Citations

OBJECTIVE Open resective surgery (ORS) has become the standard of care for focal drug-resistant epilepsy (DRE). However, minimally invasive surgical alternatives, such as laser interstitial thermal therapy (LITT), have also been shown to be safe and effective. A meta-analysis comparing both treatments is warranted to assess the benefits of each modality for focal DRE. METHODS A literature search was conducted until March 14, 2024, to identify studies comparing LITT and ORS in patients with DRE. The primary outcomes included seizure freedom (SF), length of hospital stay (LHS), and complication rate (CR). Subgroup analyses were performed based on age, epilepsy etiology, and propensity score–matched (PSM) studies. RESULTS Of 558 articles, 15 cohort studies met the authors’ inclusion criteria, encompassing 3873 patients for analysis. The rate of SF in the LITT group was 52.5% (95% CI 0.453–0.597, I 2 = 47.4%) and 67.1% (95% CI 0.602–0.739, I 2 = 57.4%) for the ORS group. LITT showed a significantly lower rate of SF compared to ORS (risk ratio [RR] 0.78, 95% CI 0.70–0.88, p ≤ 0.0001). However, when PSM studies (RR 0.85, 95% CI 0.63–1.15, p = 0.30) and studies on patients with temporal lobe epilepsy (TLE) (RR 0.88, 95% CI 0.67–1.14, p = 0.34) were analyzed, the SF rates were similar. Patients who underwent LITT had a significantly shorter LHS (mean difference 2.95 days, 95% CI 1.12–4.78, p < 0.00001), lower CR (RR 0.54, 95% CI 0.37–0.79, p < 0.002, I 2 = 32%), lower rate of ischemic stroke (RR 0.15, 95% CI 0.04–0.65, p = 0.01), and lower rate of permanent neurological deficits (RR 0.13, 95% CI 0.05–0.36, p < 0.0001). CONCLUSIONS Across unmatched studies evaluating focal DRE, ORS showed a higher rate of SF. However, pooled matched-cohort analyses showed no difference between interventions in achieving SF, a trend also noted in the authors’ PSM TLE sample. LITT, however, offered significantly shorter LHS and lower CRs. Future prospective studies should match patient populations to control for confounding factors and assess key outcomes, such as postoperative neurocognitive follow-up and quality of life measurements, in order to fully evaluate the risks and benefits of each approach.

Abstract Obesity is a chronic, heterogeneous, and complex disease associated with increased morbidity, mortality, and health-care costs. By 2030, 1 in 2 people in the United States will have obesity. Lifestyle interventions are the cornerstone of obesity management. However, they often fail to achieve clinically significant weight loss, necessitating additional treatments involving pharmacotherapy or procedures. Advancements in obesity pharmacotherapy have improved weight-loss outcomes and reduced associated comorbidities. Despite these advances, variability in response to treatment between individuals is still considerable. This variability reflects limitations in the current “one-size-fits-all” approach to obesity management. A precision medicine approach aims to address this gap by incorporating genetic, physiological, and behavioral characteristics to guide treatment selection and improve outcomes. Advances in multi-omics technologies, such as genomics, proteomics, metabolomics, and microbiome profiling, offer new opportunities to refine patient stratification and identify novel therapeutic targets. These tools may help move obesity care toward a more individualized and mechanism-based approach.

Low-grade endometrial stromal sarcomas (LG-ESS) are the second most common malignant uterine mesenchymal tumors, but in contrast to the more common leiomyosarcomas, they are often characterized by a prolonged and relatively indolent course. However, a subset of patients experience significant morbidity or die of disease, and it is difficult to predict which tumors will behave aggressively, with most published studies limited in either the number of tumors or the depth of pathologic parameters evaluated. Thus, we studied the clinicopathologic features of LG-ESS in 102 patients ranging from 21 to 74 (median: 47) years. All were treated with hysterectomy and staged according to both the FIGO 2018 system (stage IA=22, IB=36, I-not otherwise specified=5, II=16, III=13, IV=10) and the FIGO 1988 system (stage I=62, II=1, III=17, IV=22). Tumors measured 1.2-49 (median: 7) cm. Microscopically, 69 involved the endometrium while 33 were centered in the myometrium. Thirteen showed only minimal infiltration of the myometrium while the rest displayed the typical extensive myometrial permeation. The cervical stroma was involved in 18, the uterine serosa in 27, and the parametrium in 22. Conventional morphology resembling proliferative endometrial stroma was seen in 95, fibroblastic appearance in 35, smooth muscle differentiation in 23, sex cord-like differentiation in 21, stromal hyalinization in 21, and myxoid stroma in 9. Less common features included glandular differentiation resembling adenomyosis (n=5), pseudopapillary pattern (n=1), deciduoid appearance (n=2), adipocytic differentiation (n=2), multinucleated cells (n=2), and rhabdomyoblastic differentiation (n=1). Mitoses ranged from <1 to 20 per 10 high-power fields (median=3). Lymphovascular invasion and infarct-type necrosis were present in 64 and 23, respectively. Follow-up was available in all patients ranging from 16 to 358 (median: 79) months. Forty-six received adjuvant treatment as hormonal therapy (n=34), radiation (n=4), radiation and hormonal therapy (n=4), chemotherapy (n=3), or chemotherapy and radiation (n=1). Three patients had persistent unresected tumor following surgery, and an additional 34 had recurrences at intervals of 3 to 272 (median: 79) months, including 2 tumors with minimal infiltration. At last follow-up, 75 patients were alive with no evidence of disease, 14 were alive with disease, and 9 died of disease at intervals of 16 to 167 (median=70) months. Four died of unrelated causes without recurrence. Five-year recurrence-free survival (RFS) and disease-specific survival (DSS) were 80% and 94%, while 10-year RFS and DSS were 51% and 87%, respectively. On statistical analysis, cervical stromal involvement ( P =0.018) and myxoid stroma ( P <0.001) were associated with shorter recurrence-free survival. Tumors lacking a conventional component had worse disease-specific survival ( P =0.048). All other clinical and morphologic features, including stage, were not significantly associated with outcome. On multivariate analysis, only cervical stromal involvement remained an independent predictor of recurrence-free survival ( P =0.047; HR: 16.939) and no factors were independently predictive of disease-specific survival. Our findings highlight the difficulty in predicting outcomes in these tumors, likely due to slow progression and frequent treatment responses even in the recurrent setting. We confirm the potential for recurrence even in tumors initially showing minimal infiltration. Cervical stromal involvement and lack of conventional morphology are potential novel risk factors that should be further evaluated in subsequent studies.

Abstract Rationale: Application of single cell RNAseq (scRNAseq) in idiopathic pulmonary fibrosis (IPF) and multiple murine models has revealed two unique disease associated fibroblast subsets, the Cthrc1+ fibrotic population, and a population expressing inflammatory markers whose function is unclear. We, and others, have demonstrated that inflammatory fibroblasts are derived from homeostatic fibroblasts and can differentiate to Cthrc1+ fibroblasts. There is also data in mice suggesting that TGFβ inhibition prevents the emergence of Cthrc1+ fibrotic fibroblasts without impacting the inflammatory fibroblast population. Using our inducible genetic murine model of PF, reductionist organoid systems, and scRNAseq from IPF we present evidence and mechanism for inflammatory fibroblasts as a potential regenerative population in the alveolar niche. Methods: Tamoxifen administration to SftpcI73T conditional allelic knock-in mice, induces expression of mutant protein and promotes an inflammatory cascade followed by fibrogenesis. ScRNA-seq and population RNA-seq of bleomycin and SftpcI73T murine models were compared with publicly available data sets from IPF to identify population specific surface marker expression and potential epithelial ligand-receptor pairs. Flow cytometry approaches developed to isolate fibroblast populations were applied for in-vitro organoid modeling and validation of signaling pathways. In-vivo murine intervention in TGFβ signaling was further applied to confirm functional biology of inflammatory fibroblasts. Results: Informatic analysis of human and mouse inflammatory fibroblasts identifies expression of multiple BMP antagonists that have previously been associated with epithelial proliferation. Furthermore, human inflammatory fibroblasts also express key epithelial growth factors including FGF2 and FGF7. Murine organoid modeling confirms that inflammatory fibroblasts support alveolar organoid formation through the inhibition of BMP signaling. As was previously demonstrated in bleomycin, the inhibition of TGFβ signaling in SftpcI73T does not alter the inflammatory fibroblast population, rather this population is sustained, and alveolar epithelial proliferation increases. Additionally, we did not find any evidence for increase inflammation in the mouse lung due to inflammatory fibroblasts preservation. Finally, human data suggests that two populations of inflammatory fibroblasts are present in the lung with only one subset found to express the BMP antagonists and growth factors required to promote alveolar epithelial proliferation. Conclusions: Our data identifies that inflammatory fibroblasts in the alveolar niche inhibit BMP signaling and allow for epithelial expansion. We also determine differences between murine and human inflammatory fibroblasts suggesting that human inflammatory fibroblasts have a greater potential to drive epithelial expansion. These data shed light on the functional role of inflammatory fibroblasts, further refining our understanding of fibroblast heterogeneity in IPF.

Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous soft tissue sarcoma and affects an estimated 1,500 people annually in the United States. DFSP frequently exhibits extensive local infiltration. Initial treatment is through surgical excision, and care should be taken to ensure that negative margins are achieved to minimize recurrence. Although DFSP has a reported high rate of recurrence, metastasis is more uncommon. Fibrosarcomatous DFSP is an aggressive variant with an increased risk for local recurrence and metastasis. If achieving negative margins or resection is not feasible, radiation therapy or systemic treatment are options that may be considered by a multidisciplinary team. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) outline recommended treatment options available for DFSP.

OBJECTIVE To evaluate a regimen of inhaled Technosphere insulin (TI) plus insulin degludec in adults with type 1 diabetes, who prestudy were predominately using either an automated insulin delivery (AID) system or multiple daily insulin injections (MDI) with continuous glucose monitoring. RESEARCH DESIGN AND METHODS At 19 sites, adults with type 1 diabetes were randomly assigned to TI plus insulin degludec (N = 62) or usual care (UC) with continuation of prestudy insulin delivery method (N = 61) for 17 weeks. RESULTS Prestudy, AID was used by 48% and MDI by 45%. Mean ± SD HbA1c was 7.57% ± 0.97% at baseline and 7.62% ± 1.06% at 17 weeks in the TI group and 7.59% ± 0.80% and 7.54% ± 0.77%, respectively, in the UC group (adjusted difference 0.11%, 95% CI −0.10 to 0.33, P value for noninferiority = 0.01). HbA1c improved from baseline to 17 weeks by &gt;0.5% (5.5 mmol/mol) in 12 (21%) in the TI group and in 3 (5%) in the UC group and worsened by &gt;0.5% (5.5 mmol/mol) in 15 (26%) in the TI group and in 2 (3%) in the UC group. The most common TI side effect was a brief cough; eight participants discontinued TI due to side effects. CONCLUSIONS In adults with type 1 diabetes, HbA1c after 17 weeks with a regimen of TI and degludec was noninferior to UC, which consisted predominately of either AID or MDI. TI should be considered an option for people with type 1 diabetes, particularly those who are motivated to further reduce postprandial hyperglycemia.