at time of diagnosis with pCR in the breast after neoadjuvant chemotherapy, residual lymph node disease was very uncommon. Further study is warranted to select patients who may avoid breast and axillary surgery post neoadjuvant chemotherapy.

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Background Precision surgery is becoming increasingly important in the field of Orthopaedic Oncology. Image-guided percutaneous cryosurgery (CRA) has emerged as a valid treatment modality for extra-abdominal desmoid tumors (EDTs). To date, most CRA procedures use CT-based guidance which fails to properly characterize tumor segments. Computer-guided MRI navigation can address this issue however, the lack of a fixed landmark for registration remains a challenge. Successful CRA correlates directly with precision approaches facilitated by intraoperative imaging guidance. This study presents a novel approach of using skin fiducial markers to overcome the challenge of a MRI-based navigation CRA for symptomatic or progressive EDTs. Methods In this retrospective study conducted between 2018–2020, 11 patients at a single center with symptomatic or progressive EDTs were treated with CRA using intraoperative MRI navigation. Fifteen cryosurgery procedures were performed, each adhering to a personalized pre-operative plan. Total tumor size, viable and non-viable portions pre- and post-operation, and SF-36 questionnaire evaluating subjective health were recorded. Results All CRAs demonstrated 100% adherence to the predetermined plan. Overall, tumor size decreased significantly (p-value = 0.02) with significant reduction in viable tissue, (p-value = 0.03). Four patients required additional CRAs. Only one patient’s tumor did not reduce in size. According to the SIR adverse event classification guidelines, one participant experienced a mild complication. SF36 physical and mental scores improved significantly (p-value = 0.002, p-value < 0.000, respectively). Conclusion These findings demonstrate the feasibility and efficacy of performing percutaneous cryosurgery using skin fiducial marker registration for MRI-computed navigation to safely treat EDTs. This navigation approach may be implemented in other soft tissue procedures requiring precision navigated surgery.

Background: Computer-guided MRI navigation for soft tissue tumors remains a challenge due to lack of a fixed landmark for registration. Extra-abdominal Desmoid Tumors (EDTs) are soft tissue tumors for which image-guided percutaneous cryosurgery (CRA) has emerged as a valid treatment modality. Successful CRA relies on precise intraoperative image guidance. This study, present a novel approach of using skin fiducial markers to overcome this challenge and navigate insertion of MRI-based CRA needles as a treatment for symptomatic or progressive EDTs. Methods: In this retrospective study, conducted between 2018-2020, eleven patients at a single center with symptomatic or progressive EDTs were treated with CRA using intraoperative MRI navigation. 15 cryoablation procedures were performed, each adhering to a personalized pre-operative plan. We compared the total tumor size, necrotic and viable portions pre- and post-operation, and the SF-36 questionnaire evaluating subjective health.Results: All CRAs demonstrated 100% adherence to the pre-determined plan. Overall, tumor size decreased significantly (p-value=0.02). Four patients required additional CRAs. Only one patient’s tumor did not reduce in size. There was a significant reduction in viable tissue, (p-value=0.03), but not in necrotic tissue (p-value=0.66). According to the SIR adverse event classification guidelines, one participant experienced muscle necrosis, a mild complication. Both the physical and mental scores improved significantly (p-value (physical)=0.002; p-value (mental)<0.000).Conclusion: These findings demonstrate the feasibility and efficacy of performing percutaneous cryosurgery using skin fiducial marker registration and MRI-computed navigation to safely treat EDTs. This navigation approach may be implemented in other soft tissue procedures requiring precision navigated surgery. Trial Registration: Retrospectively registered.

Introduction: SARS-CoV-2 infection may cause a severe inflammatory response, inflicting severe morbidity and mortality. This risk is modestly increased in pregnant patients. Despite the hypercoagulability and immunosuppression associated with pregnancy, most pregnant women experience a mild COVID-19 infection. Maternal extracellular vesicles (EVs) may interact with endothelial and immune components to facilitate a favorable disease course. This pilot study aimed to explore the characteristics of EVs released during COVID-19 infection occurring during the third trimester of pregnancy.Methods: In this prospective study, blood samples were obtained from 16 healthy non-pregnant (NP), 18 healthy-pregnant (HP), and 22 COVID-19 positive pregnant subjects (CoV-P). Disease course and pregnancy outcomes were assessed and EVs were characterized. Of note, limited volumes of sample acquired from the subjects made it necessary to use smaller and different subsets of samples for each analysis.Results: The majority (91%) of the COVID-19-pregnant subjects (18 mild and 2 moderate disease) experienced good pregnancy-related outcomes. EV concentrations were higher in healthy-pregnant subjects compared to non-pregnant subjects (p = 0.0041) and lower in COVID-19-pregnant subjects compared to healthy-pregnant subjects (p = 0.0150). CD63 exosome marker expression was higher in EVs of healthy-pregnant subjects and COVID-19-pregnant subjects compared to EVs of non-pregnant subjects (p = 0.0149, p = 0.0028, respectively). Similar levels of SARS-CoV-2 entry proteins (ACE-2 and TMPRSS2) were found in all three groups. Cytokine content increased in healthy-pregnant subject-EVs compared to non-pregnant EVs, while IL-2 and IL-6 levels were decreased in COVID-19-pregnant subject-EVs compared to healthy-pregnant subject-EVs (p = 0.043, p = 0.0390, respectively). CD8+, cytotoxic T-cell marker, was lower in non-pregnant EVs compared to healthy-pregnant subject-EVs and to COVID-19-pregnant subjects (p = 0.0108, p &lt; 0.0001, respectively). COVID-19- pregnant subject-EVs demonstrated higher levels of platelet activation marker (CD62P) than non-pregnant (p = 0.0327) and healthy-pregnant subjects (p = 0.0365). Endothelial marker EV-CD144+ was lower in healthy-pregnant subjects versus non-pregnant subjects (p = 0.0093), but similar in COVID-19-pregnant and non-pregnant subjects. Other EVs’ coagulation markers/activity, D-Dimer and fibrinogen levels were similar in healthy-pregnant subjects and COVID-19 positive pregnant subjects.Conclusion: COVID-19 positive pregnant subjects’ EVs demonstrated an attenuated inflammatory response, with no additional activation of the coagulation system.