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J Am Coll Cardiol ; 78(21): 2060-2072, 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34794687


BACKGROUND: The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) among patients at high bleeding risk (HBR) is unknown. OBJECTIVES: The purpose of this analysis was to compare 1 vs 3 months of DAPT in HBR patients undergoing drug-eluting stent implantation. METHODS: The XIENCE Short DAPT program comprised 3 prospective, multicenter, single-arm studies of HBR patients treated with a short DAPT course followed by aspirin monotherapy after PCI with a cobalt-chromium everolimus-eluting stent. In this exploratory analysis, patients who received 1-month DAPT (XIENCE 28 USA and 28 Global) were compared with those on 3-month DAPT (XIENCE 90) using propensity score stratification. Ischemic and bleeding outcomes were assessed between 1 and 12 months after index PCI. RESULTS: A total of 3,652 patients were enrolled and 1,392 patients after 1-month DAPT and 1,972 patients after 3-month DAPT were eligible for the analyses. The primary endpoint of all-cause mortality or myocardial infarction was similar between the 2 groups (7.3% vs 7.5%; difference -0.2%; 95% CI: -2.2% to 1.7%; P = 0.41). The key secondary endpoint of BARC (Bleeding Academic Research Consortium) type 2-5 bleeding was lower with 1-month DAPT compared with 3-month DAPT (7.6% vs 10.0%; difference -2.5%; 95% CI: -4.6% to -0.3%; P = 0.012). Major BARC type 3-5 bleeding did not differ at 12 months (3.6% vs 4.7%; difference -1.1%; 95% CI: -2.6% to 0.4%; P = 0.082), but was lower with 1-month DAPT at 90 days (1.0% vs 2.1%; P = 0.015). CONCLUSIONS: Among HBR patients undergoing PCI, 1 month of DAPT, compared with 3 months of DAPT, was associated with similar ischemic outcomes and lower bleeding risk. (XIENCE 90 Study; NCT03218787; XIENCE 28 USA Study; NCT03815175; XIENCE 28 Global Study; NCT03355742).

Int J Gen Med ; 14: 6245-6250, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616177


Background: Squamous cell carcinoma is the most common subtype of malignancy found in patients with head and neck malignancy. There are other rare subtypes which are not adequately reported in medical literature. Lymphoepithelial carcinoma consists of lymphocytic infiltration in a background of undifferentiated carcinoma. They are most often seen in salivary glands but can also be found in other structures of the head and neck region. This analysis reports the nation-wide mortality of patients diagnosed with lymphoepithelial carcinoma of the head and neck. Methods: Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) Database from the years 2000 to 2014. Incidence-based mortality for all stages was queried and results were grouped by gender and race (Caucasian/White, African American/Black, American Indian/Alaskan native and Asian/Pacific Islander). Paired T-test was used to determine statistically significance difference between various subgroups. Results: Incidence-based mortality has been improving for African American/Black patients and has been worsening for Caucasian/White, American Indian/Alaskan native and Asian/Pacific Islander for the period of 2000 to 2014. The differences in mortality trends were statistically different (P < 0.05). The highest mortality rate per 1000 patients was seen in Asian/Pacific Islander population, followed by African American/Black, American Indian/Alaskan native and the least mortality was noted in Caucasian/White patients. When a similar analysis with linearized trend lines on gender was conducted, only African American/Black males and Asian/Pacific Islander females showed an improving trend in mortality. The sample size was a major limitation of this study (Caucasian/White - 134, African American/Black - 30, American Indian/Alaskan native - 5 and Asian/Pacific Islander - 87). Conclusion: Lymphoepithelial carcinoma is a rare subtype of head and neck malignancies whose incidence-based mortality showed a worsening trend. This study showed significant race and gender disparity amongst patients with lymphoepithelial carcinoma. Due to its rarity, this subtype warrants further study, especially with regards to its etiology, clinical course and cure rates.

Mol Cancer Ther ; 20(12): 2420-2432, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34607932


Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer, with a high predisposition for locally invasive and metastatic cancer. With the objective to reduce cancer metastasis, we developed small molecule inhibitors to target the drivers of metastasis, the Rho GTPases Rac and Cdc42. Of these, MBQ-167 inhibits both Rac and Cdc42 with IC50s of 103 and 78 nmol/L, respectively; and consequently, inhibits p21-activated kinase (PAK) signaling, metastatic cancer cell proliferation, migration, and mammosphere growth; induces cell-cycle arrest and apoptosis; and decreases HER2-type mammary fatpad tumor growth and metastasis (Humphries-Bickley and colleagues, 2017). Herein, we used nuclear magnetic resonance to show that MBQ-167 directly interacts with Rac1 to displace specific amino acids, and consequently inhibits Rac.GTP loading and viability in TNBC cell lines. Phosphokinome arrays in the MDA-MB-231 human TNBC cells show that phosphorylation status of kinases independent of the Rac/Cdc42/PAK pathway are not significantly changed following 200 nmol/L MBQ-167 treatment. Western blotting shows that initial increases in phospho-c-Jun and phospho-CREB in response to MBQ-167 are not sustained with prolonged exposure, as also confirmed by a decrease in their transcriptional targets. MBQ-167 inhibits tumor growth, and spontaneous and experimental metastasis in immunocompromised (human TNBC) and immunocompetent (mouse TNBC) models. Moreover, per oral administration of MBQ-167 at 100 mg/kg body weight is not toxic to immunocompetent BALB/c mice and has a half-life of 4.6 hours in plasma. These results highlight the specificity, potency, and bioavailability of MBQ-167, and support its clinical potential as a TNBC therapeutic.

JACC Cardiovasc Interv ; 14(17): 1870-1883, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34503737


OBJECTIVES: The aim of this study was to evaluate 2 abbreviated dual-antiplatelet therapy (DAPT) regimens in patients at high bleeding risk (HBR) undergoing percutaneous coronary intervention (PCI). BACKGROUND: Current-generation drug-eluting stents are preferred over bare-metal stents for HBR patients, but their optimal DAPT management remains unknown. METHODS: The XIENCE Short DAPT program included 3 prospective, multicenter, single-arm studies enrolling HBR patients who underwent successful PCI with a cobalt-chromium everolimus-eluting stent. After 1 month (XIENCE 28 USA and XIENCE 28 Global) or 3 months (XIENCE 90) of DAPT, event-free patients discontinued the P2Y12 inhibitor. The postmarketing approval XIENCE V USA study was used as historical control in a propensity score-stratified analysis. RESULTS: A total of 3,652 patients were enrolled. The propensity-adjusted rate of the primary endpoint of all-cause mortality or myocardial infarction was 5.4% among 1,693 patients on 3-month DAPT versus 5.4% in the 12-month DAPT historical control (Pnoninferiority = 0.0063) and 3.5% among 1,392 patients on 1-month DAPT versus 4.3% in the 6-month DAPT historical control (Pnoninferiority = 0.0005). Bleeding Academic Research Consortium (BARC) types 2 to 5 bleeding was not significantly lower with 3- or 1-month DAPT, while BARC types 3 to 5 bleeding was reduced in both experimental groups. The rate of definite or probable stent thrombosis was 0.2% in XIENCE 90 (P < 0.0001 for the performance goal of 1.2%) and 0.3% in XIENCE 28. CONCLUSIONS: Among HBR patients undergoing PCI with cobalt-chromium everolimus-eluting stents, DAPT for 1 or 3 months was noninferior to 6 or 12 months of DAPT for ischemic outcomes and may be associated with less major bleeding and a low incidence of stent thrombosis.

Stents Farmacológicos , Intervenção Coronária Percutânea , Quimioterapia Combinada , Everolimo/efeitos adversos , Hemorragia/induzido quimicamente , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Estudos Prospectivos , Resultado do Tratamento
Am J Stem Cells ; 10(3): 28-35, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34552815


Cancer stem cells (CSCs) are a unique population of cells found within tumors that are able to self-renew, restore the original heterogeneity of a tumor following treatment, and show increased tumorigenic potential when compared to other cancer cells. It is thought that they are responsible for the recurrence of tumors as well as the resistance to treatment that is seen clinically. CSCs are known to be involved in head and neck cancer (HNCs) specifically, as evidence for their existence can be found in head and neck squamous cell carcinoma (HNSCC), mucoepidermoid carcinoma (MEC), and adenoid cystic carcinoma (ACC), among others. Here, findings from various approaches to identifying and targeting CSCs and their downstream effectors in HNC are summarized, with an emphasis on recent advancements. Prognostic and therapeutic markers are discussed for each specific type of HNC, and novel treatment strategies and current clinical trials involving CSCs are detailed as well. The information provided here is intended to further the research on this important topic and lead to clinical impact in the battle against HNC.

Am Heart J ; 231: 147-156, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33031789


Dual antiplatelet therapy (DAPT) is key for the prevention of recurrent ischemic events after percutaneous coronary intervention (PCI); however, it increases the risk of bleeding complications. While new generation drug-eluting stents have been shown superior to bare-metal stents after a short DAPT course, the optimal DAPT duration in patients at high bleeding risk (HBR) remains to be determined. TRIAL DESIGN: The XIENCE Short DAPT program consists of three prospective, single-arm studies (XIENCE 90, XIENCE 28 Global and XIENCE 28 USA) investigating 3- or 1-month DAPT durations in HBR patients undergoing PCI with the XIENCE stent. The XIENCE 90 study is being conducted in the US and enrolled 2047 subjects who discontinued DAPT at 3 months if they were free from myocardial infarction (MI), repeat coronary revascularization, stroke, or stent thrombosis. The XIENCE 28 program includes the USA study, enrolling 642 patients in US and Canada, and the Global study, enrolling 963 patients in Europe and Asia. In XIENCE 28, patients were to discontinue DAPT at 1 month post-PCI if event-free. The primary hypothesis for both XIENCE 90 and XIENCE 28 is that a short DAPT regimen will be non-inferior to a conventional DAPT duration with respect to the composite of all-cause death or MI. Patients enrolled in the prospective multicenter post-market XIENCE V USA study will be used as historical control group in a stratified propensity-adjusted analysis. CONCLUSIONS: The XIENCE Short DAPT Program will provide insights into the safety and efficacy of 2 abbreviated DAPT regimens of 3- and 1-month duration in a large cohort of HBR patients undergoing PCI with the XIENCE stent.

Síndrome Coronariana Aguda/tratamento farmacológico , Aspirina/administração & dosagem , Stents Farmacológicos , Everolimo/administração & dosagem , Imunossupressores/administração & dosagem , Infarto do Miocárdio/prevenção & controle , Inibidores da Agregação Plaquetária/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Aspirina/efeitos adversos , Canadá , Causas de Morte , Esquema de Medicação , Stents Farmacológicos/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Humanos , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/efeitos adversos , Estudos Prospectivos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Acidente Vascular Cerebral , Trombose , Estados Unidos
World J Oncol ; 12(6): 225-231, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35059082


Background: Patients with melanoma frequently develop central nervous system metastases. Oligometastatic disease is often treated either by surgical resection or by stereotactic radiotherapy. This study investigates the trends and clinical outcomes of patients with melanoma who have undergone surgical procedures on the central nervous system during their hospitalization. Methods: A retrospective study was performed based on admissions of adult patients who underwent craniotomy for metastatic melanoma from 2000 to 2014 using the Nationwide Inpatient Sample database. The primary outcome measure was all-cause in-hospital mortality. Secondary outcomes included hospital length of stay (LOS) and discharge disposition (home/home with health care and skilled nursing facilities/long-term acute care (SNFs/LTAC)). Factors associated with in-hospital mortality were examined by multivariable logistic regression. We adjusted for patient and hospital characteristics, payer, and comorbid conditions. We also examined trends of mortality for the study years. Results: There were an estimated 1,216 discharges of patients with melanoma undergoing craniotomy during the study period. Patients undergoing surgical interventions were typically males (69%) and whites (79%). Ninety-eight percent of procedures were performed at teaching hospitals. Unadjusted all-cause in-hospital mortality was 3.1%. There was no significant difference in mortality over 13 years. Age, gender, and race were not associated with increased in-hospital mortality. LOS was longer in elderly and those with higher Charlson Comorbidity Index. Of the survivors, 76% were discharged to home or with home healthcare while 24% were discharged to SNFs/LTAC. Patients with age > 65 (odds ratio (OR): 2.9; 95% confidence interval (CI): 2.2 - 3.9, P < 0.001) and those with higher Charlson Comorbidity Index (OR: 1.2; 95% CI: 1.1 - 1.3) had higher odds for being discharged to SNFs/LTAC. Conclusions: Patients who undergo craniotomy for metastatic melanoma have a low in-hospital mortality rate. One quarter of patients were discharged to SNFs/LTAC.

Am J Cancer Res ; 10(9): 2742-2751, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042614


Resistance to treatment is one of the biggest challenges in combating head and neck squamous cell carcinoma (HNSCC). The concept of resistance, however, is often viewed as a whole without categorization into the two types of resistance: acquired and intrinsic. Comparison of the mechanisms of the two types of resistance can give further insight as to the importance of these resistance pathways, as mechanisms that are common between the two categories are more likely to be integral to cell survival. In this review, a new perspective on resistance is presented in order to identify molecular targets that have potential for wide therapeutic application. Resistance mechanisms are grouped by the primary pathway involved in order to help establish connections between studies and identify the pathways most active in HNSCC resistance. The receptor tyrosine kinase AXL is one of the targets that showed the greatest promise for overcoming resistance to cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), as it is shown to be upregulated in both acquired and intrinsically cetuximab-resistant cells. Other targets of interest are signal transducer and activator of transcription 3 (STAT3), a downstream transcription factor of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, and TWIST, a marker of epithelial-mesenchymal transition. STAT3 has been shown to be upregulated and more active in cetuximab-resistant HNSCC cell lines, and its inhibition decreased cell growth in cell lines resistant to anti-EGFR therapy. Twist has been shown to have roles in acquired resistance for both cetuximab and cisplatin, a platinum-based therapy that targets dividing cells, which suggests that it also has an integral role in resistance. Other resistance mechanisms are also summarized in this review, but further studies are needed in order to confirm their utility as targets for overcoming resistance in HNSCC.

NPJ Breast Cancer ; 4: 9, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29736411


Tumor cells disseminate early in tumor development making metastasis-prevention strategies difficult. Identifying proteins that promote the outgrowth of disseminated tumor cells may provide opportunities for novel therapeutic strategies. Despite multiple studies demonstrating that the mesenchymal-to-epithelial transition (MET) is critical for metastatic colonization, key regulators that initiate this transition remain unknown. We serially passaged lung metastases from a primary triple negative breast cancer xenograft to the mammary fat pads of recipient mice to enrich for gene expression changes that drive metastasis. An unbiased transcriptomic signature of potential metastatic drivers was generated, and a high throughput gain-of-function screen was performed in vivo to validate candidates. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) was identified as a metastatic driver. CEACAM5 overproduction enriched for an epithelial gene expression pattern and facilitated tumor outgrowth at metastatic sites. Tissues from patients with metastatic breast cancer confirmed elevated levels of CEACAM5 in lung metastases relative to breast tumors, and an inverse correlation between CEACAM5 and the mesenchymal marker vimentin was demonstrated. Thus, CEACAM5 facilitates tumor outgrowth at metastatic sites by promoting MET, warranting its investigation as a therapeutic target and biomarker of aggressiveness in breast cancer.

Rev. argent. cir ; 109(4): 1-10, dic. 2017. ilus
Artigo em Espanhol | LILACS-Express | LILACS | ID: biblio-897350


El páncreas anular (PA) es una anomalía congénita infrecuente. Se caracteriza por la presencia de tejido pancreático ectópico alrededor del duodeno y puede estar asociado a obstrucción duodenal. Se presenta un paciente con cuadro de dolor abdominal y vómitos de 12 días de evolución. El laboratorio mostró elevación de lipasa en sangre. La tomografia computarizada de abdomen evidenció estómago y primera porción duodenal distendidos, en relación con una imagen en anillo de 5 cm de diámetro ubicada entre la cabeza del páncreas y la segunda porción del duodeno, sugestiva de PA. Ante la mala respuesta al tratamiento médico con reposo digestivo, sonda nasogástrica y nutrición parenteral, se decide conducta quirúrgica confirmando el diagnóstico de obstrucción duodenal por un PA. Se realiza gastroyeyunostomía en Y de Roux con buena evolución posquirúrgica. El PA puede manifestarse clínicamente como una obstrucción duodenal. Los casos con mala respuesta al tratamiento conservador requieren conducta quirúrgica para confirmar el diagnóstico y resolver la oclusión.

Annular pancreas (AP) is a rare congenital anomaly, characterized by ectopic pancreatic tissue surroun-ding the duodenum, that may associate with duodenal obstructon. We present a patent complaining of 12 days of abdominal pain and vomitis. Blood testis showed hyper-lipasemia. Computed tomography scan demonstrated stomach and frst duodenal porton distended in relaton to a 5 cm diameter image resembling a ring between the pancreatic head and the second porton of the duodenum, a well known characteristic of AP. Following a lack of clinical response to medical treatment, surgery was performed confirming a duodenal obstructon due to AP. Roux-en-Y gastrojejunostomy was done, with good postoperative outicome. Annular pancreas may present as a duodenal obstructon. For these cases, we suggest surgical treatment to confirm diagnosis and resolve the obstructon in cases with negative clinical response to conservative treatment.

Rev. chil. cir ; 60(6): 557-560, dic. 2008. ilus
Artigo em Espanhol | LILACS | ID: lil-512409


El Tumor Desmolde o Fibromatosis Mesentérica es una enfermedad infrecuente en la que se reconocen 2 formas: una esporádica y otra asociada a poliposis familiar adenomatosa. De etiología desconocida, su diagnóstico preoperatorio es dificultoso y el tratamiento de elección es quirúrgico. Se pone en consideración un caso de esta entidad en un varón joven, que se presentó con dolor abdominal y fiebre. Se realizó cirugía resectiva agresiva, otorgándose el alta a los 18 días de la intervención.

Desmoid tumor or mesenteric fibromatosis is an uncommon disease with to variants: a sporadic form and one associated to familial adenomatous polyposis. Surgery is the treatment of choice. We report a 45 years old male presenting with abdominal pain and fever. An abdominal ultrasound informed the presence of a mass in the periumblical area. An Abdominal CAT sean showed a 13 cm diameter solid mass located in the left upper quadrant. The patient was operated and that mass is excised, requiring also a hemicolectomy, excision of the fourth portion of the duodenum and cholecystectomy. The pathology report of the excised tumor informs a mesenteric fibromatosis. The patient was discharged at the 18th postoperative day.

Humanos , Masculino , Pessoa de Meia-Idade , Fibromatose Abdominal/cirurgia , Fibromatose Abdominal/complicações , Mesentério , Neoplasias Peritoneais/cirurgia , Dor Abdominal/etiologia , Fibroma , Resultado do Tratamento
Rev. chil. cir ; 60(5): 452-456, oct. 2008. tab
Artigo em Espanhol | LILACS | ID: lil-549979


La paniculitis mesentérica es una enfermedad inflamatoria del tejido adiposo del mesenterio, de presentación infrecuente y que se caracteriza, por el engrasamiento, endurecimiento y nodularidad del mismo. Se pone en consideración un caso clínico en un varón joven, con una forma de presentación poco común que requirió de laparotomía exploradora para realizar el diagnóstico y tratamiento.

We report a 28 years old obese male presenting with abdominal pain of increasing intensity lasting 15 days. In the last days, diarrhea and fever appeared. On abdominal examination a 8 cm painful mass was palpated. An abdominal ultrasound showed an anechoic mass in the epigastrium. An abdominal CAT sean showed an inflammatory mass that involves the small bowel. The patient is subjected to a percutaneous needle aspiration, obtaining 50 mi of a purulent fluid. Due to persistence of fever, the patient was operated finding an inflammation that involved the mesentery and the great omentum and covering abscess. The pathologic study of the surgical piece reported a unspecific nodular mesenteric panniculitis.

Humanos , Masculino , Adulto , Abscesso Abdominal/complicações , Abscesso Abdominal/diagnóstico , Paniculite Peritoneal/cirurgia , Paniculite Peritoneal/complicações , Paniculite Peritoneal/diagnóstico , Drenagem , Laparotomia , Lipodistrofia/etiologia , Resultado do Tratamento