Early Interventional Treatment of High Output Chyle Leak After Esophagectomy is Associated With Improved Survival.

OBJECTIVE: To investigate overall survival and length of stay (LOS) associated with differing management for high output (>1 L over 24 hours) leaks (HOCL) after cancer-related esophagectomy. BACKGROUND: Although infrequent, chyle leak after esophagectomy is an event that can lead to significant perioperative sequelae. Low-volume leaks appear to respond to nonoperative measures, whereas HOCLs often require invasive therapeutic interventions. METHODS: From a prospective single-institution database, we retrospectively reviewed patients treated from 2001 to 2021 who underwent esophagectomy for esophageal cancer. Within that cohort, we focused on a subgroup of patients who manifested a HOCL postoperatively. Clinicopathologic and operative characteristics were collected, including hospital LOS and survival data. RESULTS: A total of 53/2299 patients manifested a HOCL. These were mostly males (77%), with a mean age of 62 years. Of this group, 15 patients received nonoperative management, 15 patients received prompt (<72 hours from diagnosis) interventional management, and 23 received late interventional management. Patients in the late intervention group had longer LOSs compared with early intervention (slope = 9.849, 95% CI: 3.431-16.267). Late intervention (hazard ratio: 4.772, CI: 1.384-16.460) and nonoperative management (hazard ratio: 4.731, CI: 1.294-17.305) were associated with increased mortality compared with early intervention. Patients with early intervention for HOCL had an overall survival similar to patients without chyle leaks in survival analysis. CONCLUSIONS: Patients with HOCL should receive early intervention to possibly reverse the prognostic implications of this potentially detrimental complication.

Rates of price disclosure associated with the surgical treatment of early-stage breast cancer one year after implementation of federal regulations.

PURPOSE: Mastectomy, breast reconstruction (BR) and breast conserving therapy (BCT) are core components of the treatment paradigm for early-stage disease but are differentially associated with significant financial burdens. Given recent price transparency regulations, we sought to characterize rates of disclosure for breast cancer-related surgery, including mastectomy, BCT, and BR (oncoplastic reconstruction, implant, pedicled flap and free flap) and identify associated factors. METHODS: For this cross-sectional analysis, cost reports were obtained from the Turquoise Health price transparency platform for all U.S. hospitals meeting national accreditation standards for breast cancer care. The Healthcare Cost Report Information System was used to collect facility-specific data. Addresses were geocoded to identify hospital referral and census regions while data from CMS was also used to identify the geographic practice cost index. We leveraged a Poisson regression model and relevant Medicare billing codes to analyze factors associated with price disclosure and the availability of an OOP price estimator. RESULTS: Of 447 identified hospitals, 221 (49.4%) disclosed prices for mastectomy and 188 42.1%) disclosed prices for both mastectomy and some form of reconstruction including oncoplastic reduction (n = 184, 97.9%), implants (n = 187, 99.5%), pedicled flaps (n = 89, 47.3%), and free flaps (n = 81, 43.1%). Non-profit status and increased market competition were associated with price nondisclosure. 121 hospitals (27.1%) had an out-of-pocket price estimator that included at least one breast surgery. CONCLUSIONS: Most eligible hospitals did not disclose prices for breast cancer surgery. Distinct hospital characteristics were associated with price disclosure. Breast cancer patients face persistent difficulty in accessing costs.

Copper-Catalyzed Synthesis of Pyrrolo[1,2-c]quinazolines and Pyrrolo[2,1-a]isoquinolines and Antiplasmodial Evaluation.

Reactions involving C(sp3)-H bonds of azaarenes have been widely studied in recent years as they allow direct functionalization of these N-heterocycles without the use of harsh reaction conditions. In this work, we describe the C(sp3)-H functionalization of 4-methylquinazolines and 1-benzylisoquinolines, employing α-substituted ß-nitrostyrenes catalyzed by inexpensive copper acetate. Under the optimized condition, 21 pyrrolo[1,2-c]quinazolines, as well as an imidazo[1,2-c]quinazoline and 4 pyrrolo[2,1-a]isoquinolines, were obtained in moderate to good yields. Furthermore, the biological activity of the pyrrolo[1,2-c]quinazolines was evaluated against Plasmodium falciparum, and promising results were obtained.

One-pot synthesis of γ-lactams from ketoaziridines.

The remarkable biological activities of γ-lactams have stimulated the search for efficient synthetic methods to achieve these scaffolds. In this work, we have developed a simple one-pot diastereoselective synthesis of new γ-lactams from ketoaziridines with moderate to good yields via the Horner-Wadsworth-Emmons reaction, followed by an intramolecular ester-aziridine cyclization and its opening in situ. Preliminary efforts towards an enantioselective version of this method are also reported.

Advances in the Asymmetric Synthesis of BINOL Derivatives.

BINOL derivatives have shown relevant biological activities and are important chiral ligands and catalysts. Due to these properties, their asymmetric synthesis has attracted the interest of the scientific community. In this work, we present an overview of the most efficient methods to obtain chiral BINOLs, highlighting the use of metal complexes and organocatalysts as well as kinetic resolution. Further derivatizations of BINOLs are also discussed.

Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma.

OBJECTIVE: Gastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial. METHODS: Extensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation. RESULTS: Overexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes (YAP-1/Sox9) that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity. CONCLUSIONS: Our preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.

Matched Pairs Comparison of an Enhanced Recovery Pathway Versus Conventional Management on Opioid Exposure and Pain Control in Patients Undergoing Lung Surgery.

OBJECTIVE: The aim of this study was to assess the effect of an enhanced recovery after surgery (ERAS) pathway on pain and opioid use following lung resection. SUMMARY BACKGROUND DATA: A major component ERAS pathways is opioid-sparing analgesia; however, the effect on postoperative pain and opioid use in patients undergoing lung resection is unknown. METHODS: Following implementation of an ERAS pathway for lung resection, 123 consecutive patients were identified. Patients were propensity-matched 1:1 with a group of consecutive patients (n = 907) undergoing lung resection before ERAS. Differences regarding in-hospital opioid consumption, discharge prescribing of opioids, and postoperative pain scores were examined. Morphine milligram equivalents were separately calculated including and excluding tramadol as an opioid medication. RESULTS: There were no significant differences between matched patients regarding age, sex, performance status, receipt of preoperative treatment, extent of lung resection, or operative approach. Epidural analgesia was used in 66% of controls and in none of the ERAS group (P < 0.001). The number of adjunct analgesics used postoperatively was greater in the ERAS group (median 3 vs 2, P < 0.001). There was a major reduction in morphine milligram equivalents in the ERAS group whether tramadol was included (median 14.2 vs 57.8, P < 0.001) or excluded (median 2.7 vs 57.8, P < 0.001) and regardless of surgical approach. Average daily pain scores were lower in the ERAS group (median 1.3 vs 1.8, P = 0.004); however, this difference was present only among patients undergoing thoracotomy. The proportion of patients who were prescribed discharge opioids varied whether tramadol was included (96% each group, P = 1.00) or excluded (39% vs 80%, P < 0.001) in the analysis. CONCLUSIONS: Implementation of an ERAS pathway was associated with effective post-operative analgesia, major reductions in in-hospital consumption of opioids, and reduced pain, compared to conventional management.

Asymmetric organocatalyzed synthesis of coumarin derivatives.

Coumarin derivatives are essential scaffolds in medicinal and synthetic chemistry. Compounds of this class have shown important activities, such as anticancer and antiparasitic, besides the commercially available drugs. These properties led to the development of efficient and greener synthetic methods to achieve the 2H-chromen-2-one core. In this context, the advances in asymmetric organocatalyzed synthesis of coumarin derivatives are discussed in this review, according to the mode of activation of the catalyst.

Green Approach for Visible-Light-Induced Direct Functionalization of 2-Methylquinolines.

A transition metal- and oxidant-free visible light-photoinduced protocol for direct functionalization of 2-methylquinolines has been developed. This protocol enabled the C-H functionalization of substituted 2-methylquinolines with diacetyl or ethyl pyruvate, under environmentally friendly conditions. A mechanistic investigation based on density functional theory (DFT) calculations provided details about the origins of reactivity and selectivity.

Time trends and predictors of survival in surgically resected early-stage non-small cell lung cancer patients.

BACKGROUND: The improvement in the management of lung cancer have the potential to improve survival in patients undergoing resection for early-stage (stage I and II) non-small cell lung cancer (NSCLC), but few studies have evaluated time trends and identified predictors of overall survival (OS). METHODS: We identified surgically resected early-stage NSCLC between 1998 and 2016. The 3-year OS (1998-2014) and 5-year OS (1998-2012) rates were calculated for each year. Joinpoint regression was used to calculate annual percentage changes (APC) and to test time trends in OS. Multivariable Cox regression was used to identify predictors of OS. RESULTS: There was a significant upward trend in the 3-year (1998, 56%; 2014, 83%; APC = 1.8) and 5-year (1998, 47%; 2012, 76%; APC = 3.1) OS. Older age; male sex; history of diabetes, coronary artery disease, and chronic obstructive pulmonary disease; high ASA score; smoking pack-years; high-grade tumor; pneumonectomy; thoracotomy; neoadjuvant therapy; nodal disease; and positive tumor margin were predictors of poor OS. CONCLUSION: The upward time trend in OS suggests that improved staging, patient selection, and management have conferred a survival benefit in early-stage NSCLC patients. The prediction model of OS could be used to refine selection criteria for resection and improve survival outcomes.

Recent advances in catalytic enantioselective multicomponent reactions.

Multicomponent reactions (MCRs) undoubtedly correspond to one of the synthetic strategies that best fit the new demands of chemistry for presenting high atom economy and enabling molecular diversity. However, many challenges still exist when products possessing stereogenic centres are formed. The field of asymmetric catalytic reactions has achieved significant progress in recent decades; new applications for chiral ligands and catalysts have been demonstrated and new catalysts have been specifically designed for challenging chemical conversions. In this sense, highly efficient approaches for classic multicomponent reactions such as the Ugi reaction and a number of new asymmetric MCRs have been described. In this review we discuss the recent developments that enable catalytic enantioselective MCRs including the proposed mechanistic pathways.

Green asymmetric synthesis of epoxypeptidomimetics and evaluation as human cathepsin K inhibitors.

Cathepsin K (CatK) is a cysteine protease known for its potent collagenolytic activity, being recognized as an important target to the development of therapies for the treatment of bone disorders. Epoxypeptidomimetics have been reported as potent inhibitors of cathepsins, thus in this work we present a green synthesis of new peptidomimetics by using a one-pot asymmetric epoxidation/Ugi multicomponent reaction. The compounds were evaluated against CatK showing selectivity when compared with cathepsin L, with an inhibition profile in the low micromolar IC50 range. Investigation of the mechanism of action carried out for compounds LSPN428 and LSPN694 suggested a mixed inhibition mode and docking studies allowed a better understanding about interactions of inhibitors with the enzyme.

Tumor characteristics associated with engraftment of patient-derived non-small cell lung cancer xenografts in immunocompromised mice.

BACKGROUND: Patient-derived xenograft (PDX) models increasingly are used in translational research. However, the engraftment rates of patient tumor samples in immunodeficient mice to PDX models vary greatly. METHODS: Tumor tissue samples from 308 patients with non-small cell lung cancer were implanted in immunodeficient mice. The patients were followed for 1.5 to approximately 6 years. The authors performed histological analysis of PDXs and some residual tumor tissues in mice with failed PDX growth at 1 year after implantation. Quantitative polymerase chain reaction and enzyme-linked immunoadsorbent assay were performed to measure the levels of Epstein-Barr virus genes and human immunoglobulin G in PDX samples. Patient characteristics were compared for PDX growth and overall survival as outcomes using Cox regression analyses. Disease staging was based on the 7th TNM staging system. RESULTS: The overall engraftment rate for PDXs from patients with non-small cell lung cancer was 34%. Squamous cell carcinomas had a higher engraftment rate (53%) compared with adenocarcinomas. Tumor samples from patients with stage II and stage III disease and from larger tumors were found to have relatively high engraftment rates. Patients whose tumors successfully engrafted had worse overall survival, particularly those individuals with adenocarcinoma, stage III or stage IV disease, and moderately differentiated tumors. Lymphoma formation was one of the factors associated with engraftment failure. Human CD8-positive and CD20-positive cells were detected in residual samples of tumor tissue that failed to generate a PDX at 1 year after implantation. Human immunoglobulin G was detected in the plasma of mice that did not have PDX growth at 14 months after implantation. CONCLUSIONS: The results of the current study indicate that the characteristics of cancer cells and the tumor immune microenvironment in primary tumors both can affect engraftment of a primary tumor sample.

Synthesis of (Z)-ß-halo α,ß-unsaturated carbonyl systems via the combination of halotrimethylsilane and tetrafluoroboric acid.

A convenient and broadly applicable method for the hydrohalogenation of ynones is described, by the combination of halotrimethylsilanes and tetrafluoroboric acid. Practically, one equivalent of HX (Brønsted acid) and BF3 (Lewis acid) is smoothly generated, which activates the carbonyl compounds. Through this protocol, 42 examples of (Z)-ß-halovinyl carbonyl compounds (Cl, Br and I) were obtained, in good yields and high stereoselectivity having 2-MeTHF as a solvent.

Stereoselective Multicomponent Reactions in the Synthesis or Transformations of Epoxides and Aziridines.

Small ring heterocycles, such as epoxides and aziridines, are present in several natural products and are also highly versatile building blocks, frequently involved in the synthesis of numerous bioactive products and pharmaceuticals. Because of the potential for increased efficiency and selectivity, along with the advantages of environmentally benign synthetic procedures, multicomponent reactions (MCRs) have been explored in the synthesis and ring opening of these heterocyclic units. In this review, the recent advances in MCRs involving the synthesis and applications of epoxides and aziridines to the preparation of other heterocycles are discussed emphasizing the stereoselectivity of the reactions.

Galectin-3 expression is prognostic in diffuse type gastric adenocarcinoma, confers aggressive phenotype, and can be targeted by YAP1/BET inhibitors.

BACKGROUND: Overexpression of Galectin-3 (Gal-3), a ß-galactoside binding protein, has been noted in many tumour types but its functional significance and clinical utility in gastric adenocarcinoma (GAC) are not well known. METHODS: We studied 184 GAC patients characterised by histologic grade, sub-phenotypes (diffuse vs intestinal), and ethnicity (Asians vs North Americans). Immunohistochemistry was performed to assess the expression of Gal-3 in human GACs and we correlated it to the clinical outcomes. Cell proliferation, invasion, co-immunoprecipitation and kinase activity assays were done in genetically stable Gal-3 overexpressing GC cell lines and the parental counterparts to delineate the mechanisms of action and activity of inhibitors. RESULTS: Most patients were men, Asian, and had a poorly differentiated GAC. Gal-3 was over-expressed in poorly differentiated (P=0.002) tumours and also in diffuse sub-phenotype (P=0.02). Gal-3 overexpression was associated with shorter overall survival (OS; P=0.026) in all patients. Although, Gal-3 over-expression was not prognostic in the Asian cohort (P=0.337), it was highly prognostic in the North American cohort (P=0.001). In a multivariate analysis, Gal-3 (P=0.001) and N-stage (P=<0.001) were independently prognostic for shorter OS. Mechanistically, Gal-3 induced c-MYC expression through increasing RalA activity and an enhanced YAP1/RalA/RalBP complex to confer an aggressive phenotype. YAP1/BET bromodomain inhibitors reduced Gal-3-mediated aggressive phenotypes in GAC cells. CONCLUSIONS: Gal-3 is an independent prognostic marker of shorter OS and a novel therapeutic target particularly in diffuse type GAC in North American patients.

Organocatalyzed Asymmetric Vinylogous Addition of Oxazole-2(3H)-thiones to α,ß-Unsaturated Ketones: An Additive-Free Approach for Diversification of Heterocyclic Scaffold.

A straightforward organocatalyzed asymmetric addition of oxazole-2(3H)-thiones to α,ß-unsaturated ketones is described. This additive-free Michael reaction in the presence of chiral cinchonine-derived primary amines as catalysts has proven to be highly effective for a wide range of cyclic and acyclic enones, leading to the Michael adducts in very good yields and excellent enantioselectivities. The absolute configuration (R) of compound 5j was unambiguously assigned by X-ray diffraction analysis. Furthermore, experimental and theoretical studies were performed and a mechanism is presented and discussed for this novel reaction.

Tumor-associated macrophage infiltration is highly associated with PD-L1 expression in gastric adenocarcinoma.

BACKGROUND: Programmed death ligand 1 (PD-L1) is a key protein upregulated by tumor cells to suppress immune responses. Tumor-associated macrophages (TAMs) play a major role in this immunosuppression, but the relationship between PD-L1 expression and TAMs remains unclear in gastric adenocarcinoma (GAC). We simultaneously examined expression of PD-L1 and TAMs in GAC. METHODS: We performed immunohistochemical staining for PD-L1, CD68 (pan-macrophage), and CD163 (M2-like macrophage) in 217 GAC samples using a tissue microarray. Expression of PD-L1 and CD68- and CD163-positive cells was evaluated using the Cytoplasmic V2.0 algorithm in Aperio ImageScope software, and logistic regression analysis was used to compare expression patterns between groups. RESULTS: Thirty-one samples (14%) were positive for PD-L1 expression. The mean (± standard error) rates of infiltration were 6.83 ± 0.38% for CD68-positive cells and 6.16 ± 0.29% for CD163-positive cells. The mean rate of CD163-positive cell infiltration was significantly higher in diffuse GAC than in intestinal GAC (diffuse n = 111, 6.91%; intestinal n = 91, 5.26%; p = 0.006), but the mean rate of CD68-positive cell infiltration was similar between these types (p = 0.38). The mean infiltration rates of CD68- and CD163-positive cells in PD-L1-positive GAC were significantly higher than in PD-L1-negative GAC (CD68 p = 0.0002; CD163 p < 0.0001). In multivariate logistic regression analyses, CD163-positive cell infiltration was associated with PD-L1 expression (odds ratio 1.13; 95% confidence interval 1.02-1.25; p = 0.021). CONCLUSION: M2-like macrophage infiltration is highly associated with PD-L1 expression in GAC cells, suggesting that macrophage infiltration can serve as a potential therapeutic target.

Quinoxaline derivatives as potential antitrypanosomal and antileishmanial agents.

Continuous efforts have been made to discover new drugs for the treatment of Chagas' disease, human African trypanosomiasis, and leishmaniasis. We have previously reported the synthesis and antileishmanial and antitrypanosomal (Y strain) properties of 2,3-disubstituted quinoxalines. Considering their promising antiparasitic potential, the present study was conducted to expand our search and take advantage of high-throughput assays to investigate the effects of quinoxaline derivatives against Leishmania donovani, Trypanosoma brucei, and Trypanosoma cruzi (Tulahuen strain). These compounds were active against the kinetoplastid parasites that were evaluated. The 2-chloro-3-methylsulfoxylsulfonyl and 2-chloro-3-methylsulfinyl quinoxalines were the most potent, and some of these derivatives were even more active than the reference drugs. Although the 2,3-diaryl-substituted quinoxalines were not active against all of the parasites, they were active against T. brucei and intracellular amastigotes of T. cruzi, without interfering with mammalian cell viability. These compounds presented encouraging results that will guide our future studies on in vivo bioassays towards the mode of action.

Predicting Lung Function Following Lobectomy: A New Method to Adjust for Inherent Selection Bias.

BACKGROUND: Predictions that overestimate post-lobectomy lung function are more likely than underestimates to lead to lobectomy. Studies of post-lobectomy lung function have included only surgical patients, so overestimates are overrepresented. This selection bias has led to incorrect estimates of prediction bias, which has led to inaccurate threshold values for determining lobectomy eligibility. OBJECTIVE: The objective of this study was to demonstrate and adjust for this selection bias in order to arrive at correct estimates of prediction bias, the 95% limits of agreement, and adjusted threshold values for determining when exercise testing is warranted. METHODS: We conducted a retrospective study of patients evaluated for lobectomy. We used multiple imputations to determine postoperative results for patients who did not have surgery because their predicted postoperative values were low. We combined these results with surgical patients to adjust for selection bias. We used the Bland-Altman method and the bivariate normal distribution to determine threshold values for surgical eligibility. RESULTS: Lobectomy evaluation was performed in 114 patients; 79 had lobectomy while 35 were ineligible based on predicted values. Prediction bias using the Bland-Altman method changed significantly after controlling for selection bias. To achieve a postoperative FEV1 > 30% and DLCO ≥30%, a predicted FEV1 > 46% and DLCO ≥53% were required. Compared to current guidelines, using these thresholds would change management in 17% of cases. CONCLUSION: The impact of selection bias on estimates of prediction accuracy was significant but can be corrected. Threshold values for determining surgical eligibility should be reassessed.