Biomedical subjects

Dominic T Moore

Publications and source records attributed to Dominic T Moore.

At least 19 recordsLinked to original sources

PubMed2006

Extended follow-up of outcome measures in multiple myeloma patients treated on a phase I study with bortezomib and pegylated liposomal doxorubicin.

A phase I study of a combination of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin showed significant anti-tumor activity against advanced multiple myeloma, with 36% of patients achieving a complete or near-complete response and 73% having a partial response or better. Given this encouraging efficacy, it was therefore of interest to update the prior experience and define parameters such as time to progression, time to retreatment, and overall survival. Additional follow-up was collected on all evaluable multiple myeloma patients and revealed a median time to progression of 9.3 months versus 3.8 months on whatever had been the patient's prior therapy. Time to retreatment was prolonged from 5.9 months after the patient's prior therapy to 24.2 months after bortezomib with pegylated liposomal doxorubicin. The median overall survival after therapy with bortezomib and pegylated liposomal doxorubicin was 38.3 months. These findings compare favorably with results reported for bortezomib alone and support the possibility that the bortezomib/pegylated liposomal doxorubicin regimen may provide superior efficacy against relapsed/refractory multiple myeloma.

Aged↗

PubMed2006

Radiation clastogenesis and cell cycle checkpoint function as functional markers of breast cancer risk.

BACKGROUND: Familial breast cancer is associated with mutations in several genes (BRCA1, BRCA2, p53, ATM) whose protein products protect against radiation-induced genotoxicity. This study tested whether sporadic breast cancer was associated with constitutive radiation hypersensitivity. METHODS: Blood lymphocytes and EBV-transformed lymphoblasts from patients with newly diagnosed breast cancer and controls without cancer were evaluated for ionizing radiation (IR)-induced chromosomal aberrations and cell cycle delays. Lymphoblasts from patients with ataxia telangiectasia (AT) and heterozygous AT carriers were tested as positive controls for radiation hypersensitivity. RESULTS: Lymphoblasts from AT patients and AT carriers displayed G2-irradiation, chromosomal hypersensitivity (GICH). Irradiated G2 phase lymphocytes from breast cancer cases and controls displayed 3-fold inter-individual variation in frequencies of chromatid damage. However, the percentage of breast cancer cases with damage frequencies in excess of 2 SD of the control mean (8/102 or 8%) was not significantly elevated compared to controls (2/48 or 4%, P=0.5). Lymphoblasts sampled 24 h after 3 Gy of IR also varied in the ratios of cells with 4N and 2N DNA content (4N/2N ratio), as a measure of cell cycle checkpoint function. 4N/2N ratios in irradiated lymphoblasts were strongly correlated with the fractions of S phase cells in un-irradiated control cultures (Pearson's correlation coefficient, r=0.87). After normalization to S fraction, the radiation-induced increment in the 4N/2N ratio was significantly elevated in AT lymphoblasts but not in lymphoblasts from AT carriers. The fraction of breast cancer cases with reduced checkpoint function (2/45 or 4%) was equal to the control fraction (2/45 or 4%). For breast cancer cases and controls, GICH in primary lymphocytes was not associated with reduced cell cycle checkpoint function in lymphoblasts. CONCLUSION: Constitutive radiation hypersensitivity in blood lymphocytes and lymphoblasts was not a useful biomarker for identifying women at increased risk of breast cancer.

Ataxia Telangiectasia Mutated Proteins↗

PubMed2006

Size of residual lymph node metastasis after neoadjuvant chemotherapy in locally advanced breast cancer patients is prognostic.

BACKGROUND: The prognostic significance of micrometastasis after neoadjuvant chemotherapy for locally advanced breast cancer is unknown. We examined the residual lymph node metastasis size in patients after treatment with neoadjuvant chemotherapy to determine the relevance of metastasis size on outcome. METHODS: Stage II/III breast cancer patients treated with neoadjuvant chemotherapy at our institution from 1991 to 2002 were included. We examined the relationship of postneoadjuvant chemotherapy lymph node metastasis size and number with distant disease-free survival (DDFS) and overall survival (OS). RESULTS: In 122 patients with a median follow-up of 5.4 years, we found not only that patients with an increasing number of residual positive nodes had progressively worse DDFS and OS (P < .0001 for both) compared with patients with negative nodes, but also that the size of the largest lymph node metastasis was associated with worse DDFS and OS (P < .0001 for both) in both univariate and multivariate analysis. Compared with negative nodes, even lymph node micrometastasis (<2 mm) was associated with worsened DDFS and OS (adjusted P = .02 and P = .005, respectively). CONCLUSIONS: Residual micrometastatic disease in the axillary lymph nodes after neoadjuvant chemotherapy is predictive of worse prognosis than negative nodes. In this study, the lymph node metastasis size and the number of involved lymph nodes were independent powerful predictors of DDFS and OS.

Adult↗

PubMed2006

Post-chemotherapy gross tumor volume is predictive of survival in patients with stage III non-small cell lung cancer treated with combined modality therapy.

PURPOSE: To evaluate the influence of clinical covariates, particularly pre-chemotherapy gross tumor volume (GTV), post-chemotherapy GTV, on overall survival in the treatment of stage III non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: We retrospectively analyzed 102 patients who were enrolled on three consecutive clinical trials, which employed the treatment paradigm of two cycles of induction chemotherapy followed by thoracic radiation therapy. The pre-chemotherapy GTV, post-chemotherapy GTV, change in GTV, histology, disease stage, performance status, age, race, treatment with concurrent chemoradiotherapy versus radiotherapy alone were evaluated to determine their impact on overall survival. The log10 of the GTV was used to normalize the data and thereby reduce the impact of exceptionally large values. RESULTS: Both the log10 of the post-chemotherapy GTV and Eastern Cooperative Oncology Group (ECOG) performance status covariates were highly prognostic for overall survival (p = 0.006 and p = 0.008, respectively). Disease stage (at diagnosis) was also significant (p = 0.048). The log10 pre-chemotherapy GTV covariate was borderline significant (p = 0.067). The strongest prognostic model was the two-covariate model, which contained the log10 post-chemotherapy GTV and ECOG performance status covariates, (model chi2 of 18.67, with p = 0.001 for each covariate). CONCLUSIONS: The log10 post-chemotherapy GTV has significant prognostic survival value when the strategy of induction chemotherapy is employed in the treatment on stage III NSCLC. ECOG performance status and stage were also significant prognostic factors for survival.

Adult↗

PubMed2006

Axillary lymph node count is lower after neoadjuvant chemotherapy.

BACKGROUND: Retrieval of fewer than 10 lymph nodes at axillary dissection (ALND) for breast cancer can represent anatomic variation or inadequate dissection. We postulated that despite aggressive ALND, a lower lymph node count is more frequent after neoadjuvant chemotherapy. METHODS: Patients who received neoadjuvant chemotherapy followed by ALND were compared with patients who received surgery first. All patients received a level I and II ALND at a single institution by one of the breast surgeons. The number of nodes retrieved at ALND was dichotomized into categories (< 10 and > or = 10), and compared using Fisher exact test. RESULTS: A total of 143 neoadjuvant and 170 surgery-first patients were studied. Patients treated with neoadjuvant chemotherapy were significantly more likely to have fewer than 10 lymph nodes retrieved at ALND than were the surgery-first patients (19/143 or 13% vs. 6/170 or 4%, P = .003). CONCLUSIONS: A low lymph node count is more common in patients after treatment with neoadjuvant chemotherapy and should not be assumed to represent an incomplete ALND.

Adult↗

PubMed2006

Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma.

Microarray profiling of invasive breast carcinomas has identified five distinct subtypes of tumors (luminal A, luminal B, normal breast-like, HER2 overexpressing, and basal-like) that are associated with different clinical outcomes. The basal-like subtype is associated with poor clinical outcomes and is the subtype observed in BRCA1-related breast cancers. The aim of this study was to characterize the histologic and immunophenotypic properties of breast basal-like carcinomas that were first positively identified using DNA microarray analysis. Detailed histologic review was performed on 56 tumors with known microarray profiles (23 basal-like, 23 luminal, and 12 HER2+). Immunohistochemistry for estrogen receptor (ER), HER2, EGFR, smooth muscle actin (SMA), p63, CD10, cytokeratin 5/6, cytokeratin 8/18, and vimentin was performed on 18 basal-like, 16 luminal, and 12 HER2+ tumors. The basal-like tumors were grade 3 ductal/NOS (21/23) or metaplastic (2/23) carcinomas that frequently showed geographic necrosis (17/23), a pushing border of invasion (14/23), and a stromal lymphocytic response (13/23). Most basal-like tumors showed immunoreactivity for vimentin (17/18), luminal cytokeratin 8/18 (15/18), EGFR (13/18), and cytokeratin 5/6 (11/18), while positivity for the myoepithelial markers SMA (4/18), p63 (4/18) and CD10 (2/18) was infrequent. All basal-like tumors tested were ER- and HER2-. Morphologic features significantly associated with the basal-like subtype included markedly elevated mitotic count (P<0.0001), geographic tumor necrosis (P=0.0003), pushing margin of invasion (P=0.0001), and stromal lymphocytic response (P=0.01). The most consistent immunophenotype seen in the basal-like tumors was negativity for ER and HER2, and positivity for vimentin, EGFR, cytokeratin 8/18, and cytokeratin 5/6. The infrequent expression of myoepithelial markers in basal-like carcinomas does not support a direct myoepithelial cell derivation of these tumors. These findings should further assist in the identification of basal-like carcinomas in clinical specimens, facilitating treatment and epidemiologic studies of this tumor subtype.

Actins↗

PubMed2006

The use of erythropoietin in patients undergoing radical prostatectomy: effects on hematocrit, transfusion rates and quality of life.

OBJECTIVE: It was the aim of this study to prospectively study the effects on hematocrit levels, transfusion rates and quality of life (QOL) indices in men preoperatively supplemented with recombinant erythropoietin (rEPO) undergoing radical prostatectomy for clinically localized prostate cancer. METHODS: Thirty men undergoing radical prostatectomy were randomized either to receive rEPO (n=25) or to serve as controls (n=25). Outcome measurements obtained preoperatively, as well as 10 days and 6 weeks postoperatively included serum hematocrit levels, transfusion rates and QOL indices (using SF-12 validated questionnaires). RESULTS: The rEPO group had a significant increase in preoperative hematocrit (median increase=4 points; p=0.002). Although there were no significant differences in hematocrit at 10 days, the rEPO had a significantly higher hematocrit value at 6 weeks (p=0.0086). No differences were observed in transfusions rates between groups (4% in each group). SF-12 mental and SF-12 physical scores were not different between the two groups at any time point. CONCLUSION: Preoperative administration of rEPO significantly increases preoperative and postoperative hematocrit levels. However, no differences were observed with regard to transfusion rates or postoperative QOL indices despite these higher hematocrit values.

Adult↗

PubMed2005

EGFR expression and HER2/neu overexpression/amplification in endometrial carcinosarcoma.

OBJECTIVE: Endometrial carcinosarcomas are aggressive biphasic neoplasms traditionally treated as a high-grade uterine sarcoma. Epidermal growth factor receptor (EGFR) and HER2/neu (HER2) tyrosine kinases have been implicated in the development and progression of several human cancers and are targets for therapeutic intervention. The aim of this study was to evaluate for HER2 and EGFR expression in cases of endometrial carcinosarcoma. METHODS: Formalin-fixed, paraffin-embedded sections from 55 cases of confirmed endometrial carcinosarcoma were immunostained with commercially available antibodies to EGFR and HER2. Fluorescent in situ hybridization for HER2 gene amplification was performed on all cases showing 2+ or 3+ HER2 staining by immunohistochemistry. HER2 gene amplification and EGFR expression were correlated with several prognostic variables. RESULTS: EGFR expression was identified in the majority of tumors (45/55, 82%). HER2 overexpression (3+) was seen in 14/55 (25%) cases and HER2 gene amplification was seen in 11 (20%) cases. EGFR expression and HER2 gene amplification did not show significant correlation with disease progression, disease-free survival or overall survival. The carcinomatous component of tumors more frequently showed HER2 overexpression as compared to the sarcomatous component (25% vs. 4%, P = 0.008). The sarcomatous component of tumors more frequently showed EGFR overexpression as compared to the carcinomatous component (44% vs. 24%, P = 0.04). CONCLUSIONS: EGFR and HER2 appear to play a role in the carcinogenesis of endometrial carcinosarcomas. The carcinomatous and sarcomatous elements of these tumors showed consistent differences in HER2 and EGFR expression patterns supporting biologic differences between these components. Studies evaluating the clinical utility of HER2 or EGFR targeted therapy in these tumors appear warranted.

Aged↗

PubMed2005

American Joint Committee on Cancer tumor-node-metastasis stage after neoadjuvant chemotherapy and breast cancer outcome.

BACKGROUND: Response to neoadjuvant chemotherapy is used as an intermediate endpoint for breast cancer relapse and survival. Most breast cancer response classification systems use pathologic complete response, either alone or in conjunction with clinical assessments, to categorize response. We examined the ability of the revised 2003 American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system, which considers both the number of involved axillary lymph nodes and the extent of tumor in the breast to predict patient survival after neoadjuvant chemotherapy for breast cancer. METHODS: We assessed the pathologic stage of residual tumor in 132 patients with nonmetastatic breast cancer after they had undergone neoadjuvant chemotherapy and examined the association between AJCC TNM stage and subsequent distant disease-free survival and overall survival. All statistical tests were two-sided. RESULTS: At a median follow-up of 5 years, pathologic stage in the surgical specimens after neoadjuvant chemotherapy using the revised AJCC system was strongly associated with both distant disease-free survival and overall survival. A higher pathologic stage of residual tumor after neoadjuvant chemotherapy was associated with a statistically significant lower rate of distant disease-free survival (stage 0: 95%, stage I: 84%, stage II: 72%, and stage III: 47%; Ptrend < .001). The 5-year distant disease-free survival for patients with residual stage IIIC tumors was only 18% (95% CI = 0% to 36%). CONCLUSION: Classification of residual tumor in the breast and axillary surgical specimens after neoadjuvant chemotherapy using the revised AJCC TNM system is useful for predicting distant relapse and survival.

Adult↗

PubMed2005

Microsatellite instability testing in colorectal carcinoma: choice of markers affects sensitivity of detection of mismatch repair-deficient tumors.

PURPOSE: Microsatellite instability (MSI) is found in 10% to 15% of sporadic colorectal tumors and is usually caused by defects in DNA mismatch repair (MMR). In 1997, a panel of microsatellite markers including mononucleotide and dinucleotide repeats was recommended by a National Cancer Institute workshop on MSI. We investigated the relationship between instability of these markers and MMR protein expression in a cohort of sporadic colorectal cancer patients. EXPERIMENTAL DESIGN: Paraffin sections of normal and tumor tissue from 262 colorectal cancer patients were examined for MSI status by PCR amplification and for MMR protein expression using antibodies against hMLH1, hPMS2, hMSH2, and hMSH6. RESULTS: Twenty-six (10%) of the patients studied had tumors with a high level of MSI (MSI-H). The frequencies of MSI were the same in African-American and Caucasian patients. Each of the MSI-H tumors had mutations in both mononucleotide and dinucleotide repeats and had loss of MMR protein expression, as did two tumors that had low levels of MSI (MSI-L). These two MSI-L tumors exhibited mutations in mononucleotide repeats only, whereas eight of the other nine MSI-L tumors had mutations in just a single dinucleotide repeat. There was not a statistically significant difference in outcomes between patients whose tumors were MMR-positive or MMR-negative, although there was a slight trend toward improved survival among those with MMR-deficient tumors. CONCLUSIONS: The choice of microsatellite markers is important for MSI testing. Examination of mononucleotide repeats is sufficient for detection of tumors with MMR defects, whereas instability only in dinucleotides is characteristic of MSI-L/MMR-positive tumors.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Epstein-Barr viral load as a marker of lymphoma in AIDS patients.

Epstein-Barr virus (EBV) is implicated in the pathogenesis of acquired immunodeficiency syndrome (AIDS) lymphoma, and viral DNA is present within the malignant cells in about half of affected patients. We examined the extent to which EBV viral load is elevated in the plasma of AIDS lymphoma patients compared to AIDS patients with opportunistic infections. Sixty-one AIDS patients were studied including 35 with lymphoma (24 non-Hodgkin, six Hodgkin, and five brain lymphoma) and 26 with various opportunistic infections. In situ hybridization revealed EBV encoded RNA (EBER) expression in the malignant cells of 17/28 AIDS lymphomas (61%). In 232 serial plasma samples from 35 lymphoma patients and in 128 samples from AIDS controls, EBV viral load was assayed by quantitative-polymerase chain reaction (Q-PCR) using a TaqMan probe targeting the BamH1W sequence. EBV was detected in plasma from all 17 EBER-positive AIDS lymphoma patients, with viral loads ranging from 34 to 1,500,000 copies per ml (median 3,210). Viral load usually fell rapidly upon initiation of lymphoma therapy and remained undetectable except in two patients with persistent tumor. In 11 AIDS patients, whose lymphoma lacked EBER expression, and in 26 control patients without lymphoma, levels of EBV in plasma were usually low or undetectable (range 0-1,995 and 0-2,409, median 0 and 0, respectively). There was no association between EBV viral load and human immunodeficiency virus (HIV) load or CD4 count. In conclusion, EBV viral load shows promise as a tool to assist in diagnosis and management of EBV-related lymphoma patients.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Cytoprotection by amifostine during autologous stem cell transplantation for advanced refractory hematologic malignancies.

This study evaluated whether amifostine protects against mucositis and other toxicities in patients with advanced, refractory, or recurrent hematologic malignancies undergoing high-dose chemotherapy and total body irradiation. Thirty-five patients (20 with non-Hodgkin lymphoma, 12 with Hodgkin disease, and 3 with acute myelogenous leukemia) who underwent autologous stem cell transplantation were conditioned with total body irradiation 2 Gy twice daily on days -8 through -6; cyclophosphamide 6 g/m(2), etoposide 1.8 g/m(2), and carboplatin 1 g/m(2) on days -5 through -3; and amifostine 500 mg/m(2) on days -8 through -2. Prior institutional experience in patients treated without amifostine was used as a historical comparison (no-amifostine group). Severe mucositis occurred in 14 (40%) of 35 patients in the amifostine group, compared with 33 (94%) of 35 in the no-amifostine group (P < .0001). Total parenteral nutrition was used by 4 (11%) of 35 amifostine-treated patients and 34 (97%) of 35 no-amifostine patients (P < .0001). The median duration of narcotic use decreased from 15.5 days with no amifostine to 11 days with amifostine (P = .002). Granulocyte and platelet engraftment times were similar. Prospective trials with innovative designs and clearly defined stopping rules are warranted to confirm whether amifostine reduces the toxicities of a myelosuppressive conditioning regimen before autologous stem cell transplantation without compromising therapeutic response.

Acute Disease↗

PubMed2005

High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype.

Focal adhesion kinase (FAK) is a protein tyrosine kinase expressed in invasive breast cancer that regulates antiapoptotic signaling. We have examined FAK expression by immunohistochemistry using anti-FAK 4.47 in breast tumor samples from a large population-based, case-control study of women participating in the University of North Carolina Breast Specialized Programs of Research Excellence (SPORE), Carolina Breast Cancer Study. In this population, 629 formalin-fixed, paraffin-embedded tissue sections were stained for FAK and scored as high (3+ or 4+ intensity and > or = 90% positive cells) or otherwise. High FAK expression was associated with poor prognostic indicators including high mitotic index (>10 mitoses per 10 consecutive high-power fields), nuclear grade 3, architectural grade 3, estrogen and progesterone receptor negative, and HER-2/neu overexpressed using CB11 antibody. The association of high FAK expression with HER-2/neu overexpression lends further support that HER-2/neu and FAK collaborate to promote tumorigenesis. The presence of strong FAK expression in many high grade, estrogen- and progesterone-negative breast carcinomas indicates that FAK may be an attractive target for therapeutic intervention.

Adult↗

PubMed2004

Induction and concurrent chemotherapy with high-dose thoracic conformal radiation therapy in unresectable stage IIIA and IIIB non-small-cell lung cancer: a dose-escalation phase I trial.

PURPOSE: Local control rates at conventional radiotherapy doses (60 to 66 Gy) are poor in stage III non-small-cell lung cancer (NSCLC). Dose escalation using three-dimensional thoracic conformal radiation therapy (TCRT) is one strategy to improve local control and perhaps survival. PATIENTS AND METHODS: Stage III NSCLC patients with a good performance status (PS) were treated with induction chemotherapy (carboplatin area under the curve [AUC] 5, irinotecan 100 mg/m(2), and paclitaxel 175 mg/m(2) days 1 and 22) followed by concurrent chemotherapy (carboplatin AUC 2 and paclitaxel 45 mg/m(2) weekly for 7 to 8 weeks) beginning on day 43. Pre- and postchemotherapy computed tomography scans defined the initial clinical target volume (CTV(I)) and boost clinical target volume (CTV(B)), respectively. The CTV(I) received 40 to 50 Gy; the CTV(B) received escalating doses of TCRT from 78 Gy to 82, 86, and 90 Gy. The primary objective was to escalate the TCRT dose from 78 to 90 Gy or to the maximum-tolerated dose. RESULTS: Twenty-nine patients were enrolled (25 assessable patients; median age, 59 years; 62% male; 45% stage IIIA; 38% PS 0; and 38% > or = 5% weight loss). Induction CIP was well tolerated (with filgrastim support) and active (partial response rate, 46.2%; stable disease, 53.8%; and early progression, 0%). The TCRT dose was escalated from 78 to 90 Gy without dose-limiting toxicity. The primary acute toxicity was esophagitis (16%, all grade 3). Late toxicity consisted of grade 2 esophageal stricture (n = 3), bronchial stenosis (n = 2), and fatal hemoptysis (n = 2). The overall response rate was 60%, with a median survival time and 1-year survival probability of 24 months and 0.73 (95% CI, 0.55 to 0.89), respectively. CONCLUSION Escalation of the TCRT dose from 78 to 90 Gy in the context of induction and concurrent chemotherapy was accomplished safely in stage III NSCLC patients.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Evidence that mitogen-activated protein kinase phosphatase-1 induction by proteasome inhibitors plays an antiapoptotic role.

Inhibitors of the proteasome, a multicatalytic proteinase complex responsible for intracellular proteolysis, activate programmed cell death in part through the c-Jun-N-terminal kinase (JNK). Proteasome inhibitors also induce mitogen-activated protein kinase phosphatase-1 (MKP-1), however, which can inactivate JNK, and we therefore considered the hypothesis that MKP-1 induction may be antiapoptotic. Over-expression of MKP-1 in A1N4-myc human mammary epithelial and BT-474 breast carcinoma cells decreased proteasome inhibitor-mediated apoptosis. On the other hand, BT-474 cells stably expressing an MKP-1 small interfering RNA (siMKP-1) and MKP-1 knockout mouse embryo fibroblasts underwent enhanced apoptosis compared with their respective controls. MKP-1-mediated inhibition of apoptosis was associated with decreased phospho-JNK levels, whereas MKP-1 suppression or inactivation enhanced phospho-JNK. Anthracyclines repress MKP-1 transcription, suggesting that they could enhance proteasome inhibitor-mediated apoptosis. Such combinations induced increased cell death in association with enhanced phospho-JNK and decreased MKP-1 levels. Inhibition of JNK signaling decreased the proapoptotic activity of the anthracycline/proteasome inhibitor regimen. Xenograft studies showed the combination was more effective at inducing tumor growth delay, associated with suppression of MKP-1 and enhancement of apoptosis and phospho-JNK. Infection of anthracycline/proteasome inhibitor-treated A1N4-myc cells with Adenoviral-MKP-1 suppressed apoptosis and phospho-JNK. Finally, the anthracycline/proteasome inhibitor regimen activated apoptosis and phospho-JNK to a greater extent in BT-474/siMKP-1 cells than controls. These findings for the first time demonstrate that proteasome inhibitor-mediated induction of MKP-1 is antiapoptotic through inhibition of JNK. Furthermore, they suggest that a proteasome inhibitor/anthracycline regimen holds potential for enhanced antitumor activity in part through repression of MKP-1, supporting clinical evaluation of such combinations.

Animals↗

PubMed2004

Central nervous system metastases in women after multimodality therapy for high risk breast cancer.

BACKGROUND: Central nervous system (CNS) relapse is increasing in breast cancer. This increase may reflect altered failure patterns from adjuvant therapy, more effective systemic therapy with improved control in non-CNS sites, or a resistant breast cancer subtype. METHODS: To determine the factors associated with clinical CNS relapse, we examined response to neoadjuvant chemotherapy (chemosensitivity), time to relapse and sites of relapse in a cohort of 140 patients without evidence of metastasis at presentation. RESULTS: At 5 years (interquartile range 3-6 years), 44 (31%) patients developed distant metastases, including 13 with CNS metastases. CNS relapse was early (median 24 months after diagnosis) and associated with relapse in bone and liver, suggesting hematogenous dissemination. Those with CNS relapse were younger at diagnosis (40 versus 49 years) and more likely to have lymphovascular invasion in the primary tumor compared with non-CNS metastases. Response to neoadjuvant chemotherapy was not different (69% versus 73% response rate) between the two groups. Extent of residual disease after chemotherapy was strongly associated with relapse outside the CNS but not CNS relapses. The CNS was an isolated or dominant site of metastasis in 8 of 13. Despite treatment, most patients with CNS involvement died of neurologic causes a median of 6 months later. CONCLUSION: Breast cancers that develop CNS metastases differ from those that develop metastases elsewhere. Both tumor behavior and reduced chemotherapy accessibility to the CNS may contribute to increased CNS involvement in breast cancer patients treated with multimodality therapy.

Adult↗

PubMed2004

Upregulation of focal adhesion kinase (FAK) expression in ductal carcinoma in situ (DCIS) is an early event in breast tumorigenesis.

Focal adhesion kinase (FAK) is a protein tyrosine kinase that is overexpressed in a subset of invasive breast cancers. FAK transmits signals that mediate several functions including tumor cell proliferation, migration, adhesion and survival. We used immunohistochemical techniques to assess FAK expression in patients with fibrocystic disease (FCD), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDC). Formalin-fixed, paraffin-embedded (FFPE) tissue sections were obtained from 119 patients (12 FCD, 38 ADH, 51 DCIS and 18 IDC). The anti-FAK 4.47 monoclonal antibody was used to detect FAK expression. FAK expression was scored as high (3 or 4 intensity and > or =90% positive cells) or low. The DCIS tissue sections demonstrated high FAK expression in 34/51 (66%) of the sections. High FAK expression was demonstrated in 6/18 (33%) of the IDC tissue sections and 8/38 (21%) of the ADH tissue sections. None (0/12) of the FCD tissues sections stained high for FAK. The pattern of FAK expression in DCIS was significantly higher than ADH (p < 0.0001) and IDC (p = 0.02). We conclude that FAK overexpression in preinvasive, DCIS tumors precedes tumor cell invasion or metastasis, suggesting that FAK may function as a survival signal and be an early event in breast tumorigenesis.

Breast Diseases↗

PubMed2004

The clinical significance of a negative loop electrosurgical cone biopsy for high-grade dysplasia.

OBJECTIVE: We sought to estimate the incidence and clinical significance of a negative therapeutic loop electrosurgical excision procedure (LEEP) and to evaluate patient specimens for limiting histologic features associated with a negative LEEP. METHODS: We identified 674 patients with biopsy-confirmed high-grade cervical dysplasia who were treated with LEEP from 1991 through 2001. The results of these LEEP procedures were reviewed for the absence of dysplasia or the presence of cervical intraepithelial neoplasia stages 1-3. Computerized pathology files of patients were then reviewed through July 2002 to determine whether dysplasia recurred. Slides of negative LEEP specimens were reviewed to confirm the absence of dysplasia and to search for histologic features that may have limited our interpretation of the specimen. RESULTS: Ninety-three (14%) of LEEP specimens reviewed were completely negative for dysplasia. Clinical follow-up was available on 75 of the 93 patients, with a median follow-up time of 2 years. Eighteen (24%) patients had subsequent positive follow-up, including carcinoma (n = 2), high-grade squamous intraepithelial lesions (n = 8), low-grade squamous intraepithelial lesion (n = 6), and atypical squamous cells of undetermined significance (n = 2). Patients with negative LEEPs had a recurrence rate similar to patients with positive LEEPs (24% versus 27%). Limiting histologic features were more commonly identified in negative LEEPs as compared with LEEPs containing dysplasia (16% versus 5%, P <.001). CONCLUSION: A negative LEEP is not an uncommon finding, occurring in 14% (95% confidence interval 11-17%) of specimens at our institution. Negative LEEPs are more likely to contain histologic features that limit pathology interpretation. A negative LEEP is not a reassuring finding and was associated with a recurrence rate similar to those of a positive LEEP. Both negative and positive populations should be carefully followed.

Adolescent↗