Characterization of adnexal lesions using photoacoustic imaging to improve sonographic O-RADS risk assessment.

OBJECTIVE: To assess the impact of photoacoustic imaging (PAI) on the assessment of ovarian/adnexal lesion(s) of different risk categories using the sonographic ovarian-adnexal imaging-reporting-data system (O-RADS) in women undergoing planned oophorectomy. METHOD: This prospective study enrolled women with ovarian/adnexal lesion(s) suggestive of malignancy referred for oophorectomy. Participants underwent clinical ultrasound (US) examination followed by coregistered US and PAI prior to oophorectomy. Each ovarian/adnexal lesion was graded by two radiologists using the US O-RADS scale. PAI was used to compute relative total hemoglobin concentration (rHbT) and blood oxygenation saturation (%sO2 ) colormaps in the region of interest. Lesions were categorized by histopathology into malignant ovarian/adnexal lesion, malignant Fallopian tube only and several benign categories, in order to assess the impact of incorporating PAI in the assessment of risk of malignancy with O-RADS. Malignant and benign histologic groups were compared with respect to rHbT and %sO2 and logistic regression models were developed based on tumor marker CA125 alone, US-based O-RADS alone, PAI-based rHbT with %sO2 , and the combination of CA125, O-RADS, rHbT and %sO2. Areas under the receiver-operating-characteristics curve (AUC) were used to compare the diagnostic performance of the models. RESULTS: There were 93 lesions identified on imaging among 68 women (mean age, 52 (range, 21-79) years). Surgical pathology revealed 14 patients with malignant ovarian/adnexal lesion, two with malignant Fallopian tube only and 52 with benign findings. rHbT was significantly higher in malignant compared with benign lesions. %sO2 was lower in malignant lesions, but the difference was not statistically significant for all benign categories. Feature analysis revealed that rHbT, CA125, O-RADS and %sO2 were the most important predictors of malignancy. Logistic regression models revealed an AUC of 0.789 (95% CI, 0.626-0.953) for CA125 alone, AUC of 0.857 (95% CI, 0.733-0.981) for O-RADS only, AUC of 0.883 (95% CI, 0.760-1) for CA125 and O-RADS and an AUC of 0.900 (95% CI, 0.815-0.985) for rHbT and %sO2 in the prediction of malignancy. A model utilizing all four predictors (CA125, O-RADS, rHbT and %sO2 ) achieved superior performance, with an AUC of 0.970 (95% CI, 0.932-1), sensitivity of 100% and specificity of 82%. CONCLUSIONS: Incorporating the additional information provided by PAI-derived rHbT and %sO2 improves significantly the performance of US-based O-RADS in the diagnosis of adnexal lesions. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Radiation therapy for vaginal and perirectal lesions in recurrent ovarian cancer.

The role for localized radiation to treat ovarian cancer (OC) patients with locally recurrent vaginal/perirectal lesions remains unclear, though we hypothesize these patients may be salvaged locally and gain long-term survival benefit. We describe our institutional outcomes using intensity modulated radiation therapy (IMRT) +/- high-dose rate (HDR) brachytherapy to treat this population. Our primary objectives were to evaluate complete response rates of targeted lesions after radiation and calculate our 5-year in-field control (IFC) rate. Secondary objectives were to assess radiation-related toxicities, chemotherapy free-interval (CFI), as well as post-radiation progression-free (PFS) and overall survival (OS). PFS and OS were defined from radiation start to either progression or death/last follow-up, respectively. This was a heavily pre-treated cohort of 17 recurrent OC patients with a median follow-up of 28.4 months (range 4.5-166.4) after radiation completion. 52.9% had high-grade serous histology and 4 (23.5%) had isolated vaginal/perirectal disease. Four (23.5%) patients had in-field failures at 3.7, 11.2, 24.5, and 27.5 months after start of radiation, all treated with definitive dosing of radiation therapy. Patients who were platinum-sensitive prior to radiation had similar median PFS (6.5 vs. 13.4 months, log-rank p = 0.75), but longer OS (71.1 vs 18.8 months, log-rank p = 0.05) than their platinum-resistant counterparts. Excluding patients with low-grade histology or who were treated with palliative radiation, median CFI was 14.2 months (range 4.7 - 33.0). Radiation was well tolerated with 2 (12.0%) experiencing grade 3/4 gastrointestinal/genitourinary toxicities. In conclusion, radiation to treat locally recurrent vaginal/perirectal lesions in heavily pre-treated OC patients is safe and may effectively provide IFC.

Long-Term Outcomes of Cervical Cancer Patients Treated With Definitive Chemoradiation Following a Complete Metabolic Response.

AIMS: A complete metabolic response (CMR) on early post-treatment 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a positive prognostic factor for cervical cancer patients treated with definitive chemoradiation, but long-term outcomes of this group of patients are unknown. Patterns of failure and risk subgroups are identified. MATERIALS AND METHODS: Patients who received curative-intent chemoradiation from 1998 to 2018 for International Federation of Gynecology and Obstetrics (FIGO) stage IB1-IVA cervical cancer and had a CMR on post-treatment FDG-PET within 5 months of treatment completion were included. Cox proportional hazards models determined factors associated with locoregional and distant failure. Kaplan-Meier estimates of freedom from any recurrence (FFR) of patient subgroups were compared with Log-rank tests. RESULTS: There were 402 patients with a CMR after chemoradiation on FDG-PET. Initial T stage was T1 (38%)/T2 (40%)/T3 (20%)/T4 (2%); initial FDG-avid nodal status was no nodes (50%)/pelvic lymph nodes (40%)/pelvic and para-aortic lymph nodes (10%). After a median follow-up of 6 years, 109 (27%) recurred. The pattern of recurrence was locoregional (27%), distant (61%) or both (12%). No factors were associated with locoregional failure. Distant recurrence was more likely in patients with T3-4 lesions (hazard ratio = 2.4, 95% confidence interval 1.5-3.8) and involvement of pelvic (hazard ratio = 1.6, 95% confidence interval 1.0-2.7) or para-aortic lymph nodes (hazard ratio = 2.7, 95% confidence interval 1.4-5.0) at diagnosis. The 5-year FFR rates for T1-2 patients with no nodes, pelvic nodes alone or para-aortic nodes at diagnosis were 85, 76 and 62%, respectively (P = 0.04, none versus para-aortic nodes). The 5-year FFR for T3-4 patients with no nodes, pelvic nodes alone or para-aortic nodes at diagnosis were 68, 56 and 25%, respectively (P = 0.09, none versus para-aortic nodes). CONCLUSIONS: T3-4 tumours and para-aortic nodal involvement at diagnosis are poor prognostic factors, even after a CMR following chemoradiation.

Endometrial carcinoma recurrence according to race and ethnicity: An NRG Oncology/Gynecologic Oncology Group 210 Study.

Non-Hispanic black (NHB) women are more likely to experience an endometrial carcinoma (EC) recurrence compared to non-Hispanic white (NHW) women. The extent to which tumor characteristics, socioeconomic status (SES) and treatment contribute to this observation is not well defined. In the NRG Oncology/Gynecology Oncology Group (GOG) 210 Study we evaluated associations between race/ethnicity and EC recurrence according to tumor characteristics with adjustment for potential confounders. Our analysis included 3,199 NHW, 532 NHB and 232 Hispanic women with EC. Recurrence was documented during follow-up. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between race/ethnicity and EC recurrence in models stratified by histologic subtype (low-grade endometrioid, high-grade endometrioid, serous, mixed cell, carcinosarcoma, clear cell) or stage (I, II, III) and adjusted for age, SES, body mass index, smoking status and treatment. In histologic subtype-stratified models, higher EC recurrence was noted in NHB women with low-grade endometrioid (HR = 1.94, 95% CI = 1.21-3.10) or carcinosarcomas (HR = 1.66, 95% CI = 0.99-2.79) compared to NHWs. In stage-stratified models, higher EC recurrence was noted among NHB women with stage I (HR = 1.48, 95% CI = 1.06-2.05) and Hispanic women with stage III disease (HR = 1.81, 95% CI = 1.11-2.95). Our observations of higher EC recurrence risk among NHB and Hispanic women, as compared to NHW women, were not explained by tumor characteristics, SES, treatment or other confounders. Other factors, such as racial differences in tumor biology or other patient factors, should be explored as contributors to racial disparities in EC recurrence.

Clinicopathologic characteristics associated with long-term survival in advanced epithelial ovarian cancer: an NRG Oncology/Gynecologic Oncology Group ancillary data study.

OBJECTIVE: To identify clinicopathologic factors associated with 10-year overall survival in epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC), and to develop a predictive model identifying long-term survivors. METHODS: Demographic, surgical, and clinicopathologic data were abstracted from GOG 182 records. The association between clinical variables and long-term survival (LTS) (>10years) was assessed using multivariable regression analysis. Bootstrap methods were used to develop predictive models from known prognostic clinical factors and predictive accuracy was quantified using optimism-adjusted area under the receiver operating characteristic curve (AUC). RESULTS: The analysis dataset included 3010 evaluable patients, of whom 195 survived greater than ten years. These patients were more likely to have better performance status, endometrioid histology, stage III (rather than stage IV) disease, absence of ascites, less extensive preoperative disease distribution, microscopic disease residual following cyoreduction (R0), and decreased complexity of surgery (p<0.01). Multivariable regression analysis revealed that lower CA-125 levels, absence of ascites, stage, and R0 were significant independent predictors of LTS. A predictive model created using these variables had an AUC=0.729, which outperformed any of the individual predictors. CONCLUSIONS: The absence of ascites, a low CA-125, stage, and R0 at the time of cytoreduction are factors associated with LTS when controlling for other confounders. An extensively annotated clinicopathologic prediction model for LTS fell short of clinical utility suggesting that prognostic molecular profiles are needed to better predict which patients are likely to be long-term survivors.

A phase I trial of paclitaxel, cisplatin, and veliparib in the treatment of persistent or recurrent carcinoma of the cervix: an NRG Oncology Study (NCT#01281852).

Background: Preclinical studies demonstrate poly(ADP-ribose) polymerase (PARP) inhibition augments apoptotic response and sensitizes cervical cancer cells to the effects of cisplatin. Given the use of cisplatin and paclitaxel as first-line treatment for persistent or recurrent cervical cancer, we aimed to estimate the maximum tolerated dose (MTD) of the PARP inhibitor veliparib when added to chemotherapy. Patients and methods: Women with persistent or recurrent cervical carcinoma not amenable to curative therapy were enrolled. Patients had to have received concurrent chemotherapy and radiation as well as possible consolidation chemotherapy; have adequate organ function. The trial utilized a standard 3 + 3 phase I dose escalation with patients receiving paclitaxel 175 mg/m2 on day 1, cisplatin 50 mg/m2 on day 2, and escalating doses of veliparib ranging from 50 to 400 mg orally two times daily on days 1-7. Cycles occurred every 21 days until progression. Dose-limiting toxicities (DLTs) were assessed at first cycle. Fanconi anemia complementation group D2 (FANCD2) foci was evaluated in tissue specimens as a biomarker of response. Results: Thirty-four patients received treatment. DLTs (n = 1) were a grade 4 dyspnea, a grade 3 neutropenia lasting ≥3 weeks, and febrile neutropenia. At 400 mg dose level (DL), one of the six patients had a DLT, so the MTD was not reached. Across DLs, the objective response rate (RR) for 29 patients with measurable disease was 34% [95% confidence interval (CI), 20%-53%]; at 400 mg DL, the RR was 60% (n = 3/5; 95% CI, 23%-88%). Median progression-free survival was 6.2 months (95% CI, 2.9-10.1), and overall survival was 14.5 months (95% CI, 8.2-19.4). FANCD2 foci was negative or heterogeneous in 31% of patients and present in 69%. Objective RR were not associated with FANCD2 foci (P = 0.53). Conclusions: Combining veliparib with paclitaxel and cisplatin as first-line treatment for persistent or recurrent cervical cancer patients is safe and feasible. Clinical trial information: NCT01281852.

The mutational spectrum of FOXA2 in endometrioid endometrial cancer points to a tumor suppressor role.

BACKGROUND: Forkhead box protein A2 (FOXA2) plays an important in development, cellular metabolism and tumorigenesis. The Cancer Genome Atlas (TCGA) identified a modest frequency of FOXA2 mutations in endometrioid endometrial cancers (EEC). The current study sought to determine the relationship between FOXA2 mutation and clinicopathologic features in EEC and FOXA2 expression. METHODS: Polymerase chain reaction (PCR) amplification and sequencing were used to identify mutations in 542 EEC. Western blot, quantitative reverse transcriptase PCR (qRT-PCR) and immunohistochemistry (IHC) were used to assess expression. Methylation analysis was performed using combined bisulfite restriction analysis (COBRA) and sequencing. Chi-squared, Fisher's exact, Student's t- and log-rank tests were performed. RESULTS: Fifty-one mutations were identified in 49 tumors (9.4% mutation rate). The majority of mutations were novel, loss of function (LOF) (78.4%) mutations, and most disrupted the DNA-binding domain (58.8%). Six recurrent mutations were identified. Only two tumors had two mutations and there was no evidence for FOXA2 allelic loss. Mutation status was associated with tumor grade and not associated with survival outcomes. Methylation of the FOXA2 promoter region was highly variable. Most tumors expressed FOXA2 at both the mRNA and protein level. In those tumors with mutations, the majority of cases expressed both alleles. CONCLUSION: FOXA2 is frequently mutated in EEC. The pattern of FOXA2 mutations and expression in tumors suggests complex regulation and a haploinsufficient or dominant-negative tumor suppressor function. In vitro studies may shed light on how mutations in FOXA2 affect FOXA2 pioneer and/or transcription factor functions in EEC.

Improved clinical trial enrollments for uterine leiomyosarcoma patients after gynecologic oncology partnership with a sarcoma center.

OBJECTIVE: A retrospective chart review was performed to determine patient outcomes before and after partnership by gynecologic oncologists (GYN/ONC) with a sarcoma center (SC) for patients with recurrent unresectable/metastatic (RM) uterine leiomyosarcoma (uLMS). METHODS: 58 RM patients, identified from medical records of uLMS patients cared for by either GYN/ONC service and/or the SC between 1/1/2000-4/1/2014, were audited for patient and tumor characteristics, outcomes, and clinical trials enrollments. RESULTS: Of the 58 patients, 26 patients (48%) were treated by GYN/ONC alone and 32 were treated by a combination of GYN/ONC and SC (52%). Age, race, tumor size, grade, presence of lymphovascular invasion, cervical involvement, and FIGO stage at diagnosis were not statistically different between the two groups. There was a significant difference between the number of clinical trial enrollments (0.07 vs 0.84 trials/patient, p<0.001) and the number of chemotherapy regimens prescribed (2.67 vs 4.29/patient, p=0.03) by GYN/ONC vs SC; the latter was driven by the number of clinical trial enrollments by the SC. Sixty-nine percent of patients referred to the SC were enrolled in at least one clinical trial, while just 8% of patients in the GYN/ONC group were enrolled in at least one clinical trial, a difference that is significant (p<0.0001). CONCLUSIONS: Referral of RM uLMS patients by GYN/ONC to a dedicated clinical trials-based SC resulted in an increase in the number of chemotherapy regimens prescribed and clinical trial enrollments. Partnership between GYN/ONC and a dedicated SC with access to clinical trials should be encouraged for all RM uLMS patients.

Pre-operative assessment of muscle mass to predict surgical complications and prognosis in patients with endometrial cancer.

BACKGROUND: Sarcopenia or loss of skeletal muscle mass is an objective measure of frailty associated with functional impairment and disability. This study aimed to examine the impact of sarcopenia on surgical complications and survival outcomes in patients with endometrial cancer. METHODS: A retrospective review of endometrial cancer patients who underwent surgery between 2005 and 2009 was performed. Sarcopenia was assessed on preoperative computed tomography (CT) scan by measurement of the lumbar psoas muscle cross-sectional area and defined as any value below the median (<4.33 cm(2)). Sarcopenic obesity was defined as sarcopenia plus a body mass index (BMI) of 30 kg/m(2) or higher. Microsatellite instability (MSI) was analyzed using the National Cancer Institute (NCI) consensus markers and tumor from hysterectomy specimens. RESULTS: Of 122 patients, 27 (22%) met the criteria for sarcopenic obesity. Sarcopenic patients were older than patients with normal muscle mass (mean age, 69.7 vs. 62.1 years; p < 0.001), had a lower BMI (31.1 vs. 39.4 kg/m(2); p < 0.001), and had more comorbidities (p = 0.048). Sarcopenia was not associated with tumor MSI, hospital stay, 90-day readmission rate, or early/late complications. Patients with sarcopenia had a shorter recurrence-free survival than nonsarcopenic patients (median 23.5 vs. 32.1 months; log-rank p = 0.02), but did not differ in terms of overall survival (log-rank p = 0.25). After adjustment for race, BMI, lymphocyte count, and tumor histology, sarcopenia was associated with a fourfold shorter recurrence-free survival (adjusted hazard ratio [HRadj], 3.99; 95% confidence interval [CI], 1.42-11.3). CONCLUSIONS: Sarcopenia has an impact on recurrence-free survival, but does not appear to have a negative impact on surgical outcomes or overall survival among endometrial cancer patients who undergo preoperative CT scan.

Concomitant chemotherapy and radiation for the treatment of advanced-stage endometrial cancer.

INTRODUCTION: Ccombination chemotherapy and radiation therapy is used for adjuvant treatment of stage III-IV endometrial cancer. The goal of this study was to review the treatment duration, toxicity, and survival for patients treated with concomitant chemotherapy and radiation. METHODS: Women with stage III-IV endometrial cancer treated with concurrent chemotherapy and radiation between 2006 and 2013 were included. Toxicities were classified per CTCAE v3.0 and RTOG/EORTC late radiation morbidity scoring. Descriptive statistics were used to quantify treatment and toxicities. Kaplan-Meier method was used to estimate survival. RESULTS: Fifty-one patients met our inclusion criteria. Median age was 60 (range 33-85). Thirty-six patients (70.6%) had endometrioid histology, 13 patients (25.5%) had serous, clear cell, or mixed histology, and 2 women (3.9%) had carcinosarcoma. Forty-eight patients had stage III disease and three patients were stage IVB. Mean treatment duration was 107 ± 19 days. Forty-two patients received all planned chemotherapy, and 16 patients required a dose reduction. Thirty-four patients (66.7%) experienced grade 3-4 toxicities, the majority of which were hematologic. There were no deaths related to therapy. Eighty-six percent of patients received leukocyte growth factors, and 25% of patients received a blood transfusion. Seven late grade 3-4 complications occurred: four gastrointestinal and two genitourinary, and one patient had ongoing neuropathy. Median progression-free survival was 42.8 months (range 4.4-81.5 months) and median overall survival was 44.9 months (range 5.1-82.6 months). Three-year overall survival was 80%. CONCLUSION: Concomitant chemotherapy and radiation is an adequately tolerated treatment modality that allows for shorter treatment duration.

The prognostic significance of lymphovascular space invasion in laparoscopic versus abdominal hysterectomy for endometrioid endometrial cancer.

INTRODUCTION: Recent reports have suggested that uterine manipulators can induce lymphovascular space involvement (LVSI) by endometrial cancer in laparoscopic hysterectomy specimens. The prognostic significance of this phenomenon known as "vascular pseudo invasion" remains elusive. MATERIALS AND METHODS: The authors conducted a retrospective, single institution study of patients who underwent initial surgery for grade 1 and grade 2 endometrioid endometrial cancers with LVSI. Cases were stratified by surgical approach (laparoscopy vs laparotomy). Clinicopathologic and procedure characteristics as well as outcome data were analyzed. Univariate and multivariate analyses were performed. Disease-free survival (DFS) was analyzed using the Kaplan-Meier product limit method. RESULTS: A total of 104 cases (20 laparoscopic, 84 laparotomy) were analyzed. Mean age (65 vs 64 years, respectively), stage distribution, mean number of lymph nodes sampled (18 vs 21, respectively) and use of adjuvant therapy was similar for both groups (p > 0.05). Mean body mass index (BMI) was 30 vs 35 kg/m2, respectively (p = 0.002). Mean follow up was 24 months (range 0.1-102). Univariate analysis demonstrated that LVSI in the laparoscopic setting was associated with worse DFS (p = 0.002). After adjusting for grade the risk of recurrence remained higher for laparoscopic cases (HR: 15.7, 95% CI 1.7-140.0, p = 0.014). CONCLUSIONS: Adjusted risk of recurrence associated with LVSI is higher in cases approached laparoscopically arguing against the concept of "vascular pseudo invasion" associated with the use of uterine manipulators and balloons. LVSI should be regarded as a serious risk factor and taken into account for triage to adjuvant therapies, even in laparoscopically treated early-stage endometrial cancer.

Inhibition of stearoyl-CoA desaturase-1 in differentiating 3T3-L1 preadipocytes upregulates elongase 6 and downregulates genes affecting triacylglycerol synthesis.

BACKGROUND: Stearoyl-CoA desaturase-1 (SCD1) is rate limiting for the conversion of saturated fatty acids palmitate (16:0) and stearate (18:0) to monounsaturated fatty acids palmitoleate (16:1n7) and oleate (18:1n9), respectively. Given that reduced SCD1 activity is associated with improved insulin sensitivity and decreased body weight, there is considerable interest to elucidate the role of this enzyme in adipocytes. During adipogenesis, SCD1 levels increase concomitantly with the accumulation of triacylglycerol (TG); however, the extent to which reduced SCD1 activity can influence TG synthesis and metabolic pathways in differentiating adipocytes remains relatively unexplored. OBJECTIVE: The aim of this work was to delineate how reduced SCD1 activity affects gene expression, protein content and cellular fatty acids in differentiating murine preadipocytes. METHODS: 3T3-L1 preadipocytes were treated with an SCD1 inhibitor (10 nM) throughout differentiation. After 7 days, global gene expression, protein content and fatty acid profiles were examined using microarrays, western blotting and gas chromatography, respectively. RESULTS: SCD1 inhibition increased the abundance of 16:0 and 18:0 (45% and 194%, respectively) and decreased 16:1n7 and 18:1n7 (61% and 35%, respectively) in differentiated preadipocytes. Interestingly, 18:1n9 levels increased by 61%. The augmented 18:0 suggested a possible increase in elongase activity. Elongase 6 (Elovl6) gene expression was increased 2.8-fold (P = 0.04); however, changes were not detected for ELOVL6 protein content. Microarray analysis revealed that genes affecting TG synthesis were downregulated with SCD1 inhibition, which coincided with a 33% decrease in cellular TG content. CONCLUSION: These results provide new mechanistic insight into the role of SCD1 as a regulator of fatty acid profiles and TG synthesis in adipocytes, and reinforce that modulating SCD1 activity may help reduce the risk of obesity-related complications.

Unraveling the adipocyte inflammomodulatory pathways activated by North American ginseng.

BACKGROUND: North American (NA) ginseng (Panax quinquefolius) is a popular natural health product (NHP) that has been demonstrated to regulate immune function, inflammatory processes and response to stress and fatigue. Recent evidence suggests that various extracts of NA ginseng may have different bioactivities because of distinct profiles of ginsenosides and polysaccharides. To date, the bioactive role of ginseng on adipocytes remains relatively unexplored. OBJECTIVE: The goal of this work was to study the extract-specific bioactivity of NA ginseng on differentiated preadipocyte gene expression and adipocytokine secretion. METHODS: In vitro differentiated 3T3-L1 preadipocytes were treated with 25 and 50 µg ml of either crude ethanol (EtOH) or aqueous (AQ) NA ginseng extracts, or polysaccharide and ginsenoside extracts isolated from the AQ extract. Global gene expression was studied with microarrays and the resulting data were analyzed with functional pathway analysis. Adipocytokine secretion was also measured in media. RESULTS: Pathway analysis indicated that the AQ extract, and in particular the polysaccharide extract, triggered a global inflammomodulatory response in differentiated preadipocytes. Specifically, the expression of Il-6 (interleukin 6), Ccl5 (chemokine (C-C motif) ligand 5), Nfκb (nuclear factor-kappaB) and Tnfα (tumor necrosis factor alpha) was increased. These effects were also reflected at the protein level through the increased secretion of IL-6 and CCL5. No effect was seen with the EtOH extract or ginsenoside extract. Using a specific toll-like receptor 4 (TLR4) inhibitor reduced the upregulation of inflammatory gene expression, indicating the relevance of this pathway for the signaling capacity of NA ginseng polysaccharides. CONCLUSION: This work emphasizes the distinct bioactivities of different ginseng extracts on differentiated preadipocyte signaling pathways, and highlights the importance of TLR4 for mediating the inflammomodulatory role of ginseng polysaccharides.

Preclinical evaluation of Mab CC188 for ovarian cancer imaging.

Cancer stem cells (CSCs) have been successfully isolated from solid tumors and are believed to be initiating cells of primary, metastatic and recurrent tumors. Imaging and therapeutic reagents targeted to CSCs have potential to detect subclinical tumors and completely eradicate the disease. Previously, we have demonstrated that Mab CC188 binds to colon cancer CD133- and CD133+ (CSCs) cells. In this study, we examined the reactivity of Mab CC188 to ovarian cancer cells including CD133+ cells and primary tumor tissues using immunofluorescence staining methods and tissue microarray technique. We also explored the feasibility of using NIR dye-labeled Mab CC188 probe to image ovarian tumors in vivo. Mab CC188 stains both CD133- and CD133+ cells of ovarian cancer. Tissue microarray analysis reveals that 75% (92/123) of ovarian cancer cases are positively stained with Mab CC188. Weak positive (±), positive (+), strong positive (++) and very strong positive (+++) stains are 14.8, 3.7, 11 and 24.4%, respectively. In contrast, Mab CC188 staining is low in normal cells and tissues. In vivo study show that significant amounts of the probe accumulates in the excretion organs in the early period postinjection. At 24 hr, the imaging probes have largely accumulates in the tumor, while the intensity of the imaging probe decreases in the liver. The tumor uptake was still evident at 120-hr postinjection. Our work suggests that Mab CC188-based imaging and therapeutic reagents are capable of detecting early stage ovarian tumors and effectively treating the tumor.

Malignant melanoma of the vulva: an extension of cutaneous melanoma?

OBJECTIVE: To determine the prognostic significance of the 2002 revisions of the American Joint Committee on Cancer (AJCC) Staging System for cutaneous melanoma in melanoma of the vulva and review the current surgical utilized for treatment of this neoplasm. METHODS: Demographic, surgical and outcomes data were obtained from the records of vulvar melanoma patients treated from 1990 to 2006 at five academic medical centers. The 2002 modifications of the AJCC staging system for cutaneous melanoma, Breslow thickness and Clark level, were applied to all subjects. Kaplan-Meier Modeling and Linear Regression analysis were utilized for data analysis. Statistics were performed with SAS v 9.1. RESULTS: Seventy-seven patients were identified with a median age of 62 years. 73% had Stage I/II disease. Surgical radicality did not impact recurrence rates or survival. Breslow thickness was associated with recurrence (p=0.002) but not survival. Only the 2002 modified AJCC staging criteria were predictive of overall survival (p=0.006) in patients with malignant melanoma of the vulva. CONCLUSIONS: In the largest multi-site series of vulvar melanoma, the AJCC-2002 staging system for cutaneous malignant melanoma appears to be applicable to primary vulvar melanoma. Moreover, surgical radicality was associated with significant morbidity but not with improvement in survival. Utilization of standard operative staging and resection principles in cutaneous melanoma should be used for all vulvar melanoma patients. Moreover, these patients should also be considered for enrollment in cutaneous melanoma clinical trials.

Pelvic exenteration in gynecologic oncology: a single institution study over 20 years.

OBJECTIVE: The profile of women with gynecologic malignancies treated with pelvic exenteration has changed since the initial description of this procedure. We sought to evaluate our experience with pelvic exenteration over the last 20 years. METHODS: Patients who underwent anterior, posterior, or total pelvic exenteration for vulvar, vaginal, and cervical cancer at Barnes-Jewish Hospital between January 1, 1990 and August 1, 2009 were identified through hospital databases. Patient characteristics, the indications for the procedure, procedural modifications, and patient outcomes were retrospectively assessed. Categorical variables were analyzed with chi-square method, and survival data was analyzed using the Kaplan-Meier method and log rank test. RESULTS: Fifty-four patients were identified who had pelvic exenteration for cervical, vaginal, or vulvar cancer. Recurrent cervical cancer was the most common procedural indication. One year overall survival from pelvic exenteration for the entire cohort was 64%, with 44% of patients still living at 2 years and 34% at 50 months. Younger age was associated with improved overall survival after exenteration (p = 0.01). Negative margin status was associated with a longer disease-free survival (p=0.014). Nodal status at the time of exenteration was not associated with time to recurrence or progression, site of recurrence, type of post-operative treatment, early or late complications, or survival. CONCLUSIONS: Despite advances in imaging and increased radical techniques, outcomes and complications after total pelvic exenteration in this cohort are similar to those described historically. Pelvic exenteration results in sustained survival in select patients, especially those that are young with recurrent disease and pathologically negative margins.

Fatty acid-gene interactions, adipokines and obesity.

It is now recognized that the low-grade inflammation observed with obesity is associated with the development of a wide range of downstream complications. As such, there is considerable interest in elucidating the regulatory mechanisms underlying the production of inflammatory molecules to improve the prevention and treatment of obesity and its co-morbidities. White adipose tissue is no longer considered a passive reservoir for storing lipids, but rather an important organ influencing energy metabolism, insulin sensitivity and inflammation by the secretion of proteins, commonly referred to as adipokines. Dysregulation of several adipokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and adiponectin, contributes to the low-grade inflammation that is a hallmark of obesity. Evidence now suggests that fatty acids represent a class of molecules that can modulate adipokine production, thereby influencing inflammatory status. Although the precise molecular mechanisms by which dietary fats regulate adipokine production remain unclear, recent findings indicate that diet-gene interactions may have an important role in the transcriptional and secretory regulation of adipokines. Single-nucleotide polymorphisms in the genes encoding TNF-α, IL-6 and adiponectin can modify circulating levels of these adipokines and, subsequently, obesity-related phenotypes. This genetic variation can also alter the influence of dietary fatty acids on adipokine production. Therefore, the current review will show that it is paramount to consider both genetic information and dietary fat intake to unravel the inter-individual variability in inflammatory response observed in intervention protocols targeting obesity.

Evidence-based review of the utility of radiation therapy in the treatment of endometrial cancer.

Endometrial cancer is the most common cancer of the female genital tract in the USA and usually presents at an early stage. Most women are cured with surgery, however, some patients may require adjuvant therapy including radiation and/or chemotherapy. Risk factors determine the need for adjuvant treatment and, based on these risk factors, patients are categorized as being at low, intermediate or high risk for recurrence. In this article we will review the best level of evidence available for the use of radiation therapy within each risk stratum. The most controversy and debate is associated with patients stratified to the intermediate-risk group.

Adipose tissue pathways involved in weight loss of cancer cachexia.

BACKGROUND: The regulatory gene pathways that accompany loss of adipose tissue in cancer cachexia are unknown and were explored using pangenomic transcriptome profiling. METHODS: Global gene expression profiles of abdominal subcutaneous adipose tissue were studied in gastrointestinal cancer patients with (n=13) or without (n=14) cachexia. RESULTS: Cachexia was accompanied by preferential loss of adipose tissue and decreased fat cell volume, but not number. Adipose tissue pathways regulating energy turnover were upregulated, whereas genes in pathways related to cell and tissue structure (cellular adhesion, extracellular matrix and actin cytoskeleton) were downregulated in cachectic patients. Transcriptional response elements for hepatic nuclear factor-4 (HNF4) were overrepresented in the promoters of extracellular matrix and adhesion molecule genes, and adipose HNF4 mRNA was downregulated in cachexia. CONCLUSIONS: Cancer cachexia is characterised by preferential loss of adipose tissue; muscle mass is less affected. Loss of adipose tissue is secondary to a decrease in adipocyte lipid content and associates with changes in the expression of genes that regulate energy turnover, cytoskeleton and extracellular matrix, which suggest high tissue remodelling. Changes in gene expression in cachexia are reciprocal to those observed in obesity, suggesting that regulation of fat mass at least partly corresponds to two sides of the same coin.