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BackgroundDehydroepiandrosterone (DHEA) is helpful for treating vaginal symptoms. This secondary analysis evaluated the impact of vaginal DHEA on hormone concentrations, bone turnover, and vaginal cytology in women with a cancer history.MethodsPostmenopausal women, diagnosed with breast or gynecologic cancer, were eligible if they reported at least moderate vaginal symptoms. Participants could be on tamoxifen or aromatase inhibitors (AIs). Women were randomized to 3.25 versus 6.5 mg/day of DHEA versus a plain moisturizer (PM) control. Sex steroid hormone levels, biomarkers of bone formation, vaginal pH, and maturation index were collected at baseline and 12 weeks. Analysis included independent t tests and Wilcoxon rank tests, comparing each DHEA arm with the control.ResultsThree hundred forty-five women contributed evaluable blood and 46 contributed evaluable cytology and pH values. Circulating DHEA-S and testosterone levels were significantly increased in those on vaginal DHEA in a dose-dependent manner compared to PM. Estradiol was significantly increased in those on 6.5 mg/day DHEA but not in those on 3.25 mg/day DHEA (p < 0.05 and p = 0.05, respectively), and not in those on AIs. Biomarkers of bone formation were unchanged in all arms. Maturation of vaginal cells was 100% (3.25 mg/day), 86% (6.5 mg/day), and 64% (PM); pH decreased more in DHEA arms.ConclusionDHEA resulted in increased hormone concentrations, though still in the lowest half or quartile of the postmenopausal range, and provided more favorable effects on vaginal cytology, compared to PM. Estrogen concentrations in women on AIs were not changed. Further research on the benefit of vaginal DHEA is warranted in hormone-dependent cancers.

ObjectivesWalking is an adaptable, inexpensive and accessible form of physical activity. However, its impact on quality of life (QoL) and symptom severity in people with advanced cancer is unknown. This study aimed to assess the feasibility and acceptability of a randomised controlled trial (RCT) of a community-based walking intervention to enhance QoL in people with recurrent/metastatic cancer.DesignWe used a mixed-methods design comprising a 2-centre RCT and nested qualitative interviews.ParticipantsPatients with advanced breast, prostate, gynaecological or haematological cancers randomised 1:1 between intervention and usual care.InterventionThe intervention comprised Macmillan's ‘Move More’ information, a short motivational interview with a recommendation to walk for at least 30 min on alternate days and attend a volunteer-led group walk weekly.OutcomesWe assessed feasibility and acceptability of the intervention and RCT by evaluating study processes (rates of recruitment, consent, retention, adherence and adverse events), and using end-of-study questionnaires and qualitative interviews. Patient-reported outcome measures (PROMs) assessing QoL, activity, fatigue, mood and self-efficacy were completed at baseline and 6, 12 and 24 weeks.ResultsWe recruited 42 (38%) eligible participants. Recruitment was lower than anticipated (goal n=60), the most commonly reported reason being unable to commit to walking groups (n=19). Randomisation procedures worked well with groups evenly matched for age, sex and activity. By week 24, there was a 45% attrition rate. Most PROMs while acceptable were not sensitive to change and did not capture key benefits.ConclusionsThe intervention was acceptable, well tolerated and the study design was judged acceptable and feasible. Results are encouraging and demonstrate that exercise was popular and conveyed benefit to participants. Consequently, an effectiveness RCT is warranted, with some modifications to the intervention to include greater tailoring and more appropriate PROMs selected.Trial registration numberISRCTN42072606.

Summary Objective Perifosine exhibits anti-tumor activity by inhibiting AKT phosphorylation. The purpose of this phase II basket trial was to evaluate the efficacy and safety of perifosine monotherapy for ovarian, endometrial, and cervical cancers. Methods Recurrent or persistent ovarian, endometrial, or cervical cancer patients were assigned to PIK3CA wild-type or mutant groups. Each patient received 600 mg oral perifosine on day 1 followed by a maintenance dose of 100 mg daily. The primary endpoint was disease control rate; secondary endpoints included response rate, progression-free survival, overall survival, and safety. Immunohistochemical staining and targeted sequencing were used to explore new biomarkers in such patients. Results Sixteen and 5 ovarian, 17 and 7 endometrial, and 18 and 8 cervical cancer patients with PIK3CA wild-type and mutant, respectively, were enrolled. Disease control rates (wild-type/mutant) were 12.5/40.0%, 47.1/14.3%, and 11.1/25.0% in ovarian, endometrial, and cervical cancer, respectively. The most common grade 3/4 toxicities were anemia (22.5%) and anorexia (11.3%). Immunohistochemical staining revealed that the disease control rate in patients with negative phosphatase and tensin homolog (PTEN) expression was 50.0%, and the odds ratio of positive to negative patients was 0.24 in all patients. Conclusions Perifosine monotherapy showed good tolerability but expected efficacy was not achieved. Modest efficacy was demonstrated in ovarian cancer patients with PIK3CA mutations and endometrial cancer patients with PIK3CA wild-type; no difference was observed between PIK3CA wild-type and mutant in cervical cancer. Absence of PTEN expression may be predictive of clinical efficacy with perifosine monotherapy.

BackgroundData suggest an association between positron emission tomography/CT (PET/CT) metabolic metrics and tumor microenvironment in several malignancies, and a potential role of PET/CT to monitor response to immunotherapy.ObjectiveTo evaluate the correlation between tumor loco-regional extension and tumor-infiltrating lymphocyte infiltration in locally advanced cervical cancer prior to concurrent chemo-radiotherapy.The secondary objective was to assess the association between tumor-infiltrating lymphocytes and PET/CT metabolic metrics.MethodsPatients with locally advanced cervical cancer and negative para-aortic extensions on PET/CT were included. Two senior nuclear medicine physicians specializing in gynecologic oncology reviewed all PET/CT exams, and extracted tumor maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis, as well as pelvic lymph node involvement. One senior gynecologic oncology pathologist assessed intraepithelial tumor-infiltrating lymphocytes and stromal tumor-infiltrating lymphocytes. Intraepithelial tumor-infiltrating lymphocytes were categorized following previous studies as <1% and >1%. The cut-off for stromal tumor-infiltrating lymphocytes was chosen empirically: intermediate <60% and high >60%.Results86 patients were included. Intraepithelial tumor-infiltrating lymphocytes were not significantly associated with tumor metabolic metrics. Intraepithelial tumor-infiltrating lymphocytes were not significantly associated with maximum standard uptake value (p=0.16), or metabolic tumor volume (p=0.19). Tumors with <1% intraepithelial tumor-infiltrating lymphocytes score were associated with a higher MRI tumor size (≥ median) (63.3% vs 39.3%, p=0.04). Patients with pelvic lymph node uptake were significantly more frequent in patients with high stromal tumor-infiltrating lymphocytes score (≥60%) (61.5% vs 31.7%, p=0.009).ConclusionsPoor or absent intraepithelial tumor-infiltrating lymphocytes were associated with more advanced disease at diagnosis and larger tumor size. Tumor-infiltrating lymphocytes were not associated with tumor metabolic activity. Intraepithelial and stroma tumor-infiltrating lymphocytes are not redundant and should be assessed separately. Further work is needed to evaluate the association between tumor metabolic profile and immune populations, including different T-cell subtypes for patient selection for immunotherapy strategies.

The objectives of this study were to describe the rate and predictors of surgical site infection (SSI) after gynecologic cancer surgery and identify any association between SSI and postoperative outcome. Patients with endometrial, cervical, or ovarian cancers from 2005 to 2011 were identified from the American College of Surgeons National Surgical Quality Improvement Program. The extent of surgical intervention was categorized into modified surgical complexity scoring (MSCS) system. Univariate and multivariate logistic regression analyses were used. Odds ratios were adjusted for patient demographics, comorbidities, preoperative laboratory values, and operative factors. Of 6854 patients, 369 (5.4%) were diagnosed with SSI. Surgical site infection after laparotomy was 3.5 times higher compared with minimally invasive surgery (7% vs 2%; P < 0.001). Among laparotomy group, independent predictors of SSI included endometrial cancer diagnosis, obesity, ascites, preoperative anemia, American Society of Anesthesiologists class greater than or equal to 3, MSCS greater than or equal to 3, and perioperative blood transfusion. Among laparoscopic cases, independent predictors of SSI included only preoperative leukocytosis and overweight. For patients with deep or organ space SSI, significant predictors included hypoalbuminemia, preoperative weight loss, respiratory comorbidities, MSCS greater than 4, and perioperative blood transfusion for laparotomy and only preoperative leukocytosis for minimally invasive surgery. Surgical site infection was associated with longer mean hospital stay and higher rate of reoperation, sepsis, and wound dehiscence. Surgical site infection was not associated with increased risk of acute renal failure or 30-day mortality. These findings were consistent in subset of patients with deep or organ space SSI. Seven percent of patients undergoing laparotomy for gynecologic malignancy developed SSI. Surgical site infection is associated with longer hospital stay and more than 5-fold increased risk of reoperation. In this study, we identified several risk factors for developing SSI among gynecologic cancer patients. These findings may contribute toward identification of patients at risk for SSI and the development of strategies to reduce SSI rate and potentially reduce the cost of care in gynecologic cancer surgery.

PurposeUnrecognised psychological distress among cancer survivors may be identified using short screening tools. We validated the accuracy of the distress thermometer (DT) to detect psychological distress on the Hospital Anxiety and Depression Scale (HADS) among early stage gynaecological cancer survivors and whether the women’s DT and HADS scores were associated with the need of an individualised supportive intervention.MethodsOne hundred sixty-five gynaecological cancer survivors answered DT and HADS before randomisation in a trial testing a nurse-led, person-centred intervention using supportive conversations. The number of conversations was decided in the woman-nurse dyad based on the woman’s perceived need. Nurses were unaware of the women’s DT and HADS scores. We validated DT’s accuracy for screening using HADS as gold standard and receiver operating characteristic curves. Associations between DT and HADS scores and the number of conversations received were investigated.ResultsFor screening of distress (HADS ≥ 15), a DT score ≥ 2, had a sensitivity of 93% (95% CI 82–98%), a specificity of 40% (32–49%), and positive and negative predictive values of 36% (28–45%), and 94% (84–98%), respectively; area under curve was 0.73 (0.64–0.81). Higher DT and HADS scores were associated with more interventional conversations.ConclusionsIn gynaecological cancer survivors, DT may perform fairly well as a first stage screening tool for distress, but a second stage is likely needed due to a high number of false positives. DT and HADS scores may predict the number of supportive conversations needed in an individualised intervention in gynaecological cancer survivors.

Background A randomized controlled trial was performed to assess the outcome of early oral postoperative feeding (EOF) compared with traditional oral feeding (TOF) in gynecologic oncology patients undergoing a complex laparotomy, including upper abdominal surgery. Methods Patients aged 18–75 years, undergoing an elective laparotomy and with a preoperative suspicion of gynecologic malignancy, were eligible. Exclusion criteria included infectious conditions, intestinal obstruction, severe malnutrition, American Society of Anesthesiologists score ≥4, intestinal resection, and postoperative stay in the intensive care unit lasting >24 h. Patients allocated to EOF received liquid diet in the first postoperative day and then regular diet. Patients received traditional feeding scheme until resolution of postoperative ileus to start liquid diet. The primary end-point of the trial was length of hospital stay. Results Between January 1, 2007, and November 17, 2007, a total of 143 patients were randomized to receive either EOF or TOF. Hospital stay for patients who received EOF ( n  = 71) was 4.7 vs. 5.8 days for the TOF group ( n  = 72) ( P  = 0.006). The mean level of postoperative satisfaction was significantly higher in the EOF group (82.8 vs. 71.7 mm, P  ≤ 0.001). Patients who received the TOF scheme had significantly higher overall postoperative complications (39 vs. 17% in EOF group, P  = 0.003) and infective complications (14% in TOF group vs. 3% in EOF group, P  = 0.017). Variables such as nausea and vomiting, analgesic and antiemetic requirement as well as level of pain and quality of life were not different between groups. Conclusions On the basis of these findings, the policy of EOF should be used after a complex gynecologic oncologic laparotomy.

Aim: To determine the efficacy of belly board device in patients receiving postoperative radiation for gynecological malignancies in terms of setup error and acute small bowel toxicity. Materials and Methods: Patients requiring postoperative radiation for gynecological malignancies were prospectively randomized to either treatment with supine position (supine arm) or prone position using belly board (prone arm). Each patient underwent computed tomography simulation in the assigned treatment position, and a three-dimensional conformal radiation was planned. Weekly two to three treatment sessions were verified using portal imaging and setup errors were noted. All patients were reviewed weekly to assess for symptoms and toxicity using a structured format. The systematic and random errors were calculated along the three axes. Results: Twenty-four patients were randomized and 22 patients were available for the final analysis. The systematic error in supine arm versus prone arm was 3.9 versus 3.5 mm, 2.1 versus 4.8 mm and 3.1 versus 3.1 mm along lateral, antero-posterior (AP) and cranio-caudal (CC) direction. The random error in supine arm versus prone arm was 5 versus 3.9 mm, 2.9 mm versus 4.4 mm and 4.3 versus 3.4 mm along lateral, AP and CC direction. The calculated planning target volume margin for supine arm was 1.3, 0.7, and 1.0 cm and margin for prone arm was 1.1, 1.5, and 1.0 cm along lateral, AP, and CC direction, respectively. One patient in supine arm developed Grade 3 toxicity. Conclusion: The systematic error and random error is more along AP direction for prone position. The acute small bowel toxicity was less using belly board.

► Development of CIN3 is rare in women aged 30 years who test HPV DNA-negative. ► Heterosexual transmission is extremely common. ► Transmission between the anus and cervix and vice versa are common in a woman. ► Prevalence of penile HPV is greater than cervical HPV but persistence is less likely. ► Persons with HIV, MSM, and women with cervical cancer are at risk for anal cancer. This chapter addresses the natural history of anogenital human papillomavirus (HPV) infection. Cervical infections are the best understood HPV infection. Cervical HPV persistence is the known necessary event for the development of cervical cancer. New infections appearing at any age are benign unless they persist. Several long-term natural history studies have now shed light on the very low risk of cervical intraepithelial neoplasia (CIN) 3+ in women past the peak of HPV acquisition (e.g., 30 or older) who are HPV-negative or clear their HPV. Although data on transmission of HPV are finally emerging, rates of transmission between heterosexual couples vary widely among studies. Factors that affect the calculations of these rates include a) intervals between testing points, b) rates of concordance or discordance at baseline, and c) difficulty in defining established infections versus contamination. Both cervix to anus and anus to cervix autoinoculation in the same woman appears to be quite common. Whether either site serves as a long-term reservoir is unknown. Studies show that anal infections in women and in men who have sex with men are quite common with cumulative rates up to 70–90%. Similarly, clearance of anal HPV is also common, with few individuals showing persistence unless they are human immunodeficiency virus (HIV)-infected. HIV strongly influences the development of anal intraepithelial neoplasia (AIN). The few studies on the natural history of AIN in HIV-infected men suggest that high-grade AIN is a precursor to invasive anal cancer. Although no natural history studies of AIN are available in women, women with other HPV-associated lesions, including CIN3+ and vulvar cancer, have higher rates of anal cancer. Data on the natural history of HPV of the male genitalia are also emerging, although penile intraepithelial neoplasia is poorly understood. Cumulative rates of HPV are extremely high in men and risks are associated with sexual behavior. Unlike women, prevalence rates are steady across all ages, suggesting that men do not develop protection against reinfection. This article forms part of a special supplement entitled “Comprehensive Control of HPV Infections and Related Diseases” Vaccine Volume 30, Supplement 5, 2012.

Background Other than for breast cancer, endocrine therapy has not been highly effective for gynecologic cancers. Endocrine therapy resistance in estrogen receptor positive gynecologic cancers is still poorly understood. In this retrospective study, we examined the estrogen receptor (ER) signaling pathway activities of breast, ovarian, endometrial, and cervical cancers to identify those that may predict endocrine therapy responsiveness. Methods Clinical and genomic data of women with breast and gynecological cancers were downloaded from cBioPortal for Cancer Genomics. Estrogen receptor alpha (ESR1) expression level and sample-level pathway enrichment scores (EERES) were calculated to classify patients into four groups (low/high ESR1 and low/high EERES). Correlation between ESR1/EERES score and survival was further validated with RNAseq data from low-grade serous ovarian cancer. Pathway analyses were performed among different ESR1/EERES groups to identify genes that correlate with endocrine resistance, which are validated using Cancer Cell Line Encyclopedia gene expression and Genomics of Drug Sensitivity in Cancer data. Results We identified a novel combined prognostic value of ESR1 expression and the corresponding estrogen response signaling (EERES score) for breast cancer. The combined prognostic value (ESR1/EERES) may be applicable to other gynecologic cancers. More importantly, we discovered that ER signaling can cross-regulate MEK pathway activation. We identified downstream genes in the MEK pathway ( EPHA2 , INAVA , MALL , MPZL2 , PCDH1 , and TNFRSF21 ) that are potential endocrine therapy response biomarkers. Conclusion This study demonstrated that targeting both the ER and the ER signaling activity related MEK pathway may aid the development of endocrine therapy strategies for personalized medicine.