ABSTRACT
Data addressing prognostication in patients with HIV related Burkitt lymphoma (HIV-BL) currently treated remain scarce. We present an international analysis of 249 (United States: 140; United Kingdom: 109) patients with HIV-BL treated from 2008 to 2019 aiming to identify prognostic factors and outcomes. With a median follow up of 4.5 years, the 3-year progression-free survival (PFS) and overall survival (OS) were 61% (95% confidence interval [CI] 55% to 67%) and 66% (95%CI 59% to 71%), respectively, with similar results in both countries. Patients with baseline central nervous system (CNS) involvement had shorter 3-year PFS (36%) compared to patients without CNS involvement (69%; P < .001) independent of frontline treatment. The incidence of CNS recurrence at 3 years across all treatments was 11% with a higher incidence observed after dose-adjusted infusional etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide (DA-EPOCH) (subdistribution hazard ratio: 2.52; P = .03 vs other regimens) without difference by CD4 count 100/mm3. In multivariate models, factors independently associated with inferior PFS were Eastern Cooperative Oncology Group (ECOG) performance status 2-4 (hazard ratio [HR] 1.87; P = .007), baseline CNS involvement (HR 1.70; P = .023), lactate dehydrogenase >5 upper limit of normal (HR 2.09; P < .001); and >1 extranodal sites (HR 1.58; P = .043). The same variables were significant in multivariate models for OS. Adjusting for these prognostic factors, treatment with cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) was associated with longer PFS (adjusted HR [aHR] 0.45; P = .005) and OS (aHR 0.44; P = .007). Remarkably, HIV features no longer influence prognosis in contemporaneously treated HIV-BL.
Subject(s)
Burkitt Lymphoma , HIV Infections , Burkitt Lymphoma/diagnosis , Burkitt Lymphoma/drug therapy , Burkitt Lymphoma/epidemiology , Disease-Free Survival , HIV Infections/drug therapy , HIV Infections/epidemiology , Humans , Neoplasm Recurrence, Local , Rituximab , United Kingdom , United States/epidemiologyABSTRACT
A series of novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines were identified as potent and selective agonists of the 5-HT2C receptor. Optimizations performed on a previously reported series of racemic tetrahydroquinoline-based tricyclic amines, delivered an advanced drug lead, (R)-4-(3,3,3-trifluoropropyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine, which displayed excellent in vitro and in vivo pharmacological profiles.
Subject(s)
Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/pharmacology , Animals , Dose-Response Relationship, Drug , Humans , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Rats , Serotonin 5-HT2 Receptor Agonists/chemical synthesis , Serotonin 5-HT2 Receptor Agonists/chemistry , Structure-Activity RelationshipABSTRACT
PURPOSE: To compare the safety and clinical outcomes of combined transjugular intrahepatic portosystemic shunt (TIPS) plus variceal obliteration to those of TIPS alone for the treatment of gastric varices (GVs). MATERIALS AND METHODS: A single-center, retrospective study of 40 patients with bleeding or high-risk GVs between 2008 and 2019 was performed. The patients were treated with combined therapy (n = 18) or TIPS alone (n = 22). There were no significant differences in age, sex, model for end-stage liver disease score, or GV type between the groups. The primary outcomes were the rates of GV eradication and rebleeding. The secondary outcomes included portal hypertensive complications and hepatic encephalopathy. RESULTS: The mean follow-up period was 15.4 months for the combined therapy group and 22.9 months for the TIPS group (P = .32). After combined therapy, there was a higher rate of GV eradication (92% vs 47%, P = .01) and a trend toward a lower rate of GV rebleeding (0% vs 23%, P = .056). The estimated rebleeding rates were 0% versus 5% at 3 months, 0% versus 11% at 6 months, 0% versus 18% at 1 year, and 0% versus 38% at 2 years after combined therapy and TIPS, respectively (P = .077). There was no difference in ascites (13% vs 11%, P = .63), hepatic encephalopathy (47% vs 55%, P = .44), or esophageal variceal bleeding (0% vs 0%, P > .999) after the procedure between the groups. CONCLUSIONS: The GV eradication rate is significantly higher after combined therapy, with no associated increase in portal hypertensive complications. This translates to a clinically meaningful trend toward a reduction in GV rebleeding. The value of a combined treatment strategy should be prospectively studied in a larger cohort to determine the optimal management of GVs.
Subject(s)
Embolization, Therapeutic , Esophageal and Gastric Varices/therapy , Gastrointestinal Hemorrhage/therapy , Portasystemic Shunt, Transjugular Intrahepatic , Sclerotherapy , Adult , Aged , Aged, 80 and over , Combined Modality Therapy , Embolization, Therapeutic/adverse effects , Esophageal and Gastric Varices/diagnostic imaging , Esophageal and Gastric Varices/etiology , Female , Gastrointestinal Hemorrhage/diagnostic imaging , Gastrointestinal Hemorrhage/etiology , Humans , Male , Middle Aged , Portasystemic Shunt, Transjugular Intrahepatic/adverse effects , Recurrence , Retrospective Studies , Sclerotherapy/adverse effects , Time Factors , Treatment OutcomeABSTRACT
We examined adults with untreated Burkitt lymphoma (BL) from 2009 to 2018 across 30 US cancer centers. Factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate Cox models. Among 641 BL patients, baseline features included the following: median age, 47 years; HIV+, 22%; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to 4, 23%; >1 extranodal site, 43%; advanced stage, 78%; and central nervous system (CNS) involvement, 19%. Treatment-related mortality was 10%, with most common causes being sepsis, gastrointestinal bleed/perforation, and respiratory failure. With 45-month median follow-up, 3-year PFS and OS rates were 64% and 70%, respectively, without differences by HIV status. Survival was better for patients who received rituximab vs not (3-year PFS, 67% vs 38%; OS, 72% vs 44%; P < .001) and without difference based on setting of administration (ie, inpatient vs outpatient). Outcomes were also improved at an academic vs community cancer center (3-year PFS, 67% vs 46%, P = .006; OS, 72% vs 53%, P = .01). In multivariate models, age ≥ 40 years (PFS, hazard ratio [HR] = 1.70, P = .001; OS, HR = 2.09, P < .001), ECOG PS 2 to 4 (PFS, HR = 1.60, P < .001; OS, HR = 1.74, P = .003), lactate dehydrogenase > 3× normal (PFS, HR = 1.83, P < .001; OS, HR = 1.63, P = .009), and CNS involvement (PFS, HR = 1.52, P = .017; OS, HR = 1.67, P = .014) predicted inferior survival. Furthermore, survival varied based on number of factors present (0, 1, 2 to 4 factors) yielding 3-year PFS rates of 91%, 73%, and 50%, respectively; and 3-year OS rates of 95%, 77%, and 56%, respectively. Collectively, outcomes for adult BL in this real-world analysis appeared more modest compared with results of clinical trials and smaller series. In addition, clinical prognostic factors at diagnosis identified patients with divergent survival rates.
Subject(s)
Burkitt Lymphoma/blood , Burkitt Lymphoma/drug therapy , Adult , Aged , Burkitt Lymphoma/genetics , Female , Gene Rearrangement/genetics , Humans , Kaplan-Meier Estimate , L-Lactate Dehydrogenase/blood , Male , Middle Aged , Prognosis , Progression-Free Survival , Proto-Oncogene Proteins c-myc/genetics , Treatment Outcome , United StatesABSTRACT
BACKGROUND: The Viatorr Controlled Expansion (VCX) stent-graft was designed to mitigate hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS) creation. AIMS: To determine the incidence and degree of HE after VCX TIPS. METHODS: Thirty-three patients (M:F 17:16, mean age 58 years, mean MELD score 12) who underwent VCX TIPS between 2018 and 2019 were retrospectively studied. 11/33 (33%) patients had medically controlled pre-TIPS HE. TIPS indications included variceal hemorrhage (n = 12, 30%) and ascites (n = 21, 70%). Measured outcomes were post-TIPS HE (overall, recurrent, de novo) graded using the West Haven system, time-to-HE occurrence, HE-related hospitalization rate, and TIPS reduction rate. RESULTS: VCX TIPS were 8 mm in 28/33 (85%) and 10 mm in 5/33 (15%). Mean final portosystemic pressure gradient was 6 mmHg. Cumulative HE incidence post-TIPS was 61% (20/33). 1-, 3-, 6-, and 12-month HE rates were 24%, 30%, 53%, and 61% over 247-day median follow-up. Median time-to-HE was 180 days. HE grades spanned grade 1 (n = 6), grade 2 (n = 8), and grade 3 (n = 6); 9 and 11 cases were recurrent and de novo HE, respectively. Medication non-compliance/infection was implicated in HE in 9/20 (45%) cases. Medical therapy addressed HE in 18/20 (90%) cases; however, HE still resulted in 39 hospitalizations among 13 patients, and median time to first hospitalization was 75 days. Shunt reduction was necessary in 2 (10%) cases of medically refractory HE. CONCLUSIONS: The incidence of HE after VCX TIPS is high. Though HE symptoms may be medically controlled, hospitalization rates are high, and shunt reduction may be necessary.
Subject(s)
Hepatic Encephalopathy/etiology , Portasystemic Shunt, Transjugular Intrahepatic/adverse effects , Portasystemic Shunt, Transjugular Intrahepatic/instrumentation , Stents/adverse effects , Female , Humans , Incidence , Male , Middle Aged , Risk Factors , Treatment OutcomeABSTRACT
A series of potential new 5-HT2 receptor scaffolds based on a simplification of the clinically studied, 5-HT2CR agonist vabicaserin, were designed. An in vivo feeding assay early in our screening process played an instrumental part in the lead identification process, leading us to focus on a 6,5,7-tricyclic scaffold. A subsequent early SAR investigation provided potent agonists of the 5-HT2C receptor that were highly selective in both functional and binding assays, had good rat PK properties and that significantly reduced acute food intake in the rat.
Subject(s)
Benzodiazepines/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/pharmacology , Animals , Benzodiazepines/chemical synthesis , Benzodiazepines/metabolism , Benzodiazepines/pharmacokinetics , Dogs , Drug Discovery , Drug Stability , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/metabolism , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Humans , Macaca fascicularis , Male , Mice , Microsomes/metabolism , Molecular Structure , Rats, Sprague-Dawley , Serotonin 5-HT2 Receptor Agonists/chemical synthesis , Serotonin 5-HT2 Receptor Agonists/metabolism , Serotonin 5-HT2 Receptor Agonists/pharmacokinetics , Structure-Activity RelationshipABSTRACT
BACKGROUND: Patients increasingly rely on online resources to make healthcare decisions. Google dominates the search engine market; first-page results receive most of the web traffic and therefore serve as an important indicator of consumer reach. OBJECTIVES: Our objective was to analyze the respective importance of physician academic pedigree, experience, and social media presence on plastic surgeon Google first-page search result placement. METHODS: A Google.com search was conducted in the top 25 United States metropolitan areas to identify the top 20 websites of board-certified plastic surgeons. Social media presence was quantified by tracking the number of followers on Facebook, Twitter, and Instagram for every surgeon as well as medical school and year of graduation. The primary outcome was website ranking in the first page of Google search results. To identify the independent predictors of presence on the front page, we performed a multivariate logistic regression. RESULTS: Total number of social medial followers was associated with Google front-page placement (P < 0.001), whereas medical school ranking and years in practice were not (P = 0.17 and 0.39, respectively). A total 19.6% of plastic surgeon practices in our study cohort still had no social media accounts whatsoever. CONCLUSIONS: For the past few decades, plastic surgery practices relied on referrals, word of mouth, and the surgeon's reputation and academic pedigree to attract new patients. It is now clear that this practice-building model is being rapidly supplanted by a new paradigm based on social media presence to reach potential patients.
Subject(s)
Internet/statistics & numerical data , Social Media/statistics & numerical data , Surgeons/statistics & numerical data , Surgery, Plastic/statistics & numerical data , Humans , Search Engine , Surgeons/standards , Surgery, Plastic/standards , United StatesABSTRACT
The syntheses, structure-activity relationships (SARs), and biological activities of tetrahydroquinoline-based tricyclic amines as 5-HT2C receptor agonists are reported. An early lead containing a highly unique 6,6,7-ring system was optimized for both in vitro potency and selectivity at the related 5-HT2B receptor. Orally bioactive, potent, and selective 6,6,6-tricyclic 5-HT2C agonists were identified.
Subject(s)
Amines/pharmacology , Quinolines/pharmacology , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/pharmacology , Administration, Oral , Amines/administration & dosage , Amines/chemistry , Animals , Dose-Response Relationship, Drug , Male , Molecular Structure , Quinolines/administration & dosage , Quinolines/chemistry , Rats , Rats, Sprague-Dawley , Serotonin 5-HT2 Receptor Agonists/administration & dosage , Serotonin 5-HT2 Receptor Agonists/chemistry , Structure-Activity RelationshipABSTRACT
Colorectal Cancer (CRC) is one of the deadliest cancers-ranking as the fourth most common cause of cancer-related deaths in the world. It is such a deadly disease because it is largely asymptomatic until the latter stages-oftentimes when the cancer has metastasized. Thus, a huge emphasis of cancer treatment is placed on early detection. Currently, there is a lack of a noninvasive, reliable, and cost-effective screening method for CRC. In recent years, microRNA (miRNA) diagnostic markers have been suggested as a viable new screening method for CRC. miRNAs play an important role in carcinogenesis, and has been observed to be dysregulated in many cancers including CRC. This review examines the diagnostic potential of circulatory and fecal miRNA markers in relation to CRC, as well as current techniques to detect them.
Subject(s)
Biomarkers, Tumor/genetics , Colorectal Neoplasms/diagnosis , MicroRNAs/metabolism , Biomarkers, Tumor/blood , Carcinoembryonic Antigen/blood , Colorectal Neoplasms/genetics , Feces/chemistry , Humans , MicroRNAs/bloodABSTRACT
The design and synthesis of a second generation GPR119-agonist clinical candidate for the treatment of diabetes is described. Compound 16 (APD597, JNJ-38431055) was selected for preclinical development based on a good balance between agonist potency, intrinsic activity and in particular on its good solubility and reduced drug-drug interaction potential. In addition, extensive in vivo studies showed a more favorable metabolic profile that may avoid the generation of long lasting metabolites with the potential to accumulate in clinical studies.
Subject(s)
Drug Discovery , Hypoglycemic Agents/chemistry , Piperidines/chemistry , Piperidines/pharmacokinetics , Pyridines/chemistry , Pyridines/pharmacokinetics , Receptors, G-Protein-Coupled/agonists , Animals , Diabetes Mellitus, Type 2/drug therapy , Disease Models, Animal , Humans , Hypoglycemic Agents/pharmacokinetics , Mice , Mice, Inbred C57BL , Molecular Structure , Rats , Rats, Sprague-DawleyABSTRACT
The design of a new clinical candidate histamine-H(3) receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnography with a duration of effect consistent with its pharmacokinetic properties. The identification of a suitable salt form of 2j allowed it to be selected for further development.
Subject(s)
Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Histamine Antagonists/chemistry , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Receptors, Histamine H3/chemistry , Sulfones/chemistry , Animals , Area Under Curve , Brain/metabolism , Central Nervous System/drug effects , Chemistry, Pharmaceutical/methods , Drug Design , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/chemistry , Histamine Antagonists/pharmacokinetics , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Pyrrolidines/antagonists & inhibitors , Rats , Sleep/drug effects , Temperature , Wakefulness/drug effectsABSTRACT
We herein outline the design of a new series of agonists of the pancreatic and GI-expressed orphan G-protein coupled receptor GPR119, a target that has been of significant recent interest in the field of metabolism, starting from our prototypical agonist AR231453. A number of key parameters were improved first by incorporation of a pyrazolopyrimidine core to create a new structural series and secondly by the introduction of a piperidine ether group capped with a carbamate. Chronic treatment with one compound from the series, 3k, showed for the first time that blood glucose and glycated hemoglobin (HbA1c) levels could be significantly reduced in Zucker Diabetic Fatty (ZDF) rats over several weeks of dosing. As a result of these and other data described here, 3k (APD668, JNJ-28630368) was the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes.
Subject(s)
Blood Glucose/drug effects , Drug Discovery , Hypoglycemic Agents/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Disease Models, Animal , Glucose/metabolism , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Molecular Structure , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Rats, ZuckerABSTRACT
Antagonism of the histamine-H(3) receptor is one tactic being explored to increase wakefulness for the treatment of disorders such as excessive daytime sleepiness (EDS) as well as other sleep or cognitive disorders. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were shown to be potent and selective antagonists of the H(3) receptor. Several of these compounds demonstrated in vivo activity in a rat model of (R)-alpha-methyl histamine (RAMH) induced dipsogenia, and one compound (4e) provided an increase in wakefulness in rats as measured by polysomnographic methods. However, more detailed analysis of the PK/PD relationship suggested the presence of a common active metabolite which may preclude this series of compounds from further development.
Subject(s)
Biphenyl Compounds/chemistry , Drug Design , Drug Inverse Agonism , Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Receptors, Histamine H3/metabolism , Sulfonamides/chemistry , Sulfonamides/pharmacology , Administration, Oral , Animals , Histamine Antagonists/administration & dosage , Histamine Antagonists/pharmacokinetics , Humans , Male , Rats , Rats, Sprague-Dawley , Sulfonamides/administration & dosage , Sulfonamides/pharmacokinetics , Thirst/drug effects , Wakefulness/drug effectsABSTRACT
GPR119 is a rhodopsin-like GPCR expressed in pancreatic beta-cells and incretin releasing cells in the GI tract. As with incretins, GPR119 increases cAMP levels in these cell types, thus making it a highly attractive potential target for the treatment of diabetes. The discovery of the first reported potent agonist of GPR119, 2-fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine (8g, AR231453), is described starting from an initial inverse agonist screening hit. Compound 8g showed in vivo activity in rodents and was active in an oral glucose tolerance test in mice following oral administration.
Subject(s)
Hypoglycemic Agents/chemistry , Receptors, G-Protein-Coupled/agonists , Administration, Oral , Animals , Blood Glucose/drug effects , Glucose Tolerance Test , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Mice , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
A new series of H(3) antagonists derived from the natural product Conessine are presented. Several compounds from these new series retain the potency and selectivity of earlier diamine based analogs while exhibiting improved PK characteristics. One compound (3u) demonstrated functional antagonism of the H(3) receptor in an in vivo pharmacological model.
Subject(s)
Alkaloids/pharmacokinetics , Chemistry, Pharmaceutical/methods , Histamine Antagonists/pharmacology , Receptors, Histamine H3/chemistry , Animals , Binding, Competitive/drug effects , Central Nervous System/drug effects , Drug Design , Histamine Antagonists/chemistry , Kinetics , Models, Chemical , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
A new family of Histamine H(3) receptor antagonists (5a-t) has been prepared based on the structure of the natural product Conessine, a known H(3) antagonist. Several members of the new series are highly potent and selective binders of rat and human H(3) receptors and display inverse agonism at the human H(3) receptor. Compound 5n exhibited promising rat pharmacokinetic properties and demonstrated functional antagonism of the H(3) receptor in an in-vivo pharmacological model.
Subject(s)
Alkaloids/chemical synthesis , Alkaloids/pharmacology , Amines/chemical synthesis , Amines/pharmacology , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacology , Alkaloids/chemistry , Amines/chemistry , Animals , CHO Cells , Cricetinae , Cricetulus , Drug Design , Histamine Agonists/pharmacology , Histamine H3 Antagonists/metabolism , Humans , Kinetics , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Rats , Receptors, Histamine H3/metabolism , Structure-Activity RelationshipABSTRACT
The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.