Segmentation of Vestibular Schwannomas on Postoperative Gadolinium-Enhanced T1-Weighted and Noncontrast T2-Weighted Magnetic Resonance Imaging Using Deep Learning.

OBJECTIVE: Surveillance of postoperative vestibular schwannomas currently relies on manual segmentation and measurement of the tumor by content experts, which is both labor intensive and time consuming. We aimed to develop and validate deep learning models for automatic segmentation of postoperative vestibular schwannomas on gadolinium-enhanced T1-weighted magnetic resonance imaging (GdT1WI) and noncontrast high-resolution T2-weighted magnetic resonance imaging (HRT2WI). STUDY DESIGN: A supervised machine learning approach using a U-Net model was applied to segment magnetic resonance imaging images into pixels representing vestibular schwannoma and background pixels. SETTING: Tertiary care hospital. PATIENTS: Our retrospective data set consisted of 122 GdT1WI and 122 HRT2WI studies in 82 postoperative adult patients with a vestibular schwannoma treated with subtotal surgical resection between September 1, 2007, and April 17, 2018. Forty-nine percent of our cohort was female, the mean age at the time of surgery was 49.8 years, and the median time from surgery to follow-up scan was 2.26 years. INTERVENTIONS: N/A. MAIN OUTCOME MEASURES: Tumor areas were manually segmented in axial images and used as ground truth for training and evaluation of the model. We measured the Dice score of the predicted segmentation results in comparison to manual segmentations from experts to assess the model's accuracy. RESULTS: The GdT1WI model achieved a Dice score of 0.89, and the HRT2WI model achieved a Dice score of 0.85. CONCLUSION: We demonstrated that postoperative vestibular schwannomas can be accurately segmented on GdT1WI and HRT2WI without human intervention using deep learning. This artificial intelligence technology has the potential to improve the postoperative surveillance and management of patients with vestibular schwannomas.

Overview of Interventional Pulmonology for Radiologists.

Interventional pulmonology is a growing field specializing in minimally invasive procedures of the mediastinum, lungs, airways, and pleura. These procedures have both diagnostic and therapeutic indications and are performed for benign and malignant diseases. Endobronchial US has been combined with transbronchial needle aspiration to extend tissue sampling beyond the airways and into the lungs and mediastinum. Recent innovations extending the peripheral access of bronchoscopy include electromagnetic navigational bronchoscopy and thinner bronchoscopes. An important indication for therapeutic bronchoscopy is the relief of central airway obstruction, which may be severe and life threatening. Techniques for restoring patency of the central airways include mechanical debulking and multiple modalities for ablation, stent placement, and balloon bronchoplasty. Bronchoscopic lung volume reduction improves quality of life in certain patients with severe emphysema and is an important less invasive alternative to lung volume reduction surgery. Bronchial thermoplasty is likewise a nonpharmacologic treatment in patients with severe uncontrolled asthma. Many of these procedures have unique selection criteria that require precise evaluations at preprocedure imaging. Postprocedure imaging is also essential in determining outcome success and the presence of complications. Radiologists should be familiar with these procedures as well as the relevant imaging features in both planning and later surveillance. Evolving techniques that may become more widely available in the near future include robotic-assisted bronchoscopy, bronchoscopic transparenchymal nodule access, transbronchial cryobiopsy, ablation of early-stage cancers, and endobronchial intratumoral chemotherapy. An invited commentary by Wayne et al is available online. ©RSNA, 2021.

Skull Base 3D Modeling of Rigid Buttress for Gasket-Seal Closure Using Operative Endoscopic Imaging: Cadaveric Feasibility.

Surgical defect closure following endonasal transsphenoidal tumor resection is a critical component of procedural success. Three-dimensional (3D) modeling of relevant skull base anatomy during resection can potentially facilitate design of a custom rigid buttress for gasket-seal closure; however, access to conventional cross-sectional imaging intraoperatively is limited and cumbersome. Endoscopic imaging, by contrast, is always available. This work demonstrates the feasibility of 3D modeling of the visible skull base through structure-from-motion photogrammetric postprocessing techniques, providing a suitable template to design a gasket-seal buttress. Additionally, endoscopic 3D reconstruction of skull base surface anatomy may represent a more robust depiction of the surgical defect than is available by conventional 3D modeling with computed tomography, which suboptimally recapitulates very thin bones and mucosal surfaces typical of this regional anatomy.

Mutational profiles of breast cancer metastases from a rapid autopsy series reveal multiple evolutionary trajectories.

Heterogeneity within and among tumors in a metastatic cancer patient is a well-established phenomenon that may confound treatment and accurate prognosis. Here, we used whole-exome sequencing to survey metastatic breast cancer tumors from 5 patients in a rapid autopsy program to construct the origin and genetic development of metastases. Metastases were obtained from 5 breast cancer patients using a rapid autopsy protocol and subjected to whole-exome sequencing. Metastases were evaluated for sharing of somatic mutations, correlation of copy number variation and loss of heterozygosity, and genetic similarity scores. Pathological features of the patients' disease were assessed by immunohistochemical analyses. Our data support a monoclonal origin of metastasis in 3 cases, but in 2 cases, metastases arose from at least 2 distinct subclones in the primary tumor. In the latter 2 cases, the primary tumor presented with mixed histologic and pathologic features, suggesting early divergent evolution within the primary tumor with maintenance of metastatic capability in multiple lineages. We used genetic and histopathological evidence to demonstrate that metastases can be derived from a single or multiple independent clones within a primary tumor. This underscores the complexity of breast cancer clonal evolution and has implications for how best to determine and implement therapies for early- and late-stage disease.

Computed Tomography Assessment of Ablation Zone Enhancement in Patients With Early-Stage Lung Cancer After Stereotactic Ablative Radiotherapy.

INTRODUCTION: Stereotactic ablative radiotherapy (SABR) offers a curative treatment for lung cancer in patients who are marginal surgical candidates. However, unlike traditional surgery the lung cancer remains in place after treatment. Thus, imaging follow-up for evaluation of recurrence is of paramount importance. MATERIALS AND METHODS: In this retrospective designed Institutional Review Board-approved study, follow-up contrast-enhanced computed tomography (CT) exams were performed on sixty one patients to evaluate enhancement pattern in the ablation zone at 1, 3, 6, and 12 months after SABR. RESULTS: Eleven patients had recurrence within the ablation zone after SABR. The postcontrast enhancement in the recurrence group showed a washin and washout phenomenon, whereas the radiation-induced lung injury group showed continuous enhancement suggesting an inflammatory process. CONCLUSIONS: The textural feature of the ablation zone of enhancement and perfusion as demonstrated in computed tomography nodule enhancement may allow early differentiation of recurrence from radiation-induced lung injury in patients' status after SABR or primary lung cancer.

Cigarette smoke induces epithelial to mesenchymal transition and increases the metastatic ability of breast cancer cells.

BACKGROUND: Recent epidemiological studies demonstrate that both active and involuntary exposure to tobacco smoke increase the risk of breast cancer. Little is known, however, about the molecular mechanisms by which continuous, long term exposure to tobacco smoke contributes to breast carcinogenesis because most previous studies have focused on short term treatment models. In this work we have set out to investigate the progressive transforming effects of tobacco smoke on non-tumorigenic mammary epithelial cells and breast cancer cells using in vitro and in vivo models of chronic cigarette smoke exposure. RESULTS: We show that both non-tumorigenic (MCF 10A, MCF-12A) and tumorigenic (MCF7) breast epithelial cells exposed to cigarette smoke acquire mesenchymal properties such as fibroblastoid morphology, increased anchorage-independent growth, and increased motility and invasiveness. Moreover, transplantation experiments in mice demonstrate that treatment with cigarette smoke extract renders MCF 10A cells more capable to survive and colonize the mammary ducts and MCF7 cells more prone to metastasize from a subcutaneous injection site, independent of cigarette smoke effects on the host and stromal environment. The extent of transformation and the resulting phenotype thus appear to be associated with the differentiation state of the cells at the time of exposure. Analysis by flow cytometry showed that treatment with CSE leads to the emergence of a CD44(hi)/CD24(low) population in MCF 10A cells and of CD44+ and CD49f + MCF7 cells, indicating that cigarette smoke causes the emergence of cell populations bearing markers of self-renewing stem-like cells. The phenotypical alterations induced by cigarette smoke are accompanied by numerous changes in gene expression that are associated with epithelial to mesenchymal transition and tumorigenesis. CONCLUSIONS: Our results indicate that exposure to cigarette smoke leads to a more aggressive and transformed phenotype in human mammary epithelial cells and that the differentiation state of the cell at the time of exposure may be an important determinant in the phenotype of the final transformed state.

Knockdown of HMGA1 inhibits human breast cancer cell growth and metastasis in immunodeficient mice.

The high mobility group A1 gene (HMGA1) has been previously implicated in breast carcinogenesis, and is considered an attractive target for therapeutic intervention because its expression is virtually absent in normal adult tissue. Other studies have shown that knockdown of HMGA1 reduces the tumorigenic potential of breast cancer cells in vitro. Therefore, we sought to determine if silencing HMGA1 can affect breast cancer development and metastatic progression in vivo. We silenced HMGA1 expression in the human breast cancer cell line MDA-MB-231 using an RNA interference vector, and observed a significant reduction in anchorage-independent growth and tumorsphere formation, which respectively indicate loss of tumorigenesis and self-renewal ability. Moreover, silencing HMGA1 significantly impaired xenograft growth in immunodeficient mice, and while control cells metastasized extensively to the lungs and lymph nodes, HMGA1-silenced cells generated only a few small metastases. Thus, our results show that interfering with HMGA1 expression reduces the tumorigenic and metastatic potential of breast cancer cells in vivo, and lend further support to investigations into targeting HMGA1 as a potential treatment for breast cancer.

Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer.

Small-cell lung cancer (SCLC) is an exceptionally aggressive disease with poor prognosis. Here, we obtained exome, transcriptome and copy-number alteration data from approximately 53 samples consisting of 36 primary human SCLC and normal tissue pairs and 17 matched SCLC and lymphoblastoid cell lines. We also obtained data for 4 primary tumors and 23 SCLC cell lines. We identified 22 significantly mutated genes in SCLC, including genes encoding kinases, G protein-coupled receptors and chromatin-modifying proteins. We found that several members of the SOX family of genes were mutated in SCLC. We also found SOX2 amplification in ∼27% of the samples. Suppression of SOX2 using shRNAs blocked proliferation of SOX2-amplified SCLC lines. RNA sequencing identified multiple fusion transcripts and a recurrent RLF-MYCL1 fusion. Silencing of MYCL1 in SCLC cell lines that had the RLF-MYCL1 fusion decreased cell proliferation. These data provide an in-depth view of the spectrum of genomic alterations in SCLC and identify several potential targets for therapeutic intervention.

Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells.

Reversal of promoter DNA hypermethylation and associated gene silencing is an attractive cancer therapy approach. The DNA methylation inhibitors decitabine and azacitidine are efficacious for hematological neoplasms at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, which do not explain the prolonged time to response observed in patients. We show that transient exposure of cultured and primary leukemic and epithelial tumor cells to clinically relevant nanomolar doses, without causing immediate cytotoxicity, produce an antitumor "memory" response, including inhibition of subpopulations of cancer stem-like cells. These effects are accompanied by sustained decreases in genomewide promoter DNA methylation, gene reexpression, and antitumor changes in key cellular regulatory pathways. Low-dose decitabine and azacitidine may have broad applicability for cancer management.

Human immunodeficiency virus infection as a prognostic factor in surgical patients with non-small cell lung cancer.

BACKGROUND: The purpose of this study was to assess the effect of human immunodeficiency virus (HIV) infection on postoperative survival among non-small cell lung cancer (NSCLC) patients. METHODS: A retrospective cohort study compared 22 HIV-infected lung cancer patients to 2,430 lung cancer patients with HIV-unspecified status who underwent resection at Johns Hopkins Hospital from 1985 to 2009. Subcohort comparative analyses were performed using individual matching methods. RESULTS: Thirty-day mortality rates did not differ between HIV-infected and HIV-unspecified patients. Survival rates for HIV-infected lung cancer patients were significantly shorter than for HIV-unspecified patients (median, 26 versus 48 months; p=0.001). After adjustment, the relative hazard of mortality among HIV-infected NSCLC patients was more than threefold that of HIV-unspecified patients (adjusted hazard ratio, 3.08; 95% confidence interval: 1.85 to 5.13). When additional surgical characteristics were modeled in a matched subcohort, the association remained statistically significant (adjusted hazard ratio, 2.31; 95% confidence interval: 1.11 to 4.81). Moreover, HIV-infected lung cancer patients with CD4 counts less than 200 cells/mm3 had shortened median survival compared with patients whose CD4 counts were 200 cells/mm3 or greater (8 versus 40 months; p=0.031). Postoperative pulmonary and infectious complications were also elevated in the HIV-infected group (p=0.001 and p<0.001, respectively). After surgery, median time to cancer progression was shorter among HIV-infected patients (20.4 months) versus HIV-unspecified patients (p=0.061). CONCLUSIONS: The HIV-infected NSCLC patients have more postoperative complications, rapid progression to disease recurrence, and poorer postoperative survival. Optimizing immune status before surgery and careful patient selection based on diffusion capacity of lung for carbon monoxide may improve patient outcomes.

Neoadjuvant chemoradiation therapy is beneficial for clinical stage T2 N0 esophageal cancer patients due to inaccurate preoperative staging.

BACKGROUND: It remains unclear if patients with clinical stage T2 N0 (cT2 N0) esophageal cancer should be offered induction therapy vs surgical intervention alone. METHODS: This was a retrospective cohort study of cT2 N0 patients undergoing induction therapy, followed by surgical resection, or resection alone, at the Johns Hopkins Hospital from 1989 to 2009. Kaplan-Meier analysis was used to compare all-cause mortality in cT2 N0 patients who had resection alone vs those who had induction chemoradiation therapy, followed by resection. RESULTS: A study cohort of 69 patients was identified and divided into two groups: 55 patients (79.7%) received induction therapy and 14 (20.3%) did not. No statistically significant difference in 5-year survival rate was observed for the two groups: 49.5% for the resection-only group and 53.8% for the induction group. More than 50% of cT2 N0 patients were understaged. CONCLUSIONS: For cT2 N0 esophageal cancer patients, the benefit of neoadjuvant therapy is still unclear. Induction therapy for cT2 N0 did not translate into a statistically significant improvement in survival. However, due to the significant understaging of T2 N0 patients, we recommend neoadjuvant therapy to all cT2N0 patients before operation.

DOTA-amide lanthanide tag for reliable generation of pseudocontact shifts in protein NMR spectra.

Structural studies of proteins and protein-ligand complexes by nuclear magnetic resonance (NMR) spectroscopy can be greatly enhanced by site-specific attachment of lanthanide ions to create paramagnetic centers. In particular, pseudocontact shifts (PCS) generated by paramagnetic lanthanides contain important and unique long-range structure information. Here, we present a high-affinity lanthanide binding tag that can be attached to single cysteine residues of proteins. The new tag has many advantageous features that are not available in this combination from previously published tags: (i) it binds lanthanide ions very tightly, minimizing the generation of nonspecific effects, (ii) it produces PCSs with high reliability as its bulkiness prevents complete motional averaging of PCSs, (iii) it can be attached to single cysteine residues, alleviating the need of detailed prior knowledge of the 3D structure of the target protein, and (iv) it does not display conformational exchange phenomena that would increase the number of signals in the NMR spectrum. The performance of the tag is demonstrated with the N-terminal domain of the E. coli arginine repressor and the A28C mutant of human ubiquitin.

A murine xenograft model of spontaneous metastases of human lung adenocarcinoma.

BACKGROUND: The flank is commonly used for primary xenografts in mice, but it is rare for these tumors to metastasize. Tail vein injection creates a pattern of metastases, but is artificial. We hypothesized that the liver is a convenient alternative xenograft site and that metastases would gradually proceed spontaneously. MATERIALS AND METHODS: Using 15 NOD.CB17-Prkdc(scid)/NcrCrl (NOD/SCID) mice, 10,000 A549 cells were xenografted into the liver while a second group of five mice were xenografted in the flank with 100,000 A549 cells as a control. Mice were euthanized and grossly dissected at 7 wk. A third group of seven mice received liver xenografts with A549 and a mouse each week was euthanized for 7 wk and evaluated. The liver, lung, and spleen were examined histologically. RESULTS: At 7 wk, 15/15 liver xenografted mice had gross primary tumor in the liver. Histologic review confirmed multiple microscopic foci of metastatic disease in all mice (15/15) throughout the lungs, mediastinal nodes, and spleen. The control group had primary tumor in the flank (4/5), but none had histologic evidence of metastases. Serially euthanized liver xenografted mice revealed evidence of a gradual spontaneous metastatic model system with the first histologic findings of micrometastases appearing in the lungs by wk 5, which became wide spread by wk 7. Splenic and mediastinal lymph node metastases developed in wk 6 and 7. CONCLUSIONS: Liver xenografting of A549 cells into NOD/SCID mice is a reliable way of developing widespread micrometastases. This model allows the study of a gradually developing solid tumor with subsequent metastatic spread.

Long-term survival outcomes by smoking status in surgical and nonsurgical patients with non-small cell lung cancer: comparing never smokers and current smokers.

BACKGROUND: Survival outcomes of never smokers with non-small cell lung cancer (NSCLC) who undergo surgery are poorly characterized. This investigation compared surgical outcomes of never and current smokers with NSCLC. METHODS: This investigation was a single-institution retrospective study of never and current smokers with NSCLC from 1975 to 2004. From an analytic cohort of 4,546 patients with NSCLC, we identified 724 never smokers and 3,822 current smokers. Overall, 1,142 patients underwent surgery with curative intent. For survival analysis by smoking status, hazard ratios (HRs) were estimated using Cox proportional hazard modeling and then further adjusted by other covariates. RESULTS: Never smokers were significantly more likely than current smokers to be women (P < .01), older (P < .01), and to have adenocarcinoma (P < .01) and bronchioloalveolar carcinoma (P < .01). No statistically significant differences existed in stage distribution at presentation for the analytic cohort (P = .35) or for the subgroup undergoing surgery (P = .24). The strongest risk factors of mortality among patients with NSCLC who underwent surgery were advanced stage (adjusted hazard ratio, 3.43; 95% CI, 2.32-5.07; P < .01) and elevated American Society of Anesthesiologists classification (adjusted hazard ratio, 2.18; 95% CI, 1.40-3.40; P < .01). The minor trend toward an elevated risk of death on univariate analysis for current vs never smokers in the surgically treated group (hazard ratio, 1.20; 95% CI, 0.98-1.46; P = .07) was completely eliminated when the model was adjusted for covariates (P = .97). CONCLUSIONS: Our findings suggest that smoking status at time of lung cancer diagnosis has little impact on the long-term survival of patients with NSCLC, especially after curative surgery. Despite different etiologies between lung cancer in never and current smokers the prognosis is equally dismal.

Antibody-dependent cell cytotoxicity to breast cancer targets despite inhibitory KIR signaling.

BACKGROUND: Natural killer (NK) cells express killer immunoglobulin-like (KIR) inhibitory receptors, which recognize certain HLA class I molecules (KIR ligands), and stimulatory receptors such as FcgammaRIII. The purpose of this study was to test the possible influence of inhibitory KIR signaling on antibody-dependent cell cytotoxicity (ADCC) mediated by allogeneic NK cells against breast cancer targets. MATERIALS AND METHODS: The cytotoxic activity of volunteer donor NK cells against the cell lines SKBR-3, T47D and MCF-7, which have high, low and no HER2 gene amplification, respectively, were studied. Both cell lines and donors were assigned to the C1 or C2 superfamily, defined by the structure of the HLA-Cw molecule. RESULTS: It was found that ADCC mediated by allogeneic NK cells occurred despite combinations of NK cells and breast cancer targets predicted to trigger inhibitory KIR signaling. CONCLUSION: We suggest that adoptive immunotherapy with allogeneic NK cells and trastuzumab may be an effective combination against breast cancer targets.