Ex vivo culture of mouse skin activates an interleukin 1 alpha-dependent inflammatory response.

Ex vivo culture of mouse and human skin causes an inflammatory response characterized by production of multiple cytokines. We used ex vivo culture of mouse tail skin specimens to investigate mechanisms of this skin culture-induced inflammatory response. Multiplex assays revealed production of interleukin 1 alpha (IL-1α), interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), chemokine C-X-C motif ligand 1 (CXCL1), granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) during skin culture, and quantitative PCR revealed transcripts for these proteins were also increased. Ex vivo cultures of skin from myeloid differentiation primary response 88 deficient mice (Myd88-/- ) demonstrated significantly reduced expression of transcripts for the aforementioned cytokines. The same result was observed with skin from interleukin 1 receptor type 1 deficient mice (Il1r1-/- ). These data suggested the IL-1R1/MyD88 axis is required for the skin culture-induced inflammatory response and led us to investigate the role of IL-1α and IL-1ß (the ligands for IL-1R1) in this process. Addition of IL-1α neutralizing antibody to skin cultures significantly reduced expression of Cxcl1, Il6 and Csf3. IL-1ß neutralization did not reduce levels of these transcripts. These studies suggest that IL-1α promotes the skin the culture-induced inflammatory response.

Long-term primary culture of a clear cell ovarian carcinoma reveals an epithelial-mesenchymal cooperative interaction.

BACKGROUND: We studied a primary culture developed from a biopsy of a clear cell carcinoma of the ovary (O-CCC) by (a) assessing its capacity to retain in vitro pathological features of the tumor of origin; (b) characterizing the main cells released from the complex mass without forced purification of any particular cellular entity; and (c) investigating its long-term proliferative capacity. METHODS: A primary cell culture was developed from a pelvic mass diagnosed as an O-CCC. The morphological analysis of the cell culture was carried out by phase contrast microscopy. Markers of epithelial, mesenchymal, and tumor initiating cells were evaluated by immunocytochemistry. Cell proliferation was studied by detection of bromodeoxyuridine (BrdU) incorporated into newly synthesized DNA. As a biomarker of O-CCC, we assessed the expression of hepatocyte nuclear factor (HNF) 1ß. RESULTS: We show that cells with epithelial morphological features express E-cadherin and expand with time in culture, a fact that the incorporation of BrdU confirms. Cells with mesenchymal-like characteristics that express the mesenchymal marker vimentin, however, allocate to the edges of the epithelial compartment. Moreover, we found that some cells with epithelial features also expressed vimentin. At the beginning of incubation, over 60 % of primary cells expressed the O-CCC marker HNF1ß; such percentage declined upon passaging. We show that epithelial not mesenchymal cells undergo DNA replication, and that few cells in both epithelial and mesenchymal compartments express the stem-like tumor antigen CD133. CONCLUSIONS: We provide proof-of-principle that cells separated in bulk from a biopsy of an O-CCC can be maintained in culture for several months, and that two consistent cellular compartments-one epithelial that retains the O-CCC marker HNF1ß, and another mesenchymal-persist, and seem to have a cooperative interaction leading to the multiplication of epithelial cells within a mesenchymal cellular environment.

Teleoncology for gynecologic cancers.

Teleoncology describes cancer care provided remotely to improve access to care in rural or underserved areas. In the United States, 14.8 million women live more than 50 miles away from the closest gynecologic oncologist; 4.3 million women live more than 100 miles distant. Teleoncology may therefore partially relieve the geographic barriers to high-quality gynecologic cancer care these women experience. Little has been published on the feasibility of remote provision of high-quality care for gynecologic cancers, perhaps owing to the particular difficulties inherent in remote management of patients who may require both medical and surgical intervention. In this article, we review the data supporting the use of telemedicine in the treatment of cancer patients with a specific focus on applicability to management of gynecologic malignancies. We further add our group's experience with the treatment of rural, underserved gynecologic cancer patients. We believe that development of teleoncologic systems is critical to ensure that all women have access to high-quality gynecologic cancer care, regardless of where they reside.

A phase II trial of oxaliplatin, docetaxel, and bevacizumab as first-line therapy of advanced cancer of the ovary, peritoneum, and fallopian tube.

OBJECTIVE: To determine the safety and efficacy of the novel combination of docetaxel, oxaliplatin, and bevacizumab as first-line treatment of advanced cancer of the ovary, peritoneum or fallopian tube after initial debulking surgery. METHODS: Eligible patients (stage IB-IV) were treated with 6 cycles of oxaliplatin (85 mg/m(2)), docetaxel (75 mg/m(2)), and bevacizumab (15 mg/kg) every 3 weeks, followed by single-agent bevacizumab 15 mg/kg every 3 weeks to complete one year of therapy. The primary endpoint was 12-month progression-free survival (PFS). RESULTS: A total of 132 patients (80 with measurable disease at baseline; 52 with non-measurable, evaluable disease at baseline) enrolled and received study treatment. At diagnosis, 76.5% of patients had stage III disease and 20% had stage IV. 62.9% were optimally cytoreduced. The most common grade 3/4 adverse events were neutropenia (42.4%), leukopenia (13.6%), hypertension (8.3%), fatigue (6.1%), and nausea (6.1%). One patient (0.8%) had a fatal gastrointestinal perforation. The best overall confirmed response rate (complete response+partial response [measurable disease subgroup]) was 58.6% (95% CI 49%, 67%). CA-125 response rates for the measurable and non-measurable disease subgroups were 83.0% and 81.5%, respectively. The 12-month PFS rate for the measurable disease subgroup was 65.7% (95% CI 53.4%, 76.7%); median PFS was 16.3 (95% CI 12.6, 19.6) months. Median overall survival was 47.3 (95% CI 34.1, upper limit not applicable) months. CONCLUSIONS: This novel treatment regimen may provide a promising therapeutic approach for women with ovarian, primary peritoneal, or fallopian tube carcinoma. No unanticipated safety concerns were identified.

Is bilateral lymphadenectomy for midline squamous carcinoma of the vulva always necessary? An analysis from Gynecologic Oncology Group (GOG) 173.

OBJECTIVE: To determine which patients with near midline lesions may safely undergo unilateral groin dissection based on clinical exam and lymphoscintigraphy (LSG) results. METHODS: Patients participating in GOG-173 underwent sentinel lymph node (SLN) localization with blue dye, and radiocolloid with optional LSG before definitive inguinal-femoral lymphadenectomy (LND). This analysis interrogates the reliability of LSG alone relative to primary tumor location in those patients who had an interpretable LSG and at least one SLN identified. Primary tumor location was categorized as lateral (>2cm from midline), midline, or lateral ambiguous (LA) if located within 2cm, but not involving the midline. RESULTS: Two-hundred-thirty-four patients met eligibility criteria. Sixty-four had lateral lesions, and underwent unilateral LND. All patients with LA (N=65) and midline (N=105) tumors underwent bilateral LND. Bilateral drainage by LSG was identified in 14/64 (22%) patients with lateral tumors, 38/65 (58%) with LA tumors and in 73/105 (70%) with midline tumors. At mapping, no SLNs were found in contralateral groins among those patients with LA and midline tumors who had unilateral-only LSGs. However, in these patients groin metastases were found in 4/32 patients with midline tumors undergoing contralateral dissection; none were found in 27 patients with LA tumors. CONCLUSION: The likelihood of detectable bilateral drainage using preoperative LSG decreases as a function of distance from midline. Patients with LA primaries and unilateral drainage on LSG may safely undergo unilateral SLN.

Circumscribed Palmar Hypokeratosis With Superimposed Actinic Keratosis.

A man in his late 70s with a history of psoriasis and non-melanoma skin cancer presented with a progressive rash on his right thenar eminence. He first noticed it about one year ago. He denied any pruritus in the affected region but did note some overlying skin breakdown. He had used topical betamethasone and calcipotriene cream in the past with minimal improvement. Physical examination revealed a pink atrophic plaque with linear hyperkeratotic borders and central fissuring on the right thenar eminence extending into the first webspace. A shave biopsy revealed hypokeratosis with a rim of surrounding hyperkeratosis and associated parakeratosis, basal keratinocyte atypia, and lichenoid inflammation. These histopathological features were consistent with circumscribed palmar hypokeratosis and central actinic keratosis. Circumscribed palmar hypokeratosis is often considered a benign entity, but there have been reports suggesting an association with premalignancy. The decision was made to treat with 5-fluorouracil and calcipotriene cream twice daily for six weeks. At his two-month follow-up, he endorsed a robust reaction, which was further suggestive of premalignant change. He had a near-complete resolution of the rash. This case features circumscribed palmar hypokeratosis and suggests a novel treatment option for patients who develop concomitant actinic keratosis.

Synthesis and Antitumor Activity of Brominated-Ormeloxifene (Br-ORM) against Cervical Cancer.

Aberrant regulation of ß-catenin signaling is strongly linked with cancer proliferation, invasion, migration, and metastasis, thus, small molecules that can inhibit this pathway might have great clinical significance. Our molecular modeling studies suggest that ormeloxifene (ORM), a triphenylethylene molecule that docks with ß-catenin, and its brominated analogue (Br-ORM) bind more effectively with relatively less energy (-7.6 kcal/mol) to the active site of ß-catenin as compared to parent ORM. Herein, we report the synthesis and characterization of a Br-ORM by NMR and FTIR, as well as its anticancer activity in cervical cancer models. Br-ORM treatment effectively inhibited tumorigenic features (cell proliferation and colony-forming ability, etc.) and induced apoptotic death, as evident by pronounced PARP cleavage. Furthermore, Br-ORM treatment caused cell cycle arrest at the G1-S phase. Mechanistic investigation revealed that Br-ORM targets the key proteins involved in promoting epithelial-mesenchymal transition (EMT), as demonstrated by upregulation of E-cadherin and repression of N-cadherin, Vimentin, Snail, MMP-2, and MMP-9 expression. Br-ORM also represses the expression and nuclear subcellular localization of ß-catenin. Consequently, Br-ORM treatment effectively inhibited tumor growth in an orthotopic cervical cancer xenograft mouse model along with EMT associated changes as compared to vehicle control-treated mice. Altogether, experimental findings suggest that Br-ORM is a novel, promising ß-catenin inhibitor and therefore can be harnessed as a potent anticancer small molecule for cervical cancer treatment.

Randomized Controlled Phase II Evaluation of Two Dose Levels of Bupropion Versus Placebo for Sexual Desire in Female Cancer Survivors: NRG-CC004.

PURPOSE: Because of the negative impact of cancer treatment on female sexual function, effective treatments are warranted. The purpose of this multisite study was to evaluate the ability of two dose levels of extended-release bupropion, a dopaminergic agent, to improve sexual desire more than placebo at 9 weeks, measured by the desire subscale of the Female Sexual Function Index (FSFI), and to evaluate associated toxicities. METHODS: Postmenopausal women diagnosed with breast or gynecologic cancer and low baseline FSFI desire scores (< 3.3), who had completed definitive cancer therapy, were eligible. Women were randomly assigned to receive 150 mg or 300 mg once daily of extended-release bupropion or a matching placebo. t-tests were performed on the FSFI desire subscale to evaluate whether there was a significantly greater change from baseline to 9 weeks between placebo and each bupropion arm as the primary end point. Sixty-two patients per arm provided 80% power using a one-sided t-test. RESULTS: Two hundred thirty women were randomly assigned from 72 institutions through the NRG Oncology NCORP network. At 9 weeks, there were no statistically significant differences in change of the desire subscale scores between groups; participants in all three arms reported improvement. The mean changes for each arm were placebo 0.62 (standard deviation [SD] = 1.18), 150-mg once daily bupropion 0.64 (SD = 0.95), and 300-mg once daily bupropion 0.60 (SD = 0.89). Total and subscale scores on the FSFI were low throughout the study, indicating dysfunction in all groups. CONCLUSION: Bupropion was not more effective than placebo in improving the desire subscale of the FSFI. Subscale and total scores of the FSFI demonstrated dysfunction throughout the 9 weeks of the study. More research is needed to support sexual function in female cancer survivors.

Curcumin suppresses human papillomavirus oncoproteins, restores p53, Rb, and PTPN13 proteins and inhibits benzo[a]pyrene-induced upregulation of HPV E7.

Curcumin has great potential as a chemopreventive and chemotherapeutic agent; however, its effects on human papillomavirus (HPV)-associated molecular events are inadequately explored. This study examined the effects of curcumin on HPV-associated pathways involved in developing cervical cancer. We demonstrate for the first time that curcumin treatment suppresses cervical cancer cell growth in a three-dimensional raft culture system. Curcumin also inhibits tumorigenic characteristics as shown by decreases in both clonogenic potential and cell motility. Additionally, our findings show that curcumin treatment inhibits the transcription of HPV16 E6/E7 as early as 6 h posttreatment and restores the expression of tumor suppressor proteins p53, retinoblastoma protein, and PTPN13. While smoking is a recognized risk factor for cervical cancer, the molecular effects of smoke carcinogens on the expression of HPV E6/E7 oncogenes are not well known. We show for the first time that exposure to benzo[a]pyrene (BaP), a tobacco carcinogen, increases the expression of HPV E7 oncoprotein suggesting a molecular link between smoking and cervical cancer. Importantly, curcumin decreases the BaP induced increase in the expression of HPV E7 oncoprotein. The results of this study clearly demonstrate that curcumin alters HPV-associated molecular pathways in cervical cancer cells. These novel findings imply that curcumin may be an effective chemopreventive and therapeutic agent for cervical cancer prevention and treatment.

Risk factors for HPV infection among American Indian and white women in the Northern Plains.

OBJECTIVE: American Indian (AI) women living in the Northern Plains have high incidence and mortality rates for cervical cancer. We assessed risk factors for human papillomavirus (HPV) infection among AI and White women. METHODS: We tested cervical samples for HPV infection obtained from women ages 18-65 years attending 2 rural AI reservation clinics in South Dakota (n=235) and an urban clinic serving predominantly White women (n=246). Patients self-reported information on HPV risk factors. We used percentages and chi-square tests to compare risk factors, and logistic regression with HPV status as the outcome to quantify the association between HPV and risk factors. RESULTS: AI women had more risk factors than White women, including younger age, less education, less vegetable consumption, more sexual partners, younger age at first sexual experience and first pregnancy, and more pregnancies (p values≤0.003). AI women more often endorsed recreational drug use, history of sexually transmitted diseases, and current smoking; White women reported more alcohol consumption (p values<0.001). In multivariate analysis, younger age and current smoking were associated with higher odds of HPV infection in AI women, whereas a higher number of sexual partners was associated with higher odds of HPV infection in White women. CONCLUSIONS: AI women have a high burden of risk factors for HPV disease, and associations with HPV infection appear to differ by community. Knowledge of specific risk factors in AI populations may provide targets for public health officials to decrease HPV infection and disease.

HPV infection among rural American Indian women and urban white women in South Dakota: an HPV prevalence study.

BACKGROUND: High-risk strains of human papillomavirus (HPV) cause cervical cancer. American Indian (AI) women in the Northern Plains of the U.S. have significantly higher incidence and mortality rates for cervical cancer than White women in the same geographical area. We compared HPV prevalence, patterns of HPV types, and infection with multiple HPV types in AI and White women living in South Dakota, U.S. METHODS: We analyzed the HPV status of cervical samples collected in 2006-2008 from women aged 18-65 years who attended two rural AI reservation clinics (n = 235) or an urban clinic in the same area serving mostly White women (n = 246). Data collection occurred before HPV vaccination was available to study participants. HPV DNA was amplified by using the L1 consensus primer system and an HPV Linear Array detection assay to identify HPV types. We used chi-square tests to compare HPV variables, with percentages standardized by age and lifetime number of sexual partners. RESULTS: Compared to White women, AI women were younger (p = 0.01) and reported more sexual partners (p < 0.001). A lower percentage of AI women tested negative for HPV infection compared to Whites (58% [95% CI = 51-65] vs. 77% [95% CI = 71-82]; p < 0.001), and a higher percentage of AI women were infected by oncogenic types (30% [95% CI = 25-36] vs. 16% [95% CI = 11-21]; p = 0.001). Infections among AI women showed a wider variety and very different pattern of HPV types, including a higher prevalence of mixed HPV infections (19% [95% CI = 26-38] vs. 7% [95% CI = 4-11]; p = 0.001). AI women had a higher percentage of HPV infections that were not preventable by HPV vaccination (32% [95% CI = 26-38] vs. 15% [95% CI = 11-21]; p < 0.001). CONCLUSIONS: A higher HPV burden and a different HPV genotyping profile may contribute to the high rate of cervical cancer among AI women.

Uterine pleomorphic rhabdomyosarcoma: a case report and review of literature.

Primary pleomorphic rhabdomyosarcoma of the uterus is a very rare neoplasm. We describe a 65-year old female with this diagnosis, who underwent an abdominal hysterectomy with bilateral salpingo-oophorectomy and lymph node dissection. Also included is a discussion on the different types of rhabdomyosarcoma with reviews of their histological features, epidemiology and common sites of origin.

Clinical and cost comparisons for hysterectomy via abdominal, standard laparoscopic, vaginal and robot-assisted approaches.

INTRODUCTION: The goal of this study was to compare outcomes and costs of four methods of hysterectomy: abdominal, standard laparoscopic, vaginal and robot-assisted approaches. METHODS: We conducted a retrospective medical chart review of 1474 consecutive hysterectomy patients with benign indications. RESULTS: Implementation of a robotics program at our institution resulted in reductions in abdominal (33 percent to 8 percent) and laparoscopic (29 percent to 5 percent) hysterectomies. Robotic surgery demonstrated the least blood loss and shortest hospital stays (both p < 0.0001), despite greater case complexity. Overall complication rates were highest for abdominal procedures (14 percent) and similar across minimally invasive approaches (8 to 9 percent). Conversion rates were four times greater in laparoscopic than vaginal or robotic hysterectomy (p = 0.01). Vaginal hysterectomy, performed in the least complex cases, had the lowest major complication rate (1.5 percent) and lowest costs. Costs for robotic surgery were similar to abdominal and laparoscopic approaches when robots were not depreciated as direct surgical expenses. CONCLUSIONS: Vaginal hysterectomy was the least expensive surgical option. Robotic surgery reduced morbidity, conversions and hospital stays even in complex cases, without incurring additional costs beyond purchase of the robotic system.

Ovarian small cell carcinoma, hypercalcemic type exhibiting a response to high-dose chemotherapy.

A gravida 2, para 2 25-year-old woman three months post-partum presented to her primary physician with abdominal pain and bloating; a 20-cm complex cystic pelvic mass was identified by ultrasound. No ovarian masses were noted during ultrasound exam at the prior pregnancy, less than one year earlier. Her labs included hypercalcemia (11.8 mg/dL, normal less than 10.5) and an elevated CA 125 (160 U/mL, normal less than 35). An exploratory laparotomy revealed a 20-cm right ovarian mass. Frozen section was performed and a sex cord-stromal tumor was favored. Permanent sections of the specimen, however, revealed round, closely packed neoplastic cells with a high nuclear to cytoplasm ratio and high mitotic rate growing in a diffuse pattern with scattered follicle-like, ill-defined microcystic spaces. Immunohistochemical stains revealed the neoplasm to be focally positive for keratin and negative for inhibin. The final diagnosis rendered was small cell carcinoma of the ovary, hypercalcemic type. Further staging revealed para-aortic lymph node involvement (stage IIIC). Current literature suggests a very poor prognosis for these neoplasms despite aggressive therapy, with an overall survival rate of 10 percent. Rare response has been noted, however, with high-dose chemotherapy followed by autologous peripheral blood stem cell transplant. Our patient underwent a rigorous chemotherapeutic regimen followed by peripheral blood stem cell transplant, and as of August 2010, (17 months after initial diagnosis), the patient has had no recurrence.

Epidemiology of Human Papilloma Virus (HPV) in Cervical Mucosa.

In a worldwide scenario, human papillomavirus (HPV) infection is the second leading cause of cancer-related morbidity and mortality among women due to its very close association with cervical cancer. More than 100 different types of HPV genotypes have been characterized to date. Among these, approximately 24 HPV genotypes specifically infect the genital and oral mucosal system. The mucosal HPVs are most frequently sexually transmitted, and they are responsible for the most common sexually transmitted diseases throughout the world. In a majority of the cases, oncogenic/nononcogenic HPV infections spontaneously clear by themselves without any medical intervention. However, a persistent and long-term HPV infection usually leads to cervical cancer, which remains difficult to treat. In recent years, advance understanding of the structure of HPV and its pathogenesis has led to a variety of new treatments to combat HPV-related diseases, including a Food and Drug Administration-approved HPV vaccine that is very effective in young women. To effectively use this HPV vaccine worldwide, a clear understanding of HPV genotypes in different geographical populations is imperative. In this chapter, we have focused briefly on HPV genotypes and HPV prevalence in the women of different geographical populations.

The first 100 da Vinci hysterectomies: an analysis of the learning curve for a single surgeon.

BACKGROUND: Robotic gynecologic procedures were FDA-approved in March 2005. Published average times for robotic hysterectomies vary from 192 minutes to 242 minutes and one report indicated operative times ranging from 4.5 to ten hours. Many critics cite learning curves and increased operative times as a deterrent to performing robotic hysterectomies. METHODS: This is a retrospective review of surgical times (learning curve) for the first 100 consecutive extrafascial hysterectomies with or without salpingo-oophorectomy for a single surgeon. Operating times were recorded by operating room nursing staff for each case. The times reported are from "skin to skin," which is defined as from when the surgeon started to place anything vaginally until the last suture was placed to close the trocar sites. We report average times for hysterectomy per 20 cases. RESULTS: The average time for hysterectomies was as follows: First 20 cases--124 minutes, second 20 cases--94 minutes, third 20 cases--85 minutes, fourth 20 cases--88 minutes, fifth 20 cases--81 minutes. Age, body mass index and uterine weights were comparable between groups. Complications were highest in the first 20 at 15 percent, compared with 5 percent for the remaining groups, but this did not reach statistical significance. CONCLUSIONS: The learning curve for da Vinci hysterectomies is steep, with the maximum improvement in surgical times in the first 20 cases. Minimal improvement was demonstrated after this.

Comparison of outcomes and cost for endometrial cancer staging via traditional laparotomy, standard laparoscopy and robotic techniques.

OBJECTIVES: The study purpose was to compare hysterectomy and lymphadenectomy completed via robotic assistance, laparotomy, and laparoscopy for endometrial cancer staging with respect to operative and peri-operative outcomes, complications, adequacy of staging, and cost. METHODS: One hundred and ten patients underwent hysterectomy with bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy for endometrial cancer staging. All cases were performed by a single surgeon, at a single institution (40 robotic, 40 laparotomy, and 30 laparoscopic) and were retrospectively reviewed to compare demographics and peri-operative variables including, operative time, estimated blood loss, lymph node count, hospital stay, complications, and return to normal activity. Additionally, a cost comparison between all three modalities was performed. RESULTS: Patients undergoing robotic assisted hysterectomy and staging experienced longer operative time than the laparotomy cohort with no difference in comparison to the laparoscopic cohort (184 min, 108.6 min, 171 min, p<0.0001, p=0.14). Estimated blood loss was significantly reduced for the robotic cohort in comparison to the laparotomy cohort and comparable to laparoscopic cohort (166 cc, 316 cc, 253 cc, p=0.01, p=0.25). The complication rate was lowest in the robotic cohort (7.5%) relative to the laparotomy (27.5%) and laparoscopic cohorts (20%) (p=0.015, p=0.03). Average return to normal activity for the robotic patients was significantly shorter than those undergoing laparotomy (24.1 days versus 52 days, p<0.0001) and those undergoing laparoscopy (31.6 days, p=0.005). Lymph node retrieval did not differ between the 3 groups (robotic 17 nodes, laparotomy 14 nodes, laparoscopic 17 nodes). The total average cost for hysterectomy with staging completed via laparotomy was $12,943.60, for standard laparoscopy $7569.80, and for robotic assistance $8212.00. The difference in cost between laparotomy and robotic cohorts was significant p=0.0001 while there was no statistically significant difference in cost between laparoscopy and robotic cohorts p=0.06. CONCLUSIONS: Robotic hysterectomy provides comparable node retrieval to laparotomy and laparoscopic procedures in the case of the experienced laparoscopic surgeon. While robotic hysterectomy takes longer to perform than hysterectomy completed via laparotomy, it is equivalent to laparoscopic hysterectomy and provides the patient with a more expeditious return to normal activity with reduced post-operative morbidity. Additionally, the average cost for hysterectomy and staging was highest for laparotomy, followed by robotic, and least for standard laparoscopy.

Combined staining of TAG-72, MUC1, and CA125 improves labeling sensitivity in ovarian cancer: antigens for multi-targeted antibody-guided therapy.

Single antigen-targeted intraperitoneal radioimmunotherapy for ovarian cancer has shown limited success. Due to the heterogeneous expression of tumor antigens on cancer cells, a multi-antigen targeting approach appears logical to augment the therapeutic efficacy of antibody-guided therapy. In the interest of developing this novel approach, ovarian cancer tissue microarray slides containing cancer and benign/non-neoplastic tissue samples (n=92) were processed for single-, double-, and triple-antigen labeling using antibodies for the tumor-associated antigens TAG-72, MUC1, and CA125. Among all ovarian cancer types, 72%, 61%, and 50% of the samples showed immunolabeling for TAG-72, MUC1, and CA125, respectively. Expression level of these antigens was significantly (p<0.005) higher in advanced stage carcinomas compared with early stage. Of the 48 epithelial ovarian cancer samples, individual anti-TAG-72, MUC1, and CA125 antibody probing showed labeling in 89.5%, 87.5%, and 73.0% of the cases, respectively. In the majority of the cancer samples (>70%), a heterogeneous labeling pattern was observed (only 30-40% of the cancer cells within the sample were labeled). However, upon combining the three antigens (triple-antigen labeling), 98% of the epithelial ovarian cancer samples were labeled and >95% of the cancer cells within each sample were labeled. Our data indicate that the heterogeneous expression of cancer antigens appears to be a major obstacle in antibody-guided therapy, and this can be overcome by multiple antigen targeting. Therapeutic efficacy of antibody-guided therapy for ovarian cancer treatment will be enhanced by the combined targeting of TAG-72, MUC1, and CA125.