RESUMEN
Treatment of Epstein-Barr virus (EBV)-related lymphomas with lytic-inducing agents is an attractive targeted approach for eliminating virus-infected tumor cells. Zidovudine (AZT) is an excellent substrate for EBV-thymidine kinase: it can induce EBV lytic gene expression and apoptosis in primary EBV+ lymphoma cell lines. We hypothesized that the combination of AZT with lytic-inducing chemotherapy agents would be effective in treating EBV+ lymphomas. We report a retrospective analysis of 19 patients with aggressive EBV+ non-Hodgkin lymphoma, including nine cases of acquired immune deficiency syndrome-associated primary central nervous system lymphoma (AIDS-PCNSL) treated with AZT-based chemotherapy. Our results demonstrate that high-dose AZT-methotrexate is efficacious in treating highly aggressive systemic EBV+ lymphomas in the upfront setting. In primary EBV+ lymphoma cell lines, the combination of AZT with hydroxyurea resulted in synergistic EBV lytic induction and cell death. Further, AZT-hydroxyurea treatment resulted in dramatic responses in patients with AIDS-PCNSL. The combination of AZT with chemotherapy, especially lytic-inducing agents, should be explored further in clinical trials for the treatment of EBV-related lymphomas.
Asunto(s)
Antivirales/uso terapéutico , Infecciones por Virus de Epstein-Barr/complicaciones , Herpesvirus Humano 4 , Linfoma/tratamiento farmacológico , Linfoma/etiología , Zidovudina/uso terapéutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antivirales/administración & dosificación , Antivirales/efectos adversos , Línea Celular Tumoral , Terapia Combinada , Femenino , Herpesvirus Humano 4/efectos de los fármacos , Humanos , Linfoma/diagnóstico , Linfoma/mortalidad , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Estadificación de Neoplasias , Inducción de Remisión , Estudios Retrospectivos , Tomografía Computarizada de Emisión de Fotón Único , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Zidovudina/administración & dosificación , Zidovudina/efectos adversosRESUMEN
We compared the cancer outcomes and care-associated service defects between Jackson Memorial Hospital (ABC), a large public safety-net hospital, and Sylvester Comprehensive Cancer Center (XYZ), a private not-for-profit cancer center in patients with stage II-III colorectal cancer (CC) who received adjuvant chemotherapy (AC) and in patients with diffuse large B cell lymphoma (DLBCL). Colorectal cancer patients treated at ABC were more likely to have undergone urgent surgery. While in the CC cohort, three-year overall survival and relapse-free survival rates were significantly higher among patients treated at XYZ compared with those treated at ABC, there was no significant difference between patients treated for DLBCL in the two hospitals. Colorectal cancer patients treated at ABC were more likely to have undergone urgent surgery, to have delays before surgery or during chemotherapy, and to experience a system/patient-related service defect; whereas were less likely to complete a full course of AC.
Asunto(s)
Instituciones Oncológicas , Neoplasias Colorrectales/tratamiento farmacológico , Hospitales Generales , Proveedores de Redes de Seguridad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/clasificación , Supervivencia sin Enfermedad , Femenino , Hospitales Filantrópicos , Humanos , Masculino , Persona de Mediana Edad , Pobreza , Resultado del Tratamiento , Adulto JovenRESUMEN
Perioperative chemotherapy plus surgery improves survival compared to surgery alone in GE junctional (GEJ) and gastric adenocarcinomas. The docetaxel/cisplatin/5-fluorouracil (DCF) combination is superior to CF in patients with metastatic gastric cancer. We retrospectively evaluated the safety and efficacy of preoperative DCF chemotherapy in patients with locally advanced gastric and GEJ cancer. Twenty-one gastric and 10 gastroesophageal junctional (GEJ) cancer patients received 2-3 cycles of preoperative docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1, 5-FU 750 mg/m(2) (continuous infusion) on days 1-5 every 3 weeks. Clinical response was evaluated by comparing pre- and postchemotherapy CT scans. Overall survival (OS) and progression-free survival (PFS) were calculated from the initiation of chemotherapy. None of the patients achieved complete clinical remission while 11 (35%) patients achieved partial clinical remission. Ten patients with GEJ cancer (100%) and 13 with gastric cancer (62%) underwent curative surgery (P = 0.023). Seventeen (55%) patients experienced grade 3-4 chemotherapy-related adverse events. The most common adverse events were anemia, nausea/vomiting, diarrhea, and febrile neutropenia. At a median follow-up of 17.0 months, median OS and PFS were 26.1 months (95% CI: 22.7-29.5) and 18.8 months (95% CI: 9.9-27.7), respectively. The DCF regimen is active in patients with gastric and GEJ adenocarcinoma in the preoperative setting.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Supervivencia sin Enfermedad , Docetaxel , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Unión Esofagogástrica/patología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Clasificación del Tumor , Estadificación de Neoplasias , Estudios Retrospectivos , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Taxoides/administración & dosificación , Taxoides/efectos adversos , Resultado del TratamientoRESUMEN
Patients with acute myeloid leukemia (AML) and internal tandem duplication of FMS-like tyrosine kinase receptor-3 gene (FLT3-ITD) mutation have poor prognoses and are often treated with allogeneic hematopoietic stem cell transplantation (HSCT). Sorafenib, an inhibitor of multiple kinases including FLT3, has shown promising activity in FLT3-ITD-positive AML. We treated 16 patients with FLT3-ITD-positive AML who relapsed after HSCT with sorafenib alone (n = 8) or in combination with cytotoxic chemotherapy (n = 8). The number of circulating blasts decreased in 80% of cases, but none of the patients achieved complete remission (CR); 3 achieved partial remission. Two patients were bridged to a second transplantation but both relapsed within 3 months of the transplantation. Median overall survival (OS) was 83 days, with none surviving more than a year. Sorafenib is not effective in the treatment of FLT3-ITD-positive AML relapsing after HSCT. Preventive strategies after HSCT may be more suitable for these high-risk patients.
Asunto(s)
Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/cirugía , Piridinas/uso terapéutico , Trasplante Homólogo/métodos , Tirosina Quinasa 3 Similar a fms/biosíntesis , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencenosulfonatos/administración & dosificación , Terapia Combinada , Femenino , Humanos , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Pronóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/administración & dosificación , Recurrencia , Estudios Retrospectivos , Sorafenib , Adulto Joven , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
Hematopoietic stem cell transplantation from haploidentical donors is an attractive method of transplantation due to the immediate donor availability, ease of stem cell procurement and the possibility to collect additional donor cells for cellular therapy, if needed. Historically, maintaining T-cells in the graft has been associated with very high rates of graft-versus-host disease, while T-cell depleted haploidentical transplantation has been limited by a higher incidence of graft rejection and delayed immune reconstitution post-transplant. Recent approaches attempt to maintain the T-cells in the graft while effectively preventing the development of graft-versus-host disease post-transplant. Selective depletion of alloreactive T-cells post-transplant using high-dose post-transplant cyclophosphamide is under investigation as a promising alternative in haploidentical transplantation. While engraftment has improved and graft-versus-host disease is controlled with this approach, future directions should focus on optimizing conditioning regimens and the prevention of disease relapse post-transplant.
Asunto(s)
Humanos , Trasplante de Médula Ósea , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Linfocitos T/inmunologíaRESUMEN
The activation of human epidermal growth factor receptor-2 (HER2) results in the activation of the mitogen-activated protein kinase (MAPK) cascade that may lead to the resistance to anti-estrogen therapy in estrogen receptor (ERα) expressing breast cancer by means of phosphorylation of ERα in the N-terminal region by phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) and by means of decreasing ERα expression. Immunohistochemistry is the most widely used technique for the detection of ERα and HER2 in breast cancer specimens, however, is inadequate in its ability to assess the relationship between ERα, HER2, and MAPK cascade at the single cell level. To clear this major hurdle, we devised a novel flow cytometric method to quantify the expression of ERα, HER2, and the activation of MAPK cascade simultaneously in single cells. The method was validated by concurrent Western blotting in established cell lines: MDA-231 (ERα and HER2-negative), MCF-7 (ERα-positive, HER2-negative), MCF-7 cells overexpressing ERα after long-term incubation in estrogen-free medium, and HER2 transfected MCF7 cells. Using the flow cytometry method, we confirmed the previous finding that ERα expression is down-regulated upon epidermal growth factor mediated ERK1/2 phosphorylation in EGFR/MCF-7 cells. To our knowledge, this is the first such assay to incorporate simultaneous single cell measurement for all of these pathways, which may prove useful to determine the intratumoral heterogeneity in breast tumors or the receptor status in circulating tumor cells.
Asunto(s)
Neoplasias de la Mama/enzimología , Receptor alfa de Estrógeno/metabolismo , Citometría de Flujo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Receptor ErbB-2/metabolismo , Western Blotting , Neoplasias de la Mama/genética , Línea Celular Tumoral , Activación Enzimática , Estradiol/metabolismo , Femenino , Humanos , Fosforilación , Receptor ErbB-2/genética , Reproducibilidad de los Resultados , Factores de Tiempo , TransfecciónAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Aminoglicósidos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Azacitidina/uso terapéutico , Gemtuzumab , Humanos , Persona de Mediana Edad , Inducción de Remisión/métodos , Estudios Retrospectivos , Terapia Recuperativa/métodos , Adulto JovenRESUMEN
One-fifth of the newly diagnosed multiple myeloma (MM) patients present with renal failure (RF) [1-3]. Glucocorticoids (GCs) may improve RF in MM by (1) rapid reduction of paraprotein production, (2) lessening inflammation and fibrosis in renal parenchyma, and (3) decreasing serum calcium level. We hypothesized that lower dose GCs may be less effective in restoring renal function and retrospectively compared the RF reversibility between the newly diagnosed MM patients who were treated with GCs equivalent to ≥160 mg DX over 4 days (high-dose GC group, n = 16) versus those who were treated with <160 mg (low-dose/no GC group, n = 8). There was no difference in age, baseline calcium, and creatinine levels between the two groups. Renal function was restored in seven patients in the high-dose GC group (44%) and in none of the patients in the low-dose/no GC group (P = 0.026). The only other factor found to impact the RF reversibility was the delay of GC initiation. Four and 1 patients developed a severe infection in the high- and low-dose/no GC groups, respectively. The use of higher dose GCs in the newly diagnosed MM patients who present with RF increases the likelihood of renal function restoration.
Asunto(s)
Glucocorticoides/administración & dosificación , Mieloma Múltiple/complicaciones , Insuficiencia Renal/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Glucocorticoides/uso terapéutico , Humanos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/prevención & control , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Insuficiencia Renal/complicaciones , Estudios Retrospectivos , Análisis de Supervivencia , Factores de TiempoRESUMEN
Hematopoietic stem cell transplantation from haploidentical donors is an attractive method of transplantation due to the immediate donor availability, ease of stem cell procurement and the possibility to collect additional donor cells for cellular therapy, if needed. Historically, maintaining T-cells in the graft has been associated with very high rates of graft-versus-host disease, while T-cell depleted haploidentical transplantation has been limited by a higher incidence of graft rejection and delayed immune reconstitution post-transplant. Recent approaches attempt to maintain the T-cells in the graft while effectively preventing the development of graft-versus-host disease post-transplant. Selective depletion of alloreactive T-cells post-transplant using high-dose post-transplant cyclophosphamide is under investigation as a promising alternative in haploidentical transplantation. While engraftment has improved and graft-versus-host disease is controlled with this approach, future directions should focus on optimizing conditioning regimens and the prevention of disease relapse post-transplant.
RESUMEN
BACKGROUND: It is unclear whether delays in commencing adjuvant chemotherapy after surgical resection of colon adenocarcinoma adversely impact survival. METHODS: Patients with stage II-III colon adenocarcinoma who received adjuvant chemotherapy at 2 centers were identified through the institutional tumor registry. Time to adjuvant chemotherapy, overall survival (OS), and relapse-free survival (RFS) were calculated from the day of surgery. Patients were dichotomized into early (time to adjuvant chemotherapy ≤ 60 days) and late treatment (time to adjuvant chemotherapy >60 days) groups. OS and RFS were compared using log-rank test and multivariate analysis by the Cox proportional hazards model. RESULTS: Of 186 patients included in the study, 49 (26%) had received adjuvant chemotherapy >60 days after surgical resection. Thirty percent of the delays were system related (eg, late referrals, insurance authorizations). Time to adjuvant chemotherapy >60 days was associated with significantly worse OS in both univariate analysis and a Cox proportional hazards model (hazard ratio, 2.17; 95% confidence interval, 1.08-4.36). Although difference in RFS between the 2 groups favored time to adjuvant chemotherapy <60, this did not reach statistical significance. CONCLUSIONS: Adjuvant chemotherapy delay >60 days after surgical resection of colon cancer is associated with worse OS.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Antineoplásicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Quimioterapia Adyuvante , Neoplasias del Colon/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Factores de Riesgo , Factores de TiempoRESUMEN
In spite of advances made in the management of the other more common cancers of the gastrointestinal tract, significant progress in the treatment of pancreatic cancer remains elusive. Nearly as many deaths occur from pancreatic cancer as are diagnosed each year reflecting the poor prognosis typically associated with this disease. Until recently, the only treatment with an impact on survival was surgery. In the palliative setting, gemcitabine (Gem) has been a standard treatment for advanced pancreatic cancer since it was shown a decade ago to result in a superior clinical benefit response and survival compared with bolus 5-fluorouracil. Since then, clinical trials have explored the pharmacokinetic modulation of Gem by fixed dose administration and the combination of Gem with other cytotoxic or the biologically "targeted" agents. However, promising trial results in small phase II trials have not translated into survival improvements in larger phase III randomized trials in the advanced disease setting. Two trials have recently reported modest survival improvements with the use of combination treatment with Gem and capecitabine (United Kingdom National Cancer Research GEMCAP trial) or erlotinib (National Cancer Institute of Canada Clinical Trials Group PA.3 trial). This review will focus on the use of systemic therapy for advanced and metastatic pancreatic cancer, summarizing the results of several recent clinical trials and discuss their implications for clinical practice. We will also discuss briefly the second-line chemotherapy options for advanced pancreatic cancer.
Asunto(s)
Quimioterapia/tendencias , Cuidados Paliativos/tendencias , Neoplasias Pancreáticas/tratamiento farmacológico , Antimetabolitos Antineoplásicos/uso terapéutico , Capecitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Progresión de la Enfermedad , Fluorouracilo/análogos & derivados , Fluorouracilo/uso terapéutico , Humanos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/secundario , GemcitabinaRESUMEN
INTRODUCTION: Atrial fibrillation was previously reported in patients with esophageal cancer as a complication of total esophagectomy or photodynamic therapy. Here, we propose that atrial fibrillation may also be caused by external compression of the left atrium by esophageal cancer. CASE PRESENTATION: We present a 58-year-old man who developed atrial fibrillation with rapid ventricular rate in the emergency room while being evaluated for dysphagia and weight loss. Atrial fibrillation lasted less than 12 hours and did not recur. Echocardiogram did not reveal any structural heart disease. A 10-cm, ulcerated mid-esophageal mass was seen during esophagogastroscopy. Microscopic examination showed squamous cell carcinoma. Computed tomography of the chest revealed esophageal thickening compressing the left atrium. CONCLUSION: External compression of the left atrium was previously reported to provoke atrial fibrillation. Similarly, esophageal cancer may precipitate atrial fibrillation by mechanical compression of the left atrium or pulmonary veins, triggering ectopic beats in susceptible patients.
RESUMEN
Our goal is to provide a detailed review of veno-occlusive disease (VOD), Budd-Chiari syndrome (BCS), and congestive hepatopathy (CH), all of which results in hepatic venous outflow obstruction. This is the first article in which all three syndromes have been reviewed, enabling the reader to compare the characteristics of these disorders. The histological findings in VOD, BCS, and CH are almost identical: sinusoidal congestion and cell necrosis mostly in perivenular areas of hepatic acini which eventually leads to bridging fibrosis between adjacent central veins. Tender hepatomegaly with jaundice and ascites is common to all three conditions. However, the clinical presentation depends mostly on the extent and rapidity of the outflow obstruction. Although the etiology and treatment are completely different in VOD, BCS, and CH; the similarities in clinical manifestations and liver histology may suggest a common mechanism of hepatic injury and adaptation in response to increased sinusoidal pressure.