Glutathionylation Inhibits the Catalytic Activity of Arabidopsis ß-Amylase3 but Not That of Paralog ß-Amylase1.

ß-Amylase3 (BAM3) is an enzyme that is essential for starch degradation in plant leaves and is also transcriptionally induced under cold stress. However, we recently reported that BAM3's enzymatic activity decreased in cold-stressed Arabidopsis leaves, although the activity of BAM1, a homologous leaf ß-amylase, was largely unaffected. This decrease in BAM3 activity may relate to the accumulation of starch reported in cold-stressed plants. The aim of this study was to explore the disparity between BAM3 transcript and activity levels under cold stress, and we present evidence suggesting BAM3 is being inhibited by post-translational modification. A mechanism of enzyme inhibition was suggested by observing that BAM3 protein levels remained unchanged under cold stress. Cold stress induces nitric oxide (NO) signaling, one result being alteration of protein activity by nitrosylation or glutathionylation through agents such as S-nitrosoglutathione (GSNO). To test whether NO induction correlates with inhibition of BAM3 in vivo, plants were treated with sodium nitroprusside, which releases NO, and a decline in BAM3 but not BAM1 activity was again observed. Treatment of recombinant BAM3 and BAM1 with GSNO caused significant, dose-dependent inhibition of BAM3 activity while BAM1 was largely unaffected. Site-directed mutagenesis, anti-glutathione Western blots, and mass spectrometry were then used to determine that in vitro BAM3 inhibition was caused by glutathionylation at cysteine 433. In addition, we generated a BAM1 mutant resembling BAM3 that was sensitive to GSNO inhibition. These findings demonstrate a differential response of two BAM paralogs to the Cys-modifying reagent GSNO and provide a possible molecular basis for reduced BAM3 activity in cold-stressed plants.

Why do we continue to overtreat stage Ia carcinoma of the cervix?

The current recommended treatment for stage Ia2 cervical cancer is a radical or modified radical hysterectomy. Although in the United States the incidence of cervical cancer is low and declining, almost 50% of the >4000 new cases will present in early stages. An estimated 2200 women each year will undergo radical hysterectomy and many will have both early- and late-onset complications. The purpose of this review is to examine if there is still a role for radical hysterectomy in the proper treatment of stage Ia2 cervical cancer given most recent data. Sufficient histological evidence suggests that although parametrial involvement and lymph node metastases can increase the risk for recurrence, they are relatively uncommon at early stages. Worldwide data that challenge radical hysterectomy as standard of care have shown that conservative management of stage Ia2 cervical cancer results in similar survival and recurrence rates. It is the recommendation based on all reviewed data that radical hysterectomy should no longer be considered standard of care in all cases of stage Ia2 cervical cancer.

Lymphovascular space invasion in uterine corpus cancer: What is its prognostic significance in the absence of lymph node metastases?

OBJECTIVE: Lymphovascular space invasion (LVSI) is a poor prognostic indicator in uterine cancer, primarily due to its association with lymph node metastases. We sought to determine if LVSI provides any prognostic information for uterine cancer subjects in the absence of nodal disease. METHODS: A retrospective review was performed using a database of women treated for uterine cancer at MUSC from 2005 to 2012. Subjects with negative nodes after complete staging were identified. Multiple regression modeling was used to adjust for demographic and histopathologic covariates. The C-index was calculated for models of survival that included LVSI and those that did not. Competing risks analysis was conducted to examine factors associated with time to recurrence. RESULTS: Two hundred and five subjects were completely staged and had negative nodes, 24 with LVSI and 181 without. Factors significantly associated with survival included age, race, stage, grade, histology, and LVSI. Regression models for recurrence-free survival (RFS) and overall survival (OS) had similar C-indices regardless of whether LVSI was included. Competing risks analysis confirmed no significant difference in time to recurrence for subjects with LVSI compared to those without, after adjusting for other prognostic factors (P=0.53). CONCLUSIONS: LVSI is associated with shorter recurrence-free and overall survival in uterine cancer subjects with negative lymph nodes. However, after adjusting for other prognostic factors, LVSI status does not provide additional prognostic information. This finding suggests that recurrence-free and overall survival for uterine cancer patients with negative lymph nodes can be estimated without factoring in LVSI.

Pain management in critically ill patients: a review of multimodal treatment options.

Pain management for critically ill patients provides physicians with the challenge of maximizing patient comfort while avoiding the risks that arise with oversedation. Preventing oversedation has become increasingly important as we better understand the negative impact it has on patients' experiences and outcomes. Current research suggests that oversedation can result in complications such as thromboembolism, pulmonary compromise, immunosuppression and delirium. Fortunately, the analgesic options available for physicians to limit these complications are growing as more treatment modalities are being researched and implemented in the intensive care unit. Our goal is to outline some of the effective and widely utilized tools available to physicians to appropriately and safely manage pain while avoiding oversedation in the critically ill population.

A case of parametrial lymph node involvement in stage IA2 squamous cell carcinoma of the cervix treated with radical hysterectomy and a review of the literature: a case report.

Cervical cancer classified as stage IA2 and IB1 according to the International Federation of Gynecology and Obstetrics has historically been treated with radical hysterectomy and bilateral lymph node dissection, but recent recommendations suggest more conservative treatment modalities. We report a woman with stage IA2 cervical cancer at low risk for parametrial spread including no lymphovascular space invasion, clear conization margins, and tumor size less than 2 cm, who underwent radical hysterectomy and was found to have a single positive metastatic parametrial lymph node. This case report is an important reminder that parametrial involvement occurs in low-risk early-stage cervical cancers.

Impact of point A asymmetry on local control and survival for low dose-rate (LDR) brachytherapy in cervical cancer.

PURPOSE: To evaluate whether Point A asymmetry in low dose-rate (LDR) brachytherapy is associated with local control (LC), disease-free survival (DFS) and/or overall survival (OS). MATERIAL AND METHODS: A retrospective analysis of disease control and survival outcomes was conducted for patients who underwent LDR brachytherapy for advanced cervical cancer. Institutional protocol entailed concurrent chemotherapy and whole pelvis radiotherapy (WPRT) over 5 weeks, followed by placement of Fletcher-Suit tandem and colpostat applicators at weeks 6 and 8. Objective Point A doses, 80-85 Gy, were accomplished by placement of Cesium-137 (Cs-137) sources. Cox proportional hazards regression models were used to assess associations between disease control and survival endpoints with variables of interest. RESULTS: The records of 50 patients with FIGO stage IB1-IVA cervical cancer undergoing LDR brachytherapy at our institution were identified. Thirty of these patients had asymmetry > 2.5%, and 11 patients had asymmetry > 5%. At a median survivor follow-up of 20.25 months, 15 patients had experienced disease failure (including 5 cervical/vaginal apex only failures and 2 failures encompassing the local site). Right/left dose asymmetry at Point A was associated with statistically significantly inferior LC (p = 0.035) and inferior DFS (p = 0.011) for patients with mean Point A dose of > 80 Gy. Insufficient evidence existed to conclude an association with OS. CONCLUSIONS: LDR brachytherapy may be associated with clinically significant dose asymmetry. The present study demonstrates that patients with Point A asymmetry have a higher risk of failure for DFS and LC.

Cost-effectiveness of combination versus sequential docetaxel and carboplatin for the treatment of platinum-sensitive, recurrent ovarian cancer.

BACKGROUND: In a randomized controlled trial (RCT) of patients with recurrent, platinum-sensitive ovarian cancer, the combination weekly docetaxel and carboplatin was associated a with progression-free survival (PFS) of 13.7 months compared with 8.4 months for sequential, single-agent docetaxel followed by carboplatin. The objective of the current study was to construct a cost-utility model to compare these 2 regimens with the incorporation of prospectively collected quality-of-life (QoL) data. METHODS: An RCT of concurrent docetaxel and carboplatin (cDC) versus docetaxel followed by carboplatin (sequential docetaxel and carboplatin [sDC]) was the basis for a Markov decision model, and the primary effectiveness outcome was PFS. Costs were estimated using US dollars based on Medicare reimbursements for chemotherapy regimens, bone marrow support, and management of adverse events. QoL data obtained using the Functional Assessment of Cancer Therapy-General questionnaire were converted to utilities. Costs and incremental cost-effectiveness ratios (ICERs) were reported in US dollars per quality-adjusted life year (QALY). Extensive 1-way sensitivity analyses and a Monte Carlo probabilistic sensitivity analysis were performed. RESULTS: The least expensive strategy was sDC, which cost an average of $20,381, compared with cDC, which cost an average of $25,122. cDC had an ICER of $25,239 per QALY compared with sDC. cDC remained cost-effective, with an ICER <$50,000 per QALY, over a range of costs and estimates. In Monte Carlo sensitivity analysis using a $50,000 per QALY willingness-to-pay threshold, cDC was either dominant or cost-effective with an ICER <$50,000 per QALY in 83% of simulations. CONCLUSIONS: Combined weekly cDC appeared to be cost-effective compared with sDC as treatment strategy for patients with platinum-sensitive ovarian cancer, even when accounting for slightly lower QoL during treatment.

A multicenter, randomized, phase 2 clinical trial to evaluate the efficacy and safety of combination docetaxel and carboplatin and sequential therapy with docetaxel then carboplatin in patients with recurrent platinum-sensitive ovarian cancer.

BACKGROUND: The aim of this randomized clinical trial was to evaluate the efficacy and safety of combination (cDC) and sequential (sDC) weekly docetaxel and carboplatin in women with recurrent platinum-sensitive epithelial ovarian cancer (EOC). METHODS: Participants were randomized to either weekly docetaxel 30 mg/m(2) on days 1 and 8 and carboplatin area under the curve (AUC) = 6 on day 1, every 3 weeks or docetaxel 30 mg/m(2) on days 1 and 8, every 3 weeks for 6 cycles followed by carboplatin AUC = 6 on day 1, every 3 weeks for 6 cycles or until disease progression. The primary endpoint was measurable progression-free survival (PFS). RESULTS: Between January 2004 and March 2007, 150 participants were enrolled. The response rate was 55.4% and 43.2% for those treated with cDC and sDC, respectively. The median PFS was 13.7 months (95% confidence interval [CI], 9.9-16.8) for cDC and 8.4 months (95% CI, 7.1-11.0) for sDC. On the basis of an exploratory analysis, patients treated with sDC were at a 62% increased risk of disease progression compared to those treated with cDC (hazard ratio = 1.62; 95% CI, 1.08-2.45; P = .02). The median overall survival time was similar in both groups (33.2 and 30.1 months, P = .2). The incidence of grade 2 or 3 neurotoxicity and grade 3 or 4 neutropenia was higher with cDC than with sDC (11.7% vs 8.5%; 36.8% vs 11.3%). The sDC group demonstrated significant improvements in the Functional Assessment for Cancer Therapy-Ovarian, Quality of Life Trial Outcome Index scores compared with the combination cohort (P = .013). CONCLUSIONS: Both cDC and sDC regimens have activity in recurrent platinum-sensitive EOC with acceptable toxicity profiles. The cDC regimen may provide a PFS advantage over sDC.

Health-related quality of life outcomes of docetaxel/carboplatin combination therapy vs. sequential therapy with docetaxel then carboplatin in patients with relapsed, platinum-sensitive ovarian cancer: results from a randomized clinical trial.

OBJECTIVES: A phase II clinical trial compared docetaxel in combination with carboplatin to sequential single agent docetaxel followed by carboplatin for treatment of recurrent platinum-sensitive ovarian, peritoneal, or tubal cancer. This manuscript reports prospectively collected health-related quality of life (HRQL). METHODS: Participants were randomized to either weekly docetaxel 30 mg/m(2)/days 1 and 8 and carboplatin AUC 6/day 1 every 3 weeks (cDC) or docetaxel 30 mg/m(2)/days 1 and 8, repeated every 3 weeks for 6 cycles followed by carboplatin AUC 6/day 1 every 3 weeks for 6 cycles or until disease progression (sDC). The primary HRQL endpoint was the trial outcome index (TOI) score of the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) instrument, and was assessed as an intent-to-treat analysis. The secondary HRQL endpoints included the FACT-O total score, the FACT-General, and several domain scores of the FACT-O instrument (physical well-being (PWB), social/family well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and the ovarian cancer specific (OCS) module). The FACT-O was administered at randomization, prior to each of 6 cycles of treatment, and at study endpoint. RESULTS: One hundred forty-eight participants were randomized to each group. Sequential docetaxel followed by carboplatin (sDC) was associated with significant improvements in the FACT-O TOI (p=0.013), FACT-O total score (p=0.033), and OCS (p=0.029) compared to the combination docetaxel and carboplatin group (cDC). CONCLUSIONS: Sequential single agent docetaxel followed by carboplatin is associated with improved HRQL when compared to cDC. The improved progression-free survival observed with cDC should be weighed against lower quality of life during treatment.

Anaemia among clinically well under-fives attending a community health centre in Venda, Limpopo Province.

BACKGROUND: Anaemia has been reported to affect 20 - 75% of children in South Africa. The range suggests the effects that geography, health, and socio-economic status can have on the observed prevalence of anaemia within a specific community. Our objective was to investigate the prevalence of anaemia in children aged under 5 presenting for well-child examinations at a community health centre in Thohoyandou, Limpopo Province. DESIGN: A cross-sectional observational study was carried out in June and July 2007. Caregivers participated in a brief interview where demographic, health, and nutritional information was collected. A blood sample was collected from each child, and haemoglobin levels were assessed with a point-of-care haemoglobin testing system. Anaemia was defined as having a haemoglobin value <2 standard deviations below age-altitude adjusted normal values. RESULTS: Three-quarters (39/52 - 75%) of children were anaemic. Girls were significantly more likely to be anaemic than boys (20/20 v. 19/32 respectively; p=0.001). Anaemic children were significantly less likely to be underweight compared with their peers (32/38 v. 5/12 respectively; p=0.007). There was no significant association between anaemia and infection with Helicobacter pylori (p=0.729), intestinal helminths (p=1.000) or food insecurity (p=0.515). CONCLUSION: We found a striking prevalence of anaemia among clinically well children <5 years old in Thohoyandou, Limpopo Province. The rates of anaemia were higher than those found in previous studies conducted in similar settings in South Africa. Future work should focus on aetiologies and interventions.

How valid are current cervical cancer prognostic factors that are used to recommend adjunctive radiation therapy after radical surgery?

Prognostic factors in early cervical cancer have been debated for many years and have been used as an indication for postradical hysterectomy radiation therapy. A recent Gynecologic Oncology Group protocol suggested that large lesions, deep invasion, or capillary-like space had better recurrence-free survival, but not overall survival, if postoperative radiation was given. When the published data were evaluated, the authors' conclusions were questioned. The choice of prognostic factors does not seem appropriate based on the data that were presented.

The role of radiotherapy in the management of resected uterine papillary serous and clear cell carcinoma.

OBJECTIVE: Primary uterine papillary serous (PS) and clear cell (CC) carcinoma are aggressive histologies characterized by elevated risk of loco-regional recurrence and disease-specific mortality following hysterectomy. The impact of adjuvant radiotherapy remains to be elucidated. The present study is a single institution, retrospective cohort comparison to determine whether post-hysterectomy radiotherapy improves loco-regional control and/or disease-specific survival outcomes in a population of women with PS and/or CC. STUDY DESIGN: Between June 1992 and November 2006, 50 women underwent hysterectomy alone (H) or hysterectomy with adjuvant radiotherapy (H+RT) for primary uterine PS and/or CC. RT involved either high dose-rate (HDR) brachytherapy, external beam RT, or both. RESULTS: At a median survivor follow-up of 27 months (range 2.7-137.3) for the H+RT group and 61 months (range 11.9-114.6) for the H group (range 3-137), patients in the H+RT group demonstrated a trend toward superior disease-free survival (not yet attained at 26 months versus 25 months; p=0.0625). For patients with > or =24 months of follow-up, disease recurrence was significantly higher in H patients over H+RT patients (45% versus 12.5%; p<0.05). Additionally, the H+RT group demonstrated significant improvement in loco-regional control (0% versus 37.5%; p<0.001), most pronounced within FIGO stages I-II H+RT patients (0% versus 70%; p<0.001). Overall survival was not significantly different between the two cohorts (H=32 months, H+RT=not yet attained at 26 months; p=non-significant). CONCLUSIONS: Hysterectomy with adjuvant radiotherapy significantly improves disease-free survival within 2 years post-hysterectomy and significantly reduces loco-regional failures over hysterectomy alone.

Controversies surrounding lymphadenectomy and postoperative radiotherapy in the treatment of carcinoma of the endometrium.

Hysterectomy and bilateral salpingo-oophorectomy have long been acknowledged to be the centerpiece of therapy for carcinoma of the endometrium. However, 30 years ago, realization of the metastatic potential of this disease, particularly to regional lymph nodes, led many clinicians to include lymphadenectomy in the surgical management of uterine cancer. Retrospective studies have since demonstrated that lymphadenectomy is associated with an acceptably low level of surgical morbidity. The incorporation of lymphadenectomy into the surgical management of uterine cancer has accompanied a dramatic reduction in the use of peri-operative radiotherapy. Though not confirmed by prospective data, retrospective series have associated complete lymphadenectomy with an improvement in survival, even in node-negative patients. Contributing to a reduction in the use of postoperative radiation in endometrial cancer have been several randomized trials demonstrating a reduction in locoregional recurrence, but at the cost of significant radiation-induced toxicity and no improvement in overall survival.

Combined adverse effect of African American race and deep stromal invasion on survival following radical hysterectomy for cervical cancer.

OBJECTIVE: The objective of the study was to explore the effect of African American race on survival following radical hysterectomy for cervical cancer. STUDY DESIGN: We reviewed all cases of stage IA-IIA cervical cancer treated with radical hysterectomy at our institution (1987-2001). Characteristics between races were compared using Mann Whitney U and chi(2) tests. Hazard ratios (HR) of survival were calculated using Cox regression. RESULTS: We identified 134 Caucasian and 66 African American patients. There was a trend toward worse survival among African Americans (81.8% vs 88.8%, P = .165). An interaction effect between race and depth of stromal invasion was observed (P = .005), and the combination of African American race and deep stromal invasion had a powerful, independent effect on survival (HR of death 7.04 [95% confidence interval 2.48 to 19.94]). CONCLUSION: The combination of African American race and deep stromal invasion has an adverse effect on survival following radical hysterectomy for cervical cancer and may warrant use of adjuvant therapy.

Serum vascular endothelial growth factor C (VEGF-C) as a specific biomarker for advanced cervical cancer: Relationship to insulin-like growth factor II (IGF-II), IGF binding protein 3 (IGF-BP3) and VEGF-A [corrected].

OBJECTIVES: An early non-invasive diagnosis of cervical cancer and its metastasis can save lives. We have shown that serum IGF-II levels can be effectively used for a specific early diagnosis of cervical cancer. Here, we shall determine if serum levels of vascular endothelial growth factors B and C (VEGF-A [corrected] VEGF-C) associated with vasculogenic and lymphogenic metastasis may be used for an early diagnosis of advanced metastatic cervical cancer and compare these levels with those of the serum IGF-II and IGF-binding protein 3 (IGF-BP3). MATERIAL AND METHODS: (a) Serum levels of IGF-II, IGF-BP3, VEGF-A [corrected] (VEGF(165)) and VEGF-C (ELISA kits) were determined in: 82 controls with normal Pap smears; 29 women with atypical squamous cells of undetermined significance (ASCUS) and normal cervical biopsy; 46 ASCUS and cervical intraepithelial neoplasia (CIN) on biopsy; 8 pre-therapy CIN-I; 23 successfully treated CIN-I; 75 persistent CIN-I; 14 CIN-II/III pre-therapy; 14 successfully treated CIN-II/III; 70 persistent CIN-II/III; 86 pre-therapy cervical cancer; 26 in early grades of cervical cancer; 21 in late grades of cervical cancer; 22 cervical cancer patients in remission; 50 persistent cervical cancer; 18 with ovarian cancer; and 57 with endometrial cancer. (b) Serial serum samples collected over 5 years in 5 women with progressing cervical cancer were also tested. (c) Serum and tissue VEGF-C were enumerated in 20 matched serum (ELISA) and tissue (semi-quantitative immunofluorescent antibody assay) samples from controls, early cervical cancer, late cervical cancer, ovarian cancer and endometrial cancer patients. Student's t test, chi-square analysis and linear regression analysis were used. RESULTS: (a) As anticipated, serum IGF-II levels were elevated as early as ASCUS with CIN on biopsy and continued to be elevated in CIN (all grades; pre-therapy and persistent) and cervical cancer (pre-therapy, early, late and persistent). Serum IGF-II levels were normal in ASCUS with normal biopsy, successfully treated CIN-I, II/III, cervical cancer as well as pre-therapy ovarian and endometrial cancers (therapy efficacy: P < 0.0001 by chi-square analysis). Serum IGF-BP3 showed a significant decrease with advancing disease. Serum VEGF-A [corrected] levels were the highest in pre-therapy, early, advanced and persistent cervical cancer, as well as in ovarian and endometrial cancers. Serum VEGF-C levels, on the other hand, were the highest in late and persistent cervical cancers, but not in ovarian or endometrial cancers. (b) In the 5 women with serial samples, the serum levels of the growth factors showed similar trends. (c) VEGF-C levels in serum and tissue were elevated in cervical cancers especially in advanced grades, while they were normal in serum and tissue from the controls and women with ovarian and endometrial cancers. There was a highly significant positive correlation between VEGF-C and IGF-II and a negative correlation between IGF-BP3 and VEGF-C (P < 0.0001). CONCLUSION: Serum IGF-II up-regulation is specific to cervical cancer and helps in the early diagnosis of malignant proliferation, while serum VEGF-C up-regulation appears to be a unique marker for an early diagnosis of cervical cancer metastasis. VEGF-C and IGF-II systems appear to be interrelated in cervical cancer, contributing to the early malignant cell proliferation and lympho-vascular metastasis. Serum IGF-BP3 and VEGF-A [corrected] appear to be common markers for all gynecological cancers.

Early non-invasive diagnosis of cervical cancer: beyond Pap smears and human papilloma virus (HPV) testing.

Cervical cancer is a major gynecologic malignancy around the world. However, current diagnostic methods such as Pap smear and human papilloma virus (HPV) testing are insufficient for an early diagnosis of cervical cancer, follow-up on therapy efficacy or to identify the women who might progress to cervical cancer (only about 1-5% of the HPV-positive women will develop cervical cancer). Patients with atypical squamous cells of undetermined significance (ASC-US) clearly need a better screening test. Developing a non-invasive method for early diagnosis of cervical cancer is essential. Our in vitro and translational research data support the hypothesis that: 1. Squamous cell cervical cancer is related to specific upregulation of tissue and serum Insulin-like Growth Factor-II levels (IGF-II; 100% sensitivity and 100% specificity). Serum IGF-I, but not IGF-II levels are elevated in other gynecological, breast, lung and prostate cancers. Serum IGF-II test helps in diagnosing cervical cancer as early as ASC-US or cervical intraepithelial neoplasia (CIN)-I and in monitoring therapy efficacy (p < 0.001 by Student's 't' test and Chi-square analysis). 2. Concomittant to increased serum IGF-II levels, IGF-Binding Protein 3 (IGF-BP3) levels are significantly decreased in persistent CIN and cervical cancer (p < 0.0001). As IGF-BP3 modulates IGF-II biological activity, significantly decreased serum IGF-BP3 levels (levels normalize after therapy; p < 0.001) may indicate a poor prognosis. Similar to serum IGF-II, serum IGF-BP3 levels help monitoring therapy efficacy in cervical cancer and advanced CIN. Measurement of serum IGF-II levels will help in early diagnosis of cervical cancer and monitoring of therapy outcome. Serum IGF-BP3 in conjunction with IGF-II levels may help in predicting prognosis as well as monitoring therapy efficacy.

Prognosis of papillary serous, clear cell, and grade 3 stage I carcinoma of the endometrium.

OBJECTIVE: The purpose of this study was to evaluate patients with uterine papillary serous carcinoma (UPSC), clear cell (CC), and grade 3 endometrioid (G3) surgically stage I endometrial cancer. METHODS: The 25th Annual Report (AR) of FIGO was used to identify patients with endometrial cancers who were surgically staged. For comparison, all cancers reported were evaluated with particular interest in patients with stage I UPSC, CC, and G3. Incidence, substage, post-surgical treatment, and survival were identified. RESULTS: Of 5694 endometrial cancer patients reported to the AR, 3996 (70%) were surgically stage I. There were 148 UPSC, 59 CC, and 325 with G3 lesions. UPSC and CC represent 5.2% of all stage I cancers while 8.1% are G3. Although there were greater number of UPSC, CC, and G3 with extrauterine disease, about 50% of UPSC and CC were stage I. This compares to 81% for G1, 68% for G2, and only 42% for G3. There were more IA cancers with UPSC and CC than G3 (22%, 33%, and 17%, respectively). Survival (5 years) for UPSC and CC was 72% and 81%, respectively, compared to 76% for G3 lesions. Postoperative radiation improved survival somewhat (6-8%) but the difference was not significant. CONCLUSION: UPSC and CC histotypes when diagnosed as stage I have a better survival than commonly perceived and equal to G3 endometrioid cancers. Postoperative radiation improves survival but not significantly so. The role of chemotherapy has not been defined.

Is lymph vascular space involvement an independent prognostic factor in early cervical cancer?

OBJECTIVE: To determine whether lymph vascular space involvement (LVSI) in women with early cervical carcinoma is an independent prognostic factor. METHODS: The literature was reviewed using Medline and known literature to determine if LVSI is an independent risk factor as determined by multivariant analysis with survival being the end point in patients undergoing radical hysterectomy and pelvic lymphadenopathy. RESULTS: A total of 25 articles were identified that satisfied the evaluation criteria. Only three (12%) identified LVSI as an independent risk factor while 88% and 61% of those evaluated, noted lymph node metastasis and tumor size/depth of invasion to be significant risk factors for survival. CONCLUSIONS: Using LVSI as the sole determining factor for consideration of post radical hysterectomy radiotherapy appears questionable.

Circulating levels of insulin-like growth factor-II and IGF-binding protein 3 in cervical cancer.

OBJECTIVE: We aimed to further document that elevated levels of circulating insulin-like growth factor II (IGF-II) are associated with cervical cancer and to test the hypothesis that there may be an inverse association between IGF-II and IGF-binding protein 3 (IGF-BP3). METHODS: Serum IGF-II and IGF-BP3 levels were measured, using ELISA kits (Diagnostic Systems Laboratories), in 23 controls; 16 ASC-US with normal biopsies; 14 ASC-US with advanced CIN; 2 pretherapy CIN-I; 8 successfully treated CIN-I; 24 persistent CIN I; 14 pretherapy CIN II/III; 10 posttherapy CIN II/III with normal biopsies; 18 persistent CIN-II/III; 7 with pretherapy cervical cancer; 19 with posttherapy cervical cancer under remission; 15 with posttherapy persistent/recurrent cervical cancer; 10 with persistent ovarian or endometrial cancer; and 3 with endometrial or vulvar with cervical cancer. Student's t test and linear regression analysis were used. RESULTS: Compared to controls (493 +/- 90 ng/ml) and women with other gynecological cancers, serum IGF-II levels were significantly increased in women with ASC-US, with advanced CIN on biopsy (P < 0.0001), persistent CIN-I (993 +/- 262 ng/ml; P < 0.0001), pretherapy advanced CIN (1086 +/- 240; P < 0.0001), pretherapy cervical cancer patients (1746 +/- 318 ng/ml; P < 0.0001) and posttherapy persistent/recurrent CIN (1094 +/- 300; P < 0.0001); and cervical cancer (1395 +/- 189; P < 0.0001). After therapy, the IGF-II levels returned to normal in both CIN and cervical cancer patients under remission. Elevated serum IGF-II levels had 100% sensitivity and 87% specificity for cervical cancer and 81% sensitivity and 82% specificity for CIN. The levels of IGF-BP3 were significantly reduced in women with CIN before and after therapy (P < 0.0001) and in cervical cancer patients before and after therapy (P < 0.001). There was an inverse relationship between serum IGF-II and BP-3 levels (P < 0.01). Decreased serum IGF-BP3 levels had a sensitivity of 72% and specificity of 75% for cervical cancer and 81% sensitivity and 83% specificity for CIN. When both markers were considered together the sensitivity was 72% and specificity 84% for cervical cancer, while for CIN, the sensitivity was 57% and specificity 81%. CONCLUSION: Serum IGF-II may be a reliable marker for early diagnosis and monitoring therapy efficacy (sensitivity and specificity of 100% versus normal controls), while IGF-BP3 levels can be reliably used to predict prognosis.