RESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is increasing in incidence and the majority of patients are not candidates for radical therapies. Therefore, interest in minimally invasive therapies in growing. METHODS: A Phase I dose escalation trial was conducted at Indiana University to determine the feasibility and toxicity of stereotactic body radiation therapy (SBRT) for primary HCC. Eligible patients had Child-Turcotte-Pugh's Class (CTP) A or B, were not candidates for resection, had 1-3 lesions and cumulative tumour diameter less than or equal to 6 cm. Dose escalation started at 36 Gy in 3 fractions (12 Gy/fraction) with a subsequent planned escalation of 2 Gy/ fraction/level. Dose-limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events v3.0 grade 3 or greater toxicity. RESULTS: Seventeen patients with 25 lesions were enrolled. Dose was escalated to 48 Gy (16 Gy/fraction) in CTP-A patients without DLT. Two patients with CPC-B disease developed grade 3 hepatic toxicity at the 42-Gy (14 Gy/fraction) level. The protocol was amended for subsequent CTP-B patients to receive a regimen of 5 fractions starting at 40 Gy (8 Gy/fraction) with one patient experiencing progressive liver failure. Four additional patients were enrolled (one died of unrelated causes after an incomplete SBRT course) without DLT. The only factor related to more than one grade 3 or greater liver toxicity or death within 6 months was the CTP score (p=0.03). Six patients underwent a liver transplant. Ten patients are alive without progression with a median FU of 24 months (10-42 months), with local control/stabilisation of the disease of 100%. One and two-year Kaplan-Meier estimates for overall survival are 75% and 60%, respectively. CONCLUSIONS: SBRT is a non-invasive feasible and well tolerated therapy in adequately selected patients with HCC. The preliminary local control and survival are encouraging. A confirmatory Phase II trial is currently open to accrual.
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Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , Radiocirugia/efectos adversos , Radiocirugia/métodos , Anciano , Anciano de 80 o más Años , Estudios de Factibilidad , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana EdadRESUMEN
BACKGROUND: Gefitinib has demonstrated activity in patients with non-small cell lung cancer (NSCLC). Clinical trials have not demonstrated a relationship between response to gefitinib and over-expression of the epidermal growth factor receptor (EGFR). Although, EGFR is not over-expressed in small cell lung cancer (SCLC), we postulated that gefitinib might affect tumor growth through other mechanisms. Agents that are active in NSCLC usually are also effective in SCLC. METHODS: The primary objective was to assess the clinical control rate: complete response (CR) partial response (PR) and stable disease (SD > 90 days), of gefitinib in patients with chemo-resistant and chemo-sensitive small cell cancers. Eligibility criteria included pathologic proof of a neuroendocrine tumor, especially small cell cancer, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2, prior treatment with one or two prior chemotherapy regimens and adequate end-organ function. Patients received gefitinib, 250 mg p.o. daily until disease progression or intolerable side effects. RESULTS: From April 2003 to March 2004, 19 patients were enrolled. Small cell lung cancer accounted for 18 of the 19 patients and one patient had metastatic Merkel cell carcinoma. Twelve patients (63%) had chemo-sensitive disease, defined as progression greater than three months from completion of prior chemotherapy; 7 (37%) had chemo-refractory disease; 13 (68%) had one prior chemotherapy regimen. Other patient characteristics: mean age 64 years (range 52-79 years); ECOG PS 0/1/2 = 7/9/3, M:F = 9:10. Grade 3 toxicities included: fatigue in three patients (15.8%), pulmonary toxicities in three (15.8%) and one patient (5.3%) each with hyperglycemia or pain. Four patients had grade four toxicities: one patient (5.3%) with fatigue and three patients (15.8%) with dyspnea. There were no patients with grade 3 or 4 rash or diarrhea. Two patients had stable disease (<90 days) and 17 had progressive disease as their best response. This study was a two-stage design and because the continuing criterion for stage one was not met, stage 2 was not performed. Median time to progression (TTP) was 50 days (95% CI = 21-58 days). One year overall survival (OS) was 21% (95% CI = 6-45.6%). CONCLUSION: Although gefitinib has activity in select patients with NSCLC, this study failed to demonstrate benefit in patients with small cell lung cancer.
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Antimetabolitos Antineoplásicos/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/uso terapéutico , Anciano , Carcinoma de Células Pequeñas/patología , Femenino , Gefitinib , Humanos , Neoplasias Pulmonares/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Previous studies have demonstrated a higher mean peak frequency of the hippocampal (HPC) theta rhythm during REM sleep in alcohol-nonpreferring (NP) rats when compared with alcohol-preferring (P) rats. Burst firing neurons of the medial septal area (MS/VDB) are thought to pace the HPC theta rhythm during REM sleep and ambulation. Therefore, extracellular action potentials of MS/VDB burst firing neurons and HPC-CA1 field potentials were recorded simultaneously in ambulating P and NP rats. These recordings revealed that the mean peak frequency of the HPC theta rhythm during ambulation was higher in NP rats (7.62 +/- 0.12 Hz) as compared with P rats (7.21 +/- 0.14 Hz) (P < 0.05). Consistent with the difference in the HPC theta rhythm, the burst pattern of MS/VDB neurons exhibited a shorter inter-burst interval in the NP rats (NP 82.4 +/- 5.4 ms, P 97.4 +/- 8 1 ms P < 0.05). The difference in the inter-burst interval was confirmed by the distribution of inter-spike intervals in cumulative inter-spike interval histograms and the frequency of peaks in the mean cumulative autocorrelation histograms for P and NP rats. The mean cumulative autocorrelation histograms for P and NP rats also revealed that the regularity of the burst pattern in NP rats was sustained over a longer time period as determined by the decay constant. The cross-correlation of MS/VDB burst activity and the HPC theta rhythm showed a strong relationship between the two signals in P and NP rats. In both P and NP rats, two similar phase relationships were observed between MS/VDB bursting neurons and the HPC theta rhythm. These findings are in agreement with the hypothesis that MS/VDB burst firing neurons are responsible for the variation in the HPC theta rhythm between the two lines. Other mechanisms consistent with these findings are also discussed.
Asunto(s)
Hipocampo/fisiología , Potenciales de la Membrana/fisiología , Neuronas/fisiología , Núcleos Septales/fisiología , Animales , Etanol/farmacología , Masculino , RatasRESUMEN
Through bidirectional selective breeding, lines of rats that differ greatly in their voluntary alcohol drinking behavior have been developed--namely, the alcohol-preferring (P) and high-alcohol-drinking (HAD) lines and the alcohol-nonpreferring (NP) and low-alcohol-drinking (LAD) lines. The present experiments were designed to determine if an association exists between ethanol preference and features of the electroencephalogram (EEG) during various sleep-wake behaviors. Of the EEG parameters measured, only theta activity in the hippocampus revealed differences in the lines. However, these differences were not generally associated with ethanol preference. The peak frequency and distribution mean of hippocampal theta activity during REM sleep were significantly higher in NP rats than in P, HAD, and LAD rats. In addition, theta frequency during alert immobility tended to be higher in NP rats than in P, HAD, and LAD rats. A qualitative comparison of these data with published data from unselected rats further suggested that the NP rats are uniquely different with respect to theta frequency.