Eugenio Maiorano

Prognostic and Predictive Value of Centrally Reviewed Expression of Estrogen and Progesterone Receptors in a Randomized Trial Comparing Letrozole and Tamoxifen Adjuvant Therapy for Postmenopausal Early Breast Cancer: BIG 1-98

PURPOSE To evaluate locally versus centrally assessed estrogen (ER) and progesterone (PgR) receptor status and the impact of PgR on letrozole adjuvant therapy compared with tamoxifen in postmenopausal women with early breast cancer. PATIENTS AND METHODS Breast International Group (BIG) 1-98 randomly assigned 8,010 patients to four arms comparing letrozole and tamoxifen with sequences of each agent. The Central Pathology Office received material for 6,549 patients (82%), of which 79% were assessable (6,291 patients). Prognostic and predictive value of both local and central hormone receptor expression on disease-free survival (DFS) were evaluated among 3,650 assessable patients assigned to the monotherapy arms. Prognostic value and the treatment effect were estimated for centrally assessed ER and PgR expression levels using the Subpopulation Treatment Effect Pattern Plot. RESULTS Central review confirmed 97% of tumors as hormone receptor-positive (ER and/or PgR > or =10%). Of 105 tumors locally ER-negative, 73 were found to have more than 10% positive cells, and eight had 1% to 9%. Of 6,100 tumors locally ER positive, 66 were found to have no staining, and 54 had only 1% to 9%. Discordance was more marked for PgR than ER. Patients with tumors reclassified centrally as ER-negative, or as hormone receptor-negative, had poor DFS. Centrally assessed ER and PgR showed prognostic value. Among patients with centrally assessed ER-expressing tumors, letrozole showed better DFS than tamoxifen, irrespective of PgR expression level. CONCLUSION Central review changed the assessment of receptor status in a substantial proportion of patients, and should be performed whenever possible in similar trials. PgR expression did not affect the relative efficacy of letrozole over tamoxifen.

Predicting the Risk for Additional Axillary Metastases in Patients With Breast Carcinoma and Positive Sentinel Lymph Node Biopsy

Objective:To assess whether the risk for nonsentinel node metastases may be predicted, thus sparing a subgroup of patients with breast carcinoma and a positive sentinel lymph node (SLN) biopsy completion axillary lymph node dissection (ALND). Summary Background Data:The SLN is the only involved axillary lymph node in the majority of the patients undergoing ALND for a positive SLN biopsy. A model to predict the status of nonsentinel axillary lymph nodes could help tailor surgical therapy to those patients most likely to benefit from completion ALND. Methods:All the axillary sentinel and nonsentinel lymph nodes of 1228 patients were reviewed histologically and reclassified according to the current TNM classification of malignant tumors as bearing isolated tumor cells only, micrometastases, or (macro)metastases. The prevalence of metastases in nonsentinel lymph nodes was correlated to the type of SLN involvement and the size of the metastasis, the number of affected SLNs, and the prospectively collected clinicopathologic variables of the primary tumors. Results:In multivariate analysis, further axillary involvement was significantly associated with the type and size of SLN metastases, the number of affected SLNs, and the occurrence of peritumoral vascular invasion in the primary tumor. A predictive model based on the characteristics most strongly associated with nonsentinel node metastases was able to identify subgroups of patients at significantly different risk for further axillary involvement. Conclusions:Patients with the most favorable combination of predictive factors still have no less than 13% risk for nonsentinel lymph node metastases and should be offered completion ALND outside of clinical trials of SLN biopsy without back-up axillary clearing.

Prognostic and Predictive Value of Centrally Reviewed Ki-67 Labeling Index in Postmenopausal Women With Endocrine-Responsive Breast Cancer: Results From Breast International Group Trial 1-98 Comparing Adjuvant Tamoxifen With Letrozole

PURPOSE To evaluate the prognostic and predictive value of Ki-67 labeling index (LI) in a trial comparing letrozole (Let) with tamoxifen (Tam) as adjuvant therapy in postmenopausal women with early breast cancer. PATIENTS AND METHODS Breast International Group (BIG) trial 1-98 randomly assigned 8,010 patients to four treatment arms comparing Let and Tam with sequences of each agent. Of 4,922 patients randomly assigned to receive 5 years of monotherapy with either agent, 2,685 had primary tumor material available for central pathology assessment of Ki-67 LI by immunohistochemistry and had tumors confirmed to express estrogen receptors after central review. The prognostic and predictive value of centrally measured Ki-67 LI on disease-free survival (DFS) were assessed among these patients using proportional hazards modeling, with Ki-67 LI values dichotomized at the median value of 11%. RESULTS Higher values of Ki-67 LI were associated with adverse prognostic factors and with worse DFS (hazard ratio [HR; high:low] = 1.8; 95% CI, 1.4 to 2.3). The magnitude of the treatment benefit for Let versus Tam was greater among patients with high tumor Ki-67 LI (HR [Let:Tam] = 0.53; 95% CI, 0.39 to 0.72) than among patients with low tumor Ki-67 LI (HR [Let:Tam] = 0.81; 95% CI, 0.57 to 1.15; interaction P = .09). CONCLUSION Ki-67 LI is confirmed as a prognostic factor in this study. High Ki-67 LI levels may identify a patient group that particularly benefits from initial Let adjuvant therapy.

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.

Classical Cyclophosphamide, Methotrexate, and Fluorouracil Chemotherapy Is More Effective in Triple-Negative, Node-Negative Breast Cancer: Results From Two Randomized Trials of Adjuvant Chemoendocrine Therapy for Node-Negative Breast Cancer

PURPOSE Retrospective studies suggest that primary breast cancers lacking estrogen receptor (ER) and progesterone receptor (PR) and not overexpressing human epidermal growth factor receptor 2 (HER2; triple-negative tumors) are particularly sensitive to DNA-damaging chemotherapy with alkylating agents. PATIENTS AND METHODS Patients enrolled in International Breast Cancer Study Group Trials VIII and IX with node-negative, operable breast cancer and centrally assessed ER, PR, and HER2 were included (n = 2,257). The trials compared three or six courses of adjuvant classical cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without endocrine therapy versus endocrine therapy alone. We explored patterns of recurrence by treatment according to three immunohistochemically defined tumor subtypes: triple negative, HER2 positive and endocrine receptor absent, and endocrine receptor present. RESULTS Patients with triple-negative tumors (303 patients; 13%) were significantly more likely to have tumors > 2 cm and grade 3 compared with those in the HER2-positive, endocrine receptor-absent, and endocrine receptor-present subtypes. No clear chemotherapy benefit was observed in endocrine receptor-present disease (hazard ratio [HR], 0.90; 95% CI, 0.74 to 1.11). A statistically significantly greater benefit for chemotherapy versus no chemotherapy was observed in triple-negative breast cancer (HR, 0.46; 95% CI, 0.29 to 0.73; interaction P = .009 v endocrine receptor-present disease). The magnitude of the chemotherapy effect was lower in HER2-positive endocrine receptor-absent disease (HR, 0.58; 95% CI, 0.29 to 1.17; interaction P = .24 v endocrine receptor-present disease). CONCLUSION The magnitude of benefit of CMF chemotherapy is largest in patients with triple-negative, node-negative breast cancer.

Histologic and histomorphometric features of bisphosphonate-related osteonecrosis of the jaws: An analysis of 31 cases with confocal laser scanning microscopy

INTRODUCTION Patients undergoing bisphosphonate therapies may develop jaw lesions, mainly consisting in bone necrosis. No effective treatment has been proposed so far for such lesions, nor is there a uniform concept on the possible pathogenesis of this entity. METHODS The study population included 31 patients with bisphosphonate-related osteonecrosis of the jaws and 10 healthy donors. All patients underwent to jaw bone biopsy and the tissue samples were divided into two parts, one of which was fixed, decalcified and routinely processed. The second part was fixed, embedded in methylmetacrylate, cut and stained with methylene blue and basic fuchsine. All samples were subjected to light and confocal microscopic examination and to histomorphometric analyses to evaluate differences in bone structure between the two samples groups. RESULTS Three main histological patterns were identified in ONJ patients: 1 - Areas with active acute inflammation, characterized by predominance of soft tissues, inflammatory infiltrate, acellular necrotic debris, thin-walled and dilated blood vessel, intensely basophilic bone spiculae with scalloped borders showing prominent bone resorption. 2 - Areas characterized by predominance of bony structures showing wide acellular necrotic sequestra and large, scalloped Haversian canals containing inflammatory cells. 3 - Non-necrotic areas contained larger amounts of bone, showing increased trabecular thickness, inter-osteonic bone deposition and smaller and fewer Haversian canals. These differences were more evident after comparing the histomorphometrical data of samples from ONJ patients with controls. Also, lamellar bone from treated patients was composed of bigger osteones containing larger osteocytes. Two different types of newly-formed woven bone, mainly showing centrifugal spatial orientation, were easily detectable in these areas. Osteoclast-like cells detected in inflammatory areas from treated patients were small and contained few nuclei, but they were rare to absent in non-necrotic bone from the same patients. CONCLUSIONS These features point at a peculiar process of bone remodeling in patients undergoing bisphosphonate therapy, which showed scarce osteoclastic activity and subsequent deposition of newly-formed bone. The latter would be made up of thicker bone structures supplied by fewer blood vessels. Consequently, in case of increased metabolic requests, this modified bone would not be supported by adequate blood supply, thus leading to necrosis and superinfection.

Chemoendocrine Compared With Endocrine Adjuvant Therapies for Node-Negative Breast Cancer: Predictive Value of Centrally Reviewed Expression of Estrogen and Progesterone Receptors—International Breast Cancer Study Group

PURPOSE To centrally assess estrogen receptor (ER) and progesterone receptor (PgR) levels by immunohistochemistry and investigate their predictive value for benefit of chemo-endocrine compared with endocrine adjuvant therapy alone in two randomized clinical trials for node-negative breast cancer. PATIENTS AND METHODS International Breast Cancer Study Group Trial VIII compared cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy for 6 cycles followed by endocrine therapy with goserelin with either modality alone in pre- and perimenopausal patients. Trial IX compared three cycles of CMF followed by tamoxifen for 5 years versus tamoxifen alone in postmenopausal patients. Central Pathology Office reviewed 883 (83%) of 1,063 patients on Trial VIII and 1,365 (82%) of 1,669 on Trial IX and determined ER and PgR by immunohistochemistry. Disease-free survival (DFS) was compared across the spectrum of expression of each receptor using the Subpopulation Treatment Effect Pattern Plot methodology. RESULTS Both receptors displayed a bimodal distribution, with substantial proportions showing no staining (receptor absent) and most of the remainder showing a high percentage of stained cells. Chemo-endocrine therapy yielded DFS superior to endocrine therapy alone for patients with receptor-absent tumors, and in some cases also for those with low levels of receptor expression. Among patients with ER-expressing tumors, additional prediction of benefit was suggested in absent or low PgR in Trial VIII but not in Trial IX. CONCLUSION Low levels of ER and PgR are predictive of the benefit of adding chemotherapy to endocrine therapy. Low PgR may add further prediction among pre- and perimenopausal but not postmenopausal patients whose tumors express ER.

Warthin's tumour: a study of 78 cases with emphasis on bilaterality, multifocality and association with other malignancies

The authors reviewed the clinical records and the histopathological preparations of 78 cases of Warthins tumours (WTs), treated at the Department of Dental Sciences, Centre for the Study of Oral Tumours, of the University of Bari. All the surgical specimens had been fixed in neutral buffered formalin, sampled according to the step-serial, whole-specimen sectioning technique, embedded in paraffin and stained with haematoxylin-eosin, periodic acid Schiff and Gomoris reticulin. The results showed that Warthins tumours characteristically affect the parotid gland, and most frequently arise in adults (mean age=57 years) and in males (95%). Multiple tumours were detected in 16 cases (20.5%), and five of these were bilateral (6.5%). One of the multifocal tumours involved an intra-parotideal lymph node and the laryngeal piriform sinus. In addition, 13 cases (16.6%) were associated with other malignancies. These data indicate that multiple (synchronous or metachronous) WTs may occur more frequently than previously reported. The high rate of multiple WTs detected in the current study may result from extensive and accurate sampling of these neoplasms for histopathological evaluation. Consequently, complete preoperative work-up of patients harbouring parotideal tumours consistent with or suspicious for WT is necessary. The work-up should include CT scans and/or magnetic resonance imaging of both parotid glands, to exclude the occurrence of multiple tumours, which may be clinically undetectable. Also, fine needle aspiration biopsy may be an accurate tool for excluding malignant neoplasms and for better planning subsequent surgical procedures. These usually consist in (bilateral) superficial parotidectomy and should be followed by long term follow up of the patients, in view of possible metachronous WTs, even after prolonged time intervals.

Expression of P-Glycoprotein in Human Cerebral Cortex Microvessels

P-Glycoprotein (P-gp) is an ATP-dependent efflux transporter that extrudes non-polar molecules, including cytotoxic substances and drugs, from the cells. It was initially found in cancer cells and then was shown to be a normal component of complex transport systems working at the blood-brain barrier (BBB). Previous studies have demonstrated that, in the brain, P-gp is localized on the luminal plasmalemma of BBB endothelial cells and that it may interact with the caveolar compartment of these cells. The aim of this study was to identify the site of cellular expression of P-gp in human brain in situ and to morphologically determine whether an association may exist between P-gp and caveolin-1, a structural and functional protein of the caveolar frame. The study was carried out on human cerebral cortex by immunoconfocal microscopy with antibodies to both P-gp and caveolin-1. The results show that P-gp marks the microvessels of the cortex and that the transporter is localized in the luminal endothelial compartment, where it co-localizes with caveolin-1. The demonstration of this co-localization of P-gp with caveolin-1 contributes a morphological backing to biochemical studies on P-gp/caveolin-1 relationships and leads us to suggest that interactions between these molecules may occur at the BBB endothelia.

Plasmablastic lymphoma: a review.

Plasmablastic lymphoma (PBL) has been recently characterised as an aggressive subtype of non-Hodgkins lymphoma, most frequently arising in the oral cavity of HIV-infected patients. To date, approximately 60 cases fulfilling the clinico-pathological characteristics of PBL have been reported. PBLs are composed of large cells with eccentrically located nuclei and deeply basophilic cytoplasm with a paranuclear hof. The tumour cells are invariably immunoreactive for the plasma cell marker CD138, and show monoclonal rearrangement of the immunoglobulin heavy chain gene (IgH) and/or clonal restriction of the Ig light chain (IgL) gene expression in most of the cases. Similar to other types of AIDS-related lymphomas, there is evidence that Epstein-Barr virus and Kaposi-sarcoma associated Human Herpes Virus 8 may play a relevant role in the pathogenesis of PBL. PBL patients have been treated heterogeneously, with a combination of chemotherapy, radiotherapy and/or surgery, and their prognosis is usually poor, with a death rate of approximately 60% at 1 year.