Ossama Tawfik

Breast Conservation Therapy with Tumor Bed Irradiation Alone in a Selected Group of Patients with Stage I Breast Cancer

Abstract: Radiotherapy after breast‐conserving surgery increases local control. We tested the feasibility of limited surgery with tumor bed irradiation only with 192Ir in a selected group of patients with stage I breast cancer. Twenty‐five breasts in 24 women more than 60 years old with low‐ or intermediate‐grade stage I tumors were treated with placement of interstitial catheters at the time of lumpectomy and axillary node dissection. This procedure was followed by after‐loading with low‐dose 192Ir to deliver 20–25 Gy to the tumor bed over 24–48 hours. There were neither local recurrences in the breast nor distant recurrences at a median follow‐up of 47 months (range 25–90 months). Cosmetic appearance ranged from very good to excellent. There were no long‐term complications. It is feasible to treat a select group of patients with tumor bed irradiation, using relatively low doses of interstitial irradiation, with excellent local control and no significant morbidity.

Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet.

Nonalcoholic steatohepatitis (NASH) comprises dysregulation of lipid metabolism and inflammation. Identification of the various genetic and environmental susceptibility factors for NASH may provide novel treatments to limit inflammation and fibrosis in patients. This study utilized a mouse model of hypercholesterolemia, low-density lipoprotein receptor knockout (LDLr-/-) mice fed a high-fat diet for 5 months, to test the hypothesis that farnesoid X receptor (FXR) deficiency contributed to NASH development. Either the high-fat diet or FXR deficiency increased serum alanine aminotransferase activity, whereas only FXR deficiency increased bile acid and alkaline phosphatase levels. FXR deficiency and high-fat feeding increased serum cholesterol and triglycerides. Although high fat led to macrosteatosis and hepatocyte ballooning in livers of mice regardless of genotype, no inflammatory infiltrate was observed in the livers of LDLr-/- mice. In contrast, in the livers of LDLr-/-/FXR-/- mice, foci of inflammatory cells were observed occasionally when fed the control diet and were greatly increased when fed the high-fat diet. Consistent with enhanced inflammatory cells, hepatic levels of tumor necrosis factor α and intercellular adhesion molecule-1 mRNA were increased by the high-fat diet in LDLr-/-/FXR-/- mice. In agreement with elevated levels of procollagen 1α1 and TGF-β mRNA, type 1 collagen protein levels were increased in livers of LDLr-/-/FXR-/- mice fed a high-fat diet. In conclusion, FXR deficiency induces pathologic manifestations required for NASH diagnosis in a mouse model of hypercholesterolemia, including macrosteatosis, hepatocyte ballooning, and inflammation, which suggest a combination of FXR deficiency and high-fat diet is a risk factor for NASH development, and activation of FXR may be a therapeutic intervention in the treatment of NASH.

Evidence for coordinated interaction of cyclin D3 with p21 and cdk6 in directing the development of uterine stromal cell decidualization and polyploidy during implantation

Uterine decidualization, characterized by stromal cell proliferation, and differentiation into specialized type of cells (decidual cells) with polyploidy, during implantation is critical to the pregnancy establishment in mice. The mechanisms by which the cell cycle events govern these processes are poorly understood. The cell cycle is tightly regulated at two particular checkpoints, G1-S and G2-M phases. Normal operation of these phases involves a complex interplay of cyclins, cyclin-dependent kinases (cdks) and cdk inhibitors (CKIs). We previously observed that upregulation of uterine cyclin D3 at the implantation site is tightly associated with decidualization in mice. To better understand the role of cyclin D3 in this process, we examined cell-specific expression and associated interactions of several cell cycle regulators (cyclins, cdks and CKIs) specific to different phases of the cell cycle during decidualization in mice. Among the various cell cycle molecules examined, coordinate expression and functional association of cyclin D3 with cdk4 suggest a role for proliferation and, that of cyclin D3 with p21 and cdk6 is consistent with the development of polyploidy during stromal cell decidualization.

Malignant Peripheral Nerve Sheath Tumor With Rhabdomyosarcomatous Differentiation (Malignant Triton Tumor)

Malignant peripheral nerve sheath tumors arise from Schwann cells or within existing neurofibromas and have a strong association with type 1 neurofibromatosis. These tumors are histologically diverse and may contain malignant areas of divergent mesenchymal differentiation, the most common of which is skeletal muscle (rhabdomyosarcoma). Malignant peripheral nerve sheath tumor with rhabdomyosarcomatous differentiation is also known as malignant triton tumor. Malignant triton tumor has a worse prognosis than classic malignant peripheral nerve sheath tumor does, and the correct diagnosis requires attention to the clinical history and knowledge of the complexities regarding its differential diagnosis. In this review we discuss the clinical, histopathological, immunohistochemical, and prognostic features of this rare neoplasm.

Esthesioneuroblastoma: endoscopic nasal and anterior craniotomy resection.

Objectives/Hypothesis The objective was to illustrate the use of endoscopic techniques as an evolving surgical modality in excision of esthesioneuroblastoma. The authors advocate this method with excision with anterior craniotomy for removal of cribriform plate or anterior cranial fossa tumor extension.

Breast cancer chemoprevention phase I evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator

Purpose: Arzoxifene, a new selective estrogen receptor modulator with strong breast antiestrogen activity and absence of uterine agonist activity, was explored as a potential chemoprevention agent. We performed a multi-institutional evaluation of arzoxifene in women with newly diagnosed ductal carcinoma in situ or T1/T2 invasive cancer. Experimental Design: In a Phase IA trial, 50 pre- or postmenopausal women were randomized to 10, 20, or 50 mg of arzoxifene daily in the interval between biopsy and re-excision or were enrolled as no-treatment controls. In a Phase IB trial, 76 postmenopausal women were randomized to 20 mg of arzoxifene versus matched placebo. Serum specimens collected at entry and at re-excision were assayed for various hormones and growth factors. Tissue from biopsies (estrogen receptor + and/or progesterone receptor +) and re-excision specimens was evaluated immunohistochemically for proliferation (Ki-67 by MIB-1 and proliferating cell nuclear antigen) and other biomarkers. Results: In both trials, increases in serum sex hormone binding globulin were noted, as were decreases in insulin-like growth factor (IGF)-I and the IGF-I:IGF binding protein-3 ratio (P < 0.007 versus control/placebo). For 45 evaluable women in Phase IA, decreases in proliferation indices were more prevalent for arzoxifene (particularly 20 mg) than for controls. For 58 evaluable women in Phase IB, a decrease in estrogen receptor expression for arzoxifene was observed compared with no change with placebo (P = 0.0068). However, decreases in proliferation indices for arzoxifene were not statistically different from placebo, perhaps due to a confounding effect of stopping hormone replacement therapy before entry. Conclusion: Given the favorable side effect profile and the biomarker modulations reported here, arzoxifene remains a reasonable candidate for additional study as a breast cancer chemoprevention agent.

Small cell undifferentiated (neuroendocrine) carcinoma of the uterine cervix

BACKGROUND Small cell undifferentiated (neuroendocrine) carcinoma of the cervix is a rare and agressive tumor. Most medical centers have little experience with this tumor. The purposes of our study were to evaluate our experience and compare our findings with those reported in current literature. STUDY DESIGN Fifteen patients with small cell undifferentiated carcinoma of the cervix were treated between 1977 and 1997. Clinical data including age, pregnancy history, tumor stage, recurrence, type of therapy, presenting symptoms, location of metastasis, and survival were studied. RESULTS The ages of patients ranged from 20 to 83 years, with a mean of 47 years. Two patients were nulliparous, 2 primiparous, and 11 multiparous. Five patients (33%) were stage I, three (20%) stage II, one (7%) stage III, and six (40%) stage IV at diagnosis. Five patients (33%) progressed without response to treatment, and seven (47%) experienced a recurrence of their cancer, on average after 15 months. Treatments included surgery, radiation, chemotherapy, or a combination of them. Extrapelvic metastases developed in five patients with stage I or stage II disease. Three patients (20%) developed brain metastasis. Tumor lysis syndrome was encountered in one patient. Thirteen patients died of their disease, one remained alive 80 months after diagnosis, and one was lost to followup. CONCLUSIONS Our experience with this rare and aggressive tumor raises the question of increased incidence of central nervous system metastases with small cell undifferentiated carcinoma. Present therapy has not significantly improved outcomes. Tumor lysis syndrome is a possible risk when treating these patients.

A comparison of prognostic tumor markers obtained on image-guided breast biopsies and final surgical specimens

BACKGROUND This study was initiated to determine whether tumor markers obtained on image-guided breast biopsy specimens provide accurate prognostic information for women with invasive breast cancer. METHODS Prognostic tumor markers on preoperative image-guided biopsy and final surgical specimens were compared in 44 patients with invasive breast cancer. RESULTS Progesterone receptor (PR) discordance was 18%. In 87% of PR discordant cases, the image-guided biopsy was positive and the final specimen was negative (P = 0.03). Tumor grade was discordant in 36% of patients Discordance for estrogen receptor (ER) = 2%; MIB-1 = 18%; Her2/neu = 9%; EGFR = 10%; p53 = 9%; and bcl-2 = 0%. The discordance for these markers was random and did not reach statistical significance. CONCLUSION Image-guided core needle biopsies provide reliable information for the majority of prognostic tumor makers. A positive progesterone receptor is significantly more likely to be determined by core biopsy rather than the final surgical specimen. Tumor grade should be based upon the final surgical specimen whenever possible.

WISP-2 Gene in Human Breast Cancer: Estrogen and Progesterone Inducible Expression and Regulation of Tumor Cell Proliferation

WISP-2 mRNA and protein was overexpressed in preneoplastic and cancerous cells of human breast. Statistical analyses show a significant association between WISP-2 expression and estrogen receptor (ER) positivity. In normal breast, the expression was virtually undetected. The studies showed that WISP-2 is an estrogen-induced early response gene in MCF-7 cells and the expression was continuously increased to reach a maximum level at 24 h. The estrogen effect was inhibited by a pure antiestrogen (ICI 182,780). Human mammary epithelial cells, in which WISP-2 expression was undetected or minimally detected, responded to 17beta-estradiol by upregulating the WISP-2 gene after transfection with ER-alpha, providing further evidences that WISP-2 expression is mediated through ER-alpha. Overexpression of WISP-2 mRNA by estrogen may be accomplished by both transcriptional activation and stabilization. MCF-7 cells exposed to progesterone had a rapid but transient increase in WISP-2 expression, and PR antagonist RU38486 blocked this mRNA induction. In combination with estradiol, progesterone acted as an antagonist inhibiting the expression of WISP-2 mRNA. Moreover, disruption of WISP-2 signaling in MCF-7 cells by use of antisense oligomers caused a significant reduction in tumor cell proliferation. The results are consistent with the conclusion that WISP-2 expression is a requirement for breast tumor cells proliferation.

Ploidy differences between hormone- and chemical carcinogen–induced rat mammary neoplasms: Comparison to invasive human ductal breast cancer*

To ascertain differences between solely hormone– and chemical carcinogen–induced murine mammary gland tumors (MGTs), a direct comparison of their ploidy status was assessed. Nuclear image cytometry (NIC) was used to evaluate ploidy in ductal carcinoma in situ (DCIS) and MGTs induced solely by 17β‐estradiol (E2) in female A‐strain Copenhagen Irish hooded gene rats (ACI) and E2 plus testosterone propionate in male Noble rats. These results were compared to ploidy data from primary MGTs induced by two synthetic carcinogens, 7,12‐dimethylbenz[a]antracene and nitrosomethylurea in female Brown Lewis Norway rats and an environmental carcinogen, 6‐nitrochrysene, in female Sprague‐Dawley rats. Both DCIS and primary MGTs induced solely by hormones were highly aneuploid (> 84%), whereas MGTs induced by either synthetic or environmental carcinogens were primarily diploid (> 85%). Examination of 76 metaphase plates obtained from eight individual E2‐induced ACI female rat MGTs revealed the following consistent chromosome alterations: gains in chromosomes 7, 11, 12, 13, 19, and 20 and loss of chromosome 12. On Southern blot analysis, six of nine ACI female rat primary E2‐induced MGTs (66%) exhibited amplified copy numbers (range: 3.4–6.9 copies) of the c‐myc gene. Fluorescence in situ hybridization (FISH) analysis of these MGTs revealed specific fluorescent hybridization signals for c‐myc (7q33) on all three homologs of a trisomy in chromosome 7. NIC analysis of 140 successive nonfamilial sporadic invasive human ductal breast cancers (BCs) showed an aneuploid frequency of 61%, while 31 DCISs revealed a 71% aneuploid frequency. These results clearly demonstrate that the female ACI rat E2‐induced MGTs more closely resemble invasive human DCIS and ductal BC in two pertinent aspects: they are highly aneuploid compared with chemical carcinogen–induced MGTs and exhibit a high frequency of c‐myc amplification.