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issn:1048-891
1.  [No title available] 
PMCID: PMC3946897  PMID: 24407585
2.  Incidence and Predictors of Venous Thromboembolism After Debulking Surgery for Epithelial Ovarian Cancer 
Objective
The aim of this study was to determine the incidence and the risk factors of venous thromboembolism (VTE) within 30 days after primary surgery for epithelial ovarian cancer (EOC).
Methods
In a historical cohort study, we estimated the postoperative 30-day cumulative incidence of VTE among consecutive Mayo Clinic patients undergoing primary cytoreduction for EOC between January 2, 2003, and December 29, 2008. We tested perioperative patient characteristics and process-of-care variables (defined by the National Surgical Quality Improvement Program, >130 variables) as potential predictors of postoperative VTE using the Cox proportional hazards modeling.
Results
Among 569 cases of primary EOC cytoreduction and/or staging and no recent VTE, 35 developed symptomatic VTE within 30 days after surgery (cumulative incidence = 6.5%; 95% confidence interval, 4.4%–8.6%). Within the cohort, 95 (16.7%) received graduated compression stockings (GCSs), 367 (64.5%) had sequential compression devices + GCSs, and 69 (12.1%) had sequential compression devices + GCSs + postoperative heparin, with VTE rates of 1.1%, 7.4%, and 5.8%, respectively (P = 0.07, χ2 test). The remaining 38 (6.7%) received various other chemical and mechanical prophylaxis regimens. In the multivariate analysis, current or past tobacco smoking, longer hospital stay, and a remote history of VTE significantly increased the risk for postoperative VTE.
Conclusions
Venous thromboembolism is a substantial postoperative complication among women with EOC, and the high cumulative rate of VTE within 30 days after primary surgery suggests that a more aggressive strategy is needed for VTE prevention. In addition, because longer hospital stay is independently associated with a higher risk for VTE, methods to decrease length of stay and minimize factors that contribute to prolonged hospitalization are warranted.
doi:10.1097/IGC.0b013e3182a80aa7
PMCID: PMC4307403  PMID: 24172104
Venous thromboembolism; Deep vein thrombosis; Ovarian cancer; Surgery
3.  The Impact of Perioperative Packed Red Blood Cell Transfusion on Survival in Epithelial Ovarian Cancer 
Objective
Perioperative packed red blood cell transfusion (PRBCT) has been implicated as a negative prognostic marker in surgical oncology. There is a paucity of evidence on the impact of PRBCT on outcomes in epithelial ovarian cancer (EOC). We assessed whether PRBCT is an independent risk factor of recurrence and death from EOC.
Methods
Perioperative patient characteristics and process-of-care variables (defined by the National Surgical Quality Improvement Program) were retrospectively abstracted from 587 women who underwent primary EOC staging between January 2, 2003, and December 29, 2008. Associations with receipt of PRBCT were evaluated using univariate logistic regression models. The associations between receipt of PRBCT and disease-free survival and overall survival were evaluated using multivariable Cox proportional hazards models and using propensity score matching and stratification, respectively.
Results
The rate of PRBCT was 77.0%. The mean ± SD units transfused was 4.1 ± 3.1 U. In the univariate analysis, receipt of PRBCT was significantly associated with older age, advanced stage (≥IIIA), undergoing splenectomy, higher surgical complexity, serous histologic diagnosis, greater estimated blood loss, longer operating time, the presence of residual disease, and lower preoperative albumin and hemoglobin. Perioperative packed red blood cell transfusion was not associated with an increased risk for recurrence or death, in an analysis adjusting for other risk factors in a multivariable model or in an analysis using propensity score matching or stratification to control for differences between the patients with and without PRBCT.
Conclusions
Perioperative packed red blood cell transfusion does not seem to be directly associated with recurrence and death in EOC. However, lower preoperative hemoglobin was associated with a higher risk for recurrence. The need for PRBCT seems to be a stronger prognostic indicator than the receipt of PRBCT.
doi:10.1097/01.IGC.0000436089.03581.6b
PMCID: PMC4306564  PMID: 24172098
Perioperative red blood cell transfusion; Ovarian cancer; Disease-free survival; Overall survival
4.  Outcomes of patients undergoing radical hysterectomy for cervical cancer of high-risk histologic subtypes 
Structured Abstract
Introduction
The most common types of cervical cancer are squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma, referred to here collectively as SA cervical cancer. Other types of cervical cancer, referred to here collectively as nonsquamous/nonadenocarcinoma (NSNA) cervical cancer, include neuroendocrine, small cell, clear cell, sarcomatoid, and serous tumors. Anecdotally, NSNA tumors seem to have a worse prognosis than their SA counterparts. We sought to determine whether patients with early-stage NSNA have a worse prognosis than those with early-stage SA cervical cancer.
Methods
We retrospectively reviewed charts of women with stage IA1-IB2 NSNA cervical cancer treated by radical hysterectomy and lymph node staging at MD Anderson Cancer Center from 1990 to 2006. NSNA patients were matched 1:2 to patients with grade 3 SA lesions on the basis of stage, age at diagnosis, tumor size, and date of diagnosis.
Results
Eighteen patients with NSNA primary cervical cancer subtypes [neuroendocrine (n=7), small cell (5), clear cell (4), papillary serous (1), and sarcomatoid (1)] were matched to 36 patients with grade 3 SA lesions. There were no differences between the 2 groups in age, body mass index, clinical stage, or lesion size. The 2 groups also did not differ with respect to number of nodes resected, lymphovascular space invasion, margin status, lymph node metastasis, or adjuvant radiation therapy or chemotherapy. At a median follow-up of 44 months, median progression-free and overall survivals had not been reached; however, both progression-free survival (p=0.018) and overall survival (p=0.028) were worse for the NSNA group. The 5-year progression-free and overall survival rates were 61.2% and 67.6%, respectively, for the NSNA group, compared to 90.1% and 88.3%, respectively, for the SA group.
Conclusions
Patients with early-stage NSNA cervical cancer undergoing radical hysterectomy and pelvic lymphadenectomy have a worse prognosis than patients with grade 3 SA lesions. Patients with NSNA tumors may require a multimodality approach to their cancer care.
doi:10.1097/IGC.0b013e3181ffccc1
PMCID: PMC4283480  PMID: 21178574
Neuroendocrine; small cell; clear cell; radical hysterectomy; cervical cancer
5.  Anatomic Location of PET-Positive Aortocaval Nodes in Patients with Locally Advanced Cervical Cancer: Implications for Surgical Staging 
Objective
Pathologic evaluation of aortocaval nodes in patients with locally advanced cervical cancer in an effort to better tailor radiotherapy has gained popularity. We sought to determine which aortocaval nodes should be sampled during surgical staging procedures.
Methods
From 2004 to 2011, 246 patients with locally advanced cervical cancer underwent positron emission tomography (PET) before definitive chemoradiation. We reviewed the imaging studies to determine the location of PET-positive aortocaval nodes in relationship to the inferior mesenteric artery (IMA).
Results
Forty-two patients (17%) had PET images suggesting aortocaval metastasis. Ten patients had stage IB, 1 had stage IIA, 13 had stage IIB, 13 had stage IIIB, and 5 had stage IV disease. Of these 42 patients, 39 (93%) had FDG-avid pelvic nodes, 1 (2%) had PET-negative pelvic nodes but FDG-avid common iliac nodes, and 2 (5%) had direct spread to the aortocaval nodes. Three patients (7%) had FDG-avid aortocaval nodes above the IMA without FDG-avid nodes between the aortic bifurcation and IMA. All 3 of these patients also had FDG-avid nodes in the pelvis. Nineteen patients (45%) had FDG-avid nodes above and below the IMA, and 20 (48%) had FDG-avid nodes below the IMA only.
Conclusions
This hypothesis-generating study revealed that a small number of patients have PET-positive aortocaval nodes above the IMA only. For patients undergoing surgical staging for locally advanced cervical cancer, dissection to the renal vessels may be necessary. A future international, randomized study will prospectively evaluate the locations of pathologically positive aortocaval lymph nodes.
doi:10.1097/IGC.0b013e31825e523a
PMCID: PMC4283482  PMID: 22810967
cervical cancer; surgical staging; lymph nodes
7.  Causes and Palliation of Transfusion-Associated Vaginal Bleeding in Patients with Metastatic Cancer 
PURPOSE
The current study was undertaken 1) to capture a clinically relevant, systematically-collected series of patients with metastatic cancer and transfusion-associated vaginal bleeding and 2) to provide insight into how best to palliate this bleeding.
METHODS/RESULTS
As part of a single-institution review, 46 patients with metastatic cancer and transfusion-associated vaginal bleeding were identified. In a minority, 14 (30%), the cancer itself was directly responsible for the bleeding, and, under these circumstances, a gynecological cancer was the most frequent cause. In 13 patients (28%), more than one palliative intervention was attempted. Of all the interventions, a hysterectomy was used most frequently and was successful in 11 patients. The use of ablation or embolization procedures was rarely tried but successful in 4 patients. However, 2 patients died from the vaginal bleeding, despite multiple palliative procedures to control bleeding, including tumor embolization in one.
CONCLUSIONS
Transfusion-associated vaginal bleeding in patients with metastatic cancer can arise from non-malignant causes, often assumes an uneventful course, but can, at times, be serious and difficult to control.
doi:10.1097/IGC.0000000000000017
PMCID: PMC3925342  PMID: 24270998
vaginal bleeding; uterine bleeding; palliation; hemorrhage; anemia
8.  A Phase II Study of Oxaliplatin Combined with Continuous Infusion Topotecan for Patients with Previously Treated Ovarian Cancer 
Background
Phase II trials suggest that prolonged intravenous (IV) infusion of the topoisomerase-1 inhibitor topotecan may be less toxic than when given by standard IV bolus 5-day administration. Oxaliplatin exhibits efficacy in platinum- pretreated disease and shows preclinical synergy with topoisomerase-I inhibitors. We sought to determine the efficacy and safety of oxaliplatin plus infusion topotecan in recurrent platinum-pretreated ovarian cancer.
Methods
Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers previously treated with 1–2 prior regimens including a platinum and taxane received oxaliplatin (85 mg/m2 day 1, 15) and topotecan (0.4 mg/m2/day) by continuous IV infusion over 14 days every 4 weeks. The primary objective of the trial was to estimate the objective response rate in platinum-resistant disease (stratum I) and in platinum-sensitive disease (stratum II). Toxicities were assessed in all patients.
Results
Thirty-eight patients received 144 cycles of therapy (median 4, range 1–6). The most common grade 3/4 toxicities included thrombocytopenia (37% grade 3, 19% grade 4), neutropenia (37% grade 3, 11% grade 4) and anemia (15% grade 3). Response occurred in 4 of 19 patients in stratum I (21%, 95% confidence intervals [CI] 6%, 46%) and 9 of 19 patients in stratum II (47%, 95% CI 24%, 71%). Three in each stratum had lengthy complete responses.
Conclusions
Biweekly oxaliplatin plus a 14-day continuous IV infusion of topotecan, given monthly, is an active regimen in platinum-pretreated ovarian cancer and merits additional evaluation.
doi:10.1097/IGC.0b013e3182a809e0
PMCID: PMC3869398  PMID: 24172094
9.  Association Between Bone Marrow Dosimetric Parameters and Acute Hematologic Toxicity in Cervical Cancer Patients Undergoing Concurrent Chemoradiotherapy 
Objective
We compare different dosimetric parameters in cervical cancer patients receiving concurrent chemotherapy and three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiation therapy (IMRT) and explore the incidence of hematological toxicity (HT) in these patients.
Methods
Twenty patients receiving 3DCRT or IMRT and 4 weekly doses of cisplatin (25 mg/m2/w) were studied. The volumes of bone marrow receiving 10, 20, 30, 40 and 50 Gy or greater (V10, V20, V30, V40, and V50, respectively) were calculated. The HT was graded according to the guidelines of the Radiation Therapy Oncology Group system. The associations between dosimetric parameters and HT and chemotherapy delivery were analyzed.
Results
The bone marrows V30, V40, and V50 were lower in the IMRT group than in the 3DCRT group (62.93% vs 76.91%, 31.36% vs 39.60%, and 9.79% vs 15.44%, respectively). No statistical difference was observed for both V10 and V20. Acute hematologic toxicity occurred in both groups but was more frequent in the 3DCRT group. The percentage of patients with grade 2 and worse leukopenia and neutropenia was 90% and 80% in the 3DCRT group, whereas it was 80% and 40% in the IMRT group. The median nadir of white blood cells and the absolute neutrophil count were significantly lower in the 3DCRT group than in the IMRT group (1.96 × 109 vs 2.72 × 109 and 1.09 × 109 vs 1.86 × 109, respectively).
Conclusion
The IMRT reduced the volume of bone marrow irradiated at the higher doses and the incidence and severity of acute hematologic toxicity in cervical cancer patients undergoing concurrent chemoradiotherapy.
doi:10.1097/IGC.0000000000000292
PMCID: PMC4215915  PMID: 25275663
Hematological toxicity; Cervical cancer; Concurrent chemoradiotherapy; Three-dimensional conformal radiotherapy; Intensity-modulated radiation therapy; Bone marrow
10.  Immunolocalization of Corticotropin-Releasing Hormone (CRH) and Its Receptors (CRHR1 and CRHR2) in Human Endometrial Carcinoma 
Supplemental digital content is available in the text.
Objective
Corticotropin-releasing hormone (CRH), a major regulator of the stress response, regulates various biological functions through its interaction with CRH receptors 1 (CRHR1) and 2 (CRHR2). CRH, CRHR1, and CRHR2 have recently been reported in several types of carcinoma, but the significance of these proteins has remained largely unknown in human endometrial carcinoma.
Materials and Methods
A total of 87 endometrial carcinoma specimens were obtained from Japanese female patients who underwent surgical treatment, fixed in 10% formalin, and embedded in paraffin wax. Immunohistochemistry for CRH, CRHR1, and CRHR2 was performed, and clinical data were obtained from the medical records.
Results
Immunopositivity of CRH, CRHR1, and CRHR2 in the specimens was 26%, 15%, and 10%, respectively. Univariate analysis revealed that immunohistochemical CRH status was positively associated with CRHR1 and CRHR2 status and that CRHR1 status was significantly associated with the risk of recurrence and poorer clinical outcome, whereas CRHR2 status was marginally associated with better prognosis for overall survival. Multivariate analysis demonstrated CRHR1 status as an independent prognostic factor for both disease-free and overall survival.
Conclusions
These results suggest that intratumoral CRH-CRHR1 signaling plays an important role in the progression of endometrial carcinoma and that CRHR1 is a potent prognostic factor in patients with this disease.
doi:10.1097/IGC.0000000000000269
PMCID: PMC4215916  PMID: 25254562
Corticotropin-releasing hormone; Corticotropin-releasing hormone receptor 1; Endometrial cancer; Immunohistochemistry; Prognosis
11.  The impact of body weight on ovarian cancer outcomes 
Background
Obesity is a known risk factor and poor prognostic factor for much co-morbidity including cancer. However, the influence of body mass index (BMI) on ovarian cancer outcomes is inconclusive. Therefore, the objective of this study was to evaluate the impact of BMI and weight changes on survival in patients with advanced ovarian cancer after primary treatment.
Methods and Materials
All patients diagnosed with advanced epithelial ovarian cancer from 1/00–12/07 undergoing primary cytoreductive surgery and adjuvant chemotherapy were identified. Patients were divided into three categories: under/normal weight (BMI<25), overweight (BMI 25–30), and obese (BMI>30). Adjusted hazard ratios for progression free (PFS) and overall survival (OS) were calculated via Cox proportional hazard models.
Results
One hundred ninety-eight patients met inclusion criteria. For all patients, the mean BMI was 26 (range 16.4–49.1) with 43% of patients being classified as normal weight, 29% overweight, and 28% as obese. Median 5-yr OS was 48.2 months (95% CI 16.4–49.1 months), and no differences in OS were noted between BMI groups. Unadjusted median PFS for patients with normal weight was 13.7 months, compared to 15.5 and 17.9 months for the overweight and obese group. Adjusted analysis of BMI over time indicates a trend of increased risk for patients who gain weight in the 6 months after primary therapy on disease progression (HR: 1.68, 95% CI 0.87–3.26).
Conclusions
After adjustment for confounders, such as stage, grade, histology, age and debulking status, data suggest a trend towards a shorter PFS in patients with a normal BMI. However, OS was not significantly related to BMI and weight change in the 6 months after completion of treatment had no effect on PFS or OS. Further research should be directed at elucidating relationships between weight and cancer biology.
doi:10.1097/IGC.0b013e31822d2aa3
PMCID: PMC4175395  PMID: 21997171
ovarian cancer; body mass index; obesity
12.  Multiple-type HPV infections: a cross-sectional analysis of the prevalence of specific types in 309,000 women referred for HPV testing at the time of cervical cytology 
Objectives
To determine the frequency of multiple type cervical HPV infections, and whether any types are involved in multiple type infections more or less frequently than might be expected if these infections occur randomly.
Methods
In this retrospective analysis of type-specific HPV testing, results from women 18-65 years old with samples collected between July 2007 and May 2011 were considered. Multivariate logistic regression analysis was used to model the presence of each of the 24 most prevalent HPV types, adjusting for one other HPV type, age, laboratory region, and age by region interactions.
Results
HPV infection was present in 74,543 of 309,471 women (24.1%) and 65,492 (21.1%) were positive for one of the top 24 most prevalent HPV types. The most common HPV type was HPV type 16, occurring in 4.1 of the entire sample%. 14,181 women were positive for 2 or more HPV types (4.6% of entire sample, 19.0% of HPV positive sample). Two-way HPV type comparisons were analyzed. Types 52, 53, 81, and 83 more likely to occur in multiple infections with other types, and types 16, 58, and 66 were less likely to occur in multiple infections with other types. HPV types 72 and 81 have the strongest positive relationship (OR=5.2, 95% CI: 3.6, 7.4). HPV types 33 and 66 have the strongest negative relationship (OR 0.4, 95% CI: 0.2, 0.6).
Conclusions
In this population, multiple type HPV infections were present in 4.6% of all women. Our findings suggest that there may be both competitive and cooperative interactions between HPV types.
doi:10.1097/IGC.0b013e31829e9fb4
PMCID: PMC3882063  PMID: 23970156
DNA Probes; HPV; Epidemiology
13.  Cancer-Related Concerns among Women Newly Diagnosed with Gynecological Cancer: An Exploration of Age Group Differences 
Objective
The study aimed to characterize cancer-related concerns among women newly diagnosed with gynecological cancer from a developmental life stage perspective. The study compared degree of cancer-related concern between young women (≤ 45 years), middle age women (46–64 years), and older women (≥ 65 years).
Methods/Materials
Data from women (N =243) diagnosed with primary gynecological cancer who were participating in a randomized control trial were analyzed. Women completed a measure that assessed degree of concern in twelve cancer-related domains (physical functioning, cancer treatment, emotional functioning, sexual functioning, disease progression/death, own well-being, partner well-being, relationship with spouse/partner, body image, relationship with others, employment, and finances). Multivariate comparisons were made between the three age groups on the cancer-related concerns.
Results
There were age group differences in overall cancer-related concern and specific cancer-related domains. Young women reported the greatest cancer-related concern (p < .001). They reported greater concern over emotional functioning (p < .001) and sexual functioning (p < .001) compared to the middle and older age groups. Older women reported less concern over the impact of cancer on finances (p = 007). There were no differences between age groups in concern over physical impairment, cancer treatment, disease progression/death, own well-being, partner well-being, relationship with spouse/partner, body image, and relationship with others.
Conclusions
Age may play an important role in the impact of a gynecological cancer diagnosis in domains of functioning, specifically emotional functioning, sexual functioning, and finances. Other cancer-related areas may represent more universal degree of impact. Professionals may benefit form considering the impact of cancer from a developmental life stage perspective.
doi:10.1097/IGC.0000000000000010
PMCID: PMC4118576  PMID: 24346489
gynecological cancer; cancer-related concern; age; developmental stage; quality of life
14.  Pathologic Ultrastaging Improves Micrometastasis Detection in Sentinel Lymph Nodes during Endometrial Cancer Staging 
Objective
To describe the incidence of low-volume, ultrastage-detected metastases in sentinel lymph nodes (SLNs) identified at surgical staging for endometrial carcinoma and to correlate it with depth of myoinvasion (DMI) and tumor grade.
Methods
We reviewed all patients who underwent primary surgery for endometrial carcinoma with successful mapping of at least one SLN at our institution from 9/2005-12/2011. All patients underwent a cervical injection for mapping. The SLN ultrastaging protocol involved cutting an additional two adjacent 5-μm sections at each of two levels, 50-μm apart, from each paraffin block lacking metastatic carcinoma on routine H&E. At each level, one slide was stained with H&E and with immunohistochemistry (IHC) using anti-cytokeratin AE1:AE3.
Micrometastases (tumor deposits <0.2mm and ≤2mm) and isolated tumor cells (≤0.2mm) were classified as low-volume, ultrastage-detected metastases if pathologic ultrastaging was the only method allowing detection of such nodal disease.
Results
Of 508 patients with successful mapping, 413(81.3%) had endometrioid carcinoma. Sixty-four(12.6%) of 508 patients had positive nodes: routine H&E detected 35 patients(6.9%), ultrastaging detected an additional 23 patients(4.5%) who would have otherwise been missed (4 micrometastases, 19 isolated tumor cells), and 6 patients(1.2%) had metastatic disease in their non-SLNs. The incidence of low-volume, ultrastagedetected nodal metastases in grade 1, 2, and 3 patients was 3.8%, 3.4%, and 6.9%, respectively. The frequency of low-volume, ultrastage-detected metastases in patients with a DMI of 0, <50%, and ≥50% was 0.8%, 8.0%, and 7.4%, respectively. Lymphovascular invasion was present in 20(87%) of the cases containing low-volume, ultrastage-detected metastases in the lymph nodes.
Conclusions
SLN mapping with pathologic ultrastaging in endometrial carcinoma detects additional low-volume metastases(4.5%) that would otherwise go undetected with routine evaluations. Our data support the incorporation of pathologic ultrastaging of SLNs in endometrial carcinoma with any degree of myoinvasion. The oncologic significance of lowvolume nodal metastases requires long-term follow-up.
doi:10.1097/IGC.0b013e3182954da8
PMCID: PMC4079038  PMID: 23694985
sentinel lymph node; endometrial carcinoma; ultrastaging; micrometastasis; low-volume metastasis
15.  Inhibition of Enhancer of Zeste Homolog 2 (EZH2) expression is associated with decreased tumor cell proliferation, migration and invasion in endometrial cancer cell lines 
Objective
To investigate the impact of Enhancer of Zeste Homolog 2 (EZH2) expression on endometrial cancer cell line behavior.
Methods/materials
EZH2 expression levels were compared between the non-malignant endometrial cell line T-HESC, and 3 endometrial cancer cell lines, ECC-1, RL95-2 and HEC1-A. Stable EZH2 knockdown cell lines were created and the impact on cellular proliferation, migration and invasion were determined. Fluorescent activated cell sorting was used to examine effects of EZH2 silencing on cell cycle progression. EZH2 expression in endometrial cancer tissue specimens was examined using immunohistochemistry. Comparison of differences between control and shEZH2 cell lines was performed using student's t test and Fischer's exact test.
Results
EZH2 protein expression was increased in all 3 cancer cell lines, and human endometrial cancer tissue specimens relative to control. RNA interference of EZH2 expression in ECC-1, RL95-2, and HEC1-A significantly decreased cell proliferation, migration and invasion. Down regulation of EZH2 expression resulted in a significant increase in the proportion of cells arrested in G2/M. RNA interference of EZH2 expression was associated with an increase in the expression of Wnt pathway inhibitors sFRP1 and DKK3, and a concomitant decrease in β-catenin. EZH2 expression in human tissue samples was significantly associated with increased stage, grade, depth of invasion and nodal metastasis.
Conclusions
EZH2 expression is associated with tumor cell proliferation, migration and invasion in 3 endometrial cancer cell lines, as well as increased stage, grade, depth of invasion and nodal metastasis in human cancer tissue specimens. Further investigation into this potential therapeutic target is warranted.
doi:10.1097/IGC.0b013e318296a265
PMCID: PMC3694282  PMID: 23792601
EZH2; endometrial cancer; pathology
16.  The Impact of Maximum Rectal Distention and Tandem Angle on Rectal Dose in 3D Planned Gynecologic High-Dose-Rate Brachytherapy for Locally Advanced Cervical Cancer 
Objective
Computed tomography (CT)-based treatment planning for cervical cancer has allowed investigation into the volumetric radiation dose delivered to the rectum. The goal of intracavitary brachytherapy is to maximize the tumor dose while decreasing the dose to normal tissue like the rectum. We investigated the effects of tandem angle and maximum rectal distention on rectal dose delivered in HDR brachytherapy for locally advanced cervical cancer.
Methods and Materials
Between July 2007 and January 2010, 97 brachytherapy treatment planning CT scans from the first and last implant of 51 patients with locally advanced cervical cancer were reviewed. The rectum was manually contoured from the ischial tuberosity to the bottom of the sacroiliac joint. The maximum rectal distention was determined by measuring the largest anterior-posterior diameter of the rectum superior to the tandem ring and inferior to the end of the applicator. A volumetric measurement of the maximum and mean rectal dose, dose to 2cc (D2cc), dose to 1cc (D1cc) of the rectum was calculated. The tandem angle and the ICRU rectal point were recorded, and a dose volume histogram was referenced.
Results
The mean maximum rectal distention was 3.01cm. The mean D1cc, D2cc, mean rectal dose, maximum rectal dose, and ICRU rectal dose were 3.03 Gy, 2.78 Gy, 4.19 cGy, 1.40 cGy, and 2.99 Gy per treatment, respectively. In a multivariate analysis controlling for surface area, tandem angle, and body mass index (BMI), there was a significant increase in D2cc with increasing rectal distention (P=.016). There were no significant findings when observing the effects of tandem angle on D2cc.
Conclusion
Rectal distention significantly impacts D2cc delivered in HDR brachytherapy. In contrast, tandem angle does not. Concerted efforts to decrease rectal distention should be considered during treatment planning and delivery.
doi:10.1097/IGC.0b013e3182959030
PMCID: PMC3706279  PMID: 23792603
Tandem angle; Brachytherapy; Rectal Distention; CT; Cervical Cancer
17.  Risk Factors for Ovarian Cancers with and without Microsatellite Instability 
Objective
In a population-based sample of epithelial ovarian cancers, to evaluate the association between microsatellite instability status and: 1) Ovarian cancer risk factors and 2) The distribution of the specific histologic subtypes.
Patients and methods
Participants were drawn from three population-based studies of primary epithelial ovarian cancer: Tumor DNA was analyzed using five standardized microsatellite markers to assess microsatellite instability (MSI) status. Patients were divided into three groups (MSI-high, MSI-low and MSI-stable) according to NCI criteria. We compared the prevalence of specific known risk and protective factors among the three subgroups, including BMI, smoking history, parity, BRCA1 and BRCA2 mutation status, past oral contraceptive use, and tubal ligation. Similarly, we compared the distribution of the histologic subtypes among the three subgroups.
Results
A total of 917 ovarian cancer patients were included. One hundred twenty seven (13.8%) cancers were MSI-high. Subgroup analyses according to smoking, BMI, parity, past oral contraceptive use and past tubal ligation did not reveal any statistically significance differences among the groups. Among the 29 patients with BRCA1 mutations, 20.7% had MSI-high cancers compared with 5.9% among 17 BRCA2-mutation patients. The proportions of different ovarian cancer histologies among the various microsatellite instability subgroups were similar.
Conclusions
The prevalence of risk and protective factors among ovarian cancer patients is similar for cancers with and without microsatellite instability. The distributions of microsatellite instability do not differ significantly among ovarian cancers with different histologies. Ovarian cancer patients with BRCA1 mutations had a 21% rate of MSI-high tumors, compared to 6% among patients with BRCA2 mutations, but this difference was not statistically significant.
doi:10.1097/IGC.0b013e31829a5527
PMCID: PMC3740723  PMID: 23748177
18.  CA125 Level Association with Chemotherapy Toxicity and Functional Status in Older Women with Ovarian Cancer 
Objective
Older women with ovarian cancer have increased cancer-related mortality and chemotherapy toxicity. CA125 is a sensitive biomarker for tumor burden. The study evaluates the association between CA125, geriatric assessment (GA), and treatment toxicity.
Methods
This is a secondary subset analysis of patients age ≥65 with ovarian cancer accrued to a multicenter prospective study that developed a predictive toxicity score for older adults with cancer. Clinical and geriatric covariates included sociodemographics, GA (comorbidity, social support, functional, nutritional, psychological, cognitive status), treatment, and labs. Utilizing bivariate analyses, we determined the association of abnormal CA125 (≥35 U/mL) with baseline GA, grade 3–5 toxicity (CTCAE v.3), dose adjustments, and hospitalization. Logistic regression analysis was used to check for potential confounder for association between CA125 and chemotherapy toxicity.
Results
Fifty-one (10%) of 500 patients accrued to the primary study had a diagnosis of ovarian (92%), peritoneal (4%), or fallopian tube (4%) cancer. Median age was 72 (range, 65–86). Forty-six patients (90%) had stage III–IV disease. Twenty-three patients (45%) received first-line chemotherapy, and 34 (67%) received platinum-doublet therapy. Thirty-six (71%) had an abnormal CA125. Grade 3–5 toxicity occurred in 19 patients (37%). Abnormal CA125 was associated with assistance with instrumental activities of daily living (IADL) (p<0.05), lower performance status (p=0.05), grade 3–5 toxicity (p=0.03), non-heme toxicity (p=0.04), and dose reductions (p=0.01). No association between CA125 level and total toxicity score was observed.
Conclusions
Among older women with ovarian cancer, abnormal CA125 was associated with poor pre-treatment functional status and an increased probability of chemotherapy toxicity and dose reduction.
doi:10.1097/IGC.0b013e318299438a
PMCID: PMC3772622  PMID: 23765208
CA125; older women; ovarian cancer; chemotherapy toxicity; functional status
19.  Brief Report: Knowledge, attitudes, practices and perceived risk of cervical cancer among Kenyan women 
OBJECTIVES
Eastern Africa has the highest incidence and mortality rates from cervical cancer worldwide. It is important to describe the differences among women and their perceived risk of cervical cancer in order to determine target groups to increase cervical cancer screening.
METHOD
In this cross-sectional study we surveyed women seeking reproductive health services in Kisumu, Kenya to assess their perceived risk of cervical cancer and risk factors influencing cervical cancer screening uptake. Chi-square statistics and t-tests were used to determine significant factors, which were incorporated into a logistic model to determine factors independently associated with cervical cancer risk perception.
RESULTS
While 91% of the surveyed women had heard of cancer, only 29% of the 388 surveyed women had previously heard of cervical cancer. The majority had received their information from healthcare workers. Few women (6%) had ever been screened for cervical cancer and cited barriers such as fear, time, and lacking knowledge about cervical cancer. Nearly all previously screened women (22/24, 92%) believed that cervical cancer was curable if detected early, and that screening should be conducted annually (86%). Most women (254/388, 65%) felt they were at risk for cervical cancer. Women with perceived risk of cervical cancer were older (OR=1.06, 95% CI 1.02, 1.10), reported a history of marriage (OR=2.08, CI 1.00, 4.30), were less likely to feel adequately informed about cervical cancer by healthcare providers (OR= 0.76, CI 0.18, 0.83) and more likely to intend to have cervical cancer screening in the future (OR= 10.59, CI 3.96, 28.30). Only 5% of women reported that they would not be willing to undergo screening, regardless of cost.
Conclusions
Cervical cancer is a major health burden for women in sub-Saharan Africa, yet only one-third of women had ever heard of cervical cancer in Kisumu, Kenya. Understanding factors associated with women’s perceived risk of cervical cancer could guide future educational and clinical interventions to increase cervical cancer screening.
doi:10.1097/IGC.0b013e31828e425c
PMCID: PMC3662490  PMID: 23694983
Screening; Barriers; Cervical Cancer; Africa
20.  CA-125 Level as a Prognostic Indicator in Type I and Type II Epithelial Ovarian Cancer 
Objective
The majority of patients with epithelial ovarian cancer achieved a complete clinical remission with normal CA-125 will still relapse and die from their disease. The present study was to determine whether CA-125 levels before, during and after primary treatment provided prognostic information for both Type I and Type II ovarian cancer.
Methods
In this retrospective study, we identified 410 epithelial ovarian cancer patients who had achieved a CCR between 1984 and 2011. A Cox proportional hazards model and log-rank test were used to assess associations between the nadir CA-125, histotype, and prognosis.
Results
The baseline serum CA-125 concentration was higher in patients with type II ovarian cancer than in those with type I (p < 0.001). The nadir CA-125 was an independent predictor of PFS (p < 0.001) and OS (p = 0.035) duration. The PFS and OS durations were 21.7 and 79.4 months in patients with CA-125 ≤ 10 U/ml and 13.6 and 64.6 months in those with 11-35 U/ml (p = 0.01 and 0.002, respectively). Histotype was an independent predictor of PFS (p = 0.041): the PFS and OS durations of type I patients were longer than those in type II (p < 0.001 and < 0.001, respectively).
Conclusions
The nadir CA-125 and the histotype are predictive of PFS and OS duration in ovarian cancers experienced a CCR. PFS and OS durations were shorter in patients with CA-125 levels of 11-35 U/ml and type II disease than in those with ≤ 10 U/ml and type I.
doi:10.1097/IGC.0b013e31828f7a24
PMCID: PMC3760786  PMID: 23669443
ovarian cancer; CA-125; prognosis factors; tumor marker; pathological type
21.  Characterizing the efficacy of fermented wheat germ extract against ovarian cancer and defining the genomic basis of its activity 
Objective
The majority of women with advanced-stage epithelial ovarian cancer (OVCA) ultimately develop chemo-resistant, recurrent disease. Therefore, a great need exists to develop new, more active, and less toxic agents and/or to optimize the efficacy of existing agents.
Methods
In this study, we investigated the activity of Avemar®, a natural, non-toxic, fermented wheat germ extract (FWGE), against a range of OVCA cell lines, both alone and in combination with cisplatin chemotherapy, and delineated the molecular signaling pathways that underlie FWGE activity at a genome-wide level.
Results
We found that FWGE exhibited significant anti-proliferative effects against 12 human OVCA cell lines and potentiated cisplatin-induced apoptosis. Pearson’s correlation of FWGE sensitivity and gene expression data identified 2,142 genes (FDR<0.2) representing 27 biological pathways (p<0.05) to be significantly associated with FWGE sensitivity. A parallel analysis of genomic data for 59 human cancer cell lines matched to chemo-sensitivity data for 2,6-dimethoxy-p-benzoquinone, a proposed active component of FWGE, identified representation of 13 pathways common to both FWGE and 2,6-dimethoxy-p-benzoquinone sensitivity.
Conclusions
Our findings confirm the value of FWGE as a natural product with anti-cancer properties that may also enhance the activity of existing therapeutic agents. Furthermore, our findings provide substantial insights into the molecular basis of FWGE’s effect on human cancer cells.
doi:10.1097/IGC.0b013e318258509d
PMCID: PMC4036555  PMID: 22740002
Fermented wheat germ extract; Avemar; ovarian cancer; apoptosis; cisplatin
22.  SIX-YEAR REGRESSION AND PROGRESSION OF CERVICAL LESIONS OF DIFFERENT HPV VIRAL LOADS IN VARIED HISTOLOGICAL DIAGNOSES 
Objective
This study aims to evaluate HPV viral load as a biomarker for triage into colposcopy and CIN2 therapy, in order to reduce the colposcopy referral rate and CIN2 over treatment in low resource settings.
Methods
In 1999, 1997 women aged 35–45 in Shanxi, China, received six cervical screenings with pathological confirmation. In 2005, 1461 histologically normal women, 99 with cervical intraepithelial neoplasia (CIN) grade 1 (CIN1), and 30 with CIN grade 2 or worse (CIN2+) were rescreened in a follow-up study. HPV was detected by Hybrid Capture 2. Viral load, estimated by the ratio of relative light units to standard positive control, was categorized into four groups: negative (<1.0), low (≥1.0, <10.0), moderate (≥10.0, <100.0) and high (≥100.0). We estimated cumulative incidence of CIN2+ by viral load subgroups and calculated adjusted hazard ratios (aHR) for CIN2+ using Cox proportional hazards regression.
Results
Cumulative incidence of CIN2+ increased with baseline HPV viral load among normal women and women with CIN1 at baseline (P-trend<0.001). Repeat moderate-high viral load was associated with the highest risk for CIN2+ (aHR=188.8, 95% confidence interval: 41.2–864.1). Raising the RLU/PC cutoff from 1.0 to 10.0 for colposcopy greatly reduced the referral rate from 18.1% to 12.9%. It also increased the specificity (84.8% vs. 90.4%), the positive predictive value (22.5% vs. 28.9%), and the positive likelihood ratio (6.4 vs. 8.9), yet with loss of the sensitivity by 12% (97.6% vs. 85.7%). Among women with CIN2 at baseline, 56% regressed to normal, 24% regressed to CIN1, 4% remained CIN2, and 16% progressed to CIN3+.
Conclusions
Locales using HPV testing as the primary screening method, and lacking high-quality cytology-based screening, should consider viral load as an alternative to colposcopy triage for women over age 35. Viral load may also predict CIN2 progression until additional biomarkers become available.
doi:10.1097/IGC.0b013e318286a95d
PMCID: PMC3636161  PMID: 23455757
Cervical Intraepithelial Neoplasia (CIN); Hazard Ratios (HR); Human Papillomavirus (HPV) viral load; Regression; Progression
23.  Ribonucleotide Reductase Expression in Cervix Cancer: a Radiation Therapy Oncology Group Translational Science Analysis 
Objective
To evaluate pretherapy ribonucleotide reductase (RNR) expression and its effect upon radiochemotherapeutic outcome in women with cervical cancer.
Methods/Materials
Pretherapy RNR M1, M2, M2b immunohistochemistry was done on cervical cancer specimens retrieved from women treated on Radiation Therapy Oncology Group (RTOG) 0116 and 0128 clinical trials. RTOG 0116 enrollees (node-positive stage IA-IVA) received weekly cisplatin (40mg/m2) with amifostine (500mg) and extended-field radiation then brachytherapy (85Gy). RTOG 0128 enrollees (node-positive or bulky ≥ 5cm stage IB-IIA, or stage IIB-IVA) received day 1, 23, 43 cisplatin (75mg/m2), 5-FU (4-day 1gm/m2) during pelvic radiation then brachytherapy (85Gy), plus celecoxib (400mg twice daily, day 1 through 1 year). Disease-free survival (DFS) was estimated univariately by the Kaplan-Meier method. Cox proportional hazards models evaluated the impact of RNR immunoreactivity on DFS.
Results
51 tissue samples were analyzed; 13 from RTOG 0116 and 38 from RTOG 0128. M1, M2, and M2b overexpression (3+) frequencies were 2%, 80%, and 47%, respectively. Low-level (0–1+, n=44/51) expression of the regulatory subunit M1 did not associate with DFS (p=0.38). High (3+) M2 expression occurred in most (n=41/51), but without impact alone upon DFS (hazard ratio (HR): 0.54, 95% confidence interval [CI]: 0.2–1.4; p=0.20). After adjusting for M2b status, pelvic node-positive women had increased hazard for relapse or death (HR: 5.5, 95% CI: 2.2–13.8; p=0.0003).
Conclusions
These results suggest that RNR subunit expression may discriminate cervical cancer phenotype and radiochemotherapy outcome. Future RNR biomarker studies are warranted.
doi:10.1097/IGC.0b013e31828b4eb5
PMCID: PMC3662019  PMID: 23552804
ribonucleotide reductase; radiosensitivity; cervical cancer
24.  The Risk of Lymph-Node Metastasis with Positive Peritoneal Cytology in Endometrial Cancer 
Objective
To determine the correlation between positive peritoneal cytology (PPC) and lymph node metastasis in patients with endometrial cancer grossly confined to the uterus.
Methods
Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Only those patients with endometrial cancer grossly confined to the uterus who had undergone a complete staging procedure (lymph-node removal) were included. Statistical analysis used Chi-square test and logistic regression models.
Results
A total of 22,947 patients were identified. PPC was present in 3.5% of patients. The incidence of lymph node metastasis was significantly higher among patients with PPC compared to those with negative peritoneal cytology for all histologic types examined (p<0.0001): endometrioid adenocarcinoma; 28.7% vs. 6.9%, adenocarcinoma not otherwise specified; 35.4% vs. 5.8%, clear cell/serous carcinoma; 41.4% vs. 19.0%, and carcinosarcoma; 38.4% vs. 14.4%. After adjusting for other contributing factors in the multivariable model, PPC remained an independent predictor of lymph node metastasis (p<0.0001).
Conclusion
Our data indicates that patients with positive washings are at significant risk of nodal metastasis and adverse prognosis. Although, no longer a part of the current FIGO staging criteria, peritoneal cytology status should continue to inform clinical decision-making in endometrial cancer.
doi:10.1097/IGC.0b013e318275afd2
PMCID: PMC3992285  PMID: 23196758
Peritoneal cytology; Lymph node; Metastasis; Endometrial cancer
25.  A New Diagnostic Test for Endometrial Cancer? 
Objective
During saline-infused sonohysterography (SIS), the distension fluid is typically discarded. If cytology analysis could identify those patients with endometrial cancer, many women would be spared from further procedures.
Methods
Thirty consecutive patients with clinical stage I or II endometrial adenocarcinoma were prospectively recruited preoperatively. Saline-infused sonohysterography was performed by instilling 5 mL of saline, withdrawing and sending for analysis. Saline was reinfused until complete SIS images were obtained and sent separately for cytology.
Results
Of the 30 women enrolled, SIS was technically successful in 29. Demographics included mean age (60.5 ± 6.99 years), body mass index (35.55 ± 8.18 kg/m2), endometrioid histology (76%), and grade (grade 1, 67%). Prestudy diagnostic method included biopsy (70%), dilatation and curettage (17%), and hysteroscopy (10%). Adequate cytology specimens were obtained in 66% of the 5mL flushes and 72% of the complete SIS collections. Of adequate specimens, the sensitivities to detect endometrial cancer for the 5-mL, complete, and combined fluid samples were 26% (95% confidence interval, 9%–51%), 36% (17%–59%), and 42% (22%–63%). Sensitivity based on the whole study sample (N = 30) was 33% (17%–53%). Statistical significance was not found in the association between a positive test and age, body mass index, grade, diagnostic method, or volume instilled or aspirated.
Conclusions
Most patients with early endometrial cancer can undergo SIS procedures with adequate cytology specimens obtained from distention media. However, the sensitivity is low, and refinements are necessary before utilizing as a diagnostic test. In cases with positive results, the patient may be able to avoid other costly and painful procedures.
doi:10.1097/IGC.0b013e31829fe8f6
PMCID: PMC3976997  PMID: 23881100
Saline-infused sonohysterography; Endometrial cancer; Cytopathology

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