Thirty- and 90-Day Morbidity and Mortality by Clavien-Dindo 30 and 90 Days after Surgery for Antireflux and Hiatal Hernia.

BACKGROUND: The historic morbidity and mortality rates of anti-reflux and hiatal hernia surgery are reported as 3-21% and 0.2-0.5%, respectively. These data come from either large national/population level or small institutional studies, with the former focusing on broad 30-day outcomes while lacking granular data on complications and their severity. Institutional studies tend to focus on long-term and quality of life outcomes. Our objective is to describe and evaluate the incidence of 30 and 90-day morbidity and mortality in a large, single institution dataset. STUDY DESIGN: We retrospectively reviewed 2342 cases of anti-reflux and hiatal hernia surgery from 2003-2020 for intra-operative complications causing post-operative sequelae, as well as morbidity and mortality within 90 days. All complications were graded using the Clavien-Dindo (CD) Grading System. The highest-grade of complication was used per patient during 30-day and 31-90-day intervals. RESULTS: Out of 2342 patients, the overall 30-day morbidity and mortality rates were 18.2% (427/2342) and 0.2% (4/2342), respectively. Most of the complications were CD<3a at 13.1% (306/2342). In the 31-90-day post-operative period, morbidity and mortality rates decreased to 3.1% (78/2338) and 0.09% (2/2338). CD<3a complications accounted for 1.9% (42/2338). CONCLUSIONS: Anti-reflux and hiatal hernia surgery are safe operations with rare mortality and modest rates of morbidity. However, the majority of complications patients experience are minor (CD<3a) and are easily managed. A minority of patients will experience major complications (CD≥3a) that require additional procedures and management to secure a safe outcome. These data are helpful to inform patients of the risks of surgery, and guide physicians for optimal consent.

Effect of Intrapleural Fibrinolytic Therapy vs Surgery for Complicated Pleural Infections: A Randomized Clinical Trial.

Importance: There is a paucity of high-quality prospective randomized clinical trials comparing intrapleural fibrinolytic therapy (IPFT) with surgical decortication in patients with complicated pleural infections. Objective: To assess the feasibility, safety, and efficacy of an algorithm comparing tissue plasminogen activator plus deoxyribonuclease therapy with surgical decortication in patients with complicated pleural infections. Design, Setting, and Participants: This parallel pilot randomized clinical trial was performed at a single urban community-based center from March 1, 2019, to December 31, 2021, with follow-up for 90 days. Seventy-four individuals were screened and 48 were excluded. Twenty-six patients 18 years or older with clinical pleural infection and positive findings of pleural fluid analysis were included. Of these, 20 patients underwent randomized selection (10 in each group), and 6 were observed. Interventions: Intrapleural tissue plasminogen activator plus deoxyribonuclease therapy vs surgical decortication. Main Outcomes and Measures: Primary outcomes were the percentage of patients enrolled to study completion and multidisciplinary adherence. Secondary outcomes included the number of patients with and the reason for inadequate screening, screening to enrollment failures, time to accrual of 20 patients or the number accrued at 1 year, and clinical data. Results: Twenty-six patients were enrolled, 10 were randomized to each group, and 6 were observed. There was 100% enrollment to study completion in each treatment group, no protocol deviations, 2 minor protocol amendments, and no screening to enrollment failures. It took 32 months to enroll 26 patients. The 20 randomized patients had a median age of 57 (IQR, 46-65) years, were predominantly men (15 [75%]), and had a median RAPID (Renal, Age, Purulence, Infection Source, and Dietary Factors) score of 2 (IQR, 1-3). Treatment failure occurred in 1 patient and 2 crossover treatments occurred, all of which were in the IPFT group. Intraprocedure and postprocedure complications were similar between the groups. There were no reoperations or in-hospital deaths. Median duration of chest tube use was comparable in the IPFT (5 [IQR, 4-8] days) and surgery (4 [IQR, 3-5] days) groups (P = .21). Median hospital stay tended to be longer in the IPFT (11 [IQR, 4-18] days) vs surgery (5 [IQR, 4-6] days) groups, although the difference as not significantly different (P = .08). There were no 30-day readmissions or 30- or 90-day deaths. Conclusions and Relevance: In this pilot randomized clinical trial, the study algorithm was feasible, safe, and efficacious. This provides evidence to move forward with a multicenter randomized clinical trial. Trial Registration: ClinicalTrials.gov Identifier: NCT03873766.

Persistent N2 After Induction Is Not a Contraindication to Surgery for Lung Cancer.

BACKGROUND: Surgical management for potentially resectable stage IIIA-N2 non-small cell lung cancer (NSCLC) is controversial. For some, persistent N2 disease after induction therapy is a contraindication to resection. We examined outcomes of a well-selected surgical cohort of postinduction IIIA-N2 NSCLC patients with persistent N2 disease. METHODS: We retrospectively reviewed all resected clinical IIIA-N2 NSCLC patients from 2001 to 2018. Thorough preoperative staging, including invasive mediastinal staging, was performed. Those with nonbulky N2 disease, appropriate restaging, and potential for a margin-negative resection were included. After resection, patients were classified as having persistent N2 disease or mediastinal downstaging (N2 to >N0/N1). Persistent N2 patients were further classified as uncertain resection (R[un]) or complete resection (R0) according to the International Association for the Study of Lung Cancer definition. Kaplan-Meier survival analysis was used. RESULTS: Fifty-four patients met inclusion criteria. After induction, 31 patients (57%) demonstrated persistent N2 disease, and 23 patients (43%) had mediastinal downstaging. Preinduction invasive mediastinal staging was performed in 98.1%. Most had clinical single-station N2 disease (75.9%). Margin-negative resections were performed in 100%. Eight patients were reclassified as R(un) due to positive highest sampled mediastinal station. The median overall survival for persistent N2 was 26 months for R(un) and 69 months for R0. Overall survival for the downstaged group was 67 months (P = .31). CONCLUSIONS: Overall survival for patients with non-R(un) or persistent N2 (true R0) was similar to those with mediastinal downstaging. Well-selected patients with persistent N2 disease experience reasonable survival after resection and should have surgery considered as part of their multimodality treatment. This study underscores the importance of classifying the extent of mediastinal involvement for persistent N2 patients, supporting the proposed International Association for the Study of Lung Cancer R(un) classification.

Showcasing Your Cardiothoracic Training Program in the Virtual Era.

As part of the response to the coronavirus disease 2019 (COVID-19) pandemic, cardiothoracic training programs quickly transitioned midinterview season toward a virtual format. This monumental and rapid undertaking led to the adoption of novel virtual interviewing techniques, many of which have been developed and partially rolled out by other specialties for years. The COVID-19 pandemic is still here, and when the end will be in sight is unclear. However, most, if not all, of the novel interview techniques that were rapidly adopted by cardiothoracic training programs during the 2020 interview season will continue to be relevant even after the pandemic and need for social distancing subsides. In this literature review, we highlight techniques that can be used by cardiothoracic training programs to virtually showcase their attributes and strengths to give applicants as realistic of a view of the program as possible. Such efforts include developing and emphasizing a social media presence, expanding information within training program websites, broadcasting virtual educational content, and creating virtual tours. In addition, we will review approaches toward structuring a virtual interview day to provide candidates with a deeper glimpse into the inner workings of the program. We can use this opportunity provided by the COVID-19 pandemic to develop innovative methods of conducting fellowship interviews that may persist long into the future, as we consider limitations historically caused by finances, scheduling, clinical responsibilities, and family needs.

Novel C-terminal heat shock protein 90 inhibitors target breast cancer stem cells and block migration, self-renewal, and epithelial-mesenchymal transition.

In patients with triple-negative breast cancer (TNBC), evidence suggests that tumor-initiating cells (TIC) have stem cell-like properties, leading to invasion and metastasis. HSP90 plays a critical role in the conformational maintenance of many client proteins in TIC development. Therefore, we hypothesize that the novel C-terminal HSP90 inhibitors KU711 and KU758 can target TIC and represent a promising strategy for overcoming metastasis. Human breast cancer cells (MDA-MB-468LN, MDA-MB-231) treated with the HSP90 inhibitors KU711, KU758, and 17-AAG showed a 50-80% decrease in TIC markers CD44 and aldehyde dehydrogenase (P < 0.01) as assessed by flow cytometry. A decrease in sphere formation, which was used to assess self-renewal, was observed after the treatment of TNBC cells starting at 2.5 µm KU711 and 0.31 µm KU758. KU compounds also blocked the invasion and migration of TNBC cells in a dose-dependent manner. The knockdown of HSP90 clients was observed without any change in prosurvival HSP70 levels. In vivo, in a murine orthotopic breast cancer model, treatment with KU758 and KU711 yielded an approximately twofold and a fourfold reduction in tumor volumes versus control, respectively, without demonstrated toxicity. In conclusion, C-terminal HSP90 inhibitors are potent novel therapeutics against TNBC in vitro and in vivo as they target TICs and block invasion, EMT transition, and self-renewal.

Mimetic sHDL nanoparticles: A novel drug-delivery strategy to target triple-negative breast cancer.

BACKGROUND: Withanolides are naturally derived heat shock protein 90 inhibitors that are potent in preclinical models of triple negative breast cancers. Conjugation to synthetic high-density lipoprotein nanoparticles improves solubility and targets delivery to the scavenger receptor B1. Triple negative breast cancers highly overexpress the scavenger receptor B1, and we hypothesize that encapsulation of the novel withalongolide A 4,19,27-triacetate by synthetic high-density lipoprotein will have enhanced efficacy against triple negative breast cancers in vivo. METHODS: Validated human triple negative breast cancer cell lines were evaluated for the scavenger receptor B1 expression by quantitative polymerase chain reaction and Western blot. Withalongolide A 4,19,27-triacetate inhibitory concentration50 values were obtained using CellTiter-Glo assays (Promega, Madison, WI, USA). The scavenger receptor B1-mediated drug uptake was evaluated in vitro under fluorescence microscopy and in vivo with IVIS imaging of mouse xenografts (MD-MBA-468LN). To evaluate drug efficacy, mice were treated with synthetic high-density lipoprotein alone, withalongolide A 4,19,27-triacetate alone, withalongolide A 4,19,27-triacetate synthetic high-density lipoprotein, and chemotherapy or Prussian blue stain (control). RESULTS: Triple negative breast cancer cell lines had greater scavenger receptor B1 expression by quantitative polymerase chain reaction and Western blot versus controls. Fluorescent-labeled synthetic high-density lipoprotein uptake was scavenger receptor B1-mediated in vitro, and in vivo tumor uptake using IVIS imaging demonstrated significantly increased tumor radiant efficiency versus control. Inhibitory concentration50 for withalongolide A 4,19,27-triacetate-treated cells with or without synthetic high-density lipoprotein encapsulation were 70-fold to 200-fold more potent than synthetic high-density lipoprotein alone. In triple negative breast cancer mouse xenografts, treatment with synthetic high-density lipoprotein withalongolide A 4,19,27-triacetate resulted in a 54% decrease in tumor volume compared with the control or with synthetic high-density lipoprotein alone. CONCLUSION: The synthetic high-density lipoprotein withalongolide A 4,19,27-triacetate nanoconjugates are potent against triple negative breast cancers and show improved scavenger receptor B1-mediated targeting. Treatment with synthetic high-density lipoprotein-encapsulated withalongolide A 4,19,27-triacetate is able to significantly decrease the growth of tumor in mice compared with the control and has better efficacy than the current standard of care, warranting further evaluation as a novel therapeutic agent.

Post-traumatic intercostal and diaphragm hernias following a sneezing episode.

Trauma and sneeze-induced or cough-induced intercostal and diaphragm hernias are both rare phenomena, especially in combination. Management of these hernias is not well described, and there is no good evidence to guide operative management. Here we describe a rare presentation of coexisting intercostal and diaphragm hernias and surgical management with primary repair via a thoracotomy.

Synthetic high-density lipoprotein nanoconjugate targets neuroblastoma stem cells, blocking migration and self-renewal.

BACKGROUND: Pathways critical for neuroblastoma cancer stem cell function are targeted by 4,19,27-triacetyl withalongolide A (WGA-TA). Because neuroblastoma cells and their cancer stem cells highly overexpress the scavenger receptor class B type 1 receptor that binds to synthetic high-density lipoprotein, we hypothesized that a novel mimetic synthetic high-density lipoprotein nanoparticle would be an ideal carrier for the delivery of 4,19,27-triacetyl withalongolide to neuroblastoma and neuroblastoma cancer stem cells. METHODS: Expression of scavenger receptor class B type 1 in validated human neuroblastoma cells was evaluated by quantitative polymerase chain reaction (qPCR) and Western blot. In vitro cellular uptake of synthetic high-density lipoprotein nanoparticles was observed with a fluorescence microscope. In vivo biodistribution of synthetic high-density lipoprotein nanoparticles was investigated with IVIS imaging. Self-renewal and migration/invasion were assessed by sphere formation and Boyden chamber assays, respectively. Viability was analyzed by CellTiter-Glo assay. Cancer stem cell markers were evaluated by flow cytometry. RESULTS: qPCR and Western blot analysis revealed a higher level of scavenger receptor class B type 1 expression and drug uptake in N-myc amplified neuroblastoma cells. In vitro uptake of synthetic high-density lipoprotein was almost completely blocked by excess synthetic high-density lipoprotein. The synthetic high-density lipoprotein nanoparticles mainly accumulated in the tumor and liver, but not in other organs. Synthetic HDL-4,19,27-triacetyl withalongolide showed a 1,000-fold higher potency than the carrier (synthetic high-density lipoprotein) alone (P < .01) to kill neuroblastoma cells. Additionally, a dose-dependent decrease in sphere formation, invasion, migration, and cancer stem cell markers was observed after treatment of neuroblastoma cells with synthetic high-density lipoprotein-4,19,27-triacetyl withalongolide A. CONCLUSION: Synthetic high-density lipoprotein is a promising platform to improve the delivery of anticancer drug 4,19,27-triacetyl withalongolide A to neuroblastomas and neuroblastoma cancer stem cells through SR-B1 targeting in vitro and in vivo.

Synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and has a 5-year survival rate of <35%. ACC cells require cholesterol for steroid hormone production, and this requirement is met via expression on the cell surface of a high level of SRB1, responsible for the uptake of high-density lipoproteins (HDLs), which carry and transport cholesterol in vivo. Here, we describe how this natural lipid carrier function of SRB1 can be utilized to improve the tumor-targeted delivery of a novel natural product derivative - withalongolide A 4,19,27-triacetate (WGA-TA) - which has shown potent antitumor efficacy, but poor aqueous solubility. Our strategy was to use synthetic HDL (sHDL) nanodisks, which are effective in tumor-targeted delivery due to their smallness, long circulation half-life, documented safety, and ability to bind to SRB1. In this study, we prepared sHDL nanodisks using an optimized phospholipid composition combined with ApoA1 mimetic peptide (22A), which has previously been tested in clinical trials, to load WGA-TA. Following optimization, WGA-TA nanodisks showed drug encapsulation efficiency of 78%, a narrow particle size distribution (9.81±0.41 nm), discoid shape, and sustained drug release in phosphate buffered saline. WGA-TA-sHDL nanodisks exhibited higher cytotoxicity in the ACC cell line H295R half maximal inhibitory concentration ([IC50] 0.26±0.045 µM) than free WGA-TA (IC50 0.492±0.115 µM, P<0.05). Fluorescent dye-loaded sHDL nanodisks efficiently accumulated in H295R adrenal carcinoma xenografts 24 hours following dosing. Moreover, daily intraperitoneal administration of 7 mg/kg WGA-TA-loaded sHDL nanodisks significantly inhibited tumor growth during 21-day administration to H295R xenograft-bearing mice compared to placebo (P<0.01). Collectively, these results suggest that WGA-TA-loaded nanodisks may represent a novel and beneficial therapeutic strategy for the treatment of ACC.

Natural Withanolides in the Treatment of Chronic Diseases.

Withanolides, and in particular extracts from Withania somnifera, have been used for over 3,000 years in traditional Ayurvedic and Unani Indian medical systems as well as within several other Asian countries. Traditionally, the extracts were ascribed a wide range of pharmacologic properties with corresponding medical uses, including adaptogenic, diuretic, anti-inflammatory, sedative/anxiolytic, cytotoxic, antitussive, and immunomodulatory. Since the discovery of the archetype withaferin A in 1965, approximately 900 of these naturally occurring, polyoxygenated steroidal lactones with 28-carbon ergostane skeletons have been discovered across 24 diverse structural types. Subsequently, extensive pharmacologic research has identified multiple mechanisms of action across key inflammatory pathways. In this chapter we identify and describe the major withanolides with anti-inflammatory properties, illustrate their role within essential and supportive inflammatory pathways (including NF-κB, JAK/STAT, AP-1, PPARγ, Hsp90 Nrf2, and HIF-1), and then discuss the clinical application of these withanolides in inflammation-mediated chronic diseases (including arthritis, autoimmune, cancer, neurodegenerative, and neurobehavioral). These naturally derived compounds exhibit remarkable biologic activity across these complex disease processes, while showing minimal adverse effects. As novel compounds and analogs continue to be discovered, characterized, and clinically evaluated, the interest in withanolides as a novel therapeutic only continues to grow.

Novel HSP90 inhibitors effectively target functions of thyroid cancer stem cell preventing migration and invasion.

BACKGROUND: Thyroid cancer stem cells (CSCs) with ALDH and CD44 markers contribute to tumor growth and aggressiveness. We hypothesized that novel HSP90 inhibitors (KU711, WGA-TA) and 17-AAG can effectively target the function of thyroid CSCs in vitro and prevent migration and invasion. METHODS: Validated papillary (TPC1), follicular (FTC238,WRO), and anaplastic (ACT1) human thyroid cancer cell lines were treated with 3 HSP90 inhibitors. CSCs were quantified for aldehyde dehydrogenase by flow cytometry, CD44 expression by Western blot, and thyrosphere formation assay. Cellular pathway proteins were analyzed by Western blot and migration/invasion by Boyden-chambers. RESULTS: WGA-TA and 17-AAG induced HSP70 compensation (not observed with KU711) on Western blot in all cell lines (>1,000 fold vs controls). Only WGA-TA degraded HSP90-Cdc37 complexing by 60-70% versus controls. Expression of HSP90 clients ß-catenin, BRAF, Akt, and phospho-Akt were significantly inhibited by WGA-TA treatment (50-80%, 50-90%, >80%, and >90%) compared with controls, KU711, and 17-AAG treatment. KU711 and WGA-TA decreased CD44 expression in all cell lines (25-60% vs controls/17-AAG), decreased ALDEFLOR activity by 69-98% (P < .005), and decreased sphere formation by 64-99% (P < .05 each). Finally, cell migration was decreased by 31-98%, 100%, and 30-38%, and invasion by 75-100%, 100%, and 47% by KU711,WGA-TA, and 17-AAG treatment (P < .05) each, respectively. CONCLUSION: KU711 and WGA-TA are novel HSP90 inhibitors targeting CSC function and inhibiting cell migration/invasion in differentiated and anaplastic thyroid cancers, warranting further translational evaluation in vivo.

The discovery and development of sorafenib for the treatment of thyroid cancer.

INTRODUCTION: Although the prognosis for most differentiated thyroid cancers (DTCs) remains excellent, recurrence and insensitivity to radioactive iodine (RAI) lead to therapeutic challenges and poorer outcomes. In defining the pathogenesis of DTC, multiple genetic alterations have been identified in key pathways focused around receptor tyrosine kinases (RTKs) and the MAPK cascade. Sorafenib was specifically developed to target rapidly accelerated fibrosarcoma (RAF) kinase in the MAPK pathway. It has been shown, however, to have potent inhibition of several key RTKs, RAF kinase and the V600E BRAF mutation, gaining FDA approval in November 2013 for advanced RAI-refractory DTC. AREAS COVERED: The authors provide a review of the targeted RAF kinase discovery strategy as well as the preclinical and clinical development of sorafenib, leading to FDA approval of DTC. The authors also provide some insight into the clinical use of sorafenib and look at important considerations for treatment. EXPERT OPINION: Sorafenib significantly improves progression-free survival in metastatic DTC patients who are RAI-refractory. However, the overall survival benefit is still unproven and requires additional follow up. Despite its cost and significant side-effect profile, which results in dose reductions in the majority of DTC patients, sorafenib should be considered for the treatment of RAI-refractory advanced DTC patients following evaluation of their individual risk-benefit stratification.

Interactions of T cells with fibroblast-like synoviocytes: role of the B7 family costimulatory ligand B7-H3.

Fibroblast-like synoviocytes (FLS) and T cells can activate each other in vitro, and in vivo interactions between these cells may be important in rheumatoid arthritis (RA), yet FLS lack significant expression of CD28 ligands. We sought to identify molecules homologous to CD28 ligands that are strongly expressed by FLS, and documented strong B7-H3 expression on FLS and by fibroblasts of other tissues, which was unaffected by a variety of cytokines. Western blot analysis of FLS lysates showed predominant expression of the larger, four Ig-like domain isoform of B7-H3. Immunohistological sections of RA synovial tissue showed strong staining for B7-H3 on FLS. Cells expressing B7-H3 were distinct from but in close proximity to cells that expressed CD45, CD20, and CD3. Confocal microscopy of FLS and T cell cocultures showed localization of B7-H3 in the region of the T cell-FLS contact point, but distinct from the localization of T cell CD11a/CD18 (LFA-1) and FLS CD54 (ICAM-1). Reduction of B7-H3 expression on FLS by RNA interference affected interactions of FLS with resting T cells or cytokine-activated T cells. Resting T cells showed increased production of TNF-alpha, IFN-gamma, and IL-2, whereas cytokine-activated T cells showed reduced cytokine production relative to control. However, cytokine production by T cells activated through their TCR was not notably altered by knock down of B7-H3. These observations suggest that B7-H3 may be important for the interactions between FLS and T cells in RA, as well as other diseases, and the outcome of such interactions depends on the activation state of the T cell.

Molecular interactions between T cells and fibroblast-like synoviocytes: role of membrane tumor necrosis factor-alpha on cytokine-activated T cells.

The mechanism of fibroblast-like synoviocyte (FLS) transformation into an inflammatory phenotype in rheumatoid arthritis (RA) is not fully understood. FLS interactions with invading leukocytes, particularly T cells, are thought to be a critical component of this pathological process. Resting T cells and T cells activated through the T-cell receptor have previously been shown to induce inflammatory cytokine production by FLS. More recently, a distinct population of T cells has been identified in RA synovium that phenotypically resembles cytokine-activated T (Tck) cells. Using time lapse microscopy, the interactions of resting, superantigen-activated, and cytokine-activated T cells with FLS were visualized. Rapid and robust adhesion of Tck and superantigen-activated T cells to FLS was observed that resulted in flattening of the T cells and a crawling movement on the FLS surface. Tck also readily activated FLS to produce interleukin IL-6 and IL-8 in a cell contact-dependent manner that was enhanced by exogenous IL-17. Although LFA-1 and ICAM-1 co-localized at the Tck-FLS synapse, blocking the LFA-1/ICAM-1 interaction did not substantially inhibit Tck effector function. However, antibody blocking of membrane tumor necrosis factor (TNF)-alpha on the Tck surface did inhibit FLS cytokine production, thus illustrating a novel mechanism for involvement of TNF-alpha in cell-cell interactions in RA synovium and for the effectiveness of TNF-alpha blockade in the treatment of RA.