Fausto Maffini

Comparative Study of Surgical Margins in Oncoplastic Surgery and Quadrantectomy in Breast Cancer

BackgroundOncoplastic surgery for breast cancer is a novel concept that combines a plastic surgical procedure with breast-conserving treatment to improve the final cosmetic results. The aim of this study was to evaluate the oncological safety of oncoplastic procedures by studying the status of the surgical margins of the excised tumor specimen in comparison with standard quadrantectomies.MethodsThirty consecutive breast cancer patients undergoing oncoplastic surgery (group 1) and 30 patients undergoing standard quadrantectomy (group 2) were prospectively studied with regard to the stage of breast cancer, the surgical procedures performed, the volume of breast tissue excised, and the histopathology of the tumor specimen, with specific details on surgical margins.ResultsPatients who underwent oncoplastic surgery (group 1) were younger (mean age, 48.73 years) than patients who had a classic quadrantectomy (group 2; mean age, 55.76 years; P = .022). The mean volume of the excised specimen in group 1 was 200.18 cm3, compared with 117.55 cm3 in group 2 (P = .016). Surgical margins were negative in 25 cases out of 30 in group 1 and 17 out of 30 in group 2 (P = .05). The average length of the surgical margin was 8.5 mm in group 1 and 6.5 mm in group 2, but the difference was not statistically significant (P = .074).ConclusionsOncoplastic surgery adds to the oncological safety of breast-conserving treatment because a larger volume of breast tissue can be excised and a wider negative margin can be obtained. It is especially indicated for large tumors, for which standard breast-conserving treatment has a high probability of leaving positive margins.

Predictive Value of Tumor Ki-67 Expression in Two Randomized Trials of Adjuvant Chemoendocrine Therapy for Node-Negative Breast Cancer

Several small studies have reported that having a high percentage of breast tumor cells that express the proliferation antigen Ki-67 (ie, a high Ki-67 labeling index) predicts better response to neoadjuvant chemotherapy. However, the predictive value of a high Ki-67 labeling index for response to adjuvant chemotherapy is unclear. To investigate whether Ki-67 labeling index predicts response to adjuvant chemoendocrine therapy, we assessed Ki-67 expression in tumor tissue from 1924 (70%) of 2732 patients who were enrolled in two randomized International Breast Cancer Study Group trials of adjuvant chemoendocrine therapy vs endocrine therapy alone for node-negative breast cancer. A high Ki-67 labeling index was associated with other factors that predict poor prognosis. Among the 1521 patients with endocrine-responsive tumors, a high Ki-67 labeling index was associated with worse disease-free survival but the Ki-67 labeling index did not predict the relative efficacy of chemoendocrine therapy compared with endocrine therapy alone. Thus, Ki-67 labeling index was an independent prognostic factor but was not predictive of better response to adjuvant chemotherapy in these studies.

p63 immunoreactivity in lung cancer: yet another player in the development of squamous cell carcinomas?

The p63 protein, a member of the p53 family of nuclear transcription factors, is characterized by different capabilities of transactivating reporter genes, inducing apoptosis, and functioning as dominant‐negative agent. This study evaluated the prevalence and prognostic implications of p63 immunoreactivity in 221 patients with stage I non‐small cell lung carcinoma (NSCLC) and in 57 patients with stage I–IV neuroendocrine tumours (NET). The results were correlated with the tumour proliferative fraction, the accumulation of p53 protein, and with patient survival. p63 immunoreactivity was seen in 109/118 squamous cell carcinomas, 15/95 adenocarcinomas, 2/2 adenosquamous carcinomas, 4/6 large cell carcinomas, 9/20 poorly differentiated NET, and 1/37 typical and atypical carcinoids (p < 0.001). Furthermore, the prevalence of p63‐immunoreactive cells increased progressively from pre‐neoplastic and pre‐invasive lesions to invasive squamous cell carcinomas. In these latter tumours, but not in adenocarcinomas, p63 immunoreactivity correlated directly with the tumour proliferative fraction (p = 0.028), and inversely with the tumour grade (p = 0.004). No relationship was found with p53 protein immunoreactivity or the other clinico‐pathological variables examined. Although p63 is likely to be involved in the development of pulmonary squamous cell carcinoma, it does not carry any prognostic implication for NSCLC patients. Copyright

Prognostic implications of neuroendocrine differentiation and hormone production in patients with Stage I nonsmall cell lung carcinoma

Approximately 10–20% of nonsmall cell lung carcinomas (NSCLC) show neuroendocrine (NE) differentiation, as evaluated by panendocrine markers or ultrastructural evidence of dense‐core secretory granules. However, little is known regarding the prevalence and clinical implications of NE differentiation in patients with Stage I NSCLC.

Laser Surgery for Early Glottic Cancer Impact of Margin Status on Local Control and Organ Preservation

OBJECTIVE To assess the impact of margin status on disease-free survival, overall survival, and organ preservation in early glottic cancer treated by endoscopic laser surgery. DESIGN Prospective nonrandomized study. SETTING Tertiary referral center. PATIENTS A total of 274 patients with untreated (possibly biopsied) cTis, cT1a/b, cT2, cN0 glottic cancer; adequate exposure of the glottic region; no contraindications to general anesthesia; and the ability to give informed consent. INTERVENTIONS European Laryngological Society laser cordectomy. Patients with negative margins (>1 mm) were followed, patients with close margins (< or =1 mm) or 1 positive margin (tumor on margin) had another operation, and patients with more than 1 positive margin had postoperative radiotherapy. Median follow-up was 58 months. MAIN OUTCOME MEASURES Eight-year disease-free survival, 5-year overall survival, and organ preservation rate. RESULTS Margins were negative in 180 patients, close in 40, and positive in 54. A second laser resection was performed in 36 of 94 patients with close or positive margins. Radiotherapy was administered to 36 patients. Patients with close or positive margins who did not undergo further treatment had a greater recurrence risk (hazard ratio, 2.53; 95% confidence interval, 0.97-6.59, P = .06) than did those with negative margins, mainly owing to relapses in 5 of the 8 protocol breakers with positive margins not treated further. Eight-year relapse-free survival was 88.2%, 5-year overall survival was 90.9%, and the larynx was preserved in 97.1%. CONCLUSIONS Laser removal of early glottic cancer is oncologically adequate with margins greater than 1 mm from the tumor edge. Positive margins require further treatment; close margins may require further treatment depending on tumor characteristics.

Randomized Dose-Ranging Trial of Tamoxifen at Low Doses in Hormone Replacement Therapy Users

PURPOSE The combination of hormone replacement therapy (HRT) and low-dose tamoxifen may retain the benefits while reducing the risks of either agent. We assessed the optimal biologic dose and schedule of tamoxifen in HRT users using surrogate end point biomarkers and menopausal symptoms. SUBJECTS AND METHODS Two hundred ten current or de novo HRT users were randomly assigned to one of the following four arms: tamoxifen 1 mg/day and placebo/week, placebo/day and tamoxifen 10 mg/week, tamoxifen 5 mg/day and placebo/week, or both placebos for 12 months. The primary end point was the change of plasma insulinlike growth factor 1 (IGF-I) through 12 months, and secondary end points were IGF-I/IGF binding protein-3 (IGFBP-3) ratio, fibrinogen, antithrombin III, C reactive protein, C-telopeptide, mammographic percent density, and endometrial thickness. Endometrial proliferation was assessed by Pipelle biopsy in superficial, deep glandular, and stromal compartments after 12 months. RESULTS Compared with placebo, IGF-I declined in all tamoxifen arms (P = .005), with a greater change on 5 mg/day (P = .019 v 10 mg/week or 1 mg/day). Tamoxifen increased IGFBP-3 and lowered antithrombin-III, C reactive protein, and mammographic density, with greater effects of 5 mg/day. Tamoxifen increased endometrial thickness but not Ki-67 expression, which was lower on 5 mg/day among the three doses. Menopausal symptoms were not significantly worsened by tamoxifen. CONCLUSION Doses of tamoxifen < or = 5 mg/day modulate favorably biomarkers of breast carcinogenesis and cardiovascular risk in HRT users with no increase of endometrial proliferation and menopausal symptoms. A dose of 5 mg/day was the most effective and has been selected for a phase III trial in HRT users.

Decreased immunoreactivity for p27 protein in patients with early-stage breast carcinoma is correlated with HER-2/neu overexpression and with benefit from one course of perioperative chemotherapy in patients with negative lymph node status: results from International Breast Cancer Study Group Trial V.

The objective of this study was to clarify the prognostic and predictive value of immunoreactivity for the cyclin‐dependent kinase inhibitor p27(Kip1) in patients with early‐stage breast carcinoma and to investigate its relation with clinicopathologic features and other markers.

Pulmonary Epithelial-Myoepithelial Tumor of Unproven Malignant Potential: Report of a Case and Review of the Literature

Epithelial-myoepithelial tumors of the lung are rare neoplasms whose biological behavior and clinical course still remain to be defined. A case of epithelial-myoepithelial tumor of the lung arising from bronchial mucosa-submucosa and occurring as a polypoid lesion of the upper left bronchus in a 47-year-old man is reported. The tumor did not infiltrate the cartilaginous wall of the bronchus and showed a biphasic histological appearance with a double layering of epithelial and myoepithelial cells. Myoepithelial spindle cells with eosinophilic cytoplasm were also observed. Mitotic figures were very rare and necrosis absent. Immunohistochemical study for epithelial and muscular markers confirmed the presence of a double-cell component in the tumor, namely epithelial and myoepithelial. The patient is alive and well, with no evidence of recurrent or metastatic disease 6 months after surgery. On the basis of the present case and the six previously reported cases, we suggest using the noncommittal term pulmonary epithelial-myoepithelial tumor of unproven malignant potential (PEMTUMP) for this type of neoplasm. In addition, we first introduce p63 as a novel marker for highlighting the myoepithelial cells of the respiratory tract and speculate on the role of these cells in the development of this unusual tumor.

Inactivation of the putative suppressor gene DOK1 by promoter hypermethylation in primary human cancers

The DOK1 gene is a putative tumour suppressor gene located on the human chromosome 2p13 which is frequently rearranged in leukaemia and other human tumours. We previously reported that the DOK1 gene can be mutated and its expression down‐regulated in human malignancies. However, the mechanism underlying DOK1 silencing remains largely unknown. We show here that unscheduled silencing of DOK1 expression through aberrant hypermethylation is a frequent event in a variety of human malignancies. DOK1 was found to be silenced in nine head and neck cancer (HNC) cell lines studied and DOK1 CpG hypermethylation correlated with loss of gene expression in these cells. DOK1 expression could be restored via demethylating treatment using 5‐aza‐2′deoxycytidine. In addition, transduction of cancer cell lines with DOK1 impaired their proliferation, consistent with the critical role of epigenetic silencing of DOK1 in the development and maintenance of malignant cells. We further observed that DOK1 hypermethylation occurs frequently in a variety of primary human neoplasm including solid tumours (93% in HNC, 81% in lung cancer) and haematopoietic malignancy (64% in Burkitts lymphoma). Control blood samples and exfoliated mouth epithelial cells from healthy individuals showed a low level of DOK1 methylation, suggesting that DOK1 hypermethylation is a tumour specific event. Finally, an inverse correlation was observed between the level of DOK1 gene methylation and its expression in tumour and adjacent non tumour tissues. Thus, hypermethylation of DOK1 is a potentially critical event in human carcinogenesis, and may be a potential cancer biomarker and an attractive target for epigenetic‐based therapy.

Progesterone receptor immunoreactivity in minute meningothelioid nodules of the lung

Abstract. Meningothelioid nodules (MNs) are not uncommon lesions of the pulmonary interstitium composed of monomorphic round to spindle cells, likely reactive in nature. Their origin is unsettled, though a derivation from arachnoid-like cells in conditions of perturbed perfusion of the pulmonary tissue has been proposed. Here we confirm the consistent occurrence of intense progesterone-receptor immunoreactivity in MNs fortuitously detected in surgical specimens of lung carcinomas. This finding corroborates the view that these proliferations exhibit arachnoid cell-like differentiation and suggests a role for sex-steroid hormones in the control of their growth.