Swei Hsueh

Randomized trial of surgical staging (extraperitoneal or laparoscopic) versus clinical staging in locally advanced cervical cancer

OBJECTIVE To define the role of pretreatment surgical staging for locally advanced cervical carcinoma. METHODS A two-step randomized trial was conducted to compare clinical staging (arm A) versus surgical staging (arm B) and to compare the laparoscopic (LAP) with the extraperitoneal (EXP) approach in previously untreated locally advanced cervical carcinoma. After the first randomization, those in arm B were randomly allocated to either LAP or EXP. An interim analysis was planned to evaluate the feasibility of LAP versus EXP, which led to the current report. RESULTS A total of 61 patients were eligible (arm A, 29; arm B, 32). The operation time, blood loss, and lymph node yield of LAP and EXP were not significantly different. Serious acute and late toxicity was not different between arm A and arm B, or LAP versus EXP. Para-aortic node metastasis was documented in 25% (95% confidence interval, 10% to 40%) of patients on arm B. An interim analysis was performed in January 2000. Patients on arm B had significantly worse progression-free survival than those on arm A. Hazard ratios of relapse/persistent or death were 3.13 (P = 0.005) and 1.76 (P = 0.150), respectively. Patient accrual was terminated according to the early stopping rules. With further follow-up till December 2001, the difference in progression-free survival remained significant (P = 0.003), and the difference in overall survival became significant (P = 0.024) as the data matured. CONCLUSION The benefit of pretreatment surgical staging for cervical carcinoma remained unproven. The detrimental effects of surgical staging observed in this study must be considered in the design of clinical guidelines or future trials.

Value of Dual-Phase 2-Fluoro-2-Deoxy-d-Glucose Positron Emission Tomography in Cervical Cancer

PURPOSE The role of positron emission tomography (PET) with fluorine-18-labeled fluoro-2-deoxy-d-glucose (FDG) in cervical cancer has not yet been well defined. We conducted a prospective study to investigate its efficacy in comparison with magnetic resonance imaging and/or computed tomography (MRI-CT). MATERIALS AND METHODS Patients with untreated locally advanced (35%) or recurrent (65%) cervical cancer were enrolled onto this study. In the first part of this study, 41 patients had a conventional FDG-PET (40 minutes after injection), and in the second part, 94 patients received dual-phase PET (at both 40 minutes and 3 hours after injection). The overall results of PET scans were compared with MRI-CT, and the two protocols of PET were also compared with each other. Lesion status was determined by pathology results or clinical follow-up. The receiver operating characteristic curve method with area under the curve (AUC) calculation was used to evaluate the discriminative power. RESULTS Overall (N = 135), FDG-PET was significantly superior to MRI-CT in identifying metastatic lesions (AUC, 0.971 v 0.879; P =.039), although the diagnostic accuracy was similar for local tumors. Dual-phase PET was also significantly better than the 40-minute PET (n = 94). The latter accurately recognized 70% of metastatic lesions and the former detected 90% (AUC, 0.943 v 0.951; P =.007). Dual-phase FDG-PET changed treatment of 29 patients (31%; upstaging 27% and downstaging 4%). CONCLUSION This study shows that dual-phase FDG-PET is superior to conventional FDG-PET or MRI-CT in the evaluation of metastatic lesions in locally advanced or recurrent cervical cancer.

Monitoring the size and response of locally advanced breast cancers to neoadjuvant chemotherapy (weekly paclitaxel and epirubicin) with serial enhanced MRI.

AbstractPurpose. To determine if early cancer size reduction seen on enhanced magnetic resonance imaging (MRI) can serve as a response predictor and to correlate final tumor sizes on MRI and excised gross tumor size to microscopic findings in patients with locally advanced breast cancers treated with preoperative neoadjuvant chemotherapy. Methods and materials. Thirty-three patients with advanced breast cancer entered this prospective chemotherapeutic study. Serial, dynamic, enhanced MRI was performed before chemotherapy induction, after the first course of chemotherapy and after the third course of chemotherapy prior to surgery. Responses were measured by image subtraction of tumor size on subsequent axial MRIs using the response evaluation criteria in solid tumors (RECIST). Early tumor size reduction, percentage of relative early tumor size reduction and final tumor size response were calculated and analyzed statistically. Sizes of residual tumors measured on MRI and gross tumors in excised breasts were correlated with microscopic findings. Results. Based on tumor sizes measured with enhanced MRI, four complete responders (CR), 19 partial responders (PR) and 10 non-responder were documented. Twelve (52%) of the 23 responders (CR and PR) had reached the criteria for PR (≥30% size reduction) after the first course of chemotherapy. All CR had a marked early size reduction (ESR) of more than 45%. Using the receiver operating characteristic (ROC) curve, a good cutoff point for early tumor size reduction was 7.4 cm, with a false positive rate of 0.1 and a false negative rate of 0.13. The percentage of ESR was 8.8%, with a false positive rate of 0.1 and a false negative rate of 0.09. Residual tumor size on MRI correlated well with microscopic findings (r = 0.982, p < 0.001) and gross tumor size in excised breasts correlated moderately with microscopic findings (r = 0.640, p < 0.001). Conclusion. Serial, dynamic, enhanced MRI monitoring of chemotherapeutic response in patients with locally advanced breast cancer can be used to assess early response to chemotherapy and post-chemotherapy tumor size change. Although the residual tumor size on MRI correlated well with the microscopic findings, surgical determination of residual cancer load is still recommended to avoid underestimation.

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.

Regulation of ovarian cancer progression by microRNA-187 through targeting Disabled homolog-2

MicroRNAs (miRNAs) play important roles in tumorigenesis by regulating oncogenes and tumor-suppressor genes. In this study, miR-187 and miR-200a were found to be expressed at higher levels in ovarian cancers than in benign tumors. In patients with ovarian cancer, however, higher levels of miR-187 and miR-200a expression were paradoxically associated with better OS and recurrence-free survival. Further, multivariate analysis showed that miR-187 served as an independent prognostic factor for patients with ovarian cancer (n=176). Computational prediction and microarray results indicated that miR-187 directly targeted Disabled homolog-2 (Dab2), and luciferase reporter assays confirmed that the target site of miR-187 was located at the 3′-UTR of the Dab2 gene. Generally considered as a tumor-suppressor gene, Dab2 may actually promote tumor progression in advanced cancers through epithelial-to-mesenchymal transition (EMT). Ectopic expression of miR-187 in cancer cells promoted cell proliferation, but continued overexpression of miR-187 suppressed Dab2 and inhibited migration. Suppression of miR-187 upregulated Dab2, which, by inhibiting E-cadherin levels while stimulating vimentin and phospho-FAK levels, promoted EMT. Reduced ovarian cancer Dab2 histoscores correlated with high miR-187 levels and improved outcomes of patients. Collectively, these results demonstrate distinct dual roles of Dab2 in cell proliferation and tumor progression. In the initial steps of tumorigenesis, upregulated miR-187 suppresses Dab2, promoting cell proliferation. During the later stages, however, continued increased levels of miR-187 inhibits the Dab2-dependent EMT that is associated with tumor invasiveness, which is presumed to be the reason why cancers with high miR-187 levels were associated with better survivals.

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.

Intraoperative Ultrasonographically Guided Excisional Biopsy or Vacuum-Assisted Core Needle Biopsy for Nonpalpable Breast Lesions

Objective: To compare duration and rates of underestimation and complete excision for nonpalpable breast lesions using either intraoperative ultrasonographically guided excisioned biopsy (IUGE) or directional vacuum-assisted biopsy (DVAB). Summary Background Data: Percutaneous ultrasonography-guided core needle biopsy is preferable to stereotactic biopsy for treatment of nonpalpable breast lesions; however, underestimation and false-negative results can occur, and rebiopsy may be required. To date, however, there has been no comparison of these two procedures in terms of diagnostic accuracy and duration. Methods: For 4 consecutive years, IUGE was performed for 104 nonpalpable breast lesions and DVAB for 128 lesions at Chang Gung Memorial Hospital. Of the DVAB cases, the handheld mammotome was used for 53 procedures, with all lesions removed as completely as possible. The duration of the two procedures was calculated from initial skin incision until completion of wound closure. Most of the patients with benign pathology underwent ultrasonographic examination at 3 months after surgery, with a follow-up examination at 1 year. Surgery was performed subsequently for all of the malignancy cases. Results: The average ages and mean tumor sizes for patients undergoing IUGE or DVAB were 46 and 47 years and 1.1 and 1.0 cm, respectively. The average IUGE and DVAB surgery durations for 88 benign tumors and 117 benign lesions were 44.3 and 21.5 minutes, respectively (P < 0.001), and 43.5 and 20.6 minutes for the malignant tumors (n = 16 and n = 11), respectively (P = 0.036). The IUGE and DVAB surgery durations for tumors <1 cm in diameter were 43.5 and 20.6 minutes, respectively, and 44.2 and 23.6 minutes for tumors over that size (P < 0.001). An older-model mammotome was used for 75 patients, with an average duration of 24 minutes in comparison to 18 minutes for the handheld variant (P < 0.001). No false-negative results were noted and, except in the case of the malignant tumors, there was no need for reexcisional biopsy. Further, there were no underestimates of the disease for the 4 cases of atypical ductal hyperplasia and the 12 of noninvasive carcinoma. No further ultrasonographic evidence of tumors was noted for 95% of the benign pathologies, with no residual abnormality detected for 13 of the 27 malignant tumors after IUGE or DVAB. Conclusions: For treatment of nonpalpable breast lesions, both IUGE and DVAB eliminate false-negative results, underestimates, and the requirement for reexcisional biopsies. In comparison to IUGE, DVAB is more convenient and time efficient for excisional biopsy of nonpalpable breast lesions.

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.