Phase II study of pemetrexed in breast cancer patients pretreated with anthracyclines.

BACKGROUND: To assess antitumor activity and toxicity of pemetrexed in metastatic breast cancer (MBC) patients previously treated with anthracyclines. PATIENTS AND METHODS: Seventy-seven MBC patients from 12 European institutions were entered into the study. Seventy-two patients were considered evaluable for response and toxicity. Forty-two patients were classified as anthracycline-failure (relapse >30 days after completion of a prior anthracycline regimen) and 30 as anthracycline-refractory (progression within 30 days after anthracycline therapy). Pemetrexed 600 mg/m(2) was administered intravenously every 3 weeks until progressive disease or unacceptable toxicity. RESULTS: There were three complete and 12 partial responders [response rate 21% (95% confidence interval 12%)]. Response rates in the anthracycline-failure and anthracycline-refractory groups were 24% and 17%, respectively. A subset of 31 patients pretreated with anthracyclines and taxanes had a response rate of 26%. Median duration of response and median survival were 5.5 and 10.7 months, respectively (13 months in the failure group and 5.7 months for refractory). Grade 3/4 toxicities included neutropenia and thrombocytopenia in 56% and 19% of patients, respectively. Nine patients (12%) experienced neutropenic fever. Grade 3/4 non-hematological toxicities included skin rash (10%), nausea (12%), fatigue (10%) and stomatitis (5%). CONCLUSION: Our trial demonstrates pemetrexed to be active in breast cancer, with manageable toxicity. Activity of pemetrexed did not appear to be adversely affected by prior taxane, 5-fluorouracil or endocrine treatments.     

Cochlear Implantation in Common Cavity Malformations Using a Transmastoid Labyrinthotomy Approach

The transmastoid facial recess approach has become the standard technique for cochlear implantation. Although this approach has been used for implantation in patients with common cavity deformities, it is not without increased risk to the facial nerve. Using a direct approach to the common cavity that circumvents the facial recess, we have successfully implanted four patients with common cavity deformities. An aberrant facial nerve in one patient would have precluded placement of the electrode array using standard cochlear implant techniques. As demonstrated in these four patients, the direct approach to the common cavity is an effective approach for placement of the electrode array, minimizes risk to the facial nerve, and may decrease the likelihood of postoperative cerebrospinal fluid leaks. Intraoperative video footage demonstrates the feasibility and facility of this approach in patients with common cavity deformities.     

Otoacoustic emissions as a screening test for hearing impairment in children recovering from acute bacterial meningitis

OBJECTIVES: To study the efficacy of otoacoustic emissions (OAEs) as a screening test for hearing impairment in children with acute bacterial meningitis. Hearing tests were performed before discharge from the hospital in an attempt to improve coverage and avoid delays in the diagnosis of postmeningitic hearing loss. METHODS: Children with bacterial meningitis were recruited from 21 centers. In the 48 hours before discharge from the hospital, all patients underwent a thorough audiologic assessment consisting of transient evoked OAEs, auditory brainstem responses (ABRs), otoscopy, and tympanometry. Hearing loss was defined as ABR threshold >/=30 dB. The results of OAE screening were compared with the gold standard of ABR threshold. RESULTS: Of 124 children recruited, we were able to perform both OAEs and ABRs on 110 children. Seven (6.3%) of the 110 children had ABR threshold >/=30 dB; 2 had sensorineural hearing loss and 5 had conductive hearing loss. At follow-up, hearing loss persisted in both cases of sensorineural hearing loss and no new cases were identified. All 7 children with hearing loss failed the OAE screening test. Ninety-four children with normal hearing thresholds passed the test, and 9 failed. Thus, the screening test had a sensitivity of 1.00 (95% confidence interval, 0.59 to 1.00), a specificity of 0.91 (0.85 to 0.97), a positive predictive value of 0. 44 (0.20 to 0.70), and a negative predictive value of 1.00 (0.96 to 1.00). CONCLUSIONS: OAE screening in children recovering from meningitis was found to be feasible and effective. The test was highly sensitive and reasonably specific. Inpatient OAE screening should allow early diagnosis of postmeningitic hearing loss and prompt auditory rehabilitation.     

Iron-induced oxidative DNA damage and its repair in primary rat hepatocyte culture

Iron-overload diseases frequently develop hepatocellular carcinoma. The genotoxic mechanism whereby iron is involved in hepatocarcinogenesis might involve an oxidative process via the intermediate production of reactive oxygen species. This was presently investigated by examining kinetics of formation and repair of DNA base lesions in primary rat hepatocyte cultures supplemented with the iron chelate, ferric nitrilotriacetate Fe-NTA (10 and 100 microM). Seven DNA base oxidation products have been identified in DNA extracts by gas chromatography- mass spectrometry, which showed a predominance of oxidized-purines (8- oxo-guanine, xanthine, fapy-adenine, 2-oxo-adenine) above oxidized pyrimidines (5-OHMe-uracil, 5-OH-uracil, 5-OH-cytosine) in control cultures. All these DNA oxidation products revealed a significant dose- dependent increase at 4 to 48 h after Fe-NTA supplementation, among which fapy-adenine showed the highest increase and 5-OH-cytosine was the least prominent. Involvement of iron in this oxidative process was established by a correlation between extent in DNA oxidation and intracellular level of toxic low molecular weight iron. DNA excision- repair activity was estimated by release of DNA oxidation products in culture medium. All the seven DNA oxidation products were detected in the medium of control cultures and showed basal repair activity. This DNA repair activity was increased in a time- and dose-dependent fashion with Fe-NTA. Oxidized-pyrimidines, among which was 5-OHMe-Uracil, were preferentially repaired, which explains the low levels detected in oxidized DNA. Since oxidized bases substantially differed from one another in terms of excision rates from cellular DNA, specific excision- repair enzymes might be involved. Our findings, however, demonstrate that even though DNA repair pathways were activated in iron-loaded hepatocyte cultures, these processes were not stimulated enough to prevent an accumulation of highly mutagenic DNA oxidative products in genomic DNA. The resulting genotoxic effect of Fe-NTA might be relevant in understanding the hepatocarcinogenic evolution of iron-overload diseases.      

Percutaneous skeletal biopsy

Percutaneous bone biopsy has become an accepted means for tissue diagnosis in indeterminate metastatic disease, whereas needle biopsy for the evaluation of primary skeletals neoplasms is controversial. Needle biopsies are also of value in the diagnosis of inflammatory lesions and eosinophilic granuloma. The diagnostic accuracy of this procedure ranges from 50 to 94% in malignant disease, but is less favorable in benign disease. The low complication rate of about 0.2% makes the percutaneous approach an attractive alternative to surgical biopsy.     

Uso de terapia con presión negativa en heridas con fístulas entéricas

Objective

Negative pressure therapy (VAC, vacuum assisted closure) is a method used still in our country. It consists of a system of aspirating a wound by means of a piece of foam and a few adhesive films. It allows the treatment of complex wounds, included (although this is still controversial) those with intestinal fistulas. We present 3 cases of treatment with VAC in this situation and a review of the published literature.

Patients and method

We have treated 10 patients, since VAC therapy was introduced into our centre of which 3 of whom had a fistula in the bed of the surgical wound. We describe the clinical information of the patients and the therapy that followed in each of the cases.

Results

Significant local clinical improvement of the disease, with control of the symptoms, was achieved in all 3 cases. We were able to re-operate to close the fistula in one of the patients, with subsequent good progression of the wound. In the other two cases it gave them a better quality of life although both died due to the overall complexity of their situation.

Conclusions

VAC therapy, although controversial in the treatment of intestinal fistulas, can help to improve the local situation of the wounds, the comfort of the patients and their general situation.     

Life expectancy analysis in patients with Chagas' disease: prognosis after one decade (1973-1983)

We studied the evolution of chronic Chagas' disease in 107 patients with a positive Guerreiro-Machado reaction and 22 non-chagasic, non-heart disease control subjects for a follow-up period of 3 to 10 years (mean follow-up of 4.9 years). After completion of invasive and non-invasive studies, chagasic patients were classified into four groups: IA (normal ECG, without heart disease; 18 patients); IB (normal ECG, early left ventricular segmental abnormalities; 13 patients); II (abnormal ECG, advanced myocardial damage, no signs of heart failure; 42 patients); and III (abnormal ECG, end-stage, congestive heart failure; 34 patients). One out of five group IA patients re-studied with invasive methods evolved to group IB (20%); 4 group IB patients evolved to group II (33%) and 6 group II patients evolved to group III (15%). The life expectancy of patients in groups IA and IB (normal ECG) was similar to that of our control group, whereas in groups II and III it was significantly decreased (P less than 0.001). Nine group II patients (23%) and 28 group III patients (82%) died during the follow-up period. Main terminal events were refractory congestive heart failure, sudden death and systemic thromboembolism. Our findings suggest that chronic Chagas' disease follows an evolutionary course from asymptomatic, normal ECG group I stage to arrhythmic (II) and congestive (III) stages. Subjects with a positive Guerreiro-Machado reaction showed a significantly lower life expectancy than our control group, but only when clinical and/or ECG abnormalities were identified.