Angel Chao

Low Value of [18F]-Fluoro-2-Deoxy-d-Glucose Positron Emission Tomography in Primary Staging of Early-Stage Cervical Cancer Before Radical Hysterectomy

PURPOSE The role of positron emission tomography (PET) with [18F]-fluoro-2-deoxy-D-glucose (FDG) in early-stage cervical cancer is unclear. We aimed to investigate the clinical benefit of FDG-PET in primary staging before radical hysterectomy and pelvic lymphadenectomy (RH-PLND). PATIENTS AND METHODS Patients with untreated stage IA2 to IIA adenocarcinoma (AD) or adenosquamous carcinoma (ASC) or nonbulky (< or = 4 cm) squamous cell carcinoma cervical cancer with magnetic resonance imaging (MRI) -defined negative nodal metastasis were enrolled onto a prospective study with a two-stage design. All patients had a preoperative dual-phase FDG-PET, technetium-99m-sulfur colloid lymphoscintigraphy, and intraoperative sentinel lymph node (LN) detection at RH-PLND. The gold standard of LN metastasis is histologic. A sample size of 120 patients was calculated to fit study aims (diagnostic efficacy of PET and sentinel LN sampling). An interim analysis was performed when 60 patients were accrued, which led to the current report. RESULTS There were 36 SCCs, 20 ADs, and four ASCs. Of the 60 patients, 10 (16.7%) had pelvic LN metastases, and one (1.7%) had para-aortic LN (PALN) metastasis histologically. FDG-PET detected the single PALN metastasis (one of one patient) but detected only one (10%) of the 10 pelvic LN metastases. The PET false-negative pelvic LN micrometastases measured a median of 4.0 x 3.0 mm (range, 0.5 x 0.5 to 7 x 6 mm). The second stage of this trial will be continued without PET. CONCLUSION This study shows that dual-phase FDG-PET has little value in primary, nonbulky, stage IA2 to IIA and MRI-defined, LN-negative cervical cancer.

Pain relief by applying transcutaneous electrical nerve stimulation (TENS) on acupuncture points during the first stage of labor: a randomized double-blind placebo-controlled trial.

Abstract Transcutaneous electrical nerve stimulation (TENS) is one of the non‐pharmacological means of pain relief for labor and delivery. We aimed to investigate the efficacy and safety of TENS on specific acupuncture points for reducing pain in the first stage of labor. In this double‐blind, placebo‐controlled trial, we randomly assigned healthy full‐term parturients in active phase of first‐stage labor to either TENS on four acupuncture points (Hegu [Li 4] and Sanyinjiao [Sp 6]) (n = 52) or the TENS placebo (n = 53). Visual analogue scale (VAS) was used to assess pain before and 30 and 60 min after treatment. The primary outcome was the rate of VAS score decrease ⩾3 in each group. A questionnaire was given at 24 h post‐partum to evaluate the satisfaction of pain relieving method and the willingness to have the same treatment again. Mode of delivery and neonatal effect were measured as secondary outcome. One hundred women were eligible for analysis. TENS group experienced VAS score reduction ⩾3 significantly more common than the TENS placebo group (31/50 [62%] vs 7/50 [14%], P < 0.001). Willingness of using the same analgesic method for a future childbirth was also significantly different (TENS: 48/50 [96%] vs TENS placebo: 33/50 [66%], P < 0.001). Operative delivery was increased in the TENS group (12/50 [24%] vs 4/50 [8%], P = 0.05), but the neonatal outcomes were not different. The application of TENS on specific acupuncture points could be a non‐invasive adjunct for pain relief in the first stage of labor.

Comparison between the Hybrid Capture II Test and an SPF1/GP6+ PCR-Based Assay for Detection of Human Papillomavirus DNA in Cervical Swab Samples

ABSTRACT We compared the efficacy of human papillomavirus (HPV) DNA detection between a PCR-based genechip (Easychip HPV Blot [hereafter referred to as HPV Blot]; King Car, Taiwan) method and Hybrid Capture II (HCII; Digene, Gaithersburg, MD) in women with previous normal (n = 146) or abnormal (≥atypical squamous cells of undetermined significance [ASCUS] [n = 208]) cytology. A total of 354 cervical swab samples were collected for HPV DNA assay by both HCII and SPF1/GP6+ PCR followed by HPV Blot tests. Colposcopy-directed biopsy was performed if clinically indicated. Of the 354 samples, HPV-positive rates by these two methods (HCII and HPV Blot) were 12.6% and 18.2% in 143 normal samples, 36.2% and 45.7% in 105 ASCUS samples, 57.4% and 57.4% in 94 low-grade squamous intraepithelial lesion samples, and 83.3% and 75.0% in 12 high-grade squamous intraepithelial lesion samples, respectively. The concordance of HPV Blot and HCII was 80.8% (286/354), and the agreement between the methods (κ value, 0.68) was substantial. Discrepancies were further investigated by at least one of the following three methods: direct sequencing, type-specific PCR, and HPV Blot genotyping of cervical biopsy tissue. In the 15 HCII-positive samples, HPV Blot detected only non-HCII HPV genotypes; results of further verification methods were consistent with the latter test in the 15 samples. Of the 20 samples with HCII-negative and HPV Blot-positive results, 18 were found to contain the 13 HCII high-risk genotypes by verification methods. In only 16.7% (3/18) of the HCII-positive but HPV Blot-negative samples, further studies detected the 13 HCII genotypes. We conclude that HPV Blot seemed comparable to HCII for detection of HPV DNA in cervical swab samples.

Role of Human Papillomavirus Genotype in Prognosis of Early-Stage Cervical Cancer Undergoing Primary Surgery

PURPOSE Our aim was to evaluate the prognostic significance of human papillomavirus (HPV) genotype in early-stage cervical carcinoma primarily treated with surgery in a large tertiary referral medical center. PATIENTS AND METHODS Consecutive patients who underwent primary surgery for invasive cervical carcinoma of International Federation of Gynecology and Obstetrics (FIGO) stage I to IIA between 1993 and 2000 were retrospectively reviewed. Polymerase chain reaction (PCR) using a general primer set followed by reverse-blot detection of 38 types of HPV DNA in a single reaction was performed for genotyping. E6 type-specific PCR was performed to validate multiple types. RESULTS A total of 1,067 eligible patients were analyzed. HPV DNA sequences were detected in 95.1% of the specimens, among which 9.6% contained multiple types. HPV 16 was detected in 63.8% of the samples, and HPV 18 was detected in 16.5% of the samples. The median follow-up time of surviving patients was 77 months. By multivariate analysis, FIGO stage, lymph node metastasis, depth of cervical stromal invasion, grade of differentiation, and HPV 18 positivity were significantly related to cancer relapse. FIGO stage II, deep stromal invasion, parametrial extension, HPV 18 positivity, and age older than 45 years were significant predictors for death. Using the seven selected variables from either recurrence-free or overall survival analysis, death-predicting (P < .0001) and relapse-predicting (P < .0001) models classifying three risk groups (low, intermediate, and high risk) were constructed and endorsed by internal validation. CONCLUSION The independent prognostic value of HPV genotype is confirmed in this study. The prognostic models could be useful in counseling patients and stratifying patients in future clinical trials.

Molecular characterization of adenocarcinoma and squamous carcinoma of the uterine cervix using microarray analysis of gene expression

In an attempt to understand the molecular mechanisms for the different clinical features between adenocarcinoma/adenosquamous carcinoma (AC/ASC) and squamous carcinoma (SC) of the uterine cervix, we analyzed gene expression profiles of different histological subtypes of cervical cancer. Cancer specimens and the surrounding normal tissue counterparts were separately collected from cervical cancer patients undergoing type III radical hysterectomy. Paired total RNA (cancer and normal tissues) was isolated and analyzed with cDNA microarrays containing duplicate spots of 7 334 sequence‐verified human cDNA clones. Selected differentially expressed genes specific for AC or SC were further verified using real‐time quantitative polymerase chain reaction (RTQ‐PCR) and immunohistochemistry. Genes, including CEACAM5, TACSTD1, S100P and MSLN were upregulated in AC. Contrarily, genes involved in epidermal differentiation complex such as S100A9 and ANXA8 were upregulated in SC. Cross‐validation of the results using an independent but comparable group of patients with known long‐term outcomes (n = 63, median follow‐up 70.3 months; range, 4–208 months) showed that the correlation between the selected 6 differentially expressed genes and histology was highly significant. CEACAM5 (p < 0.0001) and TACSTD1 (p = 0.009) were significant prognostic factors by multivariate Cox proportional hazards regression analysis. The combination of cDNA microarray, RTQ‐PCR and immunohistochemical results of this study showed that it is possible to define different gene profiles for AC and SC. Moreover, TACSTD1 expression may be a novel poor prognostic factor.

Stress-induced Phosphoprotein 1 as a Secreted Biomarker for Human Ovarian Cancer Promotes Cancer Cell Proliferation

Ovarian cancers are frequently not diagnosed until advanced stages, resulting in a high case fatality rate. Because of this, more tumor markers, in addition to CA125, for detecting and monitoring ovarian cancer are needed. During a systematic search for potential biomarkers of ovarian cancer, we compared the protein profiles between tumor interstitial fluid and normal interstitial fluid of ovaries, rationalizing that abnormal levels of proteins in tumor interstitial fluid may be detected in peripheral blood and thus serve as easily accessible tumor markers. Here, we show that stress-induced phosphoprotein 1 (STIP1) was secreted by ovarian cancer tissues into the peripheral blood of patients, resulting in a significant increase of serum levels of STIP1 in cancer patients compared with those in age-matched normal controls. Our results further indicated that combined use of CA125 and STIP1 may increase early detection of ovarian cancer. Functionally, recombinant STIP1 significantly induced ERK phosphorylation, promoted DNA synthesis, and increased Ki-67 immunoreactivity in ovarian cancer cells, suggesting that STIP1 in vitro promotes cell proliferation. Colocalization of STIP1 and phospho-ERK in human ovarian cancer tissues also supports an in vivo activation of ERK by STIP1. Further understanding of molecular roles of STIP1 in human ovarian cancer may shed light on its pathophysiology and development of novel therapeutic strategies.

Human papillomavirus genotype in cervical cancer: A population-based study†

Our aim was to investigate the human papillomavirus (HPV) genotype distribution and correlation between HPV parameters and clinicopathological variables in cervical carcinoma treated in a large tertiary referral medical center in Taiwan. Consecutive patients treated for cervical carcinoma (Stages I–IV according to the International Federation of Gynecology and Obstetrics) between 1993 and 2000 were included. HPV genotyping using SPF1/GP6+ PCR was performed, followed by hybridization with a genechip (Easychip® HPV Blot, King Car, Taiwan). E6 type‐specific PCR was performed to validate multiple‐type. HPV‐negative samples were further verified by type‐specific PCR and a repeat HPV Blot. A total of 2,118 patients were eligible for analysis. HPV DNA sequences were detected in 96.6% (95% CI, 95.8–97.4%) of the specimens, among which 82% harbored single‐type and 18% contained multiple‐type HPV sequences. Thirty‐five types of HPV were identified and the leading 8 were HPV16 (50.0%), HPV18 (17.8%), HPV58 (16.3%), HPV33 (8.7%), HPV52 (6.8%), HPV39 (3.0%), HPV45 (2.5%) and HPV31 (2.3%). HPV58 or 33 or 52 was detected in 30.3% (641/2,118). By multivariate analysis, HPV58‐ or 33‐ or 52‐infection was significantly associated with older age (p < 0.001) and primary radiotherapy or concurrent chemoradiation (RT/CCRT) (p < 0.001). Among HPV‐positive cases, multiple‐type was more frequently seen in those receiving primary RT/CCRT (p < 0.001). The knowledge of HPV genotype distribution will form a basis for guidelines in HPV‐based cervical cancer screening and cost‐effective multivalent HPV vaccine policy in Taiwan and in the world. The association between HPV parameters and clinicopathological variables warrants further investigations.

Positron emission tomography in evaluating the feasibility of curative intent in cervical cancer patients with limited distant lymph node metastases

OBJECTIVE Clinical outcomes of cervical cancer patients with distant lymph node (LN) metastases are poor. [(18)F] fluorodeoxyglucose positron emission tomography (PET) or PET/computed tomography (CT) scans could potentially benefit treatment plan. METHODS Patients with cervical cancer whose CT/magnetic resonance imaging (MRI)-based imaging showed limited metastases to para-aortic lymph node (PALN), inguinal (ILN), and/or supraclavicular (SLN) were prospectively enrolled to evaluate whether PET or PET/CT influenced management. The clinical impact of PET or PET/CT was determined on a patient basis. RESULTS Between November 2001 and April 2007, 47 patients were enrolled for suspected metastasis to PALN with (n=8) or without other distant nodal involvement (n=31), ILN (n=6), or SLN metastasis (n=2). Additional PET or PET/CT had positive clinical impact in 21 (44.7%) of the 47 study patients, 23 had no impact, and three had negative impact. Positive impact included disclosing additional curable sites (n=8), down-staging (n=6), offering metabolic biopsy (n=4) or change to palliation (n=3). The 2-year overall survival (OS) of the study patients was 56.9% with median follow-up time of 47.0 months (range: 8-71 months) in surviving patients. The 2-year OS rates for PALN (based on histology or CT/MRI-PET consensus) and histology-proven SLN metastasis were 50.6% and 24.7%, respectively. Two (40.0%) of the five patients with histology-proven ILN metastases had no evidence of disease. CONCLUSIONS PET or PET/CT added benefit to primary treatment planning in cervical cancer with MRI-defined suspected distant nodal metastasis.

Secreted Stress-Induced Phosphoprotein 1 Activates the ALK2-SMAD Signaling Pathways and Promotes Cell Proliferation of Ovarian Cancer Cells

Stress-induced phosphoprotein 1 (STIP1), a cochaperone that organizes other chaperones, heat shock proteins (HSPs), was recently shown to be secreted by human ovarian cancer cells. In neuronal tissues, binding to prion protein was required for STIP1 to activate the ERK (extracellular-regulated MAP kinase) signaling pathways. However, we report that STIP1 binding to a bone morphogenetic protein (BMP) receptor, ALK2 (activin A receptor, type II-like kinase 2), was necessary and sufficient to stimulate proliferation of ovarian cancer cells. The binding of STIP1 to ALK2 activated the SMAD signaling pathway, leading to transcriptional activation of ID3 (inhibitor of DNA binding 3), promoting cell proliferation. In conclusion, ovarian-cancer-tissue-secreted STIP1 stimulates cancer cell proliferation by binding to ALK2 and activating the SMAD-ID3 signaling pathways. Although animal studies are needed to confirm these mechanisms in vivo, our results may pave the way for developing novel therapeutic strategies for ovarian cancer.

Metabolic tumor volume by 18 F-FDG PET/CT is prognostic for stage IVB endometrial carcinoma

OBJECTIVE The objective of this study was to evaluate the potential prognostic factors in patients with primary stage IVB endometrial carcinoma, incorporating parameters from (18)F-FDG PET/CT such as standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). METHODS Patients with primary M1 endometrial carcinoma who received (18)F-FDG PET/CT before treatment were retrospectively analyzed. Histological type, histological grade, T stage, N stage, age, ECOG performance status, hormone receptor status, metastatic patterns, number of involved metastatic patterns, serum CA125 level, and (18)F-FDG PET/CT derived parameters including total body SUVmax, total body MTV, and total body TLG were considered as potential prognostic factors for overall survival. Cox proportional hazards regression model was used for statistical analysis. RESULTS Fifteen patients were eligible with a median survival of 17 months. Total body MTV and total body TLG were highly collinear (Pearsons r=0.978) and were found to be significant prognosticators (P=0.010 and 0.011 respectively). Four patients with total body MTV above 450 mL (or total body TLG above 2700 g) had a median survival of two months, while the remaining patients had a median survival of 47 months. CONCLUSION Total body MTV is a significant prognostic factor for overall survival in patients with stage IVB endometrial carcinoma. Patients with total body MTV above 450 mL had a very poor survival, while more aggressive therapy may be considered in the remaining patients in pursuit of prolonged survival.