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BACKGROUND & OBJECTIVES: Screening for pancreatic cancer is recommended for individuals with a strong family history, certain genetic syndromes, or a neoplastic cyst of the pancreas. However, limited data supports a survival benefit attributable to screening these higher-risk individuals. METHODS: All patients enrolled in screening at a High-Risk Pancreatic Cancer Clinic (HRC) from July 2013 to June 2020 were identified from a prospectively maintained institutional database and compared to patients evaluated at a Surgical Oncology Clinic (SOC) at the same institution during the same period. Clinical outcomes of patients selected for surgical resection, particularly clinicopathologic stage and overall survival, were compared. RESULTS: Among 826 HRC patients followed for a median (IQR) of 2.3 (0.8-4.2) years, 128 were selected for surgical resection and compared to 402 SOC patients selected for resection. Overall survival was significantly longer among HRC patients (median survival: not reached vs. 2.6 years, p < 0.001). Among 31 HRC and 217 SOC patients with a diagnosis of pancreatic ductal adenocarcinoma (PDAC), the majority of HRC patients were diagnosed with stage 0 disease (carcinoma in situ), while the majority of SOC patients were diagnosed with stage II disease (p < 0.001). Overall survival after resection of invasive PDAC was also significantly longer among HRC patients compared to SOC patients (median survival 5.5 vs. 1.6 years, p = 0.002). CONCLUSION: Patients at increased risk for PDAC and followed with guideline-based screening exhibited downstaging of disease and improved survival from PDAC in comparison to patients who were not screened.
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We here report the synthesis of the homoleptic iron(II) N-heterocyclic carbene (NHC) complex [Fe(miHpbmi)2](PF6)4 (miHpbmi = 4-((3-methyl-1H-imidazolium-1-yl)pyridine-2,6-diyl)bis(3-methylimidazol-2-ylidene)) and its electrochemical and photophysical properties. The introduction of the π-electron-withdrawing 3-methyl-1H-imidazol-3-ium-1-yl group into the NHC ligand framework resulted in stabilization of the metal-to-ligand charge transfer (MLCT) state and destabilization of the metal-centered (MC) states. This resulted in an improved excited-state lifetime of 16 ps compared to the 9 ps for the unsubstituted parent compound [Fe(pbmi)2](PF6)2 (pbmi = (pyridine-2,6-diyl)bis(3-methylimidazol-2-ylidene)) as well as a stronger MLCT absorption band extending more toward the red spectral region. However, compared to the carboxylic acid derivative [Fe(cpbmi)2](PF6)2 (cpbmi = 1,1'-(4-carboxypyridine-2,6-diyl)bis(3-methylimidazol-2-ylidene)), the excited-state lifetime of [Fe(miHpbmi)2](PF6)4 is the same, but both the extinction and the red shift are more pronounced for the former. Hence, this makes [Fe(miHpbmi)2](PF6)4 a promising pH-insensitive analogue of [Fe(cpbmi)2](PF6)2. Finally, the excited-state dynamics of the title compound [Fe(miHpbmi)2](PF6)4 was investigated in solvents with different viscosities, however, showing very little dependency of the depopulation of the excited states on the properties of the solvent used.
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Two iron complexes featuring the bidentate, nonconjugated N-heterocyclic carbene (NHC) 1,1'-methylenebis(3-methylimidazol-2-ylidene) (mbmi) ligand, where the two NHC moieties are separated by a methylene bridge, have been synthesized to exploit the combined influence of geometric and electronic effects on the ground- and excited-state properties of homoleptic FeIII-hexa-NHC [Fe(mbmi)3](PF6)3 and heteroleptic FeII-tetra-NHC [Fe(mbmi)2(bpy)](PF6)2 (bpy = 2,2'-bipyridine) complexes. They are compared to the reported FeIII-hexa-NHC [Fe(btz)3](PF6)3 and FeII-tetra-NHC [Fe(btz)2(bpy)](PF6)2 complexes containing the conjugated, bidentate mesoionic NHC ligand 3,3'-dimethyl-1,1'-bis(p-tolyl)-4,4'-bis(1,2,3-triazol-5-ylidene) (btz). The observed geometries of [Fe(mbmi)3](PF6)3 and [Fe(mbmi)2(bpy)](PF6)2 are evaluated through L-Fe-L bond angles and ligand planarity and compared to those of [Fe(btz)3](PF6)3 and [Fe(btz)2(bpy)](PF6)2. The FeII/FeIII redox couples of [Fe(mbmi)3](PF6)3 (-0.38 V) and [Fe(mbmi)2(bpy)](PF6)2 (-0.057 V, both vs Fc+/0) are less reducing than [Fe(btz)3](PF6)3 and [Fe(btz)2(bpy)](PF6)2. The two complexes show intense absorption bands in the visible region: [Fe(mbmi)3](PF6)3 at 502 nm (ligand-to-metal charge transfer, 2LMCT) and [Fe(mbmi)2(bpy)](PF6)2 at 410 and 616 nm (metal-to-ligand charge transfer, 3MLCT). Lifetimes of 57.3 ps (2LMCT) for [Fe(mbmi)3](PF6)3 and 7.6 ps (3MLCT) for [Fe(mbmi)2(bpy)](PF6)2 were probed and are somewhat shorter than those for [Fe(btz)3](PF6)3 and [Fe(btz)2(bpy)](PF6)2. [Fe(mbmi)3](PF6)3 exhibits photoluminescence at 686 nm (2LMCT) in acetonitrile at room temperature with a quantum yield of (1.2 ± 0.1) × 10-4, compared to (3 ± 0.5) × 10-4 for [Fe(btz)3](PF6)3.
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Thiosilvatins are a family of biologically active sulfenylated diketopiperazine natural products. The first members were reported over 40 years ago, but total synthesis of a thiosilvatin has remained elusive. Here, we describe the first, collective, synthesis of the parent epidithiodiketopiperazine (-)-dithiosilvatin and ten related thiosilvatins. Several of the targets are structurally revised. A catalytic asymmetric sulfenylation of triketopiperazines efficiently controls absolute configuration at the thioaminal units. Further synthetic highlights include a diastereoconvergent installation of the requisite cis-orientation of the sulfur atoms and a tandem epidisulfide formation/O-prenylation under mild Mitsunobu conditions. The described methods for late-stage diversification of sensitive bis(methylthio)diketopiperazines offer a blueprint for systematically exploring this interesting 3D-pharmacophore in stereochemically pure form.
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DESCRIPTION: The purpose of this American Gastroenterological Association (AGA) Clinical Practice Update Expert Review is to provide practical, evidence-based guidance to clinicians regarding the role of endoscopy for recurrent acute and chronic pancreatitis. METHODS: This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide guidance on a topic of clinical importance to the AGA membership, underwent internal peer review by the Clinical Practice Updates Committee (CPUC), and external peer review through standard procedures of Gastroenterology. This review is framed around the 8 best practice advice points agreed upon by the authors, based on the results of randomized controlled trials, observational studies, systematic reviews and meta-analyses, as well expert consensus in this field. Best Practice Advice Statements BEST PRACTICE ADVICE 1: After an unrevealing initial evaluation, endoscopic ultrasound is the preferred diagnostic test for unexplained acute and recurrent pancreatitis. Magnetic resonance imaging with contrast and cholangiopancreatography is a reasonable complementary or alternative test to endoscopic ultrasound, based on local expertise and availability. BEST PRACTICE ADVICE 2: The role of endoscopic retrograde cholangiopancreatography (ERCP) for reducing the frequency of acute pancreatitis episodes in patients with pancreas divisum is controversial, but minor papilla endotherapy may be considered, particularly for those with objective signs of outflow obstruction, such as a dilated dorsal pancreatic duct and/or santorinicele. There is no role for ERCP to treat pain alone in patients with pancreas divisum. BEST PRACTICE ADVICE 3: The role of ERCP for reducing the frequency of pancreatitis episodes in patients with unexplained recurrent acute pancreatitis and standard pancreatic ductal anatomy is controversial and should only be considered after a comprehensive discussion of the uncertain benefits and potentially severe procedure-related adverse events. When pursued, ERCP with biliary sphincterotomy alone may be preferable to dual sphincterotomy. BEST PRACTICE ADVICE 4: Surgical intervention should be considered over endoscopic therapy for long-term treatment of patients with painful obstructive chronic pancreatitis. Endoscopic intervention is a reasonable alternative to surgery for suboptimal operative candidates or those who favor a less invasive approach, assuming they are clearly informed that the best practice advice primarily favors surgery. BEST PRACTICE ADVICE 5: When ERCP is pursued, small (≤5mm) main pancreatic duct stones can be treated with pancreatography and conventional stone extraction maneuvers. For larger stones, extracorporeal shockwave lithotripsy and/or pancreatoscopy with intraductal lithotripsy may be required. BEST PRACTICE ADVICE 6: When ERCP is pursued, prolonged stent therapy (6-12 months) is effective for treating symptoms and remodeling main pancreatic duct strictures. The preferred approach is to place and sequentially add multiple plastic stents in parallel (upsizing); emerging evidence suggests that fully covered self-expanding metal stents may have a role for this indication, but additional research is necessary. BEST PRACTICE ADVICE 7: ERCP with stent insertion is the preferred treatment for benign biliary stricture due to chronic pancreatitis. FCSEMS placement is favored over multiple plastic stents whenever feasible, given similar efficacy but significantly reduced need for stent exchange procedures during the treatment course. BEST PRACTICE ADVICE 8: Celiac plexus block should not be routinely performed for the management of pain due to chronic pancreatitis. The decision to proceed with celiac plexus block in selected patients with debilitating pain in whom other therapeutic measures have failed can be considered on a case-by-case basis, but only after discussion of the unclear outcomes of this intervention and its procedural risks.
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Colangiopancreatografia Retrógrada Endoscópica , Pancreatite Crônica , Doença Aguda , Colangiopancreatografia Retrógrada Endoscópica/métodos , Humanos , Dor/etiologia , Pancreatite Crônica/diagnóstico por imagem , Pancreatite Crônica/cirurgia , Plásticos , Esfinterotomia Endoscópica/efeitos adversos , Stents , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Socioeconomic determinants of health are understudied in early stage esophageal adenocarcinoma. We aimed to assess how socioeconomic status influences initial treatment decisions and survival outcomes in patients with T1a esophageal adenocarcinoma. METHODS: We performed an observational study using the 2018 submission of the Surveillance, Epidemiology, and End Results-18 database. A total of 1526 patients from 2004 to 2015 with a primary T1aN0M0 esophageal adenocarcinoma were subdivided into 3 socioeconomic tertiles based on their median household income. Endoscopic trends over time, rates of endoscopic and surgical treatment, 2- and 5-year overall survival, cancer-specific mortality, and non-cancer-specific mortality were calculated. Statistical analysis was performed using R-studio. RESULTS: Patients within the lowest median household income tertile ($20,000-$54,390) were associated with higher cancer-specific mortality at 2 years (P < .01) and 5 years (P < .02), and lower overall survival at 2 and 5 years (P < .01) compared with patients in higher income tertiles. Patients with a higher income had a decreased hazard ratio for cancer-specific mortality (hazard ratio, 0.66; 95% CI, 0.45-0.99) in a multivariate Cox proportional hazards regression model. Patients within the higher income tertile were more likely to receive endoscopic intervention (P < .001), which was associated with improved cancer-specific mortality compared with patients who received primary surgical intervention (P = .001). The South had lower rates of endoscopy compared with other regions. CONCLUSIONS: Lower median household income was associated with higher rates of cancer-specific mortality and lower rates of endoscopic resection in T1aN0M0 esophageal adenocarcinoma. Population-based strategies aimed at identifying and rectifying possible etiologies for these socioeconomic and geographic disparities are paramount to improving patient outcomes in early esophageal cancer.
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Adenocarcinoma , Neoplasias Esofágicas , Humanos , Disparidades Socioeconômicas em Saúde , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/cirurgia , Adenocarcinoma/epidemiologia , Adenocarcinoma/terapia , Endoscopia GastrointestinalRESUMO
BACKGROUND AND AIMS: Endoscopic sleeve gastroplasty (ESG) is an incisionless, transoral, restrictive bariatric procedure designed to imitate sleeve gastrectomy (SG). Comparative studies and large-scale population-based data are limited. Additionally, no studies have examined the impact of race on outcomes after ESG. This study aims to compare short-term outcomes of ESG with SG and evaluate racial effects on short-term outcomes after ESG. METHODS: We retrospectively analyzed over 600,000 patients in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database from 2016 to 2020. We compared occurrences of adverse events (AEs), readmissions, reoperations, and reinterventions within 30 days after procedures. Multivariate regression evaluated the impact of patient factors, including race, on AEs. RESULTS: A total of 6054 patients underwent ESG and 597,463 underwent SG. AEs were low after both procedures with no significant difference in major AEs (SG vs ESG: 1.1% vs 1.4%; P > .05). However, patients undergoing ESG had more readmissions (3.8% vs 2.6%), reoperations (1.4% vs .8%), and reinterventions (2.8% vs .7%) within 30 days (P < .05). Race was not significantly associated with AEs after ESG, with black race associated with a higher risk of AEs in SG. CONCLUSIONS: ESG demonstrates a comparable major AE rate with SG. Race did not impact short-term AEs after ESG. Further prospective studies long-term studies are needed to compare ESG with SG.
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Cirurgia Bariátrica , Gastroplastia , Obesidade Mórbida , Humanos , Gastroplastia/efeitos adversos , Gastroplastia/métodos , Estudos Retrospectivos , Melhoria de Qualidade , Estudos Prospectivos , Redução de Peso , Obesidade/cirurgia , Resultado do Tratamento , Gastrectomia/métodos , Acreditação , Obesidade Mórbida/cirurgiaRESUMO
BACKGROUND AND AIMS: The benefit of rapid on-site evaluation (ROSE) on the diagnostic accuracy of endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) has never been evaluated in a randomized study. This trial aimed to test the hypothesis that in solid pancreatic lesions (SPLs), diagnostic accuracy of EUS-FNB without ROSE was not inferior to that of EUS-FNB with ROSE. METHODS: A noninferiority study (noninferiority margin, 5%) was conducted at 14 centers in 8 countries. Patients with SPLs requiring tissue sampling were randomly assigned (1:1) to undergo EUS-FNB with or without ROSE using new-generation FNB needles. The touch-imprint cytology technique was used to perform ROSE. The primary endpoint was diagnostic accuracy, and secondary endpoints were safety, tissue core procurement, specimen quality, and sampling procedural time. RESULTS: Eight hundred patients were randomized over an 18-month period, and 771 were analyzed (385 with ROSE and 386 without). Comparable diagnostic accuracies were obtained in both arms (96.4% with ROSE and 97.4% without ROSE, P = .396). Noninferiority of EUS-FNB without ROSE was confirmed with an absolute risk difference of 1.0% (1-sided 90% confidence interval, -1.1% to 3.1%; noninferiority P < .001). Safety and sample quality of histologic specimens were similar in both groups. A significantly higher tissue core rate was obtained by EUS-FNB without ROSE (70.7% vs. 78.0%, P = .021), with a significantly shorter mean sampling procedural time (17.9 ± 8.8 vs 11.7 ± 6.0 minutes, P < .0001). CONCLUSIONS: EUS-FNB demonstrated high diagnostic accuracy in evaluating SPLs independently on execution of ROSE. When new-generation FNB needles are used, ROSE should not be routinely recommended. (ClinicalTrial.gov number NCT03322592.).
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Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Neoplasias Pancreáticas/patologia , Avaliação Rápida no Local , Idoso , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/instrumentação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
Diareno[a,e]cyclooctatetraenes find widespread applications as building blocks, ligands, and responsive cores in topologically switchable materials. However, current synthetic methods to these structures suffer from low yields or operational disadvantages. Here, we describe a practical three-step approach to diareno[a,e]cyclooctatetraenes using an efficient copper(I) catalyzed double decarboxylation as the key step. The sequence relies on cheap and abundant reagents, is readily performed on scale, and is amenable also to unsymmetrical derivatives that expand the utility of this intriguing class of structures.
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Cobre , Catálise , Cobre/química , Descarboxilação , LigantesRESUMO
Fe(III) complexes with N-heterocyclic carbene (NHC) ligands belong to the rare examples of Earth-abundant transition metal complexes with long-lived luminescent charge-transfer excited states that enable applications as photosensitizers for charge separation reactions. We report three new hexa-NHC complexes of this class: [Fe(brphtmeimb)2]PF6 (brphtmeimb = [(4-bromophenyl)tris(3-methylimidazol-2-ylidene)borate]-, [Fe(meophtmeimb)2]PF6 (meophtmeimb = [(4-methoxyphenyl)tris(3-methylimidazol-2-ylidene)borate]-, and [Fe(coohphtmeimb)2]PF6 (coohphtmeimb = [(4-carboxyphenyl)tris(3-methylimidazol-2-ylidene)borate]-. These were derived from the parent complex [Fe(phtmeimb)2]PF6 (phtmeimb = [phenyltris(3-methylimidazol-2-ylidene)borate]- by modification with electron-withdrawing and electron-donating substituents, respectively, at the 4-phenyl position of the ligand framework. All three Fe(III) hexa-NHC complexes were characterized by NMR spectroscopy, high-resolution mass spectroscopy, elemental analysis, single crystal X-ray diffraction analysis, electrochemistry, Mößbauer spectroscopy, electronic spectroscopy, magnetic susceptibility measurements, and quantum chemical calculations. Their ligand-to-metal charge-transfer (2LMCT) excited states feature nanosecond lifetimes (1.6-1.7 ns) and sizable emission quantum yields (1.7-1.9%) through spin-allowed transition to the doublet ground state (2GS), completely in line with the parent complex [Fe(phtmeimb)2]PF6 (2.0 ns and 2.1%). The integrity of the favorable excited state characteristics upon substitution of the ligand framework demonstrates the robustness of the scorpionate motif that tolerates modifications in the 4-phenyl position for applications such as the attachment in molecular or hybrid assemblies.
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The naturally occurring polyether ionophore salinomycin was previously found to display promising anti-proliferative activity against bloodstream forms of Trypanosoma brucei. Here, we report the evaluation of 20-deoxysalinomycin, a naturally occurring homolog to salinomycin, for trypanocidal and cell swelling activity. The concentration of 20-deoxysalinomycin required to reduce the growth rate of bloodstream-form trypanosomes by 50% was determined to be 0.12 µM and found to be 8 times more trypanocidal than that of salinomycin. Moreover, 20-deoxysalinomycin and salinomycin displayed similar cytotoxic activity against human HL-60 cells. Measured as the ratio of cytotoxic to trypanocidal activity, 20-deoxysalinomycin thus exhibits a four-fold higher selectivity compared to salinomycin. The stronger trypanocidal activity of 20-deoxysalinomycin is attributed to an enhanced ability to induce cell swelling in trypanosomes. The findings support 20-deoxysalinomycin as a useful lead in the rational development of new and improved anti-trypanosomal drugs.
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Tripanossomicidas , Trypanosoma brucei brucei , Humanos , Tripanossomicidas/farmacologia , Células HL-60RESUMO
Asymmetric construction of dithiodiketopiperazines on otherwise achiral scaffolds remains a pivotal synthetic challenge encountered in many biologically significant natural products. Herein, we report the first total syntheses of (-)-glionitrin A/B and revise the absolute configurations. Emerging from the study is a novel oxidative sulfenylation of triketopiperazines that enables asymmetric formation of dithiodiketopiperazines on sensitive substrates. The concise route paves the way for further studies on the potent antimicrobial and antitumor activities of glionitrin A and the intriguing ability of glionitrin B to inhibit invasive ability of cancer cells.
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Dicetopiperazinas/síntese química , Piperazinas/química , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Teoria da Densidade Funcional , Dicetopiperazinas/química , Conformação Molecular , Oxirredução , Estereoisomerismo , Enxofre/químicaRESUMO
The photofunctionality of the cobalt-hexacarbene complex [Co(III)(PhB(MeIm)3)2]+ (PhB(MeIm)3 = tris(3-methylimidazolin-2-ylidene)(phenyl)borate) has been investigated by time-resolved optical spectroscopy. The complex displays a weak (Φ â¼ 10-4) but remarkably long-lived (τ â¼ 1 µs) orange photoluminescence at 690 nm in solution at room temperature following excitation with wavelengths shorter than 350 nm. The strongly red-shifted emission is assigned from the spectroscopic evidence and quantum chemical calculations as a rare case of luminescence from a metal-centered state in a 3d6 complex. Singlet oxygen quenching supports the assignment of the emitting state as a triplet metal-centered state and underlines its capability of driving excitation energy transfer processes.
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A homoleptic organometallic FeIV complex that is stable in both solution and in the solid state at ambient conditions has been synthesized and isolated as [Fe(phtmeimb)2 ](PF6 )2 (phtmeimb=[phenyl(tris(3-methylimidazolin-2-ylidene))borate]- ). This FeIV N-heterocyclic carbene (NHC) complex was characterized by 1 Hâ NMR, HR-MS, elemental analysis, scXRD analysis, electrochemistry, Mößbauer spectroscopy, and magnetic susceptibility. The two latter techniques unequivocally demonstrate that [Fe(phtmeimb)2 ](PF6 )2 is a triplet FeIV low-spin S=1 complex in the ground state, in agreement with quantum chemical calculations. The electronic absorption spectrum of [Fe(phtmeimb)2 ](PF6 )2 in acetonitrile shows an intense absorption band in the red and near IR, due to LMCT (ligand-to-metal charge transfer) excitation. For the first time the excited state dynamics of a FeIV complex was studied and revealed a ≈0.8â ps lifetime of the 3 LMCT excited state of [Fe(phtmeimb)2 ](PF6 )2 in acetonitrile.
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Neuroblastoma is a childhood solid tumour originating from undifferentiated neural progenitor cells of the sympathetic nervous system. Drug resistance of childhood cancer neuroblastoma is a serious clinical problem. In the present study, we aimed to identify novel drugs that can inhibit the growth and survival of chemoresistant neuroblastoma. High-throughput screening identified a small molecule, epi-enprioline that was able to induce apoptosis of vincristine-resistant neuroblastoma cells via the mitochondrial apoptotic pathway. Epi-enprioline reduced tumour growth in multiple preclinical models, including an orthotopic neuroblastoma patient-derived xenograft model in vivo. In summary, our data suggest that epi-enprioline can be considered as a lead compound for the treatment of vincristine-resistant neuroblastoma uncovering a novel strategy, which can be further explored as a treatment for drug-resistant neuroblastoma.
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Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neuroblastoma/tratamento farmacológico , Piridinas/farmacologia , Animais , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Ensaios de Triagem em Larga Escala/métodos , Humanos , Camundongos , Camundongos Nus , Bibliotecas de Moléculas Pequenas/farmacologia , Vincristina/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND & AIMS: It is not clear whether digital single-operator cholangioscopy (D-SOC) with electrohydraulic and laser lithotripsy is effective in removal of difficult biliary stones. We investigated the safety and efficacy of D-SOC with electrohydraulic and laser lithotripsy in an international, multicenter study of patients with difficult biliary stones. METHODS: We performed a retrospective analysis of 407 patients (60.4% female; mean age, 64.2 years) who underwent D-SOC for difficult biliary stones at 22 tertiary centers in the United States, United Kingdom, or Korea from February 2015 through December 2016; 306 patients underwent electrohydraulic lithotripsy and 101 (24.8%) underwent laser lithotripsy. Univariate and multivariable analyses were performed to identify factors associated with technical failure and the need for more than 1 D-SOC electrohydraulic or laser lithotripsy session to clear the bile duct. RESULTS: The mean procedure time was longer in the electrohydraulic lithotripsy group (73.9 minutes) than in the laser lithotripsy group (49.9 minutes; P < .001). Ducts were completely cleared (technical success) in 97.3% of patients (96.7% of patients with electrohydraulic lithotripsy vs 99% patients with laser lithotripsy; P = .31). Ducts were cleared in a single session in 77.4% of patients (74.5% by electrohydraulic lithotripsy and 86.1% by laser lithotripsy; P = .20). Electrohydraulic or laser lithotripsy failed in 11 patients (2.7%); 8 patients were treated by surgery. Adverse events occurred in 3.7% patients and the stone was incompletely removed from 6.6% of patients. On multivariable analysis, difficult anatomy or cannulation (duodenal diverticula or altered anatomy) correlated with technical failure (odds ratio, 5.18; 95% confidence interval, 1.26-21.2; P = .02). Procedure time increased odds of more than 1 session of D-SOC electrohydraulic or laser lithotripsy (odds ratio, 1.02; 95% confidence interval, 1.01-1.03; P < .001). CONCLUSIONS: In a multicenter, international, retrospective analysis, we found D-SOC with electrohydraulic or laser lithotripsy to be effective and safe in more than 95% of patients with difficult biliary stones. Fewer than 5% of patients require additional treatment with surgery and/or extracorporeal shockwave lithotripsy to clear the duct.
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Endoscopia Gastrointestinal/efeitos adversos , Endoscopia Gastrointestinal/métodos , Cálculos Biliares/terapia , Litotripsia/efeitos adversos , Litotripsia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia , Estudos Retrospectivos , Resultado do Tratamento , Reino Unido , Estados Unidos , Adulto JovemRESUMO
Salinomycin, a polyether antibiotic, is a well-known inhibitor of human cancer stem cells. Chemical modification of the allylic C20 hydroxyl of salinomycin has enabled access to synthetic analogs that display increased cytotoxic activity compared to the native structure. The aim of this study was to investigate the activity of a cohort of C20-O-acyl analogs of salinomycin on human colorectal cancer cell lines in vitro. Two human colorectal cancer cell lines (SW480 and SW620) were exposed to three C20-O-acylated analogs and salinomycin. The impact of salinomycin and its analogs on tumor cell number, migration, cell death, and cancer stem cell specifity was analyzed. Exposure of human colorectal cancer cells to the C20-O-acylated analogs of salinomycin resulted in reduced tumor cell number and impaired tumor cell migration at lower concentrations than salinomycin. When used at higher (micromolar) concentrations, these effects were accompanied by induction of apoptotic cell death. Salinomycin analogs further expose improved activity against cancer stem cells compared to salinomycin.
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Antibióticos Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Piranos/farmacologia , Acilação , Antibióticos Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/patologia , Humanos , Células-Tronco Neoplásicas/patologia , Piranos/químicaAssuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Tumor de Klatskin , Humanos , Tumor de Klatskin/cirurgia , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/cirurgia , Ductos Biliares Intra-Hepáticos , Neoplasias dos Ductos Biliares/terapia , Neoplasias dos Ductos Biliares/cirurgia , HepatectomiaRESUMO
Planar chiral 5,11-disubstiuted dibenzo[a,e]cyclo-octatetraenes (dbCOTs) have been developed as the first useful chiral homologs to dbCOT-ligands for asymmetric applications. Methods enabling the preparation of such compounds on a gram-scale in enantiomerically pure form are described. Evaluated as ligands in rhodium(I)-catalyzed 1,4- and 1,2-arylation reactions, tertiary and quarternary stereogenic centers were formed with excellent yields and selectivities of up to >99 % ee. A catalytic asymmetric synthesis of a key cyclization precursor to (-)-penifulvinâ A highlights the system in an applied context.