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INTRODUCTION: Geriatric oncology is the clinical field of cancer treatment in older adults (above 65 years) and in the oldest-old (above 80 years). As age is the most significant risk factor for cancer, and with the aging of the population, there is a vast increase in the number of older cancer patients. BACKGROUND: The cases highlight the unique challenges in geriatric oncology: disease goals may differ; treatment toxicities are higher; the extensive use of prescription medication increases the chances of harmful drug-drug interactions; finally, older adults have unique psychosocial needs. Cancer treatment in older adults poses a risk of under-treatment as well as a risk for over-treatment. DISCUSSION: 'Onco-geriatrics' is a field in geriatrics in which a comprehensive geriatric assessment (CGA) is performed. The CGA focuses on specific therapeutic challenges of the older patient, on frailty and on toxicity-risk assessment. In geriatric oncology, a field in oncology aimed at providing care to older cancer adults, the most important first step is to define treatment intent - cure or palliation. Achievement of cure usually mandates a multi-disciplinary aggressive approach. Compromising any component of the treatment may hamper its success rate, yet administering the full therapeutic plan may be too toxic. Thus, each older patient being considered for definitive treatment must be discussed in a multi-disciplinary tumor board, and preferably assessed by a dedicated geriatrician prior to decision-making. In cases in which treatment intent is palliative - i.e. prolongation of survival and/or improvement in quality of life, we propose the following scheme - accurate definition of the palliative goal; adaptation of the therapeutic regime to the patient's geriatric condition; frequent clinical monitoring and flexibility in administration; continued treatment as long as palliative benefit is achieved, and early cessation in its absence. Such a scheme maintains the principal of 'primum non nocere' while facilitating the palliative benefit for older adults.
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Fragilidad , Geriatría , Neoplasias , Anciano , Anciano de 80 o más Años , Fragilidad/diagnóstico , Fragilidad/terapia , Evaluación Geriátrica , Humanos , Neoplasias/terapia , Sobretratamiento , Calidad de VidaRESUMEN
PURPOSE: Acneiform rash, a common toxicity of epidermal growth factor receptor inhibitors (EGFRIs), can cause patient discomfort, warranting changes in treatment. This study investigated the safety, tolerability, and efficacy of a novel doxycycline foam, FDX104 4%, for managing EGFRI-related skin toxicity. METHODS: This was an exploratory phase 2, randomized, double-blind, placebo-controlled study. Subjects had metastatic colorectal cancer and were being treated with either cetuximab or panitumumab plus chemotherapy. Treatment (twice-daily topical FDX104 4% on one side of the face and vehicle foam on the other for 5 weeks) was initiated 7 ± 3 days prior to EGFRI therapy. Rash severity, safety, and tolerability were evaluated at 2 and 4 weeks after EGFRI start. RESULTS: The mean maximal rash grade was lower with FDX104 4% vs vehicle, and fewer subjects developed moderate-to-severe (grades 2-3) rash. On the Global Severity Score scale, a statistically significant difference favored FDX104 4% over vehicle (P = .047). Adverse events (AEs) (n = 68) occurred in 20 subjects; most were mild or moderate. The most common AEs were oral mucositis, nausea, and vomiting, common to chemotherapy and EGFRI treatment. Study-drug-related AEs were experienced by five subjects and consisted of mild, local skin reactions. No study-drug-related systemic side effects were reported. CONCLUSION: Twice-daily, topical administration of FDX104 4% as an adjunct to either cetuximab or panitumumab was safe and well tolerated, and appeared to prevent the onset of rash, especially severe rash. CLINICALTRIALS. GOV IDENTIFIER: Trial Registration NCT02239731.
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Erupciones Acneiformes/inducido químicamente , Erupciones Acneiformes/prevención & control , Doxiciclina/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Administración Tópica , Adulto , Anciano , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Cetuximab/administración & dosificación , Cetuximab/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Método Doble Ciego , Doxiciclina/efectos adversos , Receptores ErbB/antagonistas & inhibidores , Femenino , Humanos , Masculino , Persona de Mediana Edad , Panitumumab/administración & dosificación , Panitumumab/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Piel/efectos de los fármacosRESUMEN
BACKGROUND: Despite the ongoing decrease in the incidence of gastric cancer, this disease is still a major cause of death. It is still debatable whether D2 lymphadenectomy improves survival and whether this procedure should be performed routinely or selectively. OBJECTIVES: To compare the pathological and short-term results following radical D2-type gastric resection and lymphadenectomy versus the more limited D1 type resection and lymphadenectomy. METHODS: We conducted a retrospective study on 4 years experience treating 164 patients suffering from gastric cancer. We compared the results between the group of patients who underwent a radical D2 type gastric resection and lymphadenectomy (n = 100) and those of a relatively small group of patients who intentionally underwent the more limited D1 type (n = 34). RESULTS: The overall number of harvested lymph nodes was 9 ± 4 in the D1 group compared to 30 ± 12 (range 16-69) in the D2 group (P = 0.001). Of the 100 patients undergoing a D2 lymphadenectomy, 57% had positive nodes compared to 38% of the 34 patients in the D1 group (P = 0.045). CONCLUSIONS: We showed statistically significant differences between D1 and D2 procedures in the overall number of harvested lymph nodes and the proportion of positive nodes to the overall number. Our results support the fact that D2 resection should be recommended as the standard approach of treatment for gastric cancer patients, ensuring a larger number of retrieved lymph nodes and a comparable rate of complications and mortality.
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Adenocarcinoma/cirugía , Gastrectomía/métodos , Escisión del Ganglio Linfático/métodos , Neoplasias Gástricas/cirugía , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias Gástricas/patologíaRESUMEN
INTRODUCTION: Microsatellite stable metastatic colorectal cancer (MSS mCRC) is largely refractory to immune checkpoint inhibition. We hypothesized that a combination of intratumoral TLR9 agonist, radiosurgery and dual PD-1 and CTLA-4 blockade would induce a local focus of immune stimulation, evoking a systemic immune response. PATIENTS AND METHODS: In this phase I single-institution study, patients with MSS mCRC were treated with a priming dose of s.c vidutolimod, 3 intratumoral injections of vidutolimod and radiosurgery, combined with nivolumab and ipilimumab. Cytokine levels were measured at baseline and at 7 (± 2) weeks. Patients were accrued to 4 consecutive cohorts: (1) Safety run-in without radiosurgery, (2) Radiosurgery prior to intratumoral therapy, (3) Radiosurgery prior to intratumoral therapy with a condensed timeline, and (4) Radiosurgery to extrahepatic lesion following completion of intratumoral therapy. RESULTS: A total of 19 patients were accrued. Median age was 59 years (range 40-71), 68% were male, median number of previous systemic treatments was 3 (range 2-5). None of the patients responded, aside from 1 patient, attributed to high tumor mutational burden. Grade 3 liver toxicity was reported in 0%, 0%, 75%, and 17% in cohorts 1 to 4, respectively. Systemic levels of CXCL10 and IL-10 increased, with a median of 407 versus 78 pg/mL (P = .01), and 66 versus 40 pg/mL (P = .03), respectively. CONCLUSIONS: The combination of intratumoral vidutolimod, radiosurgery, nivolumab and ipilimumab was not found to be efficacious in MSS mCRC with liver metastases. The juxtaposition of liver irradiation and intratumoral vidutolimod injection was associated with high hepatic toxicity.
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Antineoplásicos Inmunológicos , Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias Hepáticas , Radiocirugia , Neoplasias del Recto , Humanos , Masculino , Adulto , Persona de Mediana Edad , Anciano , Femenino , Ipilimumab/uso terapéutico , Ipilimumab/efectos adversos , Nivolumab/uso terapéutico , Nivolumab/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Radiocirugia/efectos adversos , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Repeticiones de MicrosatéliteRESUMEN
OBJECTIVES: US FDA and EMA allow facilitated regulatory pathways to expedite access to new treatments. Limited supportive data may result in major postapproval variations. In Israel, partly relying on Food and Drug Administration (FDA) and European Medicines Agency (EMA), clinical data are reviewed independently by the Advisory Committee of Drug Registration (ACDR). In this study, the correlation between the number of discussions at the ACDR and major postapproval variations is examined. DESIGN: This is an observational retrospective comparative cohort study. SETTING: Applications with FDA and/or EMA approval at time of assessment in Israel were included. The timeframe was chosen to allow a minimum of 3 years of postmarketing approval experience for potential major label variations. Data regarding the number of discussions at ACDR were extracted from protocols. Data on postapproval major variations were extracted from the FDA and EMA websites. RESULTS: Between 2014 and 2016, 226 (176 drugs) applications, met the study criteria. 198 (87.6%) and 28 (12.4%) were approved following single and multiple discussions, respectively. A major postapproval variation was recorded in 129 (65.2%) compared with 23 (82.1%) applications approved following single and multiple discussions, respectively (p=0.002). Increased risk for major variation was found for medicines approved following multiple discussions (HR=1.98, 95% CI: 1.26 to 3.09) with a median time of 1.2 years, applications approved based on phase II trials (HR=2.58, 95% CI: 1.72 to 3.87), surrogate endpoints (HR=1.99, 95% CI: 1.44 to 2.74) and oncologic indications (HR=2.48, 95% CI: 1.78 to 3.45). CONCLUSIONS: Multiple ACDR discussions associated with limited supportive data are predictive for major postapproval variations. Moreover, our findings demonstrate that approval by the FDA and/or EMA does not pave the way to automatic approval in Israel. In a substantial per cent of the cases, submission of the same clinical data resulted in different safety and efficacy considerations, requiring additional supporting data in some cases or even rejection of the application in others.
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Aprobación de Drogas , Estados Unidos , Humanos , Preparaciones Farmacéuticas , United States Food and Drug Administration , Israel , Estudios de Cohortes , Estudios RetrospectivosRESUMEN
BACKGROUND: Refractory epigastric/midback pain is associated with locally advanced abdominal malignancies, especially pancreatic cancer. The pain is caused by tumor infiltration of the celiac plexus, a nerve network attached to the abdominal aorta. Contemporary palliative approaches are often inadequate. We hypothesized that ablative radiation targeted to the celiac plexus would alleviate this pain. METHODS AND MATERIALS: We performed a single-arm prospective clinical trial (ClinicalTrials.gov identifier: NCT02356406). Eligible and evaluable patients had celiac pain of at least 5 out of 10 on the Numerical Rating Scale, completed treatment per protocol, and had at least 1 posttreatment visit. The entire retroperitoneal celiac plexus was irradiated with a single 25-Gy fraction. The primary endpoint was change in the Numerical Rating Scale 3 weeks posttreatment. Toxic effects and pain interference (as measured with the Brief Pain Inventory) were secondary endpoints. RESULTS: For our study, 31 patients signed consent, and, of these, 18 patients were treated and evaluable. Median age was 68 years (range, 51-79); 89% of the patients had pancreatic cancer; the median Eastern Cooperative Oncology Group performance status was 1; and the median interval from initial diagnosis to treatment was 9 months (range, 1-36), and, in this interval, patients received a median of 1 systemic treatment line (range, 0-3). Acute toxicity was limited to grade 1 to 2. Three weeks after treatment, 16 patients (84%) reported decreased celiac pain, with median pain level falling from 6 out of 10 (interquartile range [IQR], 5.0-7.5) at baseline to 3 out of 10 (IQR, 1.0-4.3); six weeks after treatment, the Numerical Rating Scale number fell further to 2.8 out of 10 (IQR, 0-3.3; both P < .005 vs baseline), including 4 patients who reported complete eradication of their celiac pain. Total daily morphine milligram equivalents decreased from 59 pretreatment to 50 at 3 weeks, and from 50 to 45 at 6 weeks. Significant improvement was seen in pain-interference scores. CONCLUSIONS: Celiac plexus radiosurgery appears to alleviate cancer-related pain. An international multicenter phase 2 trial is currently accruing.
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Dolor en Cáncer , Plexo Celíaco , Neoplasias Pancreáticas , Radiocirugia , Anciano , Dolor en Cáncer/etiología , Dolor en Cáncer/radioterapia , Humanos , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/radioterapia , Estudios Prospectivos , Radiocirugia/efectos adversos , Neoplasias PancreáticasRESUMEN
BACKGROUND: KRAS mutations occur in 40% of colorectal cancers (CRCs), affecting the efficacy of agents targeting the epidermal growth factor receptor. However, the effect of KRAS mutation status on the activity of non-epidermal growth factor receptor-targeting chemotherapy has not been fully elucidated. The aim of the present study is to evaluate the effect of KRAS status on the activity of different chemotherapeutic regimens. PATIENTS AND METHODS: A retrospective chart review of chemotherapy-treated patients with metastatic CRC with known KRAS status was undertaken. Chemotherapy effects were measured by progression-free survival, time to chemotherapy resistance, and overall survival. Analysis was performed for the different chemotherapy regimens, and according to the KRAS mutation status while adjusting for potential confounders. RESULTS: KRAS mutations were detected in 43% of 223 patients with metastatic CRC who were treated at the Ottawa Hospital. The baseline distribution of KRAS wild-type (WT) and mutant status was similar. The median follow-up was 27.2 months. Regimens received included single agents or combinations of 2 or 3 chemotherapies. Among those treated with capecitabine-based regimens, survival was longer for patients with KRAS WT status (hazard ratio, 0.47; 95% confidence interval, 0.23-0.95; P < .0001) when compared with those with mutant status. The median overall survival was 46.7 versus 32.6 months for patients with KRAS WT versus mutant status, respectively. The time to chemotherapy resistance was also significantly longer for patients with WT status (hazard ratio, 0.49; 95% confidence interval, 0.25-0.97; P = .0398). A trend for progression-free survival did not reach statistical significance. CONCLUSION: Patients with KRAS WT tumors may benefit more from capecitabine-based treatments than patients with mutant status. Further research is needed to explain this data.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/secundario , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Extracellular signal-regulated kinases (ERKs) are signaling molecules that regulate many cellular processes. We have previously identified an alternatively spliced 46-kDa form of ERK1 that is expressed in rats and mice and named ERK1b. Here we report that the same splicing event in humans and monkeys causes, due to sequence differences in the inserted introns, the production of an ERK isoform that migrates together with the 42-kDa ERK2. Because of the differences of this isoform from ERK1b, we named it ERK1c. We found that its expression levels are about 10% of ERK1. ERK1c seems to be expressed in a wide variety of tissues and cells. Its activation by MEKs and inactivation by phosphatases are slower than those of ERK1, which is probably the reason for its differential regulation in response to extracellular stimuli. Unlike ERK1, ERK1c undergoes monoubiquitination, which is increased with elevated cell density concomitantly with accumulation of ERK1c in the Golgi apparatus. Elevated cell density also causes enhanced Golgi fragmentation, which is facilitated by overexpression of native ERK1c and is prevented by dominant-negative ERK1c, indicating that ERK1c mediates cell density-induced Golgi fragmentation. The differential regulation of ERK1c extends the signaling specificity of MEKs after stimulation by various extracellular stimuli.
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Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Empalme Alternativo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Células COS , Línea Celular , Chlorocebus aethiops , Clonación Molecular , ADN/genética , Proteínas de Unión al ADN/metabolismo , Activación Enzimática , Expresión Génica , Células HeLa , Humanos , Cinética , Ratones , Proteína Quinasa 3 Activada por Mitógenos/química , Proteína Quinasa 3 Activada por Mitógenos/genética , Datos de Secuencia Molecular , Peso Molecular , Fosforilación , Proteínas Proto-Oncogénicas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Distribución Tisular , Factores de Transcripción/metabolismo , Proteína Elk-1 con Dominio etsRESUMEN
OBJECTIVE: Taxotere-based chemotherapy is the only approach which has recently demonstrated prolongation of survival in patients with androgen-independent prostate cancer. This article presents our experience with this therapy. METHODS: Since August 1999 we treated 49 patients with Taxotere/Estramustine or Taxotere/Prednisone combinations. RESULTS: Biochemical response occurred in 27 (55.1%) patients, unaffected by prior exposure to chemotherapy. Among the 32 patients with measurable disease, 7 (21/8%) patients demonstrated partial response and an additional 16 (50%) patients obtained stable disease. Half of the patients withdrew morphine palliative therapy. The median survival of all patients was 12.6 months, significantly longer in patients with biochemical response (14.3 vs 5.4 months) and no prior chemotherapy (14.3 vs 9.1 months). The disease recurred equally among osseous and soft tissue sites (18 sites each group). The most significant toxicity was neutropenia grade 3-4 in 26 (53%) patients. Infection, among them one fatal, developed in 18 (37.3%) patients. CONCLUSIONS: Taxotere-based chemotherapy is active and tolerated in androgen-independent prostate cancer. Heavily pretreated patients are sensitive to therapy. Progression occurred in bone and soft-tissue sites.
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Neoplasias de la Próstata/tratamiento farmacológico , Taxoides/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Fitogénicos/uso terapéutico , Docetaxel , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/mortalidad , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: The number of lymph nodes harvested during gastrectomy depends on the extension of lymphadenectomy and the method of lymph node retrieval. AIM: The objective of this study was to evaluate two methods of lymph node retrieval in specimens of gastric cancer. METHODS: The number of lymph nodes was compared using two different techniques. The technique used in the first group was manual dissection following formalin fixation, and the techniques used in the second group was fat-clearing by acetone. RESULTS: Both groups were comparable for demographic and pathological variables. The average number of harvested nodes was 19.3 ± 10 for the manual group as compared to 26.1 ± 14 in the acetone group (P = 0.003). The differences in the average number of positive nodes did not reach statistical significance (4.6 compared to 6.9 nodes). CONCLUSION: The acetone clearing technique enables the evaluation of a larger number of nodes. An increase, but statistically non significant, number of positive nodes was noted in the acetone group.
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Adenocarcinoma/patología , Gastrectomía , Escisión del Ganglio Linfático/métodos , Ganglios Linfáticos/patología , Patología Quirúrgica/métodos , Neoplasias Gástricas/patología , Adenocarcinoma/cirugía , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Neoplasias Gástricas/cirugíaRESUMEN
UNLABELLED: ADH-1 (Exherin™) is a pentapeptide, which competitively inhibits N-cadherin, resulting in vascular disruptive effect of tumor vasculature in preclinical models. This study was designed to assess the toxicity of ADH-1 and to determine the maximal tolerated dose (MTD). PATIENTS AND METHODS: Adult patients with advanced measurable solid tumors were stratified according to their tumor N-cadherin status. ADH-1 was administered as a short infusion, every six weeks. Assessment of response was done every 6 weeks. PK parameters included: estimated volume of distribution of the central compartment, the α and ß phase half-lives, area under the plasma concentration- time curve (AUC), clearance, and volume of distribution. Target lesions were assessed by dynamic contrast enhancing- magnetic resonance imaging (DCE-MRI). RESULTS: 46 patients were enrolled, 25 (54%) had N-cadherin positive status. The doses administered ranged from 50 mg/m2 to 1000 mg/m2, and the MTD was not reached. The PK analysis of the concentration-time data displayed a biphasic profile. Most of the toxicities were grade 1 and 2 with fatigue, nausea, chest pain and dysgeusia being the most common. Eleven patients had disease control, the single patient who had partial response had N-cadherin positive tumor. CONCLUSION: ADH-1 is a well tolerated drug with a modest anti tumor effect in tumors which express N-cadherin.
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Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Péptidos Cíclicos/uso terapéutico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Péptidos Cíclicos/efectos adversos , Péptidos Cíclicos/farmacocinéticaRESUMEN
MicroRNAs (miRs) are short non-coding RNAs that bind complementary sequences in mRNA resulting in translation repression and/or mRNA degradation. We investigated expression of the reported metastasis-associated miRs-335, 206, 135a, 146a, 146b, 10b, 21, let7a and let7b in normal mucosa, non-metastatic and metastatic colorectal cancer (CRC). Expression of target miRs in micro-dissected paraffin embedded tissues was evaluated in 15 primary tumours with adjacent normal tissue from patients that were disease-free at 4 years (cohort A) and 19 paired primary tumours with corresponding liver metastases (cohort B) by quantitative real-time PCR. Increased expression of miR-21, mir-135a and miR-335 was associated with clinical progression of CRC, while miR-206 demonstrated an opposite trend. The levels of mir-21 did not associate with the expression of PTEN, an important tumour suppressor in CRC and one of many putative targets of miR-21, but interestingly was associated with stage of disease in the PTEN expressing tumours. Surprisingly, let7a, a KRAS-targeting miR, showed elevated expression in metastatic disease compared to normal mucosa or non-metastatic disease, and only in KRAS mutation positive tumors. Finally, a prognostic signature of miR 21,135a, 335, 206 and let-7a for detecting the presence of metastases had a specificity of 87% and sensitivity of 76% for the presence of metastases. In summary, we have shown stage-associated differential expression of five out of nine tested metastasis-associated miRs. We have further found that an analysis of these five miRs expression levels in primary tumors significantly correlates with the presence of metastatic disease, making this a potential clinically useful prognostic tool.
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Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , MicroARNs/genética , Metástasis de la Neoplasia , Anciano , Secuencia de Bases , Estudios de Cohortes , Neoplasias Colorrectales/patología , Cartilla de ADN , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Pronóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Regulación hacia ArribaRESUMEN
The epidermal growth factor receptor is a member of the receptor tyrosine kinase family whose members play a critical role in oncogenesis. In particular, EGFR has been shown to participate in colon cancer development. Due to its role in the progression of colon cancer, EGFR has become an attractive target for therapy and two different classes of biologic agents have been evaluated: the EGFR monoclonal antibodies and the tyrosine kinase inhibitors. These two groups of agents differ in the specific molecular site which they target on the EGFR and in their efficacy in the treatment of colon cancer. This review will discuss the EGFR's evolving role as a prognostic and predictive biomarker in colon cancer. Once thought to be an inherent predictive factor for anti-EGFR monoclonal antibodies (MAbs) the EGFR has been replaced by KRAS and to some extent BRAF. The efficacy of both anti-EGFR MAbs, cetuximab and panitumumab, has been clearly demonstrated to depend upon the KRAS mutational status. The anti-EGFR monoclonal antibodies and their predictive biomarkers have taken colon cancer treatment another step closer towards the goal of tailored cancer therapy.
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Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/enzimología , Receptores ErbB/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Receptores ErbB/antagonistas & inhibidores , Humanos , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal/genéticaRESUMEN
Adrenocortical Carcinoma (ACC) is rare with an annual incidence of 0.5-2 cases per million worldwide. Some ACC tumors over express N-cadherin, which correlates with metastatic potential. ADH-1 (Exherin™) is a competitive inhibitor of N-cadherin, resulting in rapid onset of tumor vascular angiolysis and apoptosis in preclinical models. Targeting N-cadherin may cause direct anti-tumor and anti-vascular effects. We report a case of ACC with benefit from ADH-1 therapy. A 24 year old woman with an N-cadherin expressing metastatic ACC was treated on a phase I trial and treated with ADH-1 subsequently received additional doses through a special access program. The patient presented with cushingoid features from cortisol over-secretion and was diagnosed with metastatic ACC in January 2003. Tumor progression followed treatment with a combination of doxorubicin, cisplatin and mitotane. In October 2003, as a part of a phase I clinical trial she was treated with as a single dose of ADH-1 at 150 mg/m(2). This resulted in transient normalization of cortisol, tumor necrosis on CT imaging, and reduction in tumor perfusion on DCE-MRI. Following progression on several additional lines of chemotherapy, she was again treated with ADH-1 under a Special Access Program (SAP). After 33 weekly doses (22 with 150 mg/m(2) and 11 with 300 mg/m(2)) radiographic tumor progression was demonstrated and treatment discontinued. She survived 40 months with metastatic disease, dying 12 months after her last dose of ADH-1. This observation merits consideration for prospectively evaluating the efficacy of ADH-1 in patients with cortisol secreting ACC that over express N-cadherin.
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Neoplasias de la Corteza Suprarrenal/terapia , Carcinoma Corticosuprarrenal/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cadherinas/antagonistas & inhibidores , Oligopéptidos/uso terapéutico , Péptidos Cíclicos/uso terapéutico , Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/secundario , Adulto , Cadherinas/metabolismo , Cisplatino/administración & dosificación , Ensayos Clínicos Fase I como Asunto , Terapia Combinada , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Previous studies indicate that drugs targeting the Epidermal Growth Factor Receptor (EGFR) signaling pathways can induce objective responses, prolong time to progression and improve survival of patients with metastatic colorectal cancer (mCRC). EGFR expression in the primary tumour may not predict response to these agents and data is conflicting regarding the correlation of EGFR expression in the primary tumour with the metastatic site. In other tumour sites, the presence of EGFR mutations was associated with efficacy in a subset of patients. OBJECTIVES: The goal of this study is to correlate tumour EGFR expression between primary and liver metastatic sites, and to assess the mutational status in the EGFR kinase domain. METHODS: This is a single center retrospective study of patients who underwent surgical resection of CRC, for whom paired paraffin-embedded tissue blocks of primary tumours and resected liver metastases were available. EGFR immunostaining and mutation analyses were preformed. RESULTS: Fifty six paired colorectal primaries and metastases were available for analysis. EGFR was detectable in 96.6% of the primary samples and in 89.7% of the metastatic samples. Perfect concordance in the intensity score between the primary and the metastases was found in 46.5% of the cases. While individual pairs were poorly concordant for intensity, the proportion of primaries with intense staining was similar to the proportion with intense staining in the metastatic samples. Overall survival did not correlate with either EGFR expression in the primary tumour, or with EGFR expression in the metastasis. There were 2 cases with mutations in the EGFR kinase domain. Both mutations were found in exon21 C>T. CONCLUSIONS: In this analysis, EGFR expression in the primary tumor site was not predictive of its level in the metastasis. EGFR expression levels in the primaries and in the metastases do not appear to be useful prognostic markers.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Neoplasias Hepáticas/secundario , Metástasis de la Neoplasia , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/uso terapéutico , Biomarcadores de Tumor , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Femenino , Técnica del Anticuerpo Fluorescente , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Estudios RetrospectivosRESUMEN
HOX genes are developmental genes that determine anterior-posterior embryonic pattern and govern the process of differentiation. Inappropriate expression of HOX genes has been implicated in developmental abnormalities and hematopoietic malignancies. In addition, HOX genes silencing by DNA methylation has been reported in cancers and related to disease aggressiveness and outcome. On the other hand, accumulating evidence suggests that epigenetic changes at HOX genes are linked to normal development and differentiation. To better understand the relationship between HOXA methylation and cancer, we analyzed the methylation pattern of HOXA genes in human primary breast and colon carcinomas, normal tissues, and normal white blood cells. Genome-wide methylation arrays of breast cancers and white blood cells demonstrated similar methylation patterns. Quantitative methylation analysis of seven representative HOXA genes revealed various levels of methylation in both normal tissues and cancers. Analysis of epithelial-enriched normal breast tissue and stroma indicated that the stroma was the major origin of HOXA methylation. Furthermore, in selected dense breast cancers, minimal increase in methylation of several HOXA genes did not correlate with the predominance of malignant epithelial cells in these tumors. Our results suggest that methylation of the HOXA cluster may be a normal developmental and cell type specific process rather than a cancer specific mechanism.
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Neoplasias de la Mama/genética , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/genética , Mama/metabolismo , Neoplasias de la Mama/sangre , Neoplasias de la Mama/metabolismo , Diferenciación Celular , Islas de CpG , Epitelio/metabolismo , Silenciador del Gen , Genoma Humano , Proteínas de Homeodominio/fisiología , Humanos , Leucocitos/metabolismo , Modelos Genéticos , Familia de Multigenes , PronósticoRESUMEN
The purpose of this study was to determine the incidence and severity of epistaxis in patients treated with paclitaxel. Patients who were treated with paclitaxel filled a questionnaire regarding their general health, medications and incidents of epistaxis. Relevant clinical information was obtained from the patients' charts. Forty-seven consecutive patients were recruited to the study. Twenty-four (51%) of the patients reported epistaxis during paclitaxel therapy. Twenty-three of 39 (59%) patients who received weekly paclitaxel had epistaxis at least once during treatment, compared with one out of eight patients who were treated every 3 weeks (P = 0.045). All episodes of epistaxis were mild, occurred with normal platelets counts and did not require blood product transfusions or treatment modification. The majority of the patients experienced the first episode of epistaxis on the third week of weekly paclitaxel treatment and then repeatedly throughout therapy. It is concluded that epistaxis is a common mild side-effect of weekly paclitaxel that has not been reported previously. In this trial, epistaxis did not have any major clinical consequences. However, when paclitaxel is combined with other drugs that may cause bleeding, such as bevacizumab, physicians should be alerted to the potential risk of this phenomenon.
Asunto(s)
Antineoplásicos Fitogénicos/efectos adversos , Epistaxis/inducido químicamente , Paclitaxel/efectos adversos , Adulto , Anciano , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Esquema de Medicación , Epistaxis/epidemiología , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Recuento de Plaquetas , Estudios Prospectivos , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVES: To conduct a trial of neoadjuvant chemohormonal therapy and radical prostatectomy for patients with poor-prognosis localized prostate cancer (prostate-specific antigen [PSA] value 20 ng/mL or greater, Gleason score 8 or higher, and clinical stage T2c or greater), who are at high risk for local and systemic relapse. METHODS: Complete androgen blockage and four cycles of docetaxel (70 mg/m2) on day 2 and estramustine (280 mg three times daily) on days 1 to 5 every 21 days were given to 22 patients before radical prostatectomy and nerve preservation. RESULTS: Patient characteristics, as median (range), were as follows: age 61 (49 to 70) years, PSA value 21.2 (3.2 to 71.6) ng/mL, and Gleason sum 7 (6 to 9). Clinical stage was T3a-c in 14 patients (64%), T2c in 4 (18%), T2b in 3 (14%), and T1c in 1 (4%). Presurgery characteristics after chemohormonal therapy were as follows: PSA value 0.21 (0.05 to 0.6) ng/mL, clinical stage T1c in 14 patients (63.7%), T2a in 6 (27.3%), and T3a in 2 (9%). The pathologic specimens revealed viable disease in all patients, organ-confined disease in 14 (63.6%), specimen-confined disease in 16 (72.7%), seminal vesicle disease in 9 (40.9%), and lymph node involvement in 4 (18.1%). To date, at a median follow-up of 23.6 (12.1 to 54.7) months, 10 patients (45.4%) relapsed, with PSA doubling time of 1.5 (0.4 to 34.3) months. Of the relapsed patients, 8 (89%) had organ/specimen involvement. CONCLUSIONS: The neoadjuvant chemohormonal approach with nerve-preservation surgery is feasible in patients with poor-prognosis localized prostate cancer. It leads to clinical tumor downstaging. The pattern of relapse suggests that local therapy, with radiotherapy for patients with surgical or capsular involvement, and additional systemic therapy should be integrated.