Identifying the palliative care needs of patients and families in gynecologic surgical oncology: A scoping review.

Introduction: Patients undergoing oncology-related gynecologic surgical procedures experience substantial symptom burden and distress. Support from specialist palliative care teams may benefit these patients and their families; however, an evidence-informed approach to the integration of palliative care and gynecologic surgical oncology is needed. To inform such an approach, a scoping review synthesizing current evidence on the palliative care needs of patients and families in gynecologic surgical oncology was conducted.Methods: Reviewers performed a structured search of online databases CINAHL, Scopus, PsycINFO, MEDLINE, and PubMed in addition to the grey literature to identify relevant studies published between 2011 and June 11th, 2021. The original search identified 993 articles, which were dually screened for study inclusion, resulting in a final sample of articles from which data were systematically extracted and synthesized.Results: This review of 59 publications predominantly consisted of European studies (n = 26, 44.1%), described quantitative study methods (n = 47, 79.6%), followed an observational study design (n = 49, 83.1%), and focused on psychological impact of treatment as a major topic of study (n = 21, 35.6%). The dataset also described sexual function of women post treatment (n = 15, 25.4%), quality of life (n = 10, 16.9%), therapeutic decision making (n = 9, 15.2%), pain assessment (n = 2, n = 3.6%), and medication for symptom management (n = 2, 3.6%). Explicit discussion of specialist palliative care involvement was rare.Conclusion: The needs of patients and families in gynecologic surgical oncology are well-suited to palliative care collaboration; however, the body of literature on palliative care services provided to this unique population is underdeveloped.

A rational diagnostic approach to the "phantom hCG" and other clinical scenarios in which a patient is thought to be pregnant but is not.

The scenario in which a patient tests positive for human chorionic gonadotropin (hCG) in the absence of pregnancy can pose a diagnostic dilemma for clinicians. The term "phantom hCG" refers to persistently positive hCG levels on diagnostic testing in a nonpregnant patient and such results often lead to a false diagnosis of malignancy and subsequent inappropriate treatment with chemotherapy or hysterectomy. There remains a need for a consistent and rational diagnostic approach to the "phantom hCG." This article aims to review the different etiologies of positive serum hCG testing in nonpregnant subjects and concludes with a practical, stepwise diagnostic approach to assist clinicians encountering this clinical dilemma.

Synchronous ovarian and endometrial carcinomas in a patient with Rubinstein-Taybi syndrome: a case report and literature review.

Rubinstein-Taybi syndrome is characterized by distinctive facial and limb features and is associated with several types of tumors. A 29-yr-old woman with this syndrome presented with a large, complex ovarian mass. She was subsequently diagnosed with a low-grade serous carcinoma of the ovary and an endometrioid adenocarcinoma of the uterus. Rubinstein-Taybi syndrome is an autosomal dominant, multiple congenital anomalies-mental retardation syndrome. Two genes, CREBBP and EP300, have been found to be associated with this disorder, although some cases do not have an identifiable cause. These genes code for proteins that acetylate histone tails, an epigenetic modification that serves to control transcription. They also serve as cofactors to several transcription factors and modulate p53. Although these patients have a predisposition to benign and malignant neoplasms, no malignant gynecologic neoplasm has been described thus far. Although no significant evidence linking CREBBP and EP300 to gynecologic malignancies has yet been found, some studies have suggested that hypoacetylation of histones may be involved in endometrial and ovarian carcinomas.

Tubal ligation frequency in Oklahoma women with cervical cancer.

OBJECTIVE: Infrequent Pap screening is an important risk factor for cervical cancer. We studied the association between contraceptive methods, screening frequency, and cancer. METHODS: Women (n=2004) enrolled in the cross-sectional Study to Understand Cervical Cancer Endpoints and Determinants (SUCCEED) underwent colposcopy to evaluate an abnormal Pap test. Questionnaire data were compared between those with cervical intraepithelial neoplasia (CIN) 3/adenocarcinoma in situ (AIS) and those with invasive cancer to identify factors associated with cancer. Logistic regression was used to calculate age-stratified measures of association between contraceptive method and Pap frequency as well as tubal ligation (TL) and cancer risk. RESULTS: In all age groups, women with TL were more likely to have had no Pap screening in the previous 5 years compared to women using other contraception: 26-35 years (OR 4.6, 95% CI 2.4-8.6; p<0.001), 36-45 years (OR 3.8, 95% CI 2.1-7.0; p<0.001), and 46-55 years (OR 2.2, 95% CI 1.0-4.9; p=0.050). Subjects with cancer (n=163) were more likely to have had a TL (41% vs. 21%, p<0.001) than those with CIN 3/AIS (n=370). Age-stratified analyses showed increased odds of tubal ligation in women with cancer versus those with CIN 3/AIS between 25 and 45 years, with a significant increase in women 26 to 35 years old (OR 3.3, 95% CI 1.4-8.1; p=0.009). Adjusting for Pap frequency changed the effect only slightly, suggesting that increased risk was not fully mediated by lack of screening. CONCLUSION: Contraceptive type is associated with Pap screening. Women with TLs obtain less frequent Pap testing and may be at an increased risk for cervical cancer.

HPV16 variant lineage, clinical stage, and survival in women with invasive cervical cancer.

BACKGROUND: HPV16 variants are associated with different risks for development of CIN3 and invasive cancer, although all are carcinogenic. The relationship of HPV 16 variants to cancer survival has not been studied. METHODS: 155 HPV16-positive cervical cancers were categorized according to European and non-European variant patterns by DNA sequencing of the E6 open reading frame. Clinico-pathologic parameters and clinical outcome were collected by chart review and death registry data. RESULTS: Of the 155 women (mean age 44.7 years; median follow-up 26.7 months), 85.2% harbored European variants while 14.8% had non-European sequences. HPV16 variants differed by histologic cell type (p = 0.03) and stage (1 vs. 2+; p = 0.03). Overall, 107 women (68.0%) were alive with no evidence of cancer, 42 (27.1%) died from cervical cancer, 2 (1.3%) were alive with cervical cancer, and 4 (2.6%) died of other causes. Death due to cervical cancer was associated with European variant status (p < 0.01). While 31% of women harboring tumors with European variants died from cervical cancer during follow-up, only 1 of 23 (4.4%) non-European cases died of cancer. The better survival for non-European cases was partly mediated by lower stage at diagnosis. CONCLUSIONS: Overall, invasive cervical cancers with non-European variants showed a less aggressive behavior than those with European variants. These findings should be replicated in a population with more non-European cases.

Risk of cervical intraepithelial neoplasia 2+ among women with a history of previous treatment for cervical intraepithelial neoplasia: ASCUS and LSIL Pap smears after treatment.

OBJECTIVE: The objective of the current study was to describe outcomes among women with low-grade abnormalities on cervical cytology screening in the setting of previous excisional or ablative treatment for cervical intraepithelial neoplasia (CIN). METHODS: Study participants were recruited into the Study to Understand Cervical Cancer Early Endpoints and Determinants. At enrollment, the patient's previous cytology results, previous colposcopic biopsy results, and previous cervical procedures were recorded. Study procedures included collection of biospecimens followed by colposcopy and biopsy. From clinical records, additional information regarding previous treatment for CIN was collected. RESULTS: Two hundred seventy-four women had an atypical squamous cells of uncertain significance (ASCUS) referral Pap and 532 women had a low-grade squamous intraepithelial lesion (LSIL) referral Pap. For patients with an ASCUS referral Pap, previous treatment was associated with an odds ratio for CIN 2+ (45.0% vs 28.2% of untreated patients) of 2.08 (95% confidence interval = 1.05-4.13, p = .04). For patients with an LSIL referral Pap, 33.3% of those women with previous treatment had CIN 2+ compared with 16.7% of those patients enrolled with no previous treatment (odds ratio = 2.49, 95% confidence interval = 1.12-5.51, p = .03). CONCLUSIONS: Patients with a history of previous treatment for CIN have a 2-fold risk of CIN 2+ at the time of colposcopy referral for ASCUS or LSIL cervical cytology.

Haptoglobin expression in endometrioid adenocarcinoma of the uterus.

OBJECTIVE: Elevated serum haptoglobin (Hp) concentrations have been reported in patients with malignant diseases. We have shown that Hp is produced by and localizes only in the stroma and not the epithelium of endometriotic lesions, which share many characteristics of carcinoma. Furthermore, Hp mRNA and protein are found exclusively in the stroma of eutopic endometrium from women with endometriosis and not those without endometriosis. We hypothesized that characteristic patterns of Hp gene expression and protein localization in endometrioid adenocarcinoma of the uterus may provide insight into the clinical utility of Hp as a tumor marker or alternative therapeutic approach. METHODS: Biopsies of endometrioid adenocarcinoma tumors of the uterus and their adjacent nonaffected endometrium were collected. Normal endometrium was collected from healthy women. Haptoglobin messenger RNA (mRNA) levels were quantified by quantitative polymerase chain reaction (Q-PCR). Haptoglobin protein cell-specific localization was identified by immunohistochemistry. RESULTS: Haptoglobin mRNA levels were significantly greater (P < .005) in endometrioid adenocarcinoma and adjacent nonaffected endometrial tissues than normal endometrium. No correlation was found between Hp levels and cancer stage (P = .673) or grade (P = .739). Haptoglobin protein localized in both stromal and glandular epithelial cells of endometrioid adenocarcinoma and their adjacent nonaffected tissue but not in control endometrium. CONCLUSIONS: Our results have identified, for the first time, unique patterns of Hp mRNA expression and protein localization in the stromal and glandular epithelial cells of endometrioid adenocarcinoma of the uterus. We propose that this unique pattern of endometrioid adenocarcinoma Hp expression may be developed as a novel diagnostic marker. Modulation of Hp, with its immunomodulatory and angiogenic properties, may generate novel methods of prevention or treatment for endometrial cancer.

An updated clinicopathologic study of early-stage uterine papillary serous carcinoma (UPSC).

OBJECTIVES: Stage I-II uterine papillary serous carcinoma (UPSC) patients have a significant risk for extrapelvic recurrence. However, clinicopathologic risk factors for recurrence are not well understood. This study was undertaken to define the prognostic factors for recurrence and survival in patients with early-stage UPSC. METHODS: A retrospective, multi-institution analysis of surgically staged I-II UPSC patients was performed. Patients were treated by various adjuvant modalities. Age, race, sub-stage, percentage UPSC histology, lymphvascular space invasion (LVSI), tumor size and adjuvant treatment modality were evaluated for their effect on recurrence and survival outcomes. RESULTS: We identified 206 patients. Forty patients (19.4%) had 5-49% UPSC, 55 (26.7%) had 50-99% and 111 patients (53.9%) had 100% UPSC in their respective uterine specimens. Twenty one percent of patients experienced a primary recurrence. On univariate analysis, age, increasing %UPSC, LVSI, and tumor size were not significantly associated with recurrence or progression-free survival (PFS). However, substage (p=0.005) and treatment with platinum/taxane-based chemotherapy (p=0.001) were associated with recurrence/PFS. On multivariate analysis, only chemotherapy (p=0.01) was a significant factor affecting PFS, whereas age (p=0.05), substage (p=0.05), and chemotherapy (p=0.02) were associated with overall survival. CONCLUSIONS: Traditional risk factors for recurrence and survival in patients with early-stage endometrial cancer may not be relevant in patients with UPSC. Patients with any percentage UPSC in their uterine specimens are at a significant risk for recurrence and poor survival outcomes. Given that current clinicopathologic data does not accurately identify women most likely to benefit from adjuvant therapy, alternative prognostic markers based on novel techniques should be explored.

Docosahexaenoic acid inhibits superoxide dismutase 1 gene transcription in human cancer cells: the involvement of peroxisome proliferator-activated receptor alpha and hypoxia-inducible factor-2alpha signaling.

Docosahexaenoic acid (DHA; n-3, 22:6) is known to have anticancer activity, but its mechanisms of action remain to be further elucidated. We recently demonstrated that DHA down-regulates superoxide dismutase (SOD) 1 gene expression, thereby weakening cellular antioxidant forces and enhancing cytotoxicity in various human cancer cells. The objective of this study was to investigate the mechanism of the inhibitory effect of DHA on SOD-1 gene expression in human cancer cells. A reporter gene assay indicated that DHA suppresses SOD-1 gene transcription in a time- and concentration-dependent manner in human cancer cells. Pretreatment with vitamin E did not block the inhibitory effect of DHA, indicating that this suppression does not depend on lipid peroxidation. The suppressive effect of DHA on SOD-1 gene transcription could be mimicked by the peroxisome proliferator-activator receptor (PPAR) alpha ligand clofibrate but not the PPARgamma ligand troglitazone, suggesting the involvement of PPARalpha signaling. Deletion analysis of the key DNA binding elements in the SOD-1 gene promoter identified the distal hypoxia response element (HRE), but not the peroxisome proliferator response element or nuclear factor-kappaB element, as essential for the suppressive effects of DHA. Coimmunoprecipitation confirmed that PPARalpha, but not PPARgamma, forms a complex with hypoxia-inducible factor (HIF)-2alpha in cancer cells. Chromatin immunoprecipitation analysis indicated that both DHA and clofibrate reduce HIF-2alpha binding to the HRE. Thus, we have identified the distal HRE in the SOD-1 gene promoter that mediates the suppression on the transcription of this gene by DHA, and we have demonstrated the involvement of PPARalpha and HIF-2alpha signaling in this event.

PPARalpha signaling mediates the synergistic cytotoxicity of clioquinol and docosahexaenoic acid in human cancer cells.

This study investigated the involvement of PPARgamma and PPARalpha signaling in the synergistic anticancer activity of clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) and docosahexaenoic acid (DHA) in human cancer cells. The synergistic cytotoxicity of DHA and clioquinol was demonstrated in nine human cancer cell lines representing different tissues of origin. A2780, a well-established ovarian cancer model system, was chosen for further characterization because of its sensitivity to DHA and clioquinol. Both PPARalpha and PPARgamma were expressed in A2780 cells when analyzed with western blotting and reporter gene technique. Treatment of the cells with clofibrate (a PPARalpha agonist) and clioquinol for three days mimicked the synergy of DHA and clioquinol, whereas this synergy could not be seen with the use of troglitazone (a PPARgamma agonist) and clioquinol, suggesting that PPARalpha signaling is involved in the synergistic action. When used alone, the IC50 of clofibrate was 513 microM in A2780 cells. However, the addition of 5 microM clioquinol to clofibrate-treated cells led to a dramatic reduction of its IC50 value (148 microM). The combination effects index (CI) analysis confirmed the synergy of clioquinol and clofibrate on inhibiting cancer cell viability. Using inhibitors to block PPARalpha signaling diminished the synergistic cytotoxicity of clioquinol and DHA. These results provide pharmacological evidence that the synergistic anticancer action of clioquinol and DHA is mediated by PPARalpha signaling in human cancer cells.

Platinum/taxane-based chemotherapy with or without radiation therapy favorably impacts survival outcomes in stage I uterine papillary serous carcinoma.

BACKGROUND: A study was undertaken to determine recurrence patterns and survival outcomes of stage I uterine papillary serous carcinoma (UPSC) patients. METHODS: A retrospective, multi-institutional study of stage I UPSC patients diagnosed from 1993 to 2006 was performed. Patients underwent comprehensive surgical staging; postoperative treatment included observation (OBS); radiotherapy alone (RT); or platinum/taxane-based chemotherapy (CT) +/- RT. RESULTS: The authors identified 142 patients with a median follow-up of 37 months (range, 7-144 months). Thirty-three patients were observed, 20 received RT alone, and 89 received CT +/- RT. Twenty-five recurrences (17.6%) were diagnosed, and 60% were extrapelvic. Chemotherapy-treated patients experienced significantly fewer recurrences than those treated without chemotherapy (P = .013). Specifically, CT +/- RT patients had a lower risk of recurrence (11.2%) compared with patients who received RT alone (25%, P = .146) or OBS (30.3%, P = .016). This effect was most pronounced in stage IB/IC (P = .007). CT- and CT + RT-treated patients experienced similar recurrence. After multivariate analysis, treatment with chemotherapy was associated with a decreased risk of recurrence (P = .047). The majority of recurrences (88%) were not salvageable. Progression-free survival (PFS) and cause-specific survival (CSS) for chemotherapy-treated patients were more favorable than for those who did not receive chemotherapy (P = .013 and .081). Five-year PFS and CSS rates were 81.5% and 87.6% in CT +/- RT, 64.1% and 59.5% in RT alone, and 64.7% and 70.2% for OBS. CONCLUSIONS: Stage I UPSC patients have significant risk for extrapelvic recurrence and poor survival. Recurrence and survival outcomes are improved in well-staged patients treated with platinum/taxane-based chemotherapy. This multi-institutional study is the largest to support systemic therapy for early stage UPSC patients.

Stage II uterine papillary serous carcinoma: Carboplatin/paclitaxel chemotherapy improves recurrence and survival outcomes.

OBJECTIVES: To determine recurrence patterns and survival outcomes of stage II uterine papillary serous carcinoma (UPSC) patients treated by various modalities with an emphasis on carboplatin/paclitaxel-based chemotherapy (CT)+/-radiotherapy (RT). METHODS: A retrospective, multi-institution study of women with stage II UPSC diagnosed from 1992 to 2006 was performed. All patients underwent comprehensive surgical staging. Treatment included observation (OBS), RT (vaginal brachytherapy, whole pelvic and/or whole abdominal therapy), or >or=3 cycles carboplatin/paclitaxel alone or with RT. Recurrence and survival outcomes were determined. RESULTS: We identified 55 subjects: 10 treated with OBS, 26 with RT alone and 19 with CT+/-RT. After a median follow-up of 33 mos (range, 10-119), 20 recurrences (36%) were observed. There was an overall difference in recurrence based upon treatment (p=.013). Specifically, all CT+/-RT treated patients had a lower risk of recurrence (11%) compared to patients treated by RT alone (50%) or OBS (50%). No patients treated with both CT+RT (n=12) experienced a recurrence. Treatment with CT was also associated with a decreased risk of recurrence on multivariate analysis (p=.015). Most recurrences were extra-pelvic (70%), occurred within 2 years (85%) and were not salvageable (84%). Five-year progression-free survival was 86% in chemotherapy-treated patients versus 41% in those not receiving chemotherapy (p=.010); overall survival was 88% in chemotherapy-treated patients versus 64% in those not receiving chemotherapy (p=.115). CONCLUSIONS: Stage II UPSC patients have a significant risk for unsalvageable, extra-pelvic recurrence. However, treatment with platinum/taxane therapy+/-RT appears to reduce this risk and is associated with improved progression free survival outcomes.

A randomized phase III trial of VH fibrin sealant to reduce lymphedema after inguinal lymph node dissection: a Gynecologic Oncology Group study.

OBJECTIVES: To evaluate VH fibrin sealant's influence on lower extremity lymphedema after inguinal lymphadenectomy in vulvar cancer patients. METHODS: Patients undergoing an inguinal lymphadenectomy during the management of vulvar malignancy were randomized to receive sutured closure (SC) vs VH fibrin sealant sprayed into the groin followed by sutured closure (FS). Leg measurements were taken preoperatively and during postoperative encounters when surgical outcomes were assessed. Grade 2 or 3 lymphedema was defined as circumferential measurement increases of 3-5 cm and >5 cm, respectively. RESULTS: 150 patients were enrolled. 137 patients were evaluable for lymphedema analysis with 67 and 70 patients in the SC arm and FS arm, respectively. The incidence of grade 2 and 3 lymphedema was 67%(45/67) in the SC arm, and 60% (42/70) FS arm (p=0.4779). The incidence of lymphedema was strongly associated with inguinal infection (p=0.0165). Lymphedema was not statistically increased in those who received adjuvant radiation. 139 patients remained evaluable for a descriptive analysis of their surgical complications. The overall incidence of complications was 61%(43/70) and 59% (41/69) for SC and FS arms, respectively. There was no statistically significant difference in duration of drains, drain output or incidence of inguinal infections, wound breakdowns or seromas. There was an increased incidence of vulvar infections in the FS arm (23/69) vs (10/70) (p=0.0098). The utilization of a Blake drain was associated with an increase in vulvar (p=0.0157) and inguinal wound breakdown (p=0.0456). CONCLUSION: VH fibrin sealant in inguinal lymphadenectomies does not reduce leg lymphedema and may increase the risk for complications in the vulvar wound.

Small cell carcinoma of the female genital tract.

Small cell carcinoma (SCC) of the female genital tract is rare, constituting less than 2% of all gynecologic malignancies. It occurs most frequently in the cervix but can also occur in the endometrium, ovary, fallopian tube, vagina, and vulva. SCC of the genital tract is microscopically indistinguishable from that of the lung. Neuroendocrine differentiation is often manifested by a histologic growth pattern, argyrophilia, ultrastructural demonstration of secretory granules, and expression of neuroendocrine markers. Patients with SCC of the female genital tract may be asymptomatic but usually present with localized pain, vaginal bleeding, abdominal bloating or a mass, or symptoms of metastasis disease to the liver, bone, lung, or regional lymph nodes. Ectopic Cushing's syndrome has been reported in SCC of the vagina, and hypercalcemia and inappropriate secretion of antidiuretic hormone have been noted with SCC of the ovary. In general, these tumors have an aggressive clinical course with a propensity for extensive local invasion and distant metastases. Therapy has included surgery, radiation, and chemotherapy akin to those regimens used for SCC of the lung. Although there are no randomized clinical trials, it appears that multimodality therapy is associated with the best results and is the treatment of choice for most patients. Despite aggressive therapy, however, the prognosis for SCC of the female genital tract is poor, with only a minority of patients enjoying a prolonged survival. Indeed, the majority of patients have an early demise with extensive distant disease. We review the clinical features, evaluation, and management of SCC of the female genital tract based on a comprehensive review of the literature.