Application of 18 F-fluorodeoxyglucose PET/CT radiomic features and machine learning to predict early recurrence of non-small cell lung cancer after curative-intent therapy.

OBJECTIVE: To predict the recurrence of non-small cell lung cancer (NSCLC) within 2 years after curative-intent treatment using a machine-learning approach with PET/CT-based radiomics. PATIENTS AND METHODS: A total of 77 NSCLC patients who underwent pretreatment 18 F-fluorodeoxyglucose PET/CT were retrospectively analyzed. Five clinical features (age, sex, tumor stage, tumor histology, and smoking status) and 48 radiomic features extracted from primary tumors on PET were used for binary classifications. These were ranked, and a subset of useful features was selected based on Gini coefficient scores in terms of associations with relapsed status. Areas under the receiver operating characteristics curves (AUC) were yielded by six machine-learning algorithms (support vector machine, random forest, neural network, naive Bayes, logistic regression, and gradient boosting). Model performances were compared and validated via random sampling. RESULTS: A PET/CT-based radiomic model was developed and validated for predicting the recurrence of NSCLC during the first 2 years after curation. The most important features were SD and variance of standardized uptake value, followed by low-intensity short-zone emphasis and high-intensity zone emphasis. The naive Bayes model with the 15 best-ranked features displayed the best performance (AUC: 0.816). Prediction models using the five best PET-derived features outperformed those using five clinical variables. CONCLUSION: The machine learning model using PET-derived radiomic features showed good performance for predicting the recurrence of NSCLC during the first 2 years after a curative intent therapy. PET/CT-based radiomic features may help clinicians improve the risk stratification of relapsed NSCLC.

Surgical Management of an Isolated Huge Innominate Artery Aneurysm Causing Tracheal Compression: A Case Report.

The innominate artery is an uncommon site for an aneurysm, and tracheal compression caused by an innominate artery aneurysm is a very rare occurrence. An innominate artery aneurysm can cause catastrophic complications, such as rupture or thromboembolism. The most common surgical approach for open repair is median sternotomy with cardiopulmonary bypass, but cerebral ischemic injury and thromboembolism can occur during surgery. We present the case of a male patient who had an isolated giant innominate artery aneurysm causing tracheal compression, which was successfully managed by surgical repair.

Necrotizing sarcoid granulomatosis simulating pulmonary malignancy: A case report.

RATIONALE: Necrotizing sarcoid granulomatosis (NSG) has recently been termed "sarcoidosis with NSG pattern" for the disease entity representing nodular sarcoidosis with granulomatous pulmonary angiitis. It is characterized by sarcoid-like granulomas, vasculitis, and a variable degree of necrosis. Its rarity and nonspecific clinical symptoms can easily lead to misdiagnosis or delayed diagnosis. PATIENT CONCERNS: We report a 67-year-old female with a biopsy-confirmed sarcoidosis with NSG pattern mimicking pulmonary malignancy on initial chest computed tomography scan. DIAGNOSES: Sarcoidosis with NSG pattern. INTERVENTIONS: The patient underwent video-assisted thoracoscopic surgery with a lung biopsy. No further treatment was performed after the lung biopsy. OUTCOMES: Follow-up imaging studies revealed spontaneous regression of the disease after 2 months. LESSONS: Awareness of this rare benign disease entity and overlapping radiologic manifestations with pulmonary malignancy or other granulomatous diseases can be helpful for making a precise diagnosis with a better differential diagnosis.

Mid-Term Results of Thoracic Endovascular Aortic Repair for Complicated Acute Type B Aortic Dissection at a Single Center.

BACKGROUND: Complicated acute type B aortic dissection is a life-threatening condition with high morbidity and mortality. The aim of this study was to report a single-center experience with endovascular stent-graft repair of acute type B dissection of the thoracic aorta and to evaluate the mid-term outcomes. METHODS: We reviewed 18 patients treated for complicated acute type B aortic dissection by thoracic endovascular aortic repair (TEVAR) from September 2011 to July 2017. The indications for surgery included rupture, impending rupture, limb ischemia, visceral malperfusion, and paraplegia. The median follow-up was 34.50 months (range, 12-80 months). RESULTS: The median interval from aortic dissection to TEVAR was 5.50 days (range, 0-32 days). There was no in-hospital mortality. All cases of malperfusion improved except for 1 patient. The morbidities included endoleak in 2 patients (11.1%), stroke in 3 patients (16.7%), pneumonia in 2 patients (11.1%), transient ischemia of the left arm in 1 patient (5.6%), and temporary visceral ischemia in 1 patient (5.6%). Postoperative computed tomography angiography at 1 year showed complete thrombosis of the false lumen in 15 patients (83.3%). CONCLUSION: TEVAR of complicated type B aortic dissection with a stent-graft was effective, with a low morbidity and mortality rate.

Development of an antibody-like T-cell engager based on VH-VL heterodimer formation and its application in cancer therapy.

Following the clinical success of immunotherapeutic antibodies, bispecific antibodies for cytotoxic effector cell redirection, tumor-targeted immunomodulation and dual immunomodulation, have received particular attentions. Here, we developed a novel bispecific antibody platform, termed Antibody-Like Cell Engager (ALiCE), wherein the Fc domain of each heavy chain of immunoglobulin G (IgG) is replaced by the VH and VL domains of an IgG specific to a second antigen while retaining the N-terminal Fab of the parent antibody. Because of specific interactions between the substituted VH and VL domains, the C-terminal stem Fv enables ALiCE to assemble autonomously into hetero-tetramers, thus simultaneously binding to two distinct antigens but with different avidities. This design strategy was used to generate ACE-05 (two anti-PD-L1 Fab × anti-CD3 Fv) and ACE-31 (two anti-CD3 Fab × anti-PD-L1 Fv), both of which bound PD-L1 and CD3. However, ACE-05 was more effective than ACE-31 in reducing off-target toxicity caused by the indiscriminate activation of T cells. Moreover, in cell-based assays and PBMC-reconstituted humanized mice harboring human non-small-cell lung cancer tumors, ACE-05 showed marked antitumor efficacy, causing complete tumor regression at a dose of 0.05 mg/kg body weight. The dual roles of ACE-05 in immune checkpoint inhibition and T-cell redirection, coupled with reduced off-target toxicity, suggest that ACE-05 may be a promising anti-cancer therapeutic agent. Moreover, the bispecific ALiCE platform can be further used for tumor-targeted or multiple immunomodulation applications.

Efficacy of novel bispecific antibody targeting TNF-α/CXCL10 in the treatment of experimental arthritis.

This study was aimed at generating and investigating the efficacy of a novel monoclonal bispecific antibody (BsAb) for the combined inhibition of tumor necrosis factor-α (TNF-α) and CXCL10 as a treatment option for rheumatoid arthritis (RA). A novel BsAb targeting TNF-α and CXCL10 was generated by conjugating a single-chain variable fragment (scFv) of the anti-CXCL10 monoclonal antibody to the Fc region of adalimumab (ADA). The effects of the BsAb on the inflammatory response in the in vitro and in vivo development of arthritis and joint destruction were evaluated in human TNF transgenic (hTNF-Tg) mice, and K/BxN serum transfer arthritis models. The BsAb inhibited CXCL10-mediated CD8+ T cell migration. The binding affinity of the BsAb to TNF-α was comparable to that of ADA and suppressed TNF-α induced cell death and inhibited TNF-α induced ICAM-1 and VCAM-1 in RA fibroblast-like synoviocytes (FLSs). The BsAb decreased the expression of TNFSF11 and the production of IL-6 in RA-FLS cells stimulated with TNF-α and CXCL10. Treatment with the BsAb attenuated the development of arthritis in hTNF-Tg mice and suppressed LPS-induced bone erosion. In the K/BxN serum transfer model, BsAb effectively attenuated ankle swelling, synovial inflammation, cartilage damage, and bone destruction, reducing the activation of osteoclasts. The additional neutralization of TNF-α and CXCL10 from treatment with the novel BsAb was more effective than TNF-α inhibition alone in the in vitro and in vivo models of RA. Thus, the BsAb, targeting both TNF-α and CXCL10, may provide a new therapeutic opportunity for RA patients who fail to respond to the blockade of a single cytokine.

Early and Atypical Radiologic Presentations of Pulmonary Langerhans Cell Histiocytosis: A Report of Two Cases.

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare, multi-systemic disease primarily affecting young male adults with a history of smoking. The two patients with PLCH in our report showed relatively early and atypical radiologic presentations at initial evaluation. On chest CT, PLCH presents variable radiologic features depending on the evolutional stage of the disease. Atypical CT features of PLCH may render precise radiologic diagnosis difficult and usually require lung biopsy for a confirmation of the diagnosis. Our case review is aimed at raising the awareness of radiologists on the atypical CT features of PLCH, to help make accurate radiologic diagnosis and prevent unnecessary and invasive diagnostic procedures.

Role and Prognosis of Extracorporeal Life Support in Patients Who Develop Cardiac Arrest during or after Office-Based Cosmetic Surgery.

BACKGROUND: Cardiac arrest during or after office-based cosmetic surgery is rare, and little is known about its prognosis. We assessed the clinical outcomes of patients who developed cardiac arrest during or after cosmetic surgery at office-based clinics. METHODS: Between May 2009 and May 2016, 32 patients who developed cardiac arrest during or after treatment at cosmetic surgery clinics were consecutively enrolled. We compared clinical outcomes, including complications, between survivors (n=19) and non-survivors (n=13) and attempted to determine the prognostic factors of mortality. RESULTS: All 32 of the patients were female, with a mean age of 30.40±11.87 years. Of the 32 patients, 13 (41%) died. Extracorporeal life support (ECLS) was applied in a greater percentage of non-survivors than survivors (92.3% vs. 47.4%, respectively; p=0.009). The mean duration of in-hospital cardiopulmonary resuscitation (CPR) was longer for the non-survivors than the survivors (31.55±33 minutes vs. 7.59±9.07 minutes, respectively; p=0.01). The mean Acute Physiology and Chronic Health Evaluation score was also higher among non-survivors than survivors (23.85±6.68 vs. 16.79±7.44, respectively; p=0.01). No predictor of death was identified in the patients for whom ECLS was applied. Of the 19 survivors, 10 (52.6%) had hypoxic brain damage, and 1 (5.3%) had permanent lower leg ischemia. Logistic regression analyses revealed that the estimated glomerular filtration rate was a predictor of mortality. CONCLUSION: Patients who developed cardiac arrest during or after cosmetic surgery at office-based clinics experienced poor prognoses, even though ECLS was applied in most cases. The survivors suffered serious complications. Careful monitoring of subjects and active CPR (when necessary) in cosmetic surgery clinics may be essential.

A bispecific soluble receptor fusion protein that targets TNF-α and IL-21 for synergistic therapy in inflammatory arthritis.

This study was aimed at investigating the therapeutic effects of BITRAP, a bispecific fusion protein targeting TNF-α and IL-21, on the development of autoimmune arthritis in humans and mice. To verify the effects of BITRAP in human, peripheral blood mononuclear cells were cultured with BITRAP under IL-17-producing T (Th17) cell-polarizing conditions or osteoclast differentiation conditions. BITRAP treatment inhibited the production of IL-17 and vascular endothelial growth factor but increased the production of IL-10 in CD4+ T cells, as well as directly suppressed osteoclastogenesis. Collagen-induced arthritis (CIA) and IL-1R antagonist (IL-1Ra) knockout mice were treated with BITRAP. Following injection in CIA mice, BITRAP rapidly migrated into the inflamed joints and remained there for 72 hours. Application of BITRAP attenuated the severity of autoimmune arthritis in CIA and IL-1Ra knockout mice by reducing the numbers of inflammatory cytokine-expressing cells and Th17 cells and antibody secretion. Finally, BITRAP suppressed STAT3 phosphorylation, as well as production of IL-17 and TNF-α, in murine splenic CD4+ T cells. These findings suggest that BITRAP, a bispecific fusion protein targeting TNF-α and IL-21, may be an effective treatment to overcome the limitations of anti-TNF therapy for patients with rheumatoid arthritis.

Primary cardiac angiosarcoma with right atrial wall rupture: A case report.

RATIONALE: Cardiac angiosarcoma is the most common malignant tumor of the heart and a rare disease with rapid disease progression and poor prognosis. Cardiac wall rupture is an extremely rare complication. PATIENT CONCERNS: A 32-year-old woman presented with an acute onset of epigastric pain and chest discomfort at first time when she visited an emergency room. DIAGNOSES: A cardiac mass was identified on echocardiography and subsequently performed chest computed tomography and cardiac magnetic resonance imaging revealed the cardiac tumor at right atrium with right atrial wall rupture and hematogenous lung metastasis. Histopathologic diagnosis of metastatic angiosarcoma was done by open lung biopsy. INTERVENTIONS: The patient was treated with palliative chemotherapy for the primary cardiac tumor and hematogenous lung metastasis. OUTCOMES: The follow-up imaging studies revealed treatment response of the primary cardiac tumor and hematogenous lung metastasis. LESSONS: Clinical and radiologic evaluation of the cardiac angiosarcoma was well performed in our case with various diagnostic imaging modalities including echocardiography, chest computed tomography, cardiac magnetic resonance imaging, and fluorodeoxyglucose-positron emission tomography/computed tomography. This case report well demonstrates typical imaging findings of a rare cardiac tumor and emphasizes importance of early investigation for accurate diagnosis and proper management of the cardiac tumor.

Hydrogels with an embossed surface: An all-in-one platform for mass production and culture of human adipose-derived stem cell spheroids.

Stem cell spheroids have been studied extensively in organoid culture and therapeutic transplantation. Herein, hydrogels with an embossed surface (HES) were developed as an all-in-one platform that can enable the rapid formation and culture of a large quantity of size-controllable stem cell spheroids. The embossed structure on the hydrogel was adjustable according to the grit designation of the sandpaper. Human adipose-derived stem cells (hADSCs) were rapidly assembled into spheroids on the hydrogel, with their size distribution precisely controlled from 95 ±â€¯6 µm to 181 ±â€¯15 µm depending on surface roughness. The hADSC spheroids prepared from the HES demonstrated expression of stemness markers and differentiation capacity. In addition, HES-based spheroids showed significantly greater VEGF secretion than spheroids grown on a commercially available low-attachment culture plate. Exploiting those advantages, the HES-based spheroids were used for 3D bioprinting, and the spheroids within the 3D-printed construct showed improved retention and VEGF secretion compared to the same 3D structure containing single cell suspension. Collectively, HES would offer a useful platform for mass fabrication and culture of stem cell spheroids with controlled sizes for a variety of biomedical applications.

Mediastinal and retroperitoneal fibrosis as a manifestation of breast cancer metastasis: A case report and literature review.

RATIONALE: Mediastinal and retroperitoneal fibrosis as a manifestation of metastasis from malignancies is rare disease and particularly, cases of mediastinal fibrosis have been rarely reported. PATIENT CONCERNS: A 60-year-old woman presented with dyspnea and bilateral flank pain. The patient had no previous history of malignancy. DIAGNOSES: A contrast-enhanced chest computed tomography scan revealed a left breast mass and infiltrative soft tissue masses in the mediastinum and retroperitoneum, which showed high fluorodeoxyglucose uptake on positron emission tomography scan. The left breast mass was proven as a malignancy on biopsy and surgical excisional biopsy of the mediastinal mass revealed metastasis from the breast cancer on histopathologic examination. INTERVENTIONS: Our patient was treated with palliative hormone therapy for the primary breast cancer and metastasis with mediastinal and retroperitoneal fibrosis. OUTCOMES: Follow-up imaging studies showed improvement of the primary breast cancer and also metastasis. LESSONS: We report this rare case to emphasize that mediastinal and retroperitoneal fibrosis can be a presentation of metastasis from various primary malignancies. We expect that appropriate diagnosis and treatment for metastatic mediastinal and retroperitoneal fibrosis can have a beneficial effect on disease course and prognosis of the patient.

Comparison of the Efficacy and Safety of Aripiprazole Versus Bupropion Augmentation in Patients With Major Depressive Disorder Unresponsive to Selective Serotonin Reuptake Inhibitors: A Randomized, Prospective, Open-Label Study.

PURPOSE: The purpose of this study was to compare the efficacy and safety of aripiprazole versus bupropion augmentation in patients with major depressive disorder (MDD) unresponsive to selective serotonin reuptake inhibitors (SSRIs). METHODS: This is the first randomized, prospective, open-label, direct comparison study between aripiprazole and bupropion augmentation. Participants had at least moderately severe depressive symptoms after 4 weeks or more of SSRI treatment. A total of 103 patients were randomized to either aripiprazole (n = 56) or bupropion (n = 47) augmentation for 6 weeks. Concomitant use of psychotropic agents was prohibited. Montgomery Asberg Depression Rating Scale, 17-item Hamilton Depression Rating scale, Iowa Fatigue Scale, Drug-Induced Extrapyramidal Symptoms Scale, Psychotropic-Related Sexual Dysfunction Questionnaire scores were obtained at baseline and after 1, 2, 4, and 6 weeks of treatment. RESULTS: Overall, both treatments significantly improved depressive symptoms without causing serious adverse events. There were no significant differences in the Montgomery Asberg Depression Rating Scale, 17-item Hamilton Depression Rating scale, and Iowa Fatigue Scale scores, and response rates. However, significant differences in remission rates between the 2 groups were evident at week 6 (55.4% vs 34.0%, respectively; P = 0.031), favoring aripiprazole over bupropion. There were no significant differences in adverse sexual events, extrapyramidal symptoms, or akathisia between the 2 groups. CONCLUSIONS: The present study suggests that aripiprazole augmentation is at least comparable to bupropion augmentation in combination with SSRI in terms of efficacy and tolerability in patients with MDD. Both aripiprazole and bupropion could help reduce sexual dysfunction and fatigue in patients with MDD. Aripiprazole and bupropion may offer effective and safe augmentation strategies in patients with MDD who are unresponsive to SSRIs. Double-blinded trials are warranted to confirm the present findings.

Structural Analysis of Thymidylate Synthase from Kaposi's Sarcoma-Associated Herpesvirus with the Anticancer Drug Raltitrexed.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a highly infectious human herpesvirus that causes Kaposi's sarcoma. KSHV encodes functional thymidylate synthase, which is a target for anticancer drugs such as raltitrexed or 5-fluorouracil. Thymidylate synthase catalyzes the conversion of 2'-deoxyuridine-5'-monophosphate (dUMP) to thymidine-5'-monophosphate (dTMP) using 5,10-methylenetetrahydrofolate (mTHF) as a co-substrate. The crystal structures of thymidylate synthase from KSHV (apo), complexes with dUMP (binary), and complexes with both dUMP and raltitrexed (ternary) were determined at 1.7 Å, 2.0 Å, and 2.4 Å, respectively. While the ternary complex structures of human thymidylate synthase and E. coli thymidylate synthase had a closed conformation, the ternary complex structure of KSHV thymidylate synthase was observed in an open conformation, similar to that of rat thymidylate synthase. The complex structures of KSHV thymidylate synthase did not have a covalent bond between the sulfhydryl group of Cys219 and C6 atom of dUMP, unlike the human thymidylate synthase. The catalytic Cys residue demonstrated a dual conformation in the apo structure, and its sulfhydryl group was oriented toward the C6 atom of dUMP with no covalent bond upon ligand binding in the complex structures. These structural data provide the potential use of antifolates such as raltitrexed as a viral induced anticancer drug and structural basis to design drugs for targeting the thymidylate synthase of KSHV.

Human soluble delta-like 1 homolog exerts antitumor effects in vitro and in vivo.

Proteolysis of delta-like 1 homolog (DLK1), a cell-surface transmembrane protein, produces an active soluble form of DLK1 (sDLK1). Both membrane-bound DLK1 and sDLK1 modulate multiple developmental processes including adipogenesis, osteogenesis, chondrogenesis and myogenesis. However, cancer-related functions of DLK1 have not yet been established. We thus evaluated the roles of extracellular sDLK1, comprising six EGF-like domains and juxtamembrane regions, in human pancreatic cancer MIA PaCa-2 cells in vitro and in vivo. We observed that sDLK1 exerted antitumor effects not only in cancer cell migration and anchorage-independent cell growth but also in in vivo tumor growth.

Fn14-Fc suppresses germinal center formation and pathogenic B cells in a lupus mouse model via inhibition of the TWEAK/Fn14 Pathway.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune-mediated chronic inflammatory disease. Half of patients with SLE suffer from lupus nephritis, which is major cause of death in SLE. TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) interactions mediate inflammatory responses that are linked to the pathogenesis of lupus nephritis. Blocking of the TWEAK/Fn14 pathway by Fn14-Fc was performed in a SLE mouse model and the likely therapeutic mechanisms were investigated. METHODS: To investigate the impact of TWEAK on B cell differentiation in SLE, the levels of AID, Blimp-1, and IRF4 messenger RNA were measured in CD19(+) B cells extracted from the spleens of sanroque mice and cultured with TWEAK. To identify the therapeutic effects of Fn14-Fc in SLE, sanroque mice were treated with Fn14-Fc or a control-Fc for 3 weeks. Immunoglobulin (Ig) G, IgG1, IgG2a, and anti-dsDNA antibody (Ab) levels were measured in the sera of each group. Spleens from each group were stained with antibodies against CD4, B220, GL-7, CD138, and PD-1. Kidneys were stained with hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS). RESULTS: Administration of TWEAK increased the mRNA levels of AID, Blimp-1, and IRF4. Treatment with Fn14-Fc suppressed levels of IgG, IgG1, IgG2a, and anti-dsDNA Ab in sera and reduced numbers of B, plasma, and follicular helper T (Tfh) cells in spleens of sanroque mice. In addition, renal protective effects of Fn14-Fc were shown. CONCLUSION: Fn14-Fc had beneficial effects in a SLE mouse model by repressing B cells, plasma cells, Tfh, and renal damage. This suggested that Fn14-Fc represents a potential therapeutic agent for SLE.

A Dual Target-directed Agent against Interleukin-6 Receptor and Tumor Necrosis Factor α ameliorates experimental arthritis.

A considerable proportion of patients with rheumatoid arthritis (RA) do not respond to monospecific agents. The purpose of our study was to generate a hybrid form of biologics, targeting tumor-necrosis factor alpha (TNFα) and interleukin-6 receptor (IL-6R), and determine its anti-arthritic properties in vitro and in vivo. A novel dual target-directed agent (DTA(A7/sTNFR2)) was generated by conjugating soluble TNF receptor 2 (sTNFR2) to the Fc region of A7, a new anti-IL-6R antibody obtained by screening the phage display human antibody library. DTA(A7/sTNFR2) inhibited the proliferation and migration of fibroblast-like synoviocytes from patients with RA (RA-FLS) more efficiently than single target-directed agents. DTA(A7/sTNFR2) also blocked osteoclastogenesis from bone marrow cells. The arthritis severity scores of the experimental arthritis mice with DTA(A7/sTNFR2) tended to be lower than those of mice with IgG, A7, or sTNFR2. Histological data suggested that DTA(A7/sTNFR2) is more efficient than single-target drugs in preventing joint destruction and bone loss. These results were confirmed in vivo using the minicircle system. Taken together, the results show that DTA(A7/sTNFR2) may be a promising therapeutic agent for the treatment of RA.

Effect of onion extract on corneal haze suppression after air assisted lamellar keratectomy.

This study evaluated the effect of onion extract on corneal haze suppression after applying the air assisted lamellar keratectomy. The air assisted lamellar keratectomy was performed on 24 canine eyes. They were treated with an artificial tear (group C), prednisolone acetate (group P), onion extract (group O) and TGF-ß1 (group T) three times per day from 7 to 28 days after the surgery. Corneal haze occurred on the all eyes and was observed beginning 7 days after the surgery. The haze was significantly decreased in groups P and O from day 14 compared with the group C using the clinical (group P; P=0.021, group O; P=0.037) and objective evaluation method (group P; P=0.021, group O; P=0.039). In contrast, it was significantly increased in group T from day 14 compared with group C based on the clinical (P=0.002) and objective evaluation method (P<0.001). Subsequently, these eyes were enucleated after euthanasia, and immunohistochemistry with α-SMA antibodies was done. The total green intensity for α-SMA was significantly more expressed in group T and significantly less expressed in groups P and O than in group C. Onion extract could have potential as a therapeutic in preventing corneal haze development by suppressing the differentiation of fibroblasts into myofibroblasts.