Rouba Ali-Fehmi

Harper University Hospital, Detroit, Michigan, United States

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Publications (117)425.23 Total impact

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    ABSTRACT: PTEN is known to be frequently mutated in uterine cancer and also dephosphorylates FAK. Here, we examined the impact of PTEN alterations on the response to treatment with a FAK inhibitor (GSK2256098). In vitro and in vivo therapeutic experiments were carried out using PTEN mutated and PTEN-wild type models of uterine cancer alone and in combination with chemotherapy. Treatment with GSK2256098 resulted in greater inhibition of pFAKY397 in PTEN-mutated (Ishikawa) than in PTEN-wild type (Hec1A) cells. Ishikawa cells were more sensitive to GSK2256098 than the treated Hec1A cells. Ishikawa cells were transfected with a wild-type PTEN construct and pFAKY397 expression was unchanged after treatment with GSK2256098. Decreased cell viability and enhanced sensitivity to chemotherapy (paclitaxel and topotecan) in combination with GSK2256098 was observed in Ishikawa cells as compared to Hec1a cells. In the Ishikawa orthoptopic murine model, treatment with GSK2256098 resulted in lower tumor weights and fewer metastases than mice inoculated with Hec1A cells. Tumors treated with GSK2256098 had lower microvessel density (CD31), less cellular proliferation (Ki67), and higher apoptosis (TUNEL) rates in the Ishikawa model when compared to the Hec1a model. From a large cohort of evaluable patients, increased FAK and pFAKY397 expression levels were significantly related to poor overall survival. Moreover, PTEN levels were inversely related to pFAKY397 expression. These preclinical data demonstrate that PTEN-mutated uterine cancer responds better to treatment FAK inhibition than does PTEN wild-type cancer. Therefore, PTEN could be a biomarker for predicting response to FAK-targeted therapy during clinical development. Copyright © 2015, American Association for Cancer Research.
    Molecular Cancer Therapeutics 04/2015; DOI:10.1158/1535-7163.MCT-14-1077 · 6.11 Impact Factor
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    ABSTRACT: A new 3-tier pattern-based system to classify endocervical adenocarcinoma was recently presented. In short, pattern A tumors were characterized by well-demarcated glands frequently forming clusters or groups with relative lobular architecture. Pattern B tumors demonstrated localized destructive invasion defined as desmoplastic stroma surrounding glands with irregular and/or ill-defined borders or incomplete glands and associated tumor cells (individual or small clusters) within the stroma. Tumors with pattern C showed diffusely infiltrative glands with associated extensive desmoplastic response. In total, 352 cases (all FIGO stages) from 12 institutions were identified. Mean patient age was 45 years (range, 20 to 83 y). Forty-nine (13.9%) cases demonstrated lymph nodes (LNs) with metastatic endocervical carcinoma. Using this new system, 73 patients (20.7%) were identified with pattern A tumors (all stage I); none had LN metastases and/or recurrences. Ninety patients (25.6%) were identified with pattern B tumors (all stage I); only 4 (4.4%) had LN metastases; 1 had vaginal recurrence. The 189 (53.7%) remaining patients had pattern C tumors; 45 (23.8%) of them had LN metastases. This new classification system demonstrated 20.7% of patients (pattern A) with negative LNs, and patients with pattern A tumors can be spared of lymphadenectomy. Patients with pattern B tumors rarely presented with metastatic LNs, and sentinel LN examination could potentially identify these patients. Aggressive treatment is justified in patients with pattern C tumors.
    American Journal of Surgical Pathology 02/2015; 39(5). DOI:10.1097/PAS.0000000000000402 · 4.59 Impact Factor
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    ABSTRACT: Cervical adenocarcinomas (ADC) have been viewed as more aggressive than squamous cell carcinoma (SCC). We analyzed an international cohort of early stage cervical cancer to determine the impact of histologic type. Retrospective analysis of patients with SCC (148 patients) and ADC (130 patients) stages IA1-IB2 who underwent surgery at our three institutions (two from Detroit, one from Mexico) from 2000-2010 was performed for: age, stage, tumor size, lymphovascular invasion (LVI), invasion depth, lymph node status (LN), recurrence and survival. Pathologic review proceeded inclusion. In the Latino population, ADC's tended to be higher grade (p=0.01), while SCC's were larger with deeper invasion (p<0.001). LVI and LN were not significantly different. Recurrence rate (RR) was 8% (8/101) in ADC and 11.8% (9/76) in SCC's. 5 year survival (OS) was equivalent (98.2% and 95.2% for ADC and SCC respectively, p=0.369). In the Detroit cohort, we noted no difference in size, grade, depth of invasion, LVI, LN. RR was 8/72 (13.7%) for SCC and 4/29 (13.7%) but not statistically different between the tumor types (p=0.5). 5 year survival was 91% and 92% for ADC and SCC, respectively. In this population 33% of the patients with SCC and 34% of the patients with ADC received adjuvant chemo-radiation (p=0.4). Histologic type demonstrated no significant outcome difference for any type of adjuvant therapy.Conclusion Comparing early stage disease of cervical ADC and SCC suggests equivalent recurrence and survival. therefore, the paradigm of more aggressive management of early stage cervical ADC warrants further investigation. Copyright © 2015. Published by Elsevier Inc.
    Gynecologic Oncology 02/2015; DOI:10.1016/j.ygyno.2015.02.005 · 3.69 Impact Factor
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    ABSTRACT: To determine the impact of adjuvant chemotherapy or pelvic radiation on risk of recurrence and outcome in stage IA non-invasive uterine papillary serous carcinoma (UPSC).
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    ABSTRACT: To investigate the impact of adjuvant vaginal brachytherapy on vaginal recurrence in stage I non-invasive uterine papillary serous carcinoma (UPSC). This is a retrospective multi-institutional study from 2000-2012. 103 patients who underwent surgical treatment with non-invasive stage IA UPSC were included. 85% and 55% underwent staging lymphadenectomy and omentectomy. 28.2% (29/103) developed recurrence. Vaginal, pelvic and extra-pelvic recurrences developed in 7.8% (8/103), 3.9% (4/103) and 16.5% (17/103) respectively. Among patients who were observed or received only chemotherapy, the rate of vaginal recurrence was 10.9% (7/64) compared to 2.6% (1/39) among those who received vaginal brachytherapy +/- chemotherapy (p=0.035). The rate of vaginal recurrence was not different between those who were observed and those who received only chemotherapy (9.3% vs. 14.3%, p=0.27). The 5-year progression free (PFS) and overall survival (OS) for the entire cohort were 88.3% and 90.6%. Patients who underwent surgical staging had longer PFS (p=0.001) and OS (p=0.0005) compared to those who did not. In multivariable analysis controlling for age, chemotherapy, brachytherapy, and staging lymphadenectomy, only lymphadenectomy was an independent predictor of PFS (HR 0.28, 95% CI 0.11-0.71, p=0.0037) and OS (HR 0.27, 95% CI 0.10-0.71, p=0.0035). Neither chemotherapy nor brachytherapy was a predictor of PFS or OS. This is the largest study reported in stage I non-invasive UPSC. The majority of recurrences were extra-pelvic. Vaginal brachytherapy has a significant role in reducing the risk of vaginal recurrence and surgical staging was the only predictor of outcome. Therefore, both should be considered in these patients. Copyright © 2014 Elsevier Inc. All rights reserved.
    Gynecologic Oncology 01/2015; DOI:10.1016/j.ygyno.2014.12.034 · 3.69 Impact Factor
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    ABSTRACT: To analyze the clinical significance of the extent of lymphovascular space invasion (LVI) in patients with uterine serous carcinoma. After IRB approval, 232 patients with uterine serous carcinoma from the pathology databases of 4 large academic institutions were included. Patients were divided into 3 groups based on extent of LVI. Extensive LVI (E-LVI) was defined as ≥3 vessel involvement; low LVI (L-LVI) was defined <3 vessel involvement; and the third group consisted of tumors with no LVI (A-LVI). The association between LVI and myometrial invasion, cervical involvement, lower uterine segment involvement, positive peritoneal washings, lymph node involvement, stage, and survival were analyzed. Of 232 patients, 47 had E-LVI (20.3%), 83 had L-LVI (35.8%), and 102 had A-LVI (44%). A total of 9.8% of the patients with A-LVI had lymph node involvement as compared with 18.1% in the L-LVI group and 55.4% in the E-LVI group (P<0.0001). Fifty-nine percent of the patients in A-LVI, 85% in L-LVI, and 100% in the E-LVI group demonstrated myometrial invasion (P<0.0001). Cervical involvement was noted in 23%, 43%, 66% (P<0.0001) and lower uterine segment involvement involvement in 31%, 43%, and 42% of A-LVI, L-LVI, and E-LVI (P<0.0001), respectively. Stage III and IV disease were seen in 29%, 38%, and 79% of the patients with A-LVI, L-LVI, and E-LVI, respectively (P<0.0001). The median overall survival was 172, 95, and 39 mo for the A-LVI, L-LVI, and E-LVI groups, respectively (P<0.0001). The racial distribution was significant with African American patients demonstrating significantly more L-LVI (27.8%) and E-LVI (40.4%) when compared with A-LVI (19.6%) (P=0.040). In a subgroup analysis including patients with Stage I and II (n=123) revealed median survivals of 172, 169, and 38 mo in the A-LVI, L-LVI, and E-LVI groups, respectively (P<0.0001). Fifty percent of these patients with E-LVI, 20% in L-LVI group, and 15% in A-LVI group had disease recurrence (P=0.040). The extent of LVI was associated with multiple pathologic factors and was found to be a negative prognostic factor for overall survival and disease recurrence.
    International Journal of Gynecological Pathology 01/2015; 34(1):47-56. DOI:10.1097/PGP.0000000000000113 · 1.63 Impact Factor
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    ABSTRACT: To analyze the impact of tumor size (TS) on risk of lymph node metastasis (PLN) and prognosis in endometrioid endometrial cancer grossly confined to the uterus (EEC). Patients with EEC grossly confined to the uterus were identified from Surveillance, Epidemiology, and End Results dataset from 1988 to 2007. Only surgically treated patients were included. TS was analyzed as a continuous and categorical variable (TS ≤ 2 cm, >2-5 cm and >5 cm). Multivariable logistic regression and Cox proportional hazards models were used. 19,692 patients met the inclusion criteria. In patients with TS ≤ 2 cm, only 2.7 % (88/3,244) had PLN; this increased to 5.8 % (372/6,355) with TS > 2-5 cm and 11.1 % (195/1,745) with TS > 5 cm. The odds of PLN increased by 14 % for each 1 cm increase in TS after controlling for age, race, depth of myometrial invasion and grade (HR 1.14, 95 % CI 1.10-1.19, p < 0.001). Further, TS was an independent predictor of disease-specific survival (DSS) even after adjusting for age, race, grade, depth of myometrial invasion, lymph node status and adjuvant radiation therapy (HR 1.13 for each 1 cm increment in TS, 95 % 1.08-1.18, p < 0.001). In multivariable analysis, larger TS (>5 cm) was significantly associated with worse DSS (HR 2.09, 95 % 1.31-3.35, p = 0.002); however, there was no significant difference between TS > 2-5 cm versus ≤2 cm (HR 1.25, 95 % 0.85-1.83, p = 0.25). The impact of TS remained significant on DSS in subset of patients who underwent lymphadenectomy with negative lymph nodes. TS was an independent predictor of lymph node metastasis and disease-specific survival in patients with EEC grossly confined to the uterus. Tumor >5 cm was a predictor of disease-specific survival but no difference in outcome was noted between tumor >2-5 cm and tumor ≤2 cm.
    Archives of Gynecology and Obstetrics 12/2014; DOI:10.1007/s00404-014-3609-6 · 1.28 Impact Factor
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    ABSTRACT: The incidence of endometrial cancers diagnosed on biopsy that have no residual cancer identified at hysterectomy is not well studied. The aim of our study was to determine the incidence and long-term follow-up of this "vanishing cancer" phenomenon. All slides from the initial biopsy/curettage and hysterectomy specimens were reviewed and the diagnosis confirmed by a gynecologic pathologist. The entire endometrium was serially sectioned and submitted for histologic examination. Clinical and pathologic variables were analyzed, including patient demographics, tumor histologic type and grade, stage, biopsy method, adjuvant therapy, surgical procedure, recurrence, and disease-specific survival. We identified 23 biopsy-proven cases of endometrial cancer with no residual disease on hysterectomy specimen. Of the 23 patients, 15 (65.2%) were diagnosed as endometrioid, 6 (26%) serous, 1 clear cell (4.3%), and 1 (4.3%) serous intraepithelial carcinoma. Seventeen underwent dilatation and curettage, and 6 had endometrial biopsy as the primary procedure. The median follow-up was 8.8 years (range, 1.2 to 17 y). Only 2 cases with serous carcinoma underwent adjuvant chemotherapy, and none received radiation therapy. Only 1 patient died of disease after 27 months and was diagnosed as FIGO grade II endometrioid carcinoma on dilatation and curettage. The inability to identify cancer in a hysterectomy specimen for biopsy-confirmed carcinoma does not indicate technical failure. Although there is no specific standard treatment for patients with "vanishing endometrial cancer," the prognosis is excellent; however, close follow-up is suggested.
    American Journal of Surgical Pathology 12/2014; 39(2). DOI:10.1097/PAS.0000000000000361 · 4.59 Impact Factor
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    ABSTRACT: /Objective(s): There is paucity of data in regards to prognostic factors and outcome of women with 2009 FIGO stage II disease. The objective of this study was to investigate prognostic factors, recurrence patterns and survival endpoints in this group of patients. /Methods: Data from four academic institutions were analyzed. 130 women were identified with 2009 FIGO stage II. All patients underwent hysterectomy, oophorectomy and lymph node evaluation with or without pelvic and paraaortic lymph node dissection and peritoneal cytology. The Kaplan-Meier approach and Cox regression analysis were used to estimate recurrence-free (RFS), disease-specific (DSS) and overall survival (OS). Median follow-up was 44months. 120 patients (92%) underwent simple hysterectomy, 78% had lymph node dissection and 95% had peritoneal cytology examination. 99 patients (76%) received adjuvant radiation treatment (RT). 5-year RFS, DSS and OS was 77%, 90%, and 72%, respectively. On multivariate analysis of RFS, adjuvant RT, the presence of lymphovascular space invasion (LVSI) and high tumor grades were significant predictors. For DSS, LVSI and high tumor grades were significant predictors while older age and high tumor grade were the only predictors of OS. In this multi-institutional study, disease-specific survival for women with FIGO stage II uterine endometrioid carcinoma is excellent. High tumor grade, lymphovascular space involvement, adjuvant radiation treatment and old age are important prognostic factors. There was no significant difference in outcome between patients who received vaginal cuff brachytherapy compared to those received pelvic external beam radiation treatment. Copyright © 2014. Published by Elsevier Inc.
    Gynecologic Oncology 12/2014; 136(2). DOI:10.1016/j.ygyno.2014.12.012 · 3.69 Impact Factor
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    ABSTRACT: A high energy balance, or caloric excess, accounts as a tumor promoting factor, while a negative energy balance via caloric restriction, has been shown to delay cancer progression. The effect of energy balance on ovarian cancer progression was investigated in an isogeneic immunocompetent mouse model of epithelial ovarian cancer kept on a regimen of regular diet, high energy diet (HED) and calorie restricted diet (CRD), prior to inoculating the animals intraperitoneally with the mouse ovarian surface epithelial ID8 cancer cells. Tumor evaluation revealed that mice group on HED displayed the most extensive tumor formation with the highest tumor score at all organ sites (diaphragm, peritoneum, bowel, liver, kidney, spleen), accompanied with increased levels of insulin, leptin, insulin growth factor-1 (IGF-1), monocyte chemoattractant protein-1 (MCP-1), VEGF and interleukin 6 (IL-6). On the other hand, the mice group on CRD exhibited the least tumor burden associated with a significant reduction in levels of insulin, IGF-1, leptin, MCP-1, VEGF and IL-6. Immunohistochemistry analysis of tumors from HED mice showed higher activation of Akt and mTOR with decreased adenosine monophosphate activated kinase (AMPK) and SIRT1 activation, while tumors from the CRD group exhibited the reverse profile. In conclusion, ovarian cancer growth and metastasis occurred more aggressively under HED conditions and was significantly curtailed under CRD. The suggested mechanism involves modulated secretion of growth factors, cytokines and altered regulation of AMPK and SIRT1 that converges on mTOR inhibition. While the role of a high energy state in ovarian cancer has not been confirnmed in the literature, the current findings support investigating the potential impact of diet modulation as adjunct to other anticancer therapies and as possible individualized treatment strategy of epithelial ovarian cancer.
    Oncotarget 07/2014; 5(15). · 6.63 Impact Factor
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    ABSTRACT: There are known disparities in endometrial cancer survival with black women experiencing a greater risk of death compared to white women. The purpose of this investigation was to evaluate the role of comorbid conditions as modifiers of endometrial cancer survival by race.
    American Journal of Obstetrics and Gynecology 06/2014; DOI:10.1016/j.ajog.2014.06.036 · 3.97 Impact Factor
  • Gynecologic Oncology 06/2014; 133:174. DOI:10.1016/j.ygyno.2014.03.458 · 3.69 Impact Factor
  • Gynecologic Oncology 06/2014; 133:95. DOI:10.1016/j.ygyno.2014.03.252 · 3.69 Impact Factor
  • Gynecologic Oncology 06/2014; 133:87. DOI:10.1016/j.ygyno.2014.03.233 · 3.69 Impact Factor
  • Gynecologic Oncology 06/2014; 133:184-185. DOI:10.1016/j.ygyno.2014.03.489 · 3.69 Impact Factor
  • Gynecologic Oncology 06/2014; 133:159-160. DOI:10.1016/j.ygyno.2014.03.421 · 3.69 Impact Factor
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    ABSTRACT: Objective Endometrial cancer mortality disproportionately affects black women and whether greater prevalence of obesity plays a role in this disparity is unknown. We examine the effect of race on post-surgical complications, length of stay, and mortality specifically in a morbidly obese population. Methods Black and white women with endometrial cancer diagnosed from 1996 to 2012 were identified from the University Pathology Group database in Detroit, Michigan, and records were retrospectively reviewed to obtain clinicopathological, demographic, and surgical information. Analysis was limited to those with a body mass index of 40 kg/m2 or greater. Differences in the distribution of variables by race were assessed by chi-squared tests and t-tests. Kaplan–Meier and Cox regression analyses were performed to examine factors associated with mortality. Results 97 white and 89 black morbidly obese women were included in this analysis. Black women were more likely to have type II tumors (33.7% versus 15.5% of white women, p-value = 0.003). Hypertension was more prevalent in black women (76.4% versus 58.8%, p-value = 0.009), and they had longer hospital stays after surgery despite similar rates of open vs minimally invasive procedures and lymph node dissection (mean days = 5.4) compared to whites (mean days = 3.5, p-value = 0.036). Wound infection was the most common complication (16.5% in whites and 14.4% in blacks, p-value = 0.888). Blacks were more likely to suffer other complications, but overall the proportions did not differ by race. In univariate analyses, black women had higher risk of endometrial cancer-related death (p-value = 0.090). No racial differences were noted in adjusted survival analyses. Conclusion A more complete investigation, incorporating socio-demographic factors, is warranted to understand the effects of morbid obesity and race on endometrial cancer.
    Gynecologic Oncology 04/2014; 133(1):38–42. DOI:10.1016/j.ygyno.2014.01.013 · 3.69 Impact Factor
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    ABSTRACT: Endometrial adenocarcinoma is the most common gynecologic cancer in the United States. The prognosis is generally favorable, however, a significant number of patients do develop local or distant recurrence. The most common site of recurrence is vaginal. Our aim was to better characterize patients with vaginal recurrence of low-grade endometrioid adenocarcinoma with respect to associated tumor parameters and clinical outcome. We compiled 255 cases of low-grade (FIGO Grade I or II) endometrioid adenocarcinoma on hysterectomy specimens with lymph node dissection. A total of 113 cases with positive lymph nodes or recurrent disease were included in our study group. Seventy-three cases (13 Grade 1, 60 Grade 2) developed extravaginal recurrence and 40 cases (7 Grade 1, 33 Grade 2) developed vaginal recurrence. We evaluated numerous tumor parameters including: percentage myoinvasion, presence of microcystic, elongated, and fragmented pattern of myoinvasion, lymphovascular space invasion, and cervical involvement. Clinical follow-up showed that 30% (34/113) of all patients with recurrent disease died as a result of their disease during our follow-up period, including 31 (42.5%) with extravaginal recurrence and 3 (7.5%) with primary vaginal recurrence (P=0.001). The 3 patients with vaginal recurrence developed subsequent extravaginal recurrence before death. Vaginal recurrence patients show increased cervical involvement by tumor, but lack other risk factors associated with recurrent disease at other sites. There were no deaths among patients with isolated vaginal recurrence, suggesting that vaginal recurrence is not a marker of aggressive tumor biology.
    International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 03/2014; 33(3). DOI:10.1097/PGP.0b013e31829c6757 · 1.63 Impact Factor
  • Cancer Research 03/2014; 73(24 Supplement):P4-15-07-P4-15-07. DOI:10.1158/0008-5472.SABCS13-P4-15-07 · 9.28 Impact Factor
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Publication Stats

1k Citations
425.23 Total Impact Points

Institutions

  • 2004–2015
    • Harper University Hospital
      Detroit, Michigan, United States
  • 2003–2015
    • Wayne State University
      • • Department of Pathology
      • • Department of Obstetrics and Gynecology
      Detroit, Michigan, United States
  • 2007–2014
    • Karmanos Cancer Institute
      • Division of Hematology and Oncology
      Detroit, Michigan, United States
  • 2013
    • University of Texas MD Anderson Cancer Center
      • Department of Thoracic Head Neck Medical Oncology
      Houston, TX, United States