BRCA1 and BRCA2 germline mutations in Uruguayan breast and breast-ovarian cancer families. Identification of novel mutations and unclassified variants.

The aim of the present study was to analyze BRCA1 and BRCA2 mutations in Uruguayan families with breast and breast/ovarian cancer. Probands from 42 families with at least three cases of female breast cancer (BC) or two cases and subcriteria (paternal transmission, ovarian cancer, bilateral BC, male BC, Ashkenazi Jewish ancestry) in the same lineage, at least one diagnosed before age 50, were screened for germline mutations. PCR amplification of all exons and intron-exon boundaries were performed, followed by protein truncation test, heteroduplex analysis, and direct sequencing. We identified seven different truncating mutations in seven families, five in BRCA2 (three in site-specific BC families and two in breast-ovarian cancer families) and two in BRCA1 (one in a site-specific BC family and the other in a breast-ovarian cancer family). Both BRCA1 mutations (5583insT and 2687T>G) and one of the five BRCA2 mutations (3829insTdel35) were not previously reported. We also detected ten sequence variants of unknown significance, five of them not described before. The low frequency of BRCA1/2 mutations (0.17) is in agreement with that reported in studies which included families with similar selection criteria. However, the observed predominance of BRCA2 (0.12) over BRCA1 mutations (0.05) is in contrast with the higher proportion of BRCA1 mutations communicated for most previous studies, even those with a predominance of site-specific BC families. Meanwhile, it has been described in one Chilean and some Spanish and Italian reports, highlighting the strong dependence between the mutational spectra and the ethnicity of the population analyzed.

Relación entre la expresión de Glicoproteína P y los hallazgos de la centellografía con Tc-99m MIBI en pacientes con cáncer mamario avanzado / Relation between P-glycoprotein expression and scintigraphic findings with Tc-99m MIBI in advanced breast cancer patients

En un estudio previo encontramos que el grado de captación tumoral pre-tratamiento de Tc-99m MIBI, un sustrato de transporte de la Glicoproteína P (Pgp), se correlaciona con la respuesta clínica a la quimioterapia basada en antraciclinas en pacientes con cáncer mamario avanzado (CMA). El objetivo del presente estudio fue determinar la relación entre la expresión tumoral de Pgp, el grado de captación tumoral de MIBI y la respuesta clínica a la quimioterapia en pacientes con CMA. Se estudiaron 27 lesiones correspondientes a 26 pacientes. La expresión de Pgp fue investigada previamente a la quimioterapia mediante inmunocitoquímica. Las imágenes centellográficas fueron realizadas dentro de la semana previa a la quimioterapia, 10 minutos (fase temprana) y 60 minutos (fase tardía) después de la inyección de 740-1110 MBq de Tc-99m MIBI. La captación lesional fue cuantificada mediante tasa de conteo tumor/fondo en las fases precoz (T/Fp) y tardía (T/Ft) del estudio. Ambos índices fueron superiores (p< 0.05) en las lesiones Pgp negativas (n=21) que en las Pgp positivas (n=6). Además, fueron más elevados en las lesiones respondedoras que en las no respondedoras (T/Fp 2.2 vs 1.4; T/Ft 1.8 vs 1.4; p< 0.05). Todas las lesiones con un índice T/Fp mayor de 1.5 respondieron a la quimioterapia. No se encontró asociación significativa entre la expresión de Pgp y la respuesta a la quimioterapia. Concluimos que la centellografía con MIBI puede predecir el fenotipo MDR1 y la respuesta a la quimioterapia basada en adriamicina en pacientes con CMA. El nivel de expresión de Pgp no sería útil para predecir dicha respuesta.

Predictive value of (99m)Tc sestamibi scintigraphy in the evaluation of doxorubicin based chemotherapy response in patients with advanced breast cancer.

Resistance to doxorubicin based chemotherapy is a major therapeutic problem limiting advanced breast cancer treatment. 99mTc hexakis-2-methoxyisobutylisonitrile ((99m)Tc-MIBI) has been reported to be extruded from tumour cells by the P-glycoprotein and multidrug resistance protein encoded by MDR1 and MRP1 genes, respectively. These proteins are involved in the cellular efflux of several chemotherapeutic agents including doxorubicin. The aim of this study was to investigate the clinical value of a standard (99m)Tc-MIBI scintimammography technique in the prediction of response to chemotherapy in advanced breast cancer patients. Fifty-six lesions from 33 female patients with locally advanced (n=27) or recurrent breast cancer (n=6) were included in the study. MIBI scintigraphy was performed 2-8 days prior to chemotherapy (FAC regimen). Images were acquired 10 min and 1 h post-injection of 740-1110 MBq of (99m)Tc-MIBI. Tumour-to-normal background tissue uptake ratios were calculated on each lesion in the early (T/B(e)) and delayed phase of the study (T/B(d)). Both T/B(e) and T/B(d) ratios were significantly higher (P<0.0001) in responders (n=43) than nonresponders (n=13). Diagnostic values of (99m)Tc-MIBI in the prediction of chemotherapy response were evaluated using the arbitrary cut-off values of 1.5 for T/B(e) and 1.4 forT/B(d). Sensitivity, specificity, positive and negative predictive values were 88.4%, 92.3%, 97.4%, 70.6%; and 90.7%, 100.0%, 100.0%, 76.6%, for T/B(e) and T/B(d), respectively. We conclude that (99m)Tc-MIBI scintigraphy may be a clinically valuable tool for guiding chemotherapy in advanced breast cancer patients.

Detection of recurrent malignant melanoma with 99mTc-MIBI scintigraphy.

Initial reports suggest that 99mTc-methoxyisobutylisonitrile (MIBI) scanning may be of clinical value in staging patients with malignant melanoma. We carried out a study to evaluate the potential of this technique in the detection of recurrent disease. Whole-body 99mTC-MIBI scans were performed in 81 patients with a history of a surgically excised MM: 28 with known recurrent lesions and 53 during follow-up without evidence of disease. Images started 10 min post-injection, using a dose of 740 MBq. Diagnoses were confirmed by cytological/histological examination or at least one conventional imaging modality. Blinded interpretations of the MIBI scans were performed. Whole-body MIBI scanning correctly detected 68 (92%) of 74 metastatic lesions in the following sites: regional lymph nodes (n=23), non-regional lymph nodes (n=10), skin (n=16), brain/cerebellum (n=6), lung (n=8), bone (n=4) and breast (n=1). The technique failed to detect three subcutaneous regressive lesions (< 1 cm), one liver metastasis, one spleen metastasis and a case of multiple small lesions of the duodenal mucous membrane. In 14 patients the procedure detected previously unknown metastatic lesions. These results suggest that 99mTc-MIBI scanning is an effective imaging modality for whole-body screening of metastatic disease in malignant melanoma patients with the potential to influence treatment planning.

[Anaplastic carcinoma of the thyroid: early clinical and histopathological stages. Therapeutic implications (author's transl)]. / Carcinome thyroïdien anaplasique. Stades cliniques histopathologiques préalables. Implications thérapeutiques.

Anaplastic carcinoma of the thyroid is generally considered a primary condition. Our study, based on ten observations, shows that anaplastic carcinoma of the thyroid with a rapidly fatal course may arise in long-standing goiters. Borderline histologic changes may be encountered; in some differentiated nodules, undifferentiated areas were found. Factors inducing transformation is equally obscure. Anaplastic changes may result from the growth of previously quiescent clones. The time-interval between benignant and malignant lesions varies widely and is difficult to establish unequivocally. In some instances, anaplastic carcinoma occurs after surgical removal of differentiated carcinoma.