Rahel Ghebre

A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer

BACKGROUND Natural killer (NK) cells derived from patients with cancer exhibit diminished cytotoxicity compared with NK cells from healthy individuals. We evaluated the tumor response and in vivo expansion of allogeneic NK cells in recurrent ovarian and breast cancer. METHODS Patients underwent a lymphodepleting preparative regimen: fludarabine 25 mg/m(2) × 5 doses, cyclophosphamide 60 mg/kg × 2 doses, and, in seven patients, 200 cGy total body irradiation (TBI) to increase host immune suppression. An NK cell product, from a haplo-identical related donor, was incubated overnight in 1000 U/mL interleukin (IL)-2 prior to infusion. Subcutaneous IL-2 (10 MU) was given three times/week × 6 doses after NK cell infusion to promote expansion, defined as detection of ≥100 donor-derived NK cells/μL blood 14 days after infusion, based on molecular chimerism and flow cytometry. RESULTS Twenty (14 ovarian, 6 breast) patients were enrolled. The median age was 52 (range 30-65) years. Mean NK cell dose was 2.16 × 10(7)cells/kg. Donor DNA was detected 7 days after NK cell infusion in 9/13 (69%) patients without TBI and 6/7 (85%) with TBI. T-regulatory cells (Treg) were elevated at day +14 compared with pre-chemotherapy (P = 0.03). Serum IL-15 levels increased after the preparative regimen (P = <0.001). Patients receiving TBI had delayed hematologic recovery (P = 0.014). One patient who was not evaluable had successful in vivo NK cell expansion. CONCLUSIONS Adoptive transfer of haplo-identical NK cells after lymphodepleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells. Strategies to augment in vivo NK cell persistence and expansion are needed.

A phase II study of fulvestrant in the treatment of multiply-recurrent epithelial ovarian cancer

Objective. The goal of treating recurrent ovarian cancer is disease control while minimizing toxicity. Fulvestrant, a novel estrogen receptor (ER) antagonist, has proven clinically beneficial and well-tolerated in treating recurrent breast cancer. Ovarian cancer often expresses ER and may respond to anti-estrogen therapy. We evaluated fulvestrant in women with recurrent ovarian or primary peritoneal cancer. Methods. Patients with ER-positive, multiply recurrent ovarian or primary peritoneal carcinoma and either measurable disease according to RECIST criteria or an abnormal and rising CA-125 were eligible for enrollment. Treatment consisted of single agent fulvestrant, 500 mg IM on Day 1, 250 mg IM on Day 15, and 250 mg IM on Day 29 and every 28 days thereafter until either intolerance or disease progression. Disease response was assessed by monthly physical exams and CA-125 levels as well as CT scans bimonthly. The primary endpoint was clinical benefit (CB=complete response (CR)+partial response (PR)+stable disease (SD)) at 90 days. Results. Thirty-one women were enrolled and 26 women (median age of 61) met inclusion criteria and received at least one dose. Patients had received a median of 5 prior chemotherapeutic regimens (range: 2-13). We observed one CR (4%), one PR (4%), and 9 patients with SD (35%) using modified-Rustin criteria (CA-125 level). Using modified-RECIST criteria 13 patients (50%) achieved SD. The median time to disease progression was 62 days (mean 86 days). Grade 1 toxicity included headache (1 patient) and bromidrosis (2 patients). Conclusions. Fulvestrant is well-tolerated and efficacious. Objective response rates are low, but disease stabilization was common.

Adeno-associated virus-mediated delivery of a mutant endostatin suppresses ovarian carcinoma growth in mice

Earlier studies have shown that a point mutation in human endostatin at position 125 (human endostatin wherein proline 125 was substituted with alanine, P125A-endostatin) improves endothelial cell binding and antiangiogenic activity. In the present study, we investigated the effect of recombinant adeno-associated virus (rAAV)-mediated gene delivery of P125A-endostatin (rAAV-P125Aendo) in a mouse model of ovarian carcinoma. Intramuscular (i.m.) injection of rAAV-P125Aendo resulted in a dose-dependent increase in serum endostatin levels. Consequently, vascular endothelial growth factor- and basic fibroblast growth factor-mediated angiogenesis was significantly inhibited in mice injected with rAAV-P125Aendo as compared to control mice injected with rAAV-LacZ. Furthermore, gene therapy using rAAV-P125Aendo construct showed sustained secretion of P125A-endostatin for up to 9 weeks after a single i.m. administration. Recombinant AAV-P125Aendo injection significantly inhibited the growth of human ovarian cancer cells in athymic nude mice. Immunofluorescence studies of residual tumors surgically removed from the rAAV-P125Aendo-treated animals showed decreased number of vessel ends and vessel length, indicating inhibition of angiogenesis. These studies suggest that recombinant AAV-mediated antiangiogenic gene therapy methods can be used to inhibit ovarian cancer growth.

Water-fat MRI for assessing changes in bone marrow composition due to radiation and chemotherapy in gynecologic cancer patients.

To assess the feasibility of using fat‐fraction imaging for measuring marrow composition changes over large regions in patients undergoing cancer therapy.

A prospective randomized trial of thalidomide with topotecan compared with topotecan alone in women with recurrent epithelial ovarian carcinoma

Thalidomide is an antiangiogenic agent with immune modulating potential. The objective of this study was to determine response rates among women who were treated for recurrent ovarian cancer using topotecan with or without thalidomide.

Screening for cervical cancer: a modeling study for the US Preventive Services Task Force.

Objective This study addresses the following 3 questions posed by the US Preventive Services Task Force: (1) at what age should screening for cervical cancer begin; (2) at what age should screening for cervical cancer end; and (3) how do the benefits and potential harms of screening strategies that use human papillomavirus DNA testing in conjunction with cytology (cotesting) compare with those strategies that use cytology only? Materials and Methods A Markov model was updated and used to quantify clinical outcomes (i.e., colposcopies, cancers, and life expectancy) associated with different screening strategies. Results Screening in the teenaged years is associated with a high number of colposcopies (harms), small differences in cancers detected and, as a result, small gains in life expectancy (benefits). Screening women beginning in the early 20s provides a reasonable balance of the harms and benefits of screening. Among women who have been screened according to the current recommendations for cervical cancer (beginning at age 21 years and conducted every 3 years with cytology), screening beyond 65 years is associated with small additional gains in life expectancy but large increases in colposcopies. For cotesting, a strategy of cytology only conducted every 3 years, followed by cotesting conducted every 5 years (for women ≥30 years), is associated with fewer colposcopies and greater gains in life expectancy compared with screening with cytology only conducted every 3 years. Conclusions The results of this modeling study support current US Preventive Services Task Force recommendations for cervical cancer screening.

State-of-the-science of patient navigation as a strategy for enhancing minority clinical trial accrual.

Patient navigation programs are emerging that aim to address disparities in clinical trial participation among medically underserved populations, including racial/ethnic minorities. However, there is a lack of consensus on the role of patient navigators within the clinical trial process as well as outcome measures to evaluate program effectiveness.

Cervical Cancer: Barriers to Screening in the Somali Community in Minnesota

Abstract This study examined barriers to and facilitators of cervical cancer screening among Somali immigrant women in Minnesota. We adopted the socioecological framework to illustrate screening barriers at multiple levels. We conducted 23 semi-structured key informant interviews and used a thematic exploratory approach to analyze the data. Barriers were classified into individual, community or health systems levels. Obstacles included lack of knowledge, religious beliefs, fatalism, fear, embarrassment, and lack of trust in the interpreters. Participants described a need for training of healthcare providers on issues surrounding Somali women’s cultural practices and sexual health. Identifying individual, community, or health system barriers and addressing them concurrently may increase use of cancer screening services among Somali women. Future interventions need to address multilevel barriers with multilevel approaches to improve utilization of cervical cancer screening services in underserved immigrant populations in the United States.

Cervical cancer screening with clinic-based Pap test versus home HPV test among Somali immigrant women in Minnesota: a pilot randomized controlled trial.

Cervical cancer is more common in the Somali immigrant population than the general population in the United States (US). There are low rates of cervical cancer screening among Somali women. This study compares cervical cancer screening test completion rates for a home human papilloma virus (HPV) test and standard clinic Pap test. Sixty‐three Somali immigrant women aged 30–70 years who had not undergone cervical cancer screening within the past 3 years were randomly assigned to a home HPV test group (intervention) or a clinic Pap test group (control). Test completion rates were measured at 3 months. Univariate and multivariate logistic regression models were used to explore factors associated with test completion (intention‐to‐treat analysis). Participants in the HPV test group were 14 times more likely to complete the test compared to those in the Pap test group (P = 0.0002). Women who reported having friends/family members to talk about cancer screening were approximately three times more likely to complete any screening test than those who did not (P = 0.127) and participants who reported residing in the US longer were more likely to complete a screening test (P = 0.011). Future research should explore the potential of using the home‐based HPV test kits as an initial approach to cervical cancer screening. Impact: The use of a self‐sampling HPV kit has the potential to increase cervical cancer screening in under‐served communities in the US.

A phase I feasibility study of multi-modality imaging assessing rapid expansion of marrow fat and decreased bone mineral density in cancer patients ☆

PURPOSE Cancer survivors are at an increased risk for fractures, but lack of effective and economical biomarkers limits quantitative assessments of marrow fat (MF), bone mineral density (BMD) and their relation in response to cytotoxic cancer treatment. We report dual energy CT (DECT) imaging, commonly used for cancer diagnosis, treatment and surveillance, as a novel biomarker of MF and BMD. METHODS We validated DECT in pre-clinical and phase I clinical trials and verified with water-fat MRI (WF-MRI), quantitative CT (QCT) and dual-energy X-ray absorptiometry (DXA). Basis material composition framework was validated using water and small-chain alcohols simulating different components of bone marrow. Histologic validation was achieved by measuring percent adipocyte in the cadaver vertebrae and compared with DECT and WF-MRI. For a phase I trial, sixteen patients with gynecologic malignancies (treated with oophorectomy, radiotherapy or chemotherapy) underwent DECT, QCT, WF-MRI and DXA before and 12months after treatment. BMD and MF percent and distribution were quantified in the lumbar vertebrae and the right femoral neck. RESULTS Measured precision (3mg/cm(3)) was sufficient to distinguish test solutions. Adiposity in cadaver bone histology was highly correlated with MF measured using DECT and WF-MRI (r=0.80 and 0.77, respectively). In the clinical trial, DECT showed high overall correlation (r=0.77, 95% CI: 0.69, 0.83) with WF-MRI. MF increased significantly after treatment (p<0.002). Chemotherapy and radiation caused greater increases in MF than oophorectomy (p<0.032). L4 BMD decreased 14% by DECT, 20% by QCT, but only 5% by DXA (p<0.002 for all). At baseline, we observed a statistically significant inverse association between MF and BMD which was dramatically attenuated after treatment. CONCLUSION Our study demonstrated that DECT, similar to WF-MRI, can accurately measure marrow adiposity. Both imaging modalities show rapid increase in MF following cancer treatment. Our results suggest that MF and BMD cannot be used interchangeably to monitor skeletal health following cancer therapy.