Objectives
A small number of Idiopathic subglottic stenosis (iSGS) patients are treated at institutions across the country. Divergence in operative techniques for endoscopic dilation (ED) of iSGS has ...been anecdotally recognized but not formally characterized. Additionally, the relationship between procedural variation and clinical outcome has not been studied.
Methods
Secondary analysis of the NoAAC iSGS1000 cohort investigated variation in procedural techniques and treatment outcomes in patients treated with ED across high‐enrolling treatment centers (enrolled >10 patients in PR‐02 trial).
Results
Thirteen NoAAC centers each enrolled >10 patients treated with ED for a total of 281 subjects. There was significant variation in procedural details and rate of recurrence among institutions. Hierarchal cluster analysis revealed significant heterogeneity among institutions and clusters in all procedural variables. However, analysis demonstrated a transient delay in disease recurrence in cluster 2 which disappeared with longer longitudinal follow‐up. Patient‐reported outcome and peak expiratory flow data supported the potential benefit of the technical variation in Cluster 2. Distinct to cluster 2, however, was routine use of adjuvant triple medical therapy (proton pump inhibitor (PPI), antibacterial agent, and steroid inhaler).
Conclusions
Both outcome and procedural technique vary among centers employing ED to treat iSGS. A transient delay in recurrence was observed among centers that routinely prescribed adjuvant medical therapy (antibiotic, inhaled corticosteroid, and PPI) to iSGS patients after endoscopic dilation, which was further supported by patient‐reported data and peak expiratory flow data. Prospective studies are needed to understand the effects of adjuvant medical therapy on recurrence after endoscopic dilation.
Level of Evidence
4 Laryngoscope, 134:3260–3266, 2024
Divergence in operative techniques for endoscopic dilation (ED) of idiopathic subglottic stenosis (iSGS) has been anecdotally recognized but not formally characterized. Our study identified that both outcome and procedural technique vary among centers employing ED to treat iSGS. A transient delay in recurrence was observed among centers that routinely prescribed adjuvant medical therapy to iSGS patients after endoscopic dilation.
Background
Lipedema exhibits excessive lower‐extremity subcutaneous adipose tissue (SAT) deposition, which is frequently misidentified as obesity until lymphedema presents. MR lymphangiography may ...have relevance to distinguish lipedema from obesity or lymphedema.
Hypothesis
Hyperintensity profiles on 3T MR lymphangiography can identify distinct features consistent with SAT edema in participants with lipedema.
Study Type
Prospective cross‐sectional study.
Subjects
Participants (48 females, matched for age mean = 44.8 years) with lipedema (n = 14), lipedema with lymphedema (LWL, n = 12), cancer treatment‐related lymphedema (lymphedema, n = 8), and controls without these conditions (n = 14).
Field Strength/Sequence
3T MR lymphangiography (nontracer 3D turbo‐spin‐echo).
Assessment
Review of lymphangiograms in lower extremities by three radiologists was performed independently. Spatial patterns of hyperintense signal within the SAT were scored for extravascular (focal, diffuse, or not apparent) and vascular (linear, dilated, or not apparent) image features.
Statistical Tests
Interreader reliability was computed using Fleiss Kappa. Fisher's exact test was used to evaluate the proportion of image features between study groups. Multinomial logistic regression was used to assess the relationship between image features and study groups. The odds ratio (OR) and 95% confidence interval (CI) of SAT extravascular and vascular features was reported in groups compared to lipedema. The threshold of statistical significance was P < 0.05.
Results
Reliable agreement was demonstrated between three independent, blinded reviewers (P < 0.001). The frequency of SAT hyperintensities in participants with lipedema (36% focal, 36% diffuse), LWL (42% focal, 33% diffuse), lymphedema (62% focal, 38% diffuse), and controls (43% focal, 0% diffuse) was significantly distinct. Compared with lipedema, SAT hyperintensities were less frequent in controls (focal: OR = 0.63, CI = 0.11–3.41; diffuse: OR = 0.05, CI = 0.00–1.27), similar in LWL (focal: OR = 1.29, CI = 0.19–8.89; diffuse: OR = 1.05, CI = 0.15–7.61), and more frequent in lymphedema (focal: OR = 9.00, CI = 0.30–274.12; diffuse: OR = 5.73, CI = 0.18–186.84).
Data Conclusion
Noninvasive MR lymphangiography identifies distinct signal patterns indicating SAT edema and lymphatic load in participants with lipedema.
Evidence Level
1
Technical Efficacy
Stage 1
Somatostatin receptor 2 (SSTR2) is overexpressed in a majority of neuroendocrine neoplasms, including small‐cell lung carcinomas (SCLCs). SSTR2 was previously considered an inhibitory receptor on ...cell growth, but its agonists had poor clinical responses in multiple clinical trials. The role of this receptor as a potential therapeutic target in lung cancer merits further investigation. We evaluated the expression of SSTR2 in a cohort of 96 primary tumors from patients with SCLC and found 48% expressed SSTR2. Correlation analysis in both CCLE and an SCLC RNAseq cohort confirmed high‐level expression and identified an association between NEUROD1 and SSTR2. There was a significant association with SSTR2 expression profile and poor clinical outcome. We tested whether SSTR2 expression might contribute to tumor progression through activation of downstream signaling pathways, using in vitro and in vivo systems and downregulated SSTR2 expression in lung cancer cells by shRNA. SSTR2 downregulation led to increased apoptosis and dramatically decreased tumor growth in vitro and in vivo in multiple cell lines with decreased AMPKα phosphorylation and increased oxidative metabolism. These results demonstrate a role for SSTR2 signaling in SCLC and suggest that SSTR2 is a poor prognostic biomarker in SCLC and potential future therapeutic signaling target.
What's new?
Small‐cell lung cancer (SCLC) is a highly aggressive and metastatic neuroendocrine carcinoma with no therapeutic improvement in decades. SSTR2 is canonically viewed as an inhibitory receptor on cell growth, but trials have shown poor clinical responses to agonists. This work shows that SCLC cell lines and primary tumors express high levels of SSTR2, and high SSTR2 expression is correlated with worse patient survival in SCLC. Furthermore, SSTR2 signaling rather serves as an important protumor survival signal in a subset of SCLC cell lines/tumor tissues, with loss of SSTR2 expression leading to profound effects on apoptosis with significant clinical implications.
Objective
Idiopathic subglottic stenosis (iSGS) is a rare, recurrent, fibroinflammatory disease affecting the larynx and proximal trachea. Given it occurs primarily in adult females, estrogen is ...speculated to play a central pathophysiological role. This study aimed to evaluate relationships between estrogen exposure, disease progression, and recurrence.
Methods
North American Airway Collaborative (NoAAC) data of adults with iSGS obstructive airway lesions, who underwent index endoscopic airway dilation, were used to identify associations between estrogen exposure, disease characteristics, and time to recurrence (TTR), and interventions were analyzed using Kruskal–Wallis test and Pearson coefficient. Cox proportional hazards regression models compared hazard ratios by estrogen exposure. Kaplan–Meier curves were plotted for TTR based on menopausal status.
Results
In all, 533 females had complete estrogen data (33% premenopausal, 17% perimenopausal, 50% postmenopausal). Median estrogen exposure was 28 years. Overall, there was no dose–response relationship between estrogen exposure and disease recurrence. Premenopausal patients had significantly shorter time from symptom manifestation to diagnosis (1.17 vs. 1.42 years perimenopausal vs. 2.08 years postmenopausal, p < 0.001), shorter time from diagnosis to index endoscopic airway dilation (1.90 vs. 2.50 vs. 3.76 years, p = 0.005), and higher number of procedures (1.73 vs. 1.20 vs. 1.08 procedures, p < 0.001).
Conclusions
We demonstrate premenopausal patients may have a more aggressive disease variant than their peri‐ and postmenopausal counterparts. However, it is unclear as to whether this is related to reduced estrogen in the peri‐ and postmenopausal states or the age‐related physiology of wound healing and inflammation, regardless of estrogen.
Level of Evidence
3 Laryngoscope, 134:825–830, 2024
Idiopathic subglottic stenosis (iSGS) occurs in an overwhelmingly homogenous population: Caucasian, middle‐aged women. Given this, we investigate whether there is a dose–response relationship between estrogen and disease progression and recurrence.
Because of inherent disease heterogeneity, targeted therapies have eluded triple-negative breast cancer (TNBC), and biomarkers predictive of treatment response have not yet been identified. This ...study was designed to determine whether the mTOR inhibitor everolimus with cisplatin and paclitaxel would provide synergistic antitumor effects in TNBC.
Patients with stage II/III TNBC were enrolled in a randomized phase II trial of preoperative weekly cisplatin, paclitaxel and daily everolimus or placebo for 12 weeks, until definitive surgery. Tumor specimens were obtained at baseline, cycle 1, and surgery. Primary endpoint was pathologic complete response (pCR); secondary endpoints included clinical responses, breast conservation rate, safety, and discovery of molecular features associated with outcome.
Between 2009 and 2013, 145 patients were accrued; 36% of patients in the everolimus arm and 49% of patients in the placebo arm achieved pCR; in each arm, 50% of patients achieved complete responses by imaging. Higher rates of neutropenia, mucositis, and transaminase elevation were seen with everolimus. Clinical response to therapy and long-term outcome correlated with increased frequency of DNA damage response (DDR) gene mutations, Basal-like1 and Mesenchymal TNBC-subtypes, AR-negative status, and high Ki67, but not with tumor-infiltrating lymphocytes.
The paclitaxel/cisplatin combination was well tolerated and active, but addition of everolimus was associated with more adverse events without improvement in pCR or clinical response. However, discoveries made from correlative studies could lead to predictive TNBC biomarkers that may impact clinical decision-making and provide new avenues for mechanistic exploration that could lead to clinical utility.
.
Tocilizumab, an IL-6 receptor antagonist, can be used to treat cytokine release syndrome (CRS), with observed improvements in a coronavirus disease 2019 (COVID-19) case series.
The goal of this study ...was to determine if tocilizumab benefits patients hospitalized with COVID-19.
This observational study of consecutive COVID-19 patients hospitalized between March 10, 2020, and March 31, 2020, and followed up through April 21, 2020, was conducted by chart review. Patients were treated with tocilizumab using an algorithm that targeted CRS. Survival and mechanical ventilation (MV) outcomes were reported for 14 days and stratified according to disease severity designated at admission (severe, ≥ 3 L supplemental oxygen to maintain oxygen saturation > 93%). For tocilizumab-treated patients, pre/post analyses of clinical response, biomarkers, and safety outcomes were assessed. Post hoc survival analyses were conducted for race/ethnicity.
Among the 239 patients, median age was 64 years; 36% and 19% were black and Hispanic, respectively. Hospital census increased exponentially, yet MV census did not. Severe disease was associated with lower survival (78% vs 93%; P < .001), greater proportion requiring MV (44% vs 5%; P < .001), and longer median MV days (5.5 vs 1.0; P = .003). Tocilizumab-treated patients (n = 153 64%) comprised 90% of those with severe disease; 44% of patients with nonsevere disease received tocilizumab for evolving CRS. Tocilizumab-treated patients with severe disease had higher admission levels of high-sensitivity C-reactive protein (120 vs 71 mg/L; P < .001) and received tocilizumab sooner (2 vs 3 days; P < .001), but their survival was similar to that of patients with nonsevere disease (83% vs 91%; P = .11). For tocilizumab-treated patients requiring MV, survival was 75% (95% CI, 64-89). Following tocilizumab treatment, few adverse events occurred, and oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor (also termed CD25) levels increased significantly. Survival in black and Hispanic patients, after controlling for age, was significantly higher than in white patients (log-rank test, P = .002).
A treatment algorithm that included tocilizumab to target CRS may influence MV and survival outcomes. In tocilizumab-treated patients, oxygenation and inflammatory biomarkers improved, with higher than expected survival. Randomized trials must confirm these findings.
The association between body mass index (BMI) and noncardia gastric cancer (NCGC) risk remains controversial. The purpose of our study was to examine the association of BMI with NCGC risk with ...consideration of Helicobacter pylori (HP) biomarkers. This international nested case–control study, composed of 1,591 incident NCGC cases and 1,953 matched controls, was established from eight cohorts in China, Japan and Korea, where the majority of NCGCs are diagnosed worldwide. HP antibody biomarkers were measured in blood collected at cohort enrollment by multiplex serology. The NCGC risk according to baseline BMI was estimated using logistic regression to produce odds ratios (ORs) and 95% confidence intervals (CIs). We found a U‐shaped association between BMI category and NCGC risk. Compared to those with reference BMI (22.6–25.0 kg/m2), those with lower and higher BMI had an increased NCGC risk (BMI <18.5 kg/m2, OR = 1.56, 95% CI = 1.04–2.34; BMI >27.5 kg/m2, OR = 1.48, 95% CI = 1.15–1.91; adjusted for age, sex and smoking). The U‐shaped association was persistent among subjects with HP infection and high‐risk biomarkers (HP+ CagA+: BMI <18.5 kg/m2, OR = 1.60, 95% CI = 1.00–2.55; BMI >27.5 kg/m2, OR = 1.59, 95% CI = 1.21–2.11; and Omp+ HP0305+: BMI <18.5 kg/m2, OR = 1.88, 95% CI = 1.04–3.42; BMI >27.5 kg/m2, OR = 1.70, 95% CI = 1.20–2.42, respectively). Our study provides evidence of significantly increased NCGC risk among individuals with low or high BMI, including in subjects with high‐risk HP biomarkers (HP+ CagA+, Omp+ HP0305+) in the high‐risk area of East Asia.
What's new?
Gastric‐cancer (GC) mortality in East Asian countries accounts for 58% of GC deaths worldwide. Does body mass index (BMI) affect GC risk in these populations? In this prospective study, the authors found a U‐shaped association between BMI and non‐cardia GC risk. This association also held true for subjects with high‐risk biomarkers for Helicobacter pylori infection. These results indicate that maintaining normal body weight is important for reducing gastric‐cancer risk in East Asia, which may help guide public health strategies.
Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) delay progression of metastatic breast cancer. However, complete responses are uncommon and tumors eventually relapse. Here, we show that ...CDK4/6i can enhance efficacy of T cell-based therapies, such as adoptive T cell transfer or T cell-activating antibodies anti-OX40/anti-4-1BB, in murine breast cancer models. This effect is driven by the induction of chemokines CCL5, CXCL9, and CXCL10 in CDK4/6i-treated tumor cells facilitating recruitment of activated CD8+ T cells, but not Tregs, into the tumor. Mechanistically, chemokine induction is associated with metabolic stress that CDK4/6i treatment induces in breast cancer cells. Despite the cell cycle arrest, CDK4/6i-treated cells retain high metabolic activity driven by deregulated PI3K/mTOR pathway. This causes cell hypertrophy and increases mitochondrial content/activity associated with oxidative stress and inflammatory stress response. Our findings uncover a link between tumor metabolic vulnerabilities and anti-tumor immunity and support further development of CDK4/6i and immunotherapy combinations.
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•Breast cancer cells treated with CDK4/6 inhibitor secrete chemokines CCL5 and CXCL10•Chemokine induction is associated with deregulated mTOR, metabolic stress, and ROS•Chemokines induced by CDK4/6 inhibitor facilitate T cell infiltration into tumors•Chemokines induced by CDK4/6 inhibitor augment adoptive T cell therapy
Inhibitors of cell cycle kinases CDK4/6 delay progression of metastatic breast cancer; however, they do not eliminate tumors. Uzhachenko et al. report that metabolic changes in CDK4/6 inhibitor-treated cancer cells make them vulnerable to T cell therapies. These data highlight potential utility of CDK4/6 inhibitors to overcome immunotherapy resistance.
Recruitment of myeloid-derived suppressor cells (MDSC) into the tumor microenvironment (TME) contributes to cancer immune evasion. MDSCs express the chemokine receptor CXCR2, and inhibiting CXCR2 ...suppresses the recruitment of MDSCs into the tumor and the premetastatic niche. Here, we compared the growth and metastasis of melanoma and breast cancer xenografts in mice exhibiting or not exhibiting targeted deletion of
in myeloid cells (CXCR2
vs. CXCR2
). Detailed analysis of leukocyte populations in peripheral blood and in tumors from CXCR2
mice revealed that loss of CXCR2 signaling in myeloid cells resulted in reduced intratumoral MDSCs and increased intratumoral CXCL11. The increase in intratumoral CXCL11 was derived in part from tumor-infiltrating B1b cells. The reduction in intratumoral MDSCs coupled with an increase in intratumoral B1b cells expressing CXCL11 resulted in enhanced infiltration and activation of effector CD8
T cells in the TME of CXCR2
mice, accompanied by inhibition of tumor growth in CXCR2
mice compared with CXCR2
littermates. Treatment of tumor-bearing mice with a CXCR2 antagonist (SX-682) also inhibited tumor growth, reduced intratumoral MDSCs, and increased intratumoral B1b cells expressing CXCL11, leading to an increase in activated CD8
T cells in the tumor. Depletion of B220
cells or depletion of CD8
T cells reversed the tumor-inhibitory properties in CXCR2
mice. These data revealed a mechanism by which loss of CXCR2 signaling in myeloid cells modulates antitumor immunity through decreasing MDSCs and enriching CXCL11-producing B1b cells in the TME, which in turn increases CD8
T-cell recruitment and activation in tumors.
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