[Show abstract][Hide abstract] ABSTRACT: Signal transducer and activator of transcription 3 (STAT3) is a point of convergence for numerous oncogenic signaling pathways. In breast cancer cell lines and xenograft models activated STAT3 participates in breast tumorigenesis, while studies in humans have demonstrated that phosphorylated (tyrosine705)-STAT3 is a marker of good prognosis in breast cancer. In order to resolve this paradox we hypothesized that in clinic, phospho-STAT3 has a predictive role of benefit from adjuvant chemotherapy; therefore the goal of this study was to determine the usefulness of phospho-STAT3 status as a predictor of benefit from adjuvant chemotherapy in breast cancer patients. Immunohistochemical analysis of phospho-STAT3 was performed on a tissue microarray of breast cancer specimens. The expression pattern of phospho-STAT3 was retrospectively correlated with pathological parameters and overall survival in patients who were or were not treated with adjuvant chemotherapy. Of 375 tissue specimens interpretable for phospho-STAT3, 134 (36 %) exhibited positive phospho-STAT3 nuclear expression. Among 234 patients who received adjuvant therapy, those with tumors displaying positive phospho-STAT3 nuclear expression had a better ten-year rate of overall survival than patients with tumors displaying negative phospho-STAT3 nuclear expression (P = 0.001). Among patients who did not received adjuvant chemotherapy, positive phospho-STAT3 nuclear status was not correlated with increased overall survival (P = 0.54). Positive phospho-STAT3 was correlated with improved overall survival only among patients who received adjuvant chemotherapy in a multivariate analysis adjusted for stage, grade, hormonal status, Her2 status, and age, irrespective of the chemotherapy regimen received (hazard ratio for death, 0.35 [95 % CI 0.188-0.667]; P = 0.001). These findings support the role of phospho-STAT3 as a marker of favorable outcome in breast cancer patients treated with adjuvant chemotherapy. Whether phospho-STAT3 has a predictive role of benefit from adjuvant chemotherapy has to be validated on prospective, randomized, controlled studies.
Breast Cancer Research and Treatment 02/2013; 138(2). · 4.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Trabectedin and thioglitazones have been documented to induce adipocytic maturation in myxoid liposarcoma; we have noted this in our experience as well. Intriguingly, we have also encountered this same phenomenon in myxoid liposarcomas exposed to various combinations of neoadjuvant doxorubicin and ifosfamide systemic chemotherapy with preoperative radiation, where the pathological effects have been less characterized. We examined the histological changes, including adipocytic maturation, associated with this treatment in patients with myxoid liposarcoma and evaluated for prognostic significance. METHODS: Twenty-two patients were identified with histologically confirmed myxoid liposarcomas (9 with variable hypercellular areas) who were treated with neoadjuvant doxorubicin (75-90 mg/m2/continous infusion over 72h every 3 week) and ifosfamide (2.5 g/m2 daily x 4 every 3 weeks) for 4-6 cycles. Twenty-one patients received pre-operative radiation including 5 with concurrent gemcitabine. Pre- and post-treatment MRI studies were compared for changes in tumor area, fat content and contrast uptake, with the latter two estimated as: none, <25%, 25-49% and >50%. Post-treatment specimens were evaluated for hyalinization, necrosis and adipocytic maturation. Clinical follow-up was obtained. RESULTS: Median age was 45 (26-72) years with a median tumor size of 11 (2-18) cm. All occurred in the lower extremities except for one case in the neck. As is common in myxoid liposarcoma, all had extensive treatment changes (>90%) with extensive hyalinization (n = 16; >90%) or prominent adipocytic maturation (n = 6; >50%) including 2 cases composed almost entirely of mature-appearing adipose tissue. Variable necrosis was identified (5-30%). MRI revealed a decrease in tumor area in all but one tumor (median, 65%), an increase in fat content in 7 tumors (n = 2, >50%;n = 2, 25-50%;n = 3,<25%), and a decrease in contrast enhancement in most tumors (n = 5, >50%; n = 9, 25-49%; n = 7, <25%). Median follow-up was 57 (12-96) months with 17 alive with no disease/metastases, 3 alive with disease and 2 dead of disease. Six patients developed metastases with median interval of 26 (22-51) months post resection. Four of 6 tumors with increased adipocytic maturation >50% on histology had increased fat detected by MRI (>25%). All 6 are alive but 2 developed metastases. In the remaining patients, 4 developed metastases with 14 alive and 2 dead of disease. CONCLUSION: Myxoid liposarcoma exposed to neoadjuvant doxorubicin and ifosfamide and pre-operative radiation can have prominent adipocytic maturation similar to trabectedin treatment. Myxoid liposarcomas exhibit extensive treatment changes with prominent hyalinization being the most common histological change. Despite this, patients develop metastases regardless of adipocytic maturation. While of unclear significance, no patient with fatty maturation died of disease.
Clinical sarcoma research. 12/2012; 2(1):25.
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[Show abstract][Hide abstract] ABSTRACT: Childbearing rates post-chemotherapy for breast cancer (BC) are affected by age and chemotherapy-type but may also depend on personal characteristics. In this single institution retrospective study we evaluated post-chemotherapy fertility and its association with offspring number and marital-status at the time of BC diagnosis. We identified 65 fertile BC patients under 38y, who received adjuvant-chemotherapy. Menses resumption and pregnancies along with offspring-number and marital-status were recorded. Menses resumed in 95.4% and 33.8% gave birth. Of those who did not give birth 46.5% had at least three children at diagnosis and of those without children 83% were unmarried. Our data associates multiparity with lower childbearing post-chemotherapy, suggesting it as a possible surrogate for women's preferences in retrospective studies. Unlike multiparity, marital status association with lower childbearing may be culture-dependent and not a universal surrogate for women's intentions and would be best investigated prospectively.
Breast (Edinburgh, Scotland) 10/2012; · 2.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: Young breast cancer patients undergoing breast-conserving surgery have a significantly higher rate of local recurrence compared with older women. The aim of this study was to assess whether the volume of tissue excised may be associated with the higher local recurrence rate seen in young patients. METHODS: Medical records of patients who underwent breast-conserving surgery at a single institution between 1987 and 2001 were reviewed retrospectively. Tumor and specimen volumes were extracted from pathology reports, and specimen-to-tumor-volume ratio (STVR) was calculated. STVR and local recurrence rates were compared for women under 40 and over 50 y of age. RESULTS: Data were available for 97 patients under age 40 and 150 women over age 50. Patients under 40 had significantly more high-grade tumors (57% versus 25%, P < 0.0005). There was no significant difference in average tumor size; however, both specimen volume and STVR (log scale) were lower in younger women: 4.63 versus 5.20, P < 0.001 and 3.81 versus 4.55, P < 0.001, respectively. Younger women also had a significantly higher rate of local recurrence: 17% versus 7%, P = 0.03. On multivariate analysis, lower STVR was significantly associated with a higher recurrence rate for the entire group (P < 0.005) and, to a lesser degree, in younger women (P = 0.05). CONCLUSIONS: The volume of tissue removed in women younger than 40 undergoing breast-conserving therapy tends to be smaller than in older women. This may contribute to the higher local recurrence rates observed in young breast cancer patients.
Journal of Surgical Research 07/2012; · 2.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gastrointestinal stromal tumors (GISTs) are driven by gain-of-function mutations of KIT or PDGFRa. The introduction of imatinib has significantly extended survival for patients. However, most patients develop resistances. Notch signaling is a conserved developmental pathway known to play a critical role in the development of several cancers, functioning as a tumor promoter or a tumor suppressor. Given that the normal progenitor cell for GIST, the interstitial cell of Cajal, has characteristics similar to those of cells of neuroendocrine origin, we hypothesized that Notch pathway impacts the biology of GIST cells. In this study, we retrovirally and pharmacologically manipulated the Notch pathway in human GIST cells. We also performed a retrospective analysis of a cohort on 15 primary tumors to determine the role of Hes1, a major target gene of Notch, as a prognostic marker for GIST. Constitutively, active intracellular domain of Notch1 (ICN1) expression potently induced growth arrest and downregulated KIT expression in vitro. Additionally, treatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid caused dose-dependent upregulation of Notch1 expression and a parallel decrease in viability in these cells. Retroviral silencing of downstream targets of Notch (dominant-negative Hes1) and pharmacological inhibition of Notch activation (γ-secretase inhibition) partially rescued GIST cells from suberoylanilide hydroxamic acid treatment. GIST patients with high Hes1 mRNA levels have a significantly longer relapse-free survival. These results identify a novel anti-tumor effect of Notch1 and cross talk between the Notch and KIT pathways. Thus, activation of this pathway by treatment with histone deacetylase inhibitors is an appealing potential therapeutic strategy for GISTs. Précis: This study is the first report of the tumor suppressor effects of Notch pathway in gastrointestinal stromal tumors via a negative feedback with the oncogene KIT and may lead the development of new therapeutic strategies for GISTs patients.
[Show abstract][Hide abstract] ABSTRACT: Myxoid liposarcoma (MLS) is a soft tissue sarcoma with adipocytic differentiation characterized by a unique chromosome rearrangement, t(12;16)(q13;p11). The exact efficacy of chemotherapy in MLS has not been clearly established.
We retrospectively analyzed the records of 37 histologically confirmed MLS patients who were treated at the University of Texas MD Anderson Cancer Center from January 2000 to December 2009 with doxorubicin 75-90 mg/m2 over 72 hours combined with ifosfamide 10 gm/m2 in the first-line setting. Response was assessed using RECIST and Choi criteria. The Kaplan-Meier method and log-rank test was used to estimate clinical outcomes.
The median follow-up period was 50.1 months. The overall response rates were 43.2% using RECIST and 86.5% using the Choi criteria. The 5-year disease-free survival rate was 90% for patients with resectable tumors. Median time to progression and overall survival time for the advanced-disease group were 23 and 31.1 months, respectively.
Our study demonstrates that doxorubicin-ifosfamide combination therapy has a role in the treatment of MLS. The Choi criteria may be more sensitive in evaluating response to chemotherapy in MLS.
[Show abstract][Hide abstract] ABSTRACT: Some of the women who undergo surgery for the removal of breast cancer will need adjuvant treatment with chemotherapy, hormonal therapy, biological therapy or radiation therapy. In patients whose tumor expresses HER2, the adjuvant treatment will include Trastuzumab. In a number of prospective randomized trials performed in recent years, Trastuzumab was proven to have a significant effect in reducing by half the incidence of the recurrence of the disease and reducing the risk of death by a third. It is important to provide Trastuzumab as early as possible, together with the chemotherapy, unless treatment with doxorubicin is needed and then Trastuzumab is given later. The most significant side effect of Trastuzumab is cardiac toxicity, which is manifested in most cases by an asymptomatic decrease of the left ventricular ejection fraction in 2.3-17.3% of patients, although in most cases this has no clinical significance. Symptomatic heart failure is a rare event in Trastuzumab treated patients, occurring in 0-4% of patients and it is generally reversible with Trastuzumab discontinuation. In this review we summarize the current perspective on Trastuzumab and discuss adjuvant treatments in HER2-positive early breast cancer.
[Show abstract][Hide abstract] ABSTRACT: Malignant peripheral nerve sheath tumour (MPNST) is a rare malignancy accounting for 3-10% of all soft tissue sarcomas. Most MPNSTs arise in association with peripheral nerves or deep neurofibromas and may originate from neural crest cells, although the specific cell of origin is uncertain. Approximately half of MPNSTs occur in the setting of neurofibromatosis type 1 (NF1), an autosomal dominant disorder with an incidence of approximately one in 3500 persons; the remainder of MPNSTs develop sporadically. In addition to a variety of clinical manifestations, approximately 8-13% of NF1 patients develop MPNSTs, which are the leading cause of NF1-related mortality. Surgical resection is the mainstay of MPNST clinical management. However, because of invasive growth, propensity to metastasise, and limited sensitivity to chemotherapy and radiation, MPNST has a guarded to poor prognosis. Five-year survival rates of only 20-50% indicate an urgent need for improved therapeutic approaches. Recent work in this field has identified several altered intracellular signal transduction cascades and deregulated tyrosine kinase receptors, posing the possibility of personalised, targeted therapeutics. However, expanded knowledge of MPNST molecular pathobiology will be needed to meaningfully apply such approaches for the benefit of afflicted patients.
Expert Reviews in Molecular Medicine 10/2009; 11:e30. · 5.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The long-term risks of in vitro fertilization (IVF) treatment remain unclear. This study was designed to determine breast cancer risk factors in women who underwent IVF, and to establish characteristics of these tumors. Records of 7,162 consecutive women who underwent IVF at a single center between 1984 and 2002 were linked with the Israel Cancer Registry to identify women who developed breast cancer. IVF-related parameters were compared between 28 breast cancer patients who had undergone IVF (IVF BC) and for whom complete IVF data were available with 140 women who underwent IVF and did not develop breast cancer (IVF non-BC). Tumor parameters were compared between 38 patients who developed breast cancer after IVF and 114 age-matched breast cancer patients who did not undergo IVF (non-IVF BC). Age over 30 at the time of first IVF treatment, even after controlling for age at first birth, was the only parameter significantly associated with increased breast cancer risk (RR = 1.24, p = 0.02, 95% CI = 1.03-1.48). There were no differences between IVF-BC and IVF non-BC patients in all other IVF-related parameters. The only statistically significant difference in tumors developing in IVF-BC patients compared with non-IVF BC patients was in grade distribution, particularly for grade II tumors. However, the significance of such a difference is unclear. Women who start IVF after the age of 30 appear to be at increased risk of developing breast cancer. The characteristics of breast tumors in women who underwent IVF are no different than in patients without previous exposure to IVF.
The Breast Journal 11/2008; 14(6):517-22. · 1.43 Impact Factor