Consecutive bilateral breast reconstruction using different autologous flaps: can symmetrical results still be achieved? A case report.

We report a 60-year-old patient who underwent bilateral mastectomy at different times, followed by immediate autologous reconstruction with different flaps: deep-inferior epigastric-perforator flap on one breast, and fat-augmented latissimus dorsi on the contralateral side. At 20-month follow-up, good symmetry was recorded; patient-reported outcome measurements revealed high satisfaction scores.

Follow-up of tissue genomics in BRCA1/2 carriers who underwent prophylactic surgeries.

PURPOSE: The genomic status of non-malignant tissues from carriers of pathogenic germline BRCA1/2 (gBRCA1/2) variants may reveal information towards individualized prophylaxis. We performed spatiotemporal tissue genotype comparisons in a real-life cohort of gBRCA1/2 carriers of Greek origin, who underwent multiple risk-reducing/prophylactic surgeries at various time points. METHODS: Fifty-three women (median age 36 years) within cancer families were observed for up to 37.5 years; 43 were cancer carriers and 10 were healthy carriers. Histology review and genotyping were performed for 187 paraffin tissues (average: 3.5 per carrier) including 46 carcinomas (40 breast) and 141 non-malignant breast and gynecological samples. RESULTS: High allelic imbalance (AI) and somatic pathogenic TP53 variants were present in cancer carriers only (p values < 0.0001). High AI was associated with gBRCA1/2 indels (p < 0.0001) and gBRCA2 alterations (p = 0.0109). Somatic (pathogenic) variants were infrequently shared between non-malignant tissues and matched carcinomas. Aberrations of gBRCA1 variant heterozygosity were noticed in tissues from cancer carriers only (13/43, 30.2%). These pertained to classic LOH (neoplastic lesions in 9/43 carriers, 20.9%) and under-representation of the germline variants (5 samples, 4 non-malignant, all in the breast). Both aberrations coexisted in matched samples in one case. Over time, germline variant heterozygosity prevailed in non-malignant tissues; intra-carrier genomic alterations were aggravated (21.1%), ameliorated (26.3%) or remained stable. CONCLUSION: This real-life case study supports the need to address tissue genotypes from prophylactic surgeries in combination with polygenic scores towards personalized prophylaxis. To this end, knowing the traditionally classified pathogenic potential of a gBRCA1/2 variant may not be enough.

Disease evolution and heterogeneity in bilateral breast cancer.

Bilateral breast cancers (BBC) are currently treated as independent tumors arising in the same patient. Herein, we investigated whether BBC indeed evolve independently at the genomic level. We examined paired targeted next generation sequencing genotypes from 155 paraffin tumors corresponding to 76 BBC patients (75 women and one man; 52 concurrent and 24 metachronous), for coding mutations (amino acid changing, minor allele frequency <0.1%) and single nucleotide polymorphism (SNP) zygosity. Germline genotypes were available for 29 patients. Mutations were present in 80 tumors (54/76 patients; 71%), were mostly tumor-private (90%), more frequent in TP53 (19%), PIK3CA (14%), CDH1, GATA3, MLL3. TP53 mutations were more frequent in metachronous tumors (P<0.001); hormone receptor negative (P<0.001); with higher Ki-67 (P=0.002); and, in younger patients (P=0.01). Hypermutated tumors, all TP53 mutated, were diagnosed as the first incidence in 5 patients; their metachronous counterparts were mutation poor without TP53 involvement. Paired tumors shared common mutations at intratumoral frequency >20% in 10/54 comparable BBC (18.5%), 8/10 concurrent. SNP zygosity status was less preserved in metachronous, compared to concurrent disease. Pathogenic germline mutations were present in 10/29 patients, 9 in BRCA1 and one in TP53 (p.Phe341Val, first report in the germline). BBC demonstrated extensive inter- and intra-patient heterogeneity in the present thus far largest series of corresponding paired genotypes. The majority evolve independently and unpredictably, supporting current clinical practice. A considerable minority though, retains clonal origin and may be regarded as a distinct group for therapeutic interventions among concurrent BBC.

Dose-dense sequential adjuvant chemotherapy followed, as indicated, by trastuzumab for one year in patients with early breast cancer: first report at 5-year median follow-up of a Hellenic Cooperative Oncology Group randomized phase III trial.

BACKGROUND: Dose-dense sequential chemotherapy including anthracyclines and taxanes has been established in the adjuvant setting of high-risk operable breast cancer. However, the preferable taxane and optimal schedule of administration in a dose-dense regimen have not been defined yet. METHODS: From July 2005 to November 2008, 1001 patients (990 eligible) were randomized to receive, every 2 weeks, 3 cycles of epirubicin 110 mg/m2 followed by 3 cycles of paclitaxel 200 mg/m2 followed by 3 cycles of intensified CMF (Arm A; 333 patients), or 3 cycles of epirubicin followed by 3 cycles of CMF, as in Arm A, followed 3 weeks later by 9 weekly cycles of docetaxel 35 mg/m2 (Arm B; 331), or 9 weekly cycles of paclitaxel 80 mg/m2 (Arm C; 326). Trastuzumab was administered for one year to HER2-positive patients post-radiation. RESULTS: At a median follow-up of 60.5 months, the 3-year disease-free survival (DFS) rate was 86%, 90% and 88%, for Arms A, B and C, respectively, while the 3-year overall survival (OS) rate was 96% in all arms. No differences were found in DFS or OS between the combined B and C Arms versus Arm A (DFS: HR = 0.81, 95% CI: 0.59-1.11, P = 0.20; OS: HR = 0.84, 95% CI: 0.55-1.30, P = 0.43). Among the 255 patients who received trastuzumab, 189 patients (74%) completed 1 year of treatment uneventfully. In all arms, the most frequently reported severe adverse events were neutropenia (30% vs. 27% vs. 26%) and leucopenia (12% vs. 13% vs. 12%), while febrile neutropenia occurred in fifty-one patients (6% vs. 4% vs. 5%). Patients in Arm A experienced more often severe pain (P = 0.002), neurological complications (P = 0.004) and allergic reactions (P = 0.004), while patients in Arm B suffered more often from severe skin reactions (P = 0.020). CONCLUSIONS: No significant differences in survival between the regimens were found in the present phase III trial. Taxane scheduling influenced the type of severe toxicities. HER2-positive patients demonstrated comparable 3-year DFS and OS rates with those reported in other similar studies. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000151033.

Differential response of immunohistochemically defined breast cancer subtypes to anthracycline-based adjuvant chemotherapy with or without paclitaxel.

BACKGROUND: The aim of the present study was to investigate the efficacy of adjuvant dose-dense sequential chemotherapy with epirubicin, paclitaxel, and CMF in subgroups of patients with high-risk operable breast cancer, according to tumor subtypes defined by immunohistochemistry (IHC). MATERIALS AND METHODS: Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 1,039 patients participating in two adjuvant dose-dense sequential chemotherapy phase III trials were centrally assessed in tissue micro-arrays by IHC for 6 biological markers, that is, estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki67, cytokeratin 5 (CK5), and EGFR. The majority of the cases were further evaluated for HER2 amplification by FISH. Patients were classified as: luminal A (ER/PgR-positive, HER2-negative, Ki67(low)); luminal B (ER/PgR-positive, HER2-negative, Ki67(high)); luminal-HER2 (ER/PgR-positive, HER2-positive); HER2-enriched (ER-negative, PgR-negative, HER2-positive); triple-negative (TNBC) (ER-negative, PgR-negative, HER2-negative); and basal core phenotype (BCP) (TNBC, CK5-positive and/or EGFR-positive). RESULTS: After a median follow-up time of 105.4 months the 5-year disease-free survival (DFS) and overall survival (OS) rates were 73.1% and 86.1%, respectively. Among patients with HER2-enriched tumors there was a significant benefit in both DFS and OS (log-rank test; p = 0.021 and p = 0.006, respectively) for those treated with paclitaxel. The subtype classification was found to be of both predictive and prognostic value. Setting luminal A as the referent category, the adjusted for prognostic factors HR for relapse for patients with TNBC was 1.91 (95% CI: 1.31-2.80, Wald's p = 0.001) and for death 2.53 (95% CI: 1.62-3.60, p<0.001). Site of and time to first relapse differed according to subtype. Locoregional relapses and brain metastases were more frequent in patients with TNBC, while liver metastases were more often seen in patients with HER2-enriched tumors. CONCLUSIONS: Triple-negative phenotype is of adverse prognostic value for DFS and OS in patients treated with adjuvant dose-dense sequential chemotherapy. In the pre-trastuzumab era, the HER2-enriched subtype predicts favorable outcome following paclitaxel-containing treatment.

Novel karyotypic changes detected by comparative genomic hybridization in a case of congenital cervical immature teratoma.

BACKGROUND: Cervical immature teratoma is a rare congenital tumor, and very few cases have been studied cytogenetically. CASE: In this article, we describe a case of this tumor type and present the findings of the karyotype of the lesion, which was performed with the bacterial artificial chromosome arrays using the comparative genomic hybridization method. The chromosomal abnormalities that we found included an amplification on 1p21.1, a 9p22 deletion, and a 1-copy gain of 17q21.33. CONCLUSIONS: None of the identified chromosomal aberrations have been previously associated with congenital extragonadal teratomas. Important genes that lie in these DNA regions may be implicated in the pathogenesis of congenital teratomas.

A simple telemedicine system to provide second-opinion advice to the patients of an Albanian diagnostic centre.

Since August 2003, the IKEDA Klinika diagnostic centre in Tirana, Albania, has offered patients telemedical help from Greece. The teleconsultation service is based on Internet technologies adapted to telemedical use, including the use of forms (e.g. for the patient history), multimedia file exchanges (e.g. for radiographs and electroencephalograms) and videoconferencing. The teleconsultants assist in treatment planning and, when necessary, in organizing the transfer of patients to Greece. The four cornerstones of the service are: the provision of second opinions by telemedicine; assistance in treatment planning; assistance to patients during transfer; and the continuity of medical care on their repatriation. Based on the first six months of operation, we estimate that, if bureaucratic visa restrictions to patient movement between Albania and Greece are removed, more than 2000 patients per year will benefit from the service and more than 400 patients will be transferred to Greek hospitals for treatment.