Ovarian cancer modulates the immunosuppressive function of CD11b+Gr1+ myeloid cells via glutamine metabolism.

OBJECTIVE: Immature CD11b + Gr1+ myeloid cells that acquire immunosuppressive capability, also known as myeloid-derived suppressor cells (MDSCs), are a heterogeneous population of cells that regulate immune responses. Our study's objective was to elucidate the role of ovarian cancer microenvironment in regulating the immunosuppressive function of CD11b+Gr1+ myeloid cells. METHODS: All studies were performed using the intraperitoneal ID8 syngeneic epithelial ovarian cancer mouse model. Myeloid cell depletion and immunotherapy were carried out using anti-Gr1 mAb, gemcitabine treatments, and/or anti-PD1 mAb. The treatment effect was assessed by a survival curve, in situ luciferase-guided imaging, and histopathologic evaluation. Adoptive transfer assays were carried out between congenic CD45.2 and CD45.1 mice. Immune surface and intracellular markers were assessed by flow cytometry. ELISA, western blot, and RT-PCR techniques were employed to assess the protein and RNA expression of various markers. Bone marrow-derived myeloid cells were used for ex-vivo studies. RESULTS: The depletion of Gr1+ immunosuppressive myeloid cells alone and in combination with anti-PD1 immunotherapy inhibited ovarian cancer growth. In addition to the adoptive transfer studies, these findings validate the role of immunosuppressive CD11b+Gr1+ myeloid cells in promoting ovarian cancer. Mechanistic investigations showed that ID8 tumor cells and their microenvironments produced recruitment and regulatory factors for immunosuppressive CD11b+Gr1+ myeloid cells. CD11b+Gr1+ myeloid cells primed by ID8 tumors showed increased immunosuppressive marker expression and acquired an energetic metabolic phenotype promoted primarily by increased oxidative phosphorylation fueled by glutamine. Inhibiting the glutamine metabolic pathway reduced the increased oxidative phosphorylation and decreased immunosuppressive markers' expression and function. Dihydrolipoamide succinyl transferase (DLST), a subunit of α-KGDC in the TCA cycle, was found to be the most significantly elevated gene in tumor-primed myeloid cells. The inhibition of DLST reduced oxidative phosphorylation, immunosuppressive marker expression and function in myeloid cells. CONCLUSION: Our study shows that the ovarian cancer microenvironment can regulate the metabolism and function of immunosuppressive CD11b + Gr1+ myeloid cells and modulate its immune microenvironment. Targeting glutamine metabolism via DLST in immunosuppressive myeloid cells decreased their activity, leading to a reduction in the immunosuppressive tumor microenvironment. Thus, targeting glutamine metabolism has the potential to enhance the success of immunotherapy in ovarian cancer.

Does a Multidisciplinary Approach to Invasive Breast Cancer Care Improve Time to Treatment and Patient Compliance?

PURPOSE: This study aimed to evaluate whether comprehensive multidisciplinary care (cMDC) for breast cancer patients affected time from diagnosis to treatment, compliance with appointments and to assess for racial disparities. METHODS: This institutional review board approved retrospective study included adult patients diagnosed with invasive breast cancer between February 2015 and February 2017 and treated at an academic health system where the cMDC program was implemented in February 2016. The cMDC and non-cMDC groups as well as black and white patients were compared to assess time from diagnosis (date of pathology result indicating invasive breast cancer) to treatment (date of surgery or chemotherapy). Compliance was measured by appointments characterized as "no shows" or "canceled due to personal reasons" in the electronic medical record. RESULTS: Of 541 patients (419 cMDC and 122 non-cMDC), mean time from diagnosis to treatment was significantly longer for blacks than whites in the non-cMDC group (46.9 ± 64.6 days vs 28.2 ± 14.8 days, p = 0.024) and the cMDC group (39.9 ± 34.1 days vs 31.4 ± 16.3 days, p = 0.001). Of 38 (7.2%) patients who started treatment > 60 days after diagnosis, 25 (65.8%) were black. Implementation of cMDC significantly improved patient compliance (missed appointments 4.9 ± 7.6 non-cMDC vs 3.2 ± 4.6 cMDC, p = 0.029). CONCLUSION: Use of cMDC for invasive breast cancer at our institution highlighted an area for improvement for care administered to blacks and improved patient compliance with appointments.

Definitive radiation therapy for cervical cancer: Non-white race and public insurance are risk factors for delayed completion, a pilot study.

This is a pilot study to assess whether racial disparities exist in time to initiation and completion of external beam pelvic radiation therapy and brachytherapy in cervical cancers treated with definitive chemoradiation. A retrospective analysis was conducted on all cervical cancer patients treated with definitive radiotherapy between 2006 and 2016 at a single institution. Patient demographics including age, race, insurance status and stage at diagnosis were obtained. Analyses were performed according to the following definitions of wait times: interval from pathologic diagnosis of cervical cancer to (Siegel et al., 2016) initiation of radiation therapy, (Yoo et al., 2017) completion of external beam radiation therapy and (DeSantis et al., 2016) completion of external beam radiation therapy plus brachytherapy if indicated. Of 50 women, 21 self-identified as white, 25 as black and 4 as Hispanic. Due to small numbers, Hispanic women were included with black women as a non-white group. The average age was 52 years for women in this cohort. Mean days to initiation of radiation therapy were 41.8 days: 33.7 days among white patients versus 47.8 days for non-white patients (p-value 0.101). Mean days from diagnosis to completion of external beam pelvic radiation therapy were 81.3 days: 70.9 days among white patients versus 88.9 days among non-white patients (p-value 0.006). Non-white patients were more likely to have public insurance, which was also associated with a longer time to completion of radiation treatment. We conclude that non-white patients experienced delays to completing external beam radiation therapy, which was no longer present after adjusting for insurance status.

Rate of Urologic Injury with Robotic Hysterectomy.

STUDY OBJECTIVE: To evaluate rates of urologic injury in patients who underwent robotic hysterectomy compared with laparoscopic, vaginal, and open hysterectomy. DESIGN: A retrospective analysis (Canadian Task Force classification II-2). SETTING: Henry Ford Health System, 2013 to 2016. PATIENTS: Women who underwent robotic, vaginal, laparoscopic, and open abdominal hysterectomy. INTERVENTIONS: Robotic hysterectomy, laparoscopic-assisted vaginal hysterectomy, total laparoscopic hysterectomy, laparoscopic supracervical hysterectomy, vaginal hysterectomy, and abdominal hysterectomy. MEASUREMENTS AND MAIN RESULTS: To identify patients with urologic injury, a departmental database for quality improvement was searched for reported urologic injuries. In addition, patients who had urology consultation within 90 days of hysterectomy were screened for injury. A total of 3114 hysterectomies were identified by retrospective chart review. One thousand eighty-eight robotic, 782 laparoscopic, 304 vaginal, and 940 abdominal hysterectomies were analyzed for urologic complications. A total of 27 injuries were confirmed (7 during laparoscopic hysterectomy, 10 during robotic hysterectomy, 1 during vaginal hysterectomy, and 9 during abdominal hysterectomy). The overall rate of urologic injury was 0.87% with a 0.55% risk of bladder injury and a 0.32% risk of injury to the ureter. When the route of hysterectomy was taken into account, the risk of urologic injury was 0.92% for robotic hysterectomy, 0.90% for laparoscopic hysterectomy, 0.33% for vaginal hysterectomy, and 0.96% for open hysterectomy. The mean body mass index (BMI) for all patients was 32.7 kg/m2; injured patients had a mean BMI of 34.6 kg/m2, and noninjured patients had a mean BMI of 32.0 kg/m2 (p = .10). CONCLUSION: Rates of urologic injury with robotic hysterectomy are similar to those of laparoscopic hysterectomy in our population. BMI was not significantly different in patients who had urologic injuries. Surgeon volume was not associated with risk for urologic injury.

Bioenergetic Adaptations in Chemoresistant Ovarian Cancer Cells.

Earlier investigations have revealed that tumor cells undergo metabolic reprogramming and mainly derive their cellular energy from aerobic glycolysis rather than oxidative phosphorylation even in the presence of oxygen. However, recent studies have shown that certain cancer cells display increased oxidative phosphorylation or high metabolically active phenotype. Cellular bioenergetic profiling of 13 established and 12 patient derived ovarian cancer cell lines revealed significant bioenergetics diversity. The bioenergetics phenotype of ovarian cancer cell lines correlated with functional phenotypes of doubling time and oxidative stress. Interestingly, chemosensitive cancer cell lines (A2780 and PEO1) displayed a glycolytic phenotype while their chemoresistant counterparts (C200 and PEO4) exhibited a high metabolically active phenotype with the ability to switch between oxidative phosphorylation or glycolysis. The chemosensitive cancer cells could not survive glucose deprivation, while the chemoresistant cells displayed adaptability. In the patient derived ovarian cancer cells, a similar correlation was observed between a high metabolically active phenotype and chemoresistance. Thus, ovarian cancer cells seem to display heterogeneity in using glycolysis or oxidative phosphorylation as an energy source. The flexibility in using different energy pathways may indicate a survival adaptation to achieve a higher 'cellular fitness' that may be also associated with chemoresistance.

The impact of lymphadenectomy on survival endpoints in women with early stage uterine endometrioid carcinoma: A matched analysis.

OBJECTIVES: The role of pelvic lymphadenectomy (LA) in women with stage I endometrial carcinoma (EC) is controversial. The objective of this study is to investigate the prognostic impact of LA on survival endpoints in matched cohorts of women with stage I EC solely of endometrioid histology. Survival endpoints included recurrence-free (RFS), disease-specific (DSS) and overall survival (OS). METHODS AND MATERIALS: Patients with FIGO stage I EC who underwent hysterectomy with LA as part of their surgical staging between 1/1990 and 6/2015 were matched to a similar group that underwent hysterectomy without lymphadenectomy (NLA), based on stage, grade and adjuvant management. Univariate and multivariate modeling with Cox regression analysis was carried out for predictors of survival endpoints. RESULTS: 870 women constituted the study cohort (435 in each group). Median number of dissected lymph node in the LA group was 9 (range, 5-75). There was no statistically significant difference between the two groups in regards to 5-year OS (87.2% for LA vs. 91.7% for NLA) (p=0.36), DSS 97.7% vs. 98% (p=0.54) and RFS (93.7% vs. 90% (p=0.08), respectively. Lymphadenectomy was not a predictor of any of the studied survival endpoints. On multivariate analysis for the entire cohort, older age, deep myometrial invasion and higher tumor grade were predictors of worse RFS. For DSS, higher tumor grade, lower uterine segment (LUS) involvement and FIGO stage IB were significant predictors of worse outcome. For OS, older age and LUS involvement were the only two independent predictors for shorter OS. CONCLUSIONS: After matching for FIGO stage, grade and adjuvant management, it appears that lymphadenectomy in women with stage I EC does not impact survival endpoints.

Is Older Age a Real Adverse Prognostic Factor in Women With Early-Stage Endometrial Carcinoma? A Matched Analysis.

OBJECTIVES: The aim of this study was to evaluate if older age alone negatively impacts survival endpoints in women with early-stage uterine endometrioid carcinoma (EC), or its reported prognostic impact is due to an interaction with other well-known adverse factors using matched-analysis methodology. METHODS: We identified 1254 patients with International Federation of Gynecology and Obstetrics stage I-II EC who underwent hysterectomy at our institution. We created 2 matched groups based on International Federation of Gynecology and Obstetrics stage, tumor grade, lymph node dissection status, and the type of adjuvant management. Recurrence-free (RFS), disease-specific (DSS) and overall survival (OS) were calculated. RESULTS: A total 297 women 70 years or older were matched with 297 women younger than 70 years. The 2 groups were well balanced except for age and higher body mass index in younger patients. There were no significant difference between older and younger patients in regard to 5-year RFS (85% vs 87%; P = 0.52) or DSS (93% for both groups with P = 0.77). Five-year OS was shorter in older patients (76% vs 88% with P < 0.001). On multivariate analysis for RFS and DSS, high tumor grade and the presence of lymphovascular space invasion (LVSI) were the only 2 predictors of shorter RFS and DSS (P = 0.01 and P = 0.02, and P = 0.01 and P = 0.01, respectively). Tumor grade and LVSI also were predictors of shorter OS. CONCLUSIONS: Our study suggests that when older patients with EC are matched with younger patients based on tumor stage, grade, and adjuvant management the prognostic impact of old age disappears. High tumor grade and LVSI remained as independent predictors of survival endpoints.

Management of gynaecologic plasmacytoma: A review article.

In contrast to multiple myeloma (MM) which exhibits diffuse bone marrow and other organ involvement, solitary plasmacytomas carry a favourable prognosis. Extramedullary plasmacytomas (EMP) are a unique form of plasma cell neoplasms. These tumours are rare in the female reproductive tract. Only 24 cases of gynaecologic plasmacytomas were reported to date (7 cases were solitary plasmacytomas and 17 cases were either part of disseminated MM with involvement of a gynaecologic organ or were lacking complete work-up to rule out MM). The standard care of gynaecologic solitary EMP is surgical resection alone when feasible. Adjuvant radiation therapy may be considered for adverse prognostic factors such as positive resection margins. MM with gynaecologic organ involvement should be managed with systemic therapy and defer local therapies to symptomatic progression.

Salvage Versus Adjuvant Radiation Treatment for Women With Early-Stage Endometrial Carcinoma: A Matched Analysis.

OBJECTIVES: Adjuvant radiation treatment (ART) has been shown to reduce local recurrences in early-stage endometrial carcinoma (EC); however, this has not translated into improved overall survival (OS) benefit. As a result, some physicians forgo ART, citing successful salvage rates in cases of recurrence. Survival end points were compared between women treated with salvage RT (SRT) for locoregional recurrence and similarly matched women treated upfront with ART. MATERIALS AND METHODS: We identified 40 patients with stage I to II type 1 EC who underwent hysterectomy and received no adjuvant RT but later developed locoregional recurrence and subsequently received SRT. An additional 374 patients who underwent hysterectomy followed by ART during the same period were identified. Patients in the SRT group were matched to those in the ART group based on FIGO (International Federation of Gynecology and Obstetrics) stage and tumor grade in a 1:3 ratio. Disease-specific survival (DSS) and OS were calculated. RESULTS: A total of 156 women were matched (39:117). Median follow-up was 56 months. The 2 groups were generally well balanced. With regard to the site of tumor recurrence, it was commonly vaginal in the SRT group (74.3% vs 28.6%, P = 0.01). More SRT patients received a combination of pelvic external-beam RT with vaginal brachytherapy (94.8% vs 35%, P < 0.001). The ART group had significantly better 5-year DSS (95% vs 77%, P < 0.001) and 5-year OS (79% vs 72%, P = 0.005) compared with those of the SRT group. CONCLUSIONS: Our study suggests that women who receive SRT for their locoregional recurrence have worse DSS and OS compared with those matched patients who received ART. Further studies are warranted to develop a high-quality cost-effectiveness analysis as well as accurate predictive models of tumor recurrence. Until then, ART should at least be considered in the management of early-stage EC patients with adverse prognostic factors.

A metabolomic approach to identifying platinum resistance in ovarian cancer.

BACKGROUND: Acquisition of metabolic alterations has been shown to be essential for the unremitting growth of cancer, yet the relation of such alterations to chemosensitivity has not been investigated. In the present study our aim was to identify the metabolic alterations that are specifically associated with platinum resistance in ovarian cancer. A global metabolic analysis of the A2780 platinum-sensitive and its platinum-resistant derivative C200 ovarian cancer cell line was performed utilizing ultra-high performance liquid chromatography/mass spectroscopy and gas chromatography/mass spectroscopy. Per-metabolite comparisons were made between cell lines and an interpretive analysis was carried out using the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic library and the Ingenuity exogenous molecule library. RESULTS: We observed 288 identified metabolites, of which 179 were found to be significantly different (t-test p < 0.05) between A2780 and C200 cells. Of these, 70 had increased and 109 had decreased levels in platinum resistant C200 cells. The top altered KEGG pathways based on number or impact of alterations involved the cysteine and methionine metabolism. An Ingenuity Pathway Analysis also revealed that the methionine degradation super-pathway and cysteine biosynthesis are the top two canonical pathways affected. The highest scoring network of altered metabolites was related to carbohydrate metabolism, energy production, and small molecule biochemistry. Compilation of KEGG analysis and the common network molecules revealed methionine and associated pathways of glutathione synthesis and polyamine biosynthesis to be most significantly altered. CONCLUSION: Our findings disclose that the chemoresistant C200 ovarian cancer cells have distinct metabolic alterations that may contribute to its platinum resistance. This distinct metabolic profile of platinum resistance is a first step towards biomarker development for the detection of chemoresistant disease and metabolism-based drug targets specific for chemoresistant tumors.

Protective effect of bisphosphonates on endometrial cancer incidence in data from the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial.

BACKGROUND: Preclinical studies have demonstrated antitumor effects of bisphosphonates. The objective of the current study was to determine the effect of exposure to bisphosphonate on the incidence of endometrial cancer. METHODS: The authors used data from the National Cancer Institute's Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, which collected data on all cancers. In year 5, all participants were asked to complete a self-administered supplemental questionnaire (SQX) that included questions regarding bone medication use. For women without a cancer diagnosis at the time of the SQX, the authors identified whether a woman reported current or former use of a nitrogenous bisphosphonate (NBP), defined as ever-use, and compared them with women never exposed to an NBP. Women with missing information were excluded as were women who reported undergoing a hysterectomy. Incidence rates and rate ratios were calculated with 95% confidence intervals (95% CIs). Cox proportional hazard ratios were also calculated and adjusted for covariates. RESULTS: A total of 29,254 women were included in the current analysis; an additional 77 cases of endometrial cancer have been diagnosed since the SQX. The incidence rate for endometrial cancer among women exposed to NBPs was 8.7 per 10,000 person-years versus 17.7 per 10,000 person-years among never-exposed women (rate ratio, 0.49; 95% CI, 0.30-0.80). The effect was similar after adjusting for all the covariates in the Cox proportional hazards analysis, with a hazard ratio of 0.56 (95% CI, 0.34-0.93). CONCLUSIONS: The results of the current study suggest that use of NBPs may have a protective effect on the incidence of endometrial cancer. However, additional studies are needed that include other potential confounders and a larger sample.

Impact of age-adjusted Charlson comorbidity score on outcomes for patients with early-stage endometrial cancer.

OBJECTIVES: To determine the impact of Age-Adjusted Charlson Comorbidity (AAC) index score on survival outcomes for patients with early stage endometrial cancer. METHODS: After IRB-approval, AAC score at time of hysterectomy was retrospectively tabulated by physician chart review for 671 patients with 2009 FIGO stage I-II endometrioid adenocarcinoma. Patients were grouped based on their AAC scores as follows: 0-1 (n=204), 2-3 (n=293) and >3 (n=174). Kaplan-Meier and log-rank test methods and univariate and multivariate modeling with Cox regression analysis was used to determine significant predictors of each survival endpoint. RESULTS: After a median follow-up of 85 months, 225 deaths were recorded (34 from EC and 191 from other causes) with a 7-year Overall (OS) and Disease-specific survival (DSS) of 77.6% and 94.0%, respectively. Based on AAC grouping, the 7-year OS, DSS, and Recurrence-free survival (RFS) were: 92.9%, 96.8%, and 94.9% for AAC 0-1; 81.7%, 95.3%, and 89.8% for AAC 2-3: and 56%, 88.2%, and 84.9% for AAC>3 (p<0.0001, p=0.005 and p=0.013, respectively). On multivariate analyses, higher AAC score, tumor grade, lower uterine segment involvement, and lymphovascular space invasion were significantly independent predictors for shorter OS, while for DSS and RFS, higher tumor grade and lymphovascular space invasion were significant predictors of worse outcome, but higher AAC score was not. CONCLUSIONS: Comorbidity score is as important as pathological features for predicting overall survival outcomes in patients with early-stage endometrioid endometrial carcinoma. Higher AAC scores accurately predicted for worse OS. Comorbidity score should be considered in prospective clinical trials of endometrial carcinoma.

Endometrial carcinoma in the baby boomer generation. Tumor characteristics and clinical outcome.

BACKGROUND: Baby boomers (BB) entering retirement represent a significant burden on medical resources. The unique lifestyle characteristics engendered by the BB may lead to different endometrial cancer characteristics that bear understanding. We sought to characterize BB with endometrioid carcinoma after hysterectomy and compare the results to those of prior to the baby boomers (PB). PATIENTS AND METHODS: After reviewing our prospectively maintained database of 1,450 patients with endometrial cancer, we identified 595 patients who underwent hysterectomy for 1988 International Federation of Gynecologic Oncology (FIGO) stage I-II uterine endometrioid carcinomas, who were born between 1926 and 1964. Their medical records were reviewed in this Institutional review board (IRB)-approved study. Patients with non-endometrioid carcinoma and those who received preoperative therapy were excluded. Patients were defined as BB (born 1946-1964) or PB (born in 1926-1945). The two groups were compared regarding patients' demographics, tumor characteristics and survival. Following a univariate analysis, multivariable modeling was carried out using Cox regression analysis. RESULTS: All patients underwent hysterectomy with a minimum of two years' follow-up. There were 234 patients (39%) in the BB group and 361 patients (61%) in the PB group. Median follow-up for the study cohort was 56 months. BB had higher body mass index (p=0.027), lower tumor grade (p=0.002), earlier FIGO stage (p=0.023), higher number of dissected lymph nodes (p=0.008), less lymphvascular space involvement (p=<0.034), less utilization of adjuvant therapy (p=<0.001), and younger age at diagnosis (p=0.002). However, there was no significant difference found between the BB and PB in regards to local control, disease-specific survival and overall survival. For the study cohort, FIGO stage and tumor grade were independent predictors of recurrence-free and disease-specific survival. There was a trend towards shorter overall survival for the PB women (p=0.063). CONCLUSION: Although tumor characteristics were more favorable in the BB group of women, local control and survival end-points were not statistically different compared to those of the PB group. As more BB are diagnosed with endometrial carcinoma, further research is warranted to further elucidate the characteristic differences in endometrial carcinoma, if any, in this generation.

Trends in the utilization of adjuvant vaginal cuff brachytherapy and/or external beam radiation treatment in stage I and II endometrial cancer: a surveillance, epidemiology, and end-results study.

PURPOSE: The optimal adjuvant radiation treatment for endometrial carcinoma (EC) remains controversial. Adjuvant vaginal cuff brachytherapy (VB) has emerged as an increasingly common treatment modality. However, the time trends for using VB, external beam radiation therapy (EBRT), or combined therapy (VB+EBRT) have not been well characterized. We therefore examined the utilization trends of VB, EBRT, and VB+EBRT for adjuvant RT in International Federation of Gynecologic Oncology (FIGO) stage I and II EC over time. METHODS AND MATERIALS: We evaluated treatment patterns for 48,122 patients with EC diagnosed between January 1995 and December 2005, using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) public use database. Chi-squared tests were used to assess differences by radiation type (VB, EBRT, and VB+EBRT) and various demographic and clinical variables. RESULTS: Analyses were limited to 9,815 patients (20.4%) with EC who met the inclusion criteria. Among women who received adjuvant RT, the proportion receiving VB increased yearly (12.9% in 1995 compared to 32.8% in 2005 (p < 0.0001). The increasing use of VB was proportional to the decreasing use of EBRT (56.1% in 1995 to 45.8% in 2005; p < 0.0001) and VB+EBRT (31.0% in 1995 to 21.4% in 2005; p < 0.001). CONCLUSIONS: This population-based report demonstrates an increasing trend in the use of VB in the adjuvant setting after hysterectomy for treatment of women with FIGO stage I-II EC. VB alone appears to be replacing pelvic EBRT and VB+EBRT therapy in the management of stage I-II EC.

A single-institution evaluation of factors important in fallopian tube carcinoma recurrence and survival.

OBJECTIVE: The aim of this study was to identify prognostic factors and markers that influence clinical outcomes in patients with primary fallopian tube carcinoma at a single tertiary health care center. These prognostic factors may be of clinical importance and can subsequently be included in future clinical trials. MATERIALS AND METHODS: A retrospective review of our Tumor Registry and Gynecologic Oncology database was conducted to include any patients with a diagnosis of fallopian tube carcinoma between the years 1994 and 2005. We identified clinicopathological data to evaluate factors important in recurrence, disease-specific and overall survival. Kaplan-Meier curves were generated, and log-rank tests were used to evaluate survival differences. RESULTS: Thirty-six patients had a diagnosis with primary fallopian tube carcinoma at a median age of 69 years. Patients most frequently presented with abdominal pain (19%) and a palpable mass (14%). The most common histological subtype was papillary serous adenocarcinoma in 56% of cases. Stage III disease (39%) and poorly differentiated tumors (81%) were most common. The median follow-up was 39.6 months. The 5-year cancer-specific survival was 42%, and the overall survival rate was 34%. Factors important in disease-free survival were International Federation of Gynecology and Obstetrics stage, tumor laterality, and serum CA-125, whereas International Federation of Gynecology and Obstetrics stage, serum CA-125, and residual disease were prognostic factors for overall survival. The most common locations of recurrence were pelvis and abdomen (63%) as opposed to distant sites. Factors associated with recurrence were stage, tumor laterality, and serum CA-125. CONCLUSIONS: Fallopian tube malignancies are rare. We have identified factors associated with recurrence, disease specific survival, and overall survival that could be further examined and included in larger clinical trials involving this uncommon malignancy.

Hysterectomy for uterine adenocarcinoma in the elderly: tumor characteristics, and long-term outcome.

OBJECTIVES: To evaluate the tumor recurrences and survival in elderly patients ≥75 years of age with uterine endometrioid carcinoma treated with surgical staging with/without adjuvant radiation therapy (RT). METHODS: We identified 675 surgically staged patients with FIGO stage I-II uterine endometrioid carcinoma who were treated between 1985 and 2009. Their medical records were retrospectively reviewed in this IRB-approved study. Patients were classified as ≥75 years vs. <75 years and compared regarding tumor recurrence and survival. Following a univariate analysis, multivariable modeling was done using Cox regression analysis. RESULTS: 121 patients (18%) were ≥75 years old at the time of hysterectomy. For this group of elderly patients, median age was 79. All patients were surgically staged and some received adjuvant RT. Older patients were found to have higher FIGO stages (p<0.001), higher grade tumors (p<0.001), more frequent deep myometrial involvement (p<0.001), and more frequent lower uterine segment involvement (p<0.001). There was no significant difference found between older and younger patients with respect to lymphovascular space involvement (LVSI) (p=0.415), number of lymph nodes dissected (p=0.440), or adjuvant RT received (p=0.089). Older patients had more tumor recurrence (15% vs 7%) (p=0.005) and lower five year relapse-free survival of 80% compared to 90% in younger patients (p=0.0016). Multivariate analysis confirmed the significance of LVSI, grade 3 tumors, and deep myometrial invasion as prognostic factors for recurrence. After adjusting for other poor prognostic factors, age was not found to be an independent prognostic factor for recurrence. CONCLUSION: Despite similar surgical staging and adjuvant radiation treatment, patients ≥75 years old diagnosed with FIGO stage I-II uterine endometrioid carcinoma were found to have more adverse pathologic features and worse relapse-free, disease-specific and overall survival than younger patients. Age ≥75 years alone may not be an independent significant prognostic factor affecting tumor recurrence.

Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients.

Noradrenergic pathways have been implicated in growth and progression of ovarian cancer. Intratumoral norepinephrine (NE) has been shown to increase with stress in an animal cancer model, but little is known regarding how tumor NE varies with disease stage and with biobehavioral factors in ovarian cancer patients. This study examined relationships between pre-surgical measures of social support, depressed mood, perceived stress, anxiety, tumor histology and tumor catecholamine (NE and epinephrine [E]) levels among 68 ovarian cancer patients. We also examined whether associations observed between biobehavioral measures and tumor catecholamines extended to other compartments. Higher NE levels were found in advanced stage (p=0.006) and higher grade (p=0.001) tumors. Adjusting for stage, grade, and peri-surgical beta blockers, patients with a perceived lack of social support had significantly higher tumor NE (ß=-0.29, p=0.012). A similar trend was seen for social support and ascites NE (adjusting for stage, peri-surgical beta blockers and caffeine: ß=-0.50, p=0.075), but not for plasma NE. Other biobehavioral factors were not related to tumor, ascites, or plasma NE (p values >0.21). Tumor E was undetectable in the majority of tumors and thus E was not further analyzed. In summary, these results suggest that tumor NE provides distinct information from circulating plasma concentrations. Tumor NE levels were elevated in relationship to tumor grade and stage. Low subjective social support was associated with elevated intratumoral NE. As beta-adrenergic signaling is related to key biological pathways involved in tumor growth, these findings may have implications for patient outcomes in ovarian cancer.

Low-dose abdominal radiation as a docetaxel chemosensitizer for recurrent epithelial ovarian cancer: a phase I study of the Gynecologic Oncology Group.

OBJECTIVES: The aim of this study was to determine the maximum tolerated dose and dose-limiting toxicity (DLT) of whole abdomen radiation as a chemosensitizer of weekly docetaxel for women with recurrent epithelial ovarian fallopian tube, or peritoneal cancers. PATIENTS AND METHODS: Women were enrolled on one of three dose levels of docetaxel (20, 25, or 30 mg/m(2)) administered weekly with concurrent low-dose whole abdominal radiation given as 60 cGy bid 2 days weekly for a total of 6 weeks. RESULTS: Thirteen women were enrolled and received 70 weekly treatments of docetaxel in combination with radiation therapy. At the first dose level, docetaxel 25mg/m(2), grade 3 fatigue and thrombocytopenia were observed. At the next dose level, docetaxel 30 mg/m(2), grade 3 febrile neutropenia, grade 4 thrombocytopenia with epistaxis, and grade 3 diarrhea were observed. Given these dose-limiting toxicities, a lower dose of docetaxel 20mg/m(2) was administered and found to be tolerable. No objective responses were observed among the 10 patients with measurable disease; however, the median progression-free survival (PFS) in all patients was 3.3 months, and 3 of the patients with measurable disease were free of tumor progression after 6 months (30%; 90% confidence interval 8.7-61%). CONCLUSIONS: Twice weekly low-dose whole abdomen radiation during weekly docetaxel 20 mg/m(2) was well-tolerated. Given the PFS demonstrated in these women with resistant ovarian cancer, further study of whole abdominal radiation and concurrent chemotherapy may be warranted.

Preservation of immune function in cervical cancer patients during chemoradiation using a novel integrative approach.

Patients receiving chemoradiation for cervical cancer are at risk for distress, chemoradiation-related side-effects, and immunosuppression. This prospective randomized clinical trial examined effects of a complementary therapy, Healing Touch (HT), versus relaxation training (RT) and usual care (UC) for (1) supporting cellular immunity, (2) improving mood and quality of life (QOL), and (3) reducing treatment-associated toxicities and treatment delay in cervical cancer patients receiving chemoradiation. Sixty women with stages IB1 to IVA cervical cancer were randomly assigned to receive UC or 4 ×/weekly individual sessions of either HT or RT immediately following radiation during their 6-week chemoradiation treatment. Patients completed psychosocial assessments and blood sampling before chemoradiation at baseline, weeks 4 and 6. Multilevel regression analyses using orthogonal contrasts tested for differences between treatment conditions over time. HT patients had a minimal decrease in natural killer cell cytotoxicity (NKCC) over the course of treatment whereas NKCC of RT and UC patients declined sharply during chemoradiation (group by time interaction: p = 0.018). HT patients showed greater decreases in two different indicators of depressed mood (CES-D depressed mood subscale and POMS depression scale) compared to RT and UC (group by time interactions: p<0.05). No between group differences were observed in QOL, treatment delay, or clinically-rated toxicities. HT may benefit cervical cancer patients by moderating effects of chemoradiation on depressed mood and cellular immunity. Effects of HT on toxicities, treatment delay, QOL, and fatigue were not observed. Long-term clinical implications of findings are not known.

A Phase II evaluation of weekly topotecan as a single agent second line therapy in persistent or recurrent carcinoma of the cervix: a Gynecologic Oncology Group study.

PURPOSE: To estimate antitumor activity and toxicity of weekly topotecan hydrochloride in patients with persistent or recurrent cervical carcinoma who failed prior treatment. PATIENTS AND METHODS: Women entered on study had or failed one prior chemotherapy regimen in addition to radiosensitizing chemotherapy, performance status less than 3, and adequate hematologic, renal, hepatic, and neurological function. Topotecan was infused at 3.0 mg/m(2) on days 1, 8, and 15 every 28 days. RESULTS: Twenty-seven patients were enrolled onto this study with 25 evaluable. Twenty-two patients had received radiation and chemotherapy prior to study. A median of two and mean of three courses of chemotherapy was given (range, one to eight courses). The most frequently severe adverse events were grade 3 anemia (28%) and grade 4 (4%) along with grade 3 neutropenia (8%) and grade 4 (8%). Two patients had grade 4 thrombocytopenia. There were no complete or partial responders. Ten patients (40%) had stable disease, twelve (48%) had increasing disease, and response could not be assessed in three (12%). The median progression-free survival was 2.4 months for the patients with increasing disease and 6.2 months (3.5-8.8 months) for those with stable disease. Disease location was equally divided within and outside the irradiated field. The 12 patients with increasing disease were more likely to have disease outside the pelvic radiation field. CONCLUSION: There were no complete or partial responders to weekly topotecan among the 25 patients in this study.