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This study (Asian Gynecologic Oncology Group [AGOG]13-001/Taiwanese Gynecologic Oncology Group [TGOG]1006) was to validate human papillomavirus (HPV)16 as an independent good prognostic factor and investigate the impact of treatment modalities to cervical adenocarcinoma and adenosquamous carcinoma (AD/ASC).Patients receiving primary treatment at AGOG and TGOG member hospitals for cervical AD/ASC were retrospectively (1993-2014) and prospectively (since 2014) enrolled. DNA extraction from paraffin-embedded tissue (FFPE) specimens was used for HPV genotyping. Those with suspected endometrial origin were excluded for analysis.A total of 354 patients with valid HPV results were enrolled, 287 (81.1%) of which had HPV-positive tumors. The top-3 types were HPV 18 (50.8%), HPV16 (22.9%) and HPV45 (4.0%). The HPV16-negativity rates varied widely across hospitals. 322 patients were eligible for prognostic analyses. By multivariate analysis, advanced stage (HR5.8, 95% confidence interval [CI] 2.1-15.8; HR5.8, 95% CI 1.6-20.5), lymph node metastasis (HR4.6, 95% CI 2.7-7.9; HR7.3, 95% CI 3.8-14.0), and HPV16-positivity (HR0.3, 95% CI 0.1-0.6; HR0.3, 95% CI 0.1-0.9) were independent prognostic factors for progression-free survival (PFS) and overall survival (OS). Stage I patients with primary surgery had better 5-year PFS (82.8% vs 50.0% p = 0.020) and OS (89.3% vs 57.1%, p = 0.017) than those with non-primary surgery, while the propensity scores distribution were similar among the treatment groups.This study confirmed that HPV16-positivity was a good prognostic factor for PFS and OS in AD/ASC, and patients seemed to have better outcome with primary surgery than non-primary surgery.

Endometrial cancer (EC) usually presented as a localized disease at diagnosis (67%), 20% of patients diagnosed with regional spread, and distant metastasis accounted for 9%. The standard treatments include hysterectomy, bilateral salpingo-oophorectomy, and pelvic with/without paraaortic lymph node dissection/biopsy. Adjuvant therapy is arranged according to risk factors and stages. Risk group classification varied among different guidelines and studies and evolved with time. Adjuvant modalities include chemotherapy, radiotherapy, chemoradiotherapy, antiangiogenesis agents, immune checkpoint inhibitors, and multi-target agents. We review the recent literature to incorporate important advances in trial results, real-world big data, and knowledge in biomarkers of EC to update appropriate adjuvant therapy and post-surgical treatment of EC patients.

We investigated whether mutations in plasma circulating tumor DNA (ctDNA) can provide prognostic insight in patients with different histological types of ovarian carcinoma. We also examined the concordance of mutations detected in ctDNA samples with those identified in the corresponding formalin-fixed paraffin-embedded (FFPE) tumor specimens.Between July 2016 and December 2017, 29 patients with ovarian carcinoma were prospectively enrolled. FFPE tumor specimens were obtained from all participants. A total of 187 blood samples for ctDNA analysis were collected before surgery (C0), immediate after surgery before adjuvant chemotherapy (C1), and at six-month intervals. Progression-free survival (PFS) and overall survival (OS) served as the main outcome measures.The study cohort consisted of 13 (44.8%) patients with high-grade serous carcinomas (HGSC), 9 (31.0%) with clear cell carcinoma, 2 (6.9%) with mucinous carcinomas, 4 (13.8%) with low-grade serous carcinomas, and 1 (3.4%) with endometrioid carcinoma. Twenty-four (82.8%) patients had at least one detectable ctDNA variant. The concordance rate between mutations identified in pretreatment ctDNA and corresponding FFPE tumor specimens was 92.3% for patients with HGSC and 58.6% for the entire cohort. The median follow-up time was 33.15 months (range: 0.79-46.13 months). Patients with an advanced stage disease more likely had detectable ctDNA mutations before surgery (C0) and after surgery at C1, while those with HGSC more likely had ctDNA mutations detected before surgery. The presence of ctDNA mutations at C1 was an independent predictor of worse OS with a hazard ratio of 6.56 (95% confidence interval, 1.07-40.17) for detectable versus undetectable C1 ctDNA variants, p = 0.042).ctDNA mutations are common in patients with ovarian carcinoma. The presence of ctDNA mutations after surgery was an independent predictor of less favorable PFS and OS.

The molecular underpinnings of seromucinous borderline tumor (SMBT) – an uncommon ovarian epithelial neoplasm characterized by association with endometriosis, frequent bilateral ovarian involvement, and occasional progression to invasive carcinoma – remain poorly understood. Here, we sought to comprehensively characterize the mutational landscape of SMBT and elucidate the clonal relationship between bilateral ovarian SMBTs. We also compared the mutational profiles between SMBTs and concurrent invasive carcinomas. Formalin-fixed, paraffin-embedded tissue specimens were retrieved from 28 patients diagnosed with SMBT. Massively parallel sequencing of 409 cancer-related genes was conducted to identify somatic mutations in 33 SMBT samples and four concurrent invasive carcinoma specimens. TERT promoter mutations were assessed by Sanger sequencing, whereas immunohistochemistry was used as a surrogate tool for detecting deletions or epigenetic silencing of relevant tumor suppressor genes. Twenty-six (92.9%) of the 28 patients were diagnosed with stage I SMBTs. Seven (25%) cases showed bilateral ovarian involvement and 13 (46%) had concomitant endometriosis. Concurrent ovarian carcinomas were identified in three patients, whereas one case had a synchronous endometrial carcinoma. Somatic mutations in the KRAS, PIK3CA, and ARID1A genes were identified in 100, 60.7, and 14.3% of SMBT samples, respectively. In contrast, TERT promoter mutations and DNA mismatch repair deficiencies were absent. Sequencing of paired specimens from patients with bilateral SMBT revealed the presence of at least two shared somatic mutations, suggestive of a clonal relationship. Similarly, we identified shared somatic mutations between SMBT samples and concurrent ovarian carcinoma specimens. Taken together, these findings demonstrated a distinct mutational landscape of SMBT in which (1) KRAS is invariably mutated, (2) PIK3CA is frequently mutated, and (3) TERT promoter mutations and DNA mismatch repair deficiencies are absent. Our findings represent the first extensive characterization of this rare ovarian neoplasm, with potential implications for disease classification and molecular diagnostics.

Background We describe a rare paratubal serous borderline tumor occurring in an adolescent and provide insight into its molecular underpinnings. Case A 14-year-old girl presented with irregular menstrual cycles and a large right pelvic mass. Computed tomography imaging revealed a cystic neoplasm arising from the right ovary with peripheral calcification. During laparotomy, a cystic tumor located at the right parametrium independent of the fallopian tube was identified. The ovary was intact and the tumor was successfully removed. Intraoperative diagnosis using the frozen section technique and subsequent pathology revealed a paratubal serous borderline tumor. Molecular analyses revealed a chromosomally stable tumor genome and a pathogenic somatic mutation (c.1799 T > A, p.Val600Glu) in the B-Raf proto-oncogene, serine/threonine kinase (BRAF) gene. Summary and Conclusion This case shows that the BRAF p.Val600Glu mutation likely acts as an oncogenic driver in this rare neoplasm.

Objectives: This multi-center international study (Asian Gynecologic Oncology Group [AGOG]13-001/Taiwanese Gynecologic Oncology Group [TGOG]1006) was to validate human papillomavirus (HPV)16 as an independent prognostic factor of cervical adenocarcinoma and adenosquamous carcinoma (AD/ASC). Methods: Retrospective and prospective collection of patients receiving primary treatment at AGOG and TGOG member hospitals for cervical AD/ASC were enrolled. The cases treated between 1993 and 2014 were retrospectively collected, and the prospective enrollment was started since 2014. Those endometrial origin (by immunohistochemistry and imaging studies) cannot rule out were excluded for analysis. Results: A total of 354 patients were enrolled, 287 (81.1%) of which had HPV-positive tumors. The top-3 types among HPV-positive cases was HPV 18 (50.8%), HPV16 (22.9%) and HPV45 (4.0%). A total of 322 patients were eligible for prognostic analyses. Patient with HPV16-positivity had significantly longer progression-free survival (PFS) and overall survivals (OS) than those without HPV16 (p=0.001 and 0.026, respectively). By multivariate analysis, advanced FIGO stage (HR5.7, 2.4-13.5), lymph node metastasis (HR4.6, 2.7-7.9), tumor size (>4 cm HR3.3), and HPV16-positivity (HR0.3, 0.1-0.7) were independent prognostic factors for PFS. Only the former 2 variables remained significant, while HPV16-positivity was marginally significant (p=0.064) for OS. HPV-negativity rates varied across hospitals, yet it seemed to be increasing over time (4.4% versus 12.5%, p Conclusions: This study confirmed that HPV16-positivity was a good prognostic factor for PFS, yet the increasing HPV-negative AD/ASCs seemed to be a trend that needs attention.

Objectives Synchronous endometrial and ovarian carcinomas (SEOCs) present gynecologic oncologists with a challenging diagnostic puzzle: discriminating between double primary cancers and single primary cancer with metastasis. We aimed to determine the clonal relationship between simultaneously diagnosed endometrial and ovarian carcinomas. Methods Fourteen pairs of SEOCs of endometrioid type and two pairs of SEOCs with disparate histologic types (control for dual primary tumors) were subjected to massively parallel sequencing (MPS) and molecular inversion probe microarrays. Results Thirteen of the 14 pairs of SEOCs harbored somatic mutations shared by both uterine and ovarian lesions, indicative of clonality. High degree of chromosomal instability in the tumors from 10 patients who received adjuvant chemotherapy, of whom 9 had synchronous carcinomas with significantly overlapping copy number alterations (CNAs), suggestive of single primary tumors with metastasis. The clonal relationship determined by genomic analyses did not agree with clinicopathological criteria in 11 of 14 cases. Minimal CNAs were identified in both ovarian and endometrial carcinomas in 4 patients, who did not receive adjuvant chemotherapy and experienced no recurrent diseases. In contrast, two of the 10 patients with chromosomally unstable cancers developed recurrent tumors. Conclusion Our findings support a recent paradigm-shifting concept that most SEOCs originate from a single tumor. It also casts doubt on the clinicopathological criteria used to distinguish between dual primary tumors and single primary tumor with metastasis. Testing of CNAs on SEOCs may help determining the need of adjuvant therapy.

The Wnt pathway is a major signaling pathway that regulates corneal epithelial stem cells. However, little is known about how the ultrastructure of the limbal epithelial basement membrane (EBM) affects Wnt activity. Due to its enhanced matrix stability, the cross-linked amniotic membrane (AM) has gained increasing interest in the field of regenerative medicine. For the first time, we used EDC/NHS cross-linked denuded AM (CLDAM) as a simulated EBM substrate to investigate this mechanism. Human limbal epithelial (HLE) cells were cultured on dishes (HLE/dish), denuded AM (HLE/DAM) or CLDAM (HLE/CLDAM). Compared with HLE/dish or HLE/DAM cultures, HLE/CLDAM cultures showed greater BrdU retention and colony formation efficiency and expressed higher levels of p63, ABCG2, integrin β1, and integrin-linked kinase (ILK). Nuclear β-catenin and TCF-4 levels were higher in HLE/CLDAM cultures compared with HLE cells cultured on collagen IV, laminin, Matrigel, or DAM. Silencing of ILK in HLE/CLDAM cultures resulted in decreased levels of nuclear β-catenin, TCF-4 and deltaNp63α, whereas cytokeratin 12 expression increased. Over-expression of ILK in HLE/dish cultures had the opposite effects. Accordingly, we proposed that the CLDAM matrix, with its higher rigidity and rougher ultrastructure, better preserved HLE progenitor cells in vitro, possibly by activating integrin β1/ILK, which indirectly activated Wnt/β-catenin and subsequently deltaNp63α. Crosstalk between the integrin β1/ILK and Wnt/β-catenin pathways appears to play a crucial role in limbal progenitor cell survival on EBM. Statement of significance We demonstrated the superior capability of carbodiimide cross-linked denuded amniotic membrane (CLDAM) than natural DAM to preserve limbo-corneal epithelial progenitor cells in vitro, then we used CLDAM as a simulated epithelial basement membrane (EBM) to study how EBM maintains limbal epithelial stem cells (LESCs). We found that integrin-linked kinase (ILK) is an important mediator that transfers survival signals detected by integrin β1 to the Wnt/β-catenin pathway, which in turn up-regulates deltaNp63α, a master gene that regulates LESC function. The rougher surface of the limbal EBM suggests that the surface complexity of the LESC niche may be important in regulating LESC function, which is triggered by the recognition of topographic cues by integrin β1, followed by activation of the ILK/Wnt/β-catenin/p63 cascade.

Objective To investigate the efficacy and toxicity of immunomodulatory therapy (IMT) alone or as an add-on to palliative/salvage chemotherapy in patients with refractory/recurrent epithelial ovarian cancer (EOC). Materials and methods We retrospectively analyzed the efficacy and toxicity of IMT in 15 patients with refractory/recurrent EOC who had previously received multiple chemotherapy regimens. Results The median age of the patients was 56 years (range, 41–75 years). Three patients were platinum-sensitive, two were platinum-resistant, and the remaining 10 patients were refractory to platinum-based front-line chemotherapy. IMT consisted of picibanil (OK-432) on Day 1, interleukin-2 and/or interferon-α on Day 2 administered by subcutaneous injection (every week or 2-weekly). Five patients never received metronomic oral cyclophosphamide. After IMT, three patients achieved partial remission (PR, lasting for 11 months, ≥ 12 months, and 16 months), and six patients had stable disease (SD). The disease stabilizing rate (PR+SD) was 60% (3/3 in platinum-sensitive and 6/12 in platinum-resistant/refractory patients). The absolute lymphocyte count (ALC) at 1 month after IMT was significantly higher in the PR+SD group (median 1242.0/μL) than in the progression group (median 325.0/μL) ( p = 0.012). No ≥ Grade 3 toxicities were observed. The median post-IMT survival time was 12 months (range, 2–39 months). Conclusion IMT alone or add-on to palliative/salvage chemotherapy for refractory/recurrent EOC achieves a substantial disease stabilizing rate without severe toxicity, which might be a potential option in selected patients. The ALC 1 month after IMT could be an early indicator to disease stabilization.

Objective To identify candidate microRNAs (miRNAs) in the serum of patients with clear cell carcinomas in monitoring disease progression. Materials and methods The sera of patients with diagnosed ovarian clear cell carcinoma were collected from 2009 to 2012. Real-time quantitative polymerase chain reaction (PCR) analysis for 270 miRNAs was performed. To offset the potential extraction bias, an equal amount of Caenorhabditis elegans cel-miR-238 was added to each serum specimen before miRNA isolation. miRNA expression was analyzed using the ΔCt method, with cel-miR-238 as controls. Results Twenty-one patients with clear cell carcinoma were included. In the discovery phase on four pairs of pre- and postoperative sera, 18 differentially expressed miRNAs were selected from 270 miRNAs. In the validation phase on an independent set of 11 pairs of pre- and postoperative sera, 4 miRNAs (hsa-miR-130a, hsa-miR-138, hsa-miR-187, and hsa-miR-202) were confirmed to be higher in the preoperative sera. In the application phase, hsa-miR-130a remained consistent with the different time points in seven of the 10 patients during clinical follow-up periods. More importantly, in three patients, hsa-miR-130a levels were elevated in early disease recurrences before CA125 was found to be elevated. Conclusion Hsa-miR-130a may be a useful serum biomarker for detecting recurrence of ovarian clear cell cancer, and warrants further studies.

Objectives The purpose of this review is to summarize literature pertaining to clinical roles of positron emission tomography (PET) or integrated PET and computed tomography (PET/CT) scans, magnetic resonance imaging (MRI) and emerging techniques of these two molecular imaging tools for gynecologic malignancies. Methods PubMed and MEDLINE databases search for articles published before June 2014 was performed. Only English-language articles were considered. Search terms included "cervical cancer", "endometrial cancer", "uterine cancer", "uterine sarcoma", "ovarian cancer" and "vulvar cancer", in association with "FDG", "PET", "PET/CT", "MRI", "PET/MR", "diffusion", "spectroscopy" and "clinical trial". Results Topics explored included PET, PET/CT and MRI for diagnosis of malignancy, prognostic implications, clinical staging of disease extent, monitoring treatment response, post-therapy surveillance, diagnosis of treatment failure and restaging, and follow-up after salvage therapy in gynecologic malignancies. Conclusions Molecular imaging (mainly PET and MRI) plays important roles in the management of gynecologic malignancies. Molecular imaging has various impacts in different clinical scenarios. Emerging technologies will continuously improve our practice. Prospective studies with defined endpoints are necessary to evaluate roles of these novel tools in management of gynecologic malignancies.

Background Although human papillomavirus (HPV) infections have been causally linked to oral cavity squamous cell carcinoma (OSCC), the potential role of low-risk HPV (LR-HPV) types in the pathogenesis of this malignancy remains unclear. Objectives We sought to investigate the distribution of HPV genotypes and their prognostic significance in OSCC patients treated by radical surgery, either with or without adjuvant therapy. Study design We studied two non-overlapping OSCC cohorts for the periods 2005–2006 (2005 cohort, n = 204) and 2010–2011 (2010 cohort, n = 206). Paraffin-embedded tissue blocks were collected, and the HPV genotype was determined using PCR plus HPV blot tests. The primary study endpoint was the prevalence of HPV genotypes. The secondary endpoints were the 2-year therapeutic outcomes. Results The overall prevalence of HPV infections did not differ significantly in the two study cohorts. However, the prevalence of LR-HPV was significantly higher in the 2010 cohort than in the 2005 cohort ( p = 0.002). The overall prevalence of HPV infections was not significantly associated with the 2-year outcomes. However, multivariate analysis demonstrated that LR-HPV infection was a predictor of poor 2-year disease-free survival ( p = 0.036, hazard ratio [HR] = 3.1), disease-specific survival ( p = 0.014, HR = 3.8), and overall survival ( p = 0.016, HR = 3.2) in the subgroups of OSCC patients with poor differentiation, pN2 lymph node metastases, or extracapsular spread ( n = 150). Conclusions LR-HPV infections may have an important role in determining the clinical outcomes of certain OSCC patients bearing specific risk factors.

Objective It is not clear whether the prognostic value of pretreatment serum CA125 levels is independent or through association with other clinicopathological features in endometrial cancer. Methods All patients with endometrial cancer treated between 2000 and 2010 were retrospectively reviewed. The correlation of clinicopathological characteristics, CA125 and treatment outcomes was analyzed. Receiver operating characteristics (ROC) curves were used to determine the CA125 cut-off values. Cox proportional hazard regression was used for multivariate analysis. Results Of the 923 eligible patients, 757 had serum CA125 levels measured before treatment. We identified 264 (34.9%) patients with pretreatment serum CA125>35U/mL. By multivariate analysis, advanced stage ( P =0.001), serous or clear cell carcinoma ( P =0.008), positive peritoneal cytology ( P =0.042), and lymph node metastases ( P =0.004) were significant risk factors for cancer-specific survival (CSS), while serum CA125>35U/mL ( P =0.067) was of borderline statistical significance. Using ROC curve stratified by age, we found that a serum CA125>35U/mL was significant for CSS (HR=2.34, 95% CI=1.04–5.29) among patients >49years old. After adjustment for confounding factors, serum CA125>105U/mL was significant (HR=6.03, 95% CI=1.19–30.63) in patients ≤49years old. Conclusions These results suggest that an age-stratified cut-off level for CA125 (35U/mL in patients >49years old and 105U/mL in patients ≤49years old) can improve the prognostic stratification of patients with endometrial cancer.

Studies conducted in Western countries have reported an increased risk for second primary malignancies after cervical cancer. There is little documentation of ethnic differences in this increased risk, and most of the Asian studies are hospital-based studies with small case numbers.Using population-based data from the Taiwan Cancer Registry for the period 1979-2008, we quantified standardized incidence ratios (SIRs) among 52,972 women with initial diagnoses of cervical cancer.Among the 52,972 women, 3061 (5.78%) developed second primary cancers during 433,571 person-years of follow-up. Overall, the SIR for developing a subsequent second cancer was significantly greater than that of the general population (1.36 [95% CI, 1.32-1.41]). There was a greater risk for cancers of the esophagus, stomach, small intestine, rectum, lung, bone, non-melanoma skin, uterine corpus, vagina/vulva, bladder, kidney, and leukemia. When further examining age at diagnosis of cervical cancer (50 and ≥50) for these 12 sites, we found that the risk of second cancers (SIR,50 and ≥50: 3.08 vs. 1.63) was higher not only in younger patients, except for non-melanoma skin cancer and endometrial cancer, but also within the first 5 years after diagnosis of cervical cancer. The median overall survival for women with cervical cancer was 18.58 years. The second cancers had a negative impact on overall survival after adjusting for age (P0.001).SIR for second cancers was significantly greater than the general population in cervical cancer patients. A young age at the diagnosis of cervical cancer predicted an increased risk. The second cancers worsened overall survival.

Objective To evaluate the efficacy and toxicity of topical imiquimod for the treatment of persistent human papillomavirus (HPV) infection in patients with or without cervical/vaginal intraepithelial neoplasia (CIN/VAIN). Methods Patients with persistent HPV infection (≥1 year) after a history of treatment for cervical or vaginal neoplasm but normal histology and cytology, abnormal Papanicolaou (Pap) smears without abnormal histology, and untreated histology-documented CIN/VAIN Grade 1/2/3 with HPV-positive testing were recruited. Patients were instructed to apply 250 mg of 5% imiquimod cream intravaginally on consecutive days or at least twice weekly on an outpatient basis for a minimum of 12 doses. A group of age- and previous diagnosis-matched, imiquimod-untreated historical controls ( n = 20) were selected. The main outcome measures included HPV DNA detection, cytology, and colposcopy/histology at 6 months after treatment. Results A total of 72 patients were eligible for analysis. At a median follow-up of 33.6 months, 37 patients (51.4%) had cytological/histological regression and tested HPV-negative. Six patients (8.3%) had progressive cytology/histology with persistent HPV infections. Of the 72 treated patients, 26 patients who had a normal Pap test but were persistently HPV-positive for at least 1 year had a complete regression rate of 65.4%, which was significantly different from the rate (30%) observed in the untreated historical control ( p = 0.036). Six patients with histologically proven CIN2/3 or VAIN2/3 had a complete regression rate of 66.6% (4/6). Conclusions The tolerability of intravaginal self-administered imiquimod is confirmed. Its efficacy in the treatment of women with persistent HPV infection and normal cytology warrants further randomized, controlled trials to determine appropriate dosages and scheduling.

Purpose To study the prognostic value of human papillomavirus (HPV) genotypes in patients with advanced cervical cancer treated with radiation therapy (RT) alone or concurrent chemoradiation therapy (CCRT). Methods and Materials Between August 1993 and May 2000, 327 patients with advanced squamous cell carcinoma of the cervix (International Federation of Gynecology and Obstetrics stage III/IVA or stage IIB with positive lymph nodes) were eligible for this study. HPV genotypes were determined using the Easychip® HPV genechip. Outcomes were analyzed using Kaplan-Meier survival analysis and the Cox proportional hazards model. Results We detected 22 HPV genotypes in 323 (98.8%) patients. The leading 4 types were HPV16, 58, 18, and 33. The 5-year overall and disease-specific survival estimates for the entire cohort were 41.9% and 51.4%, respectively. CCRT improved the 5-year disease-specific survival by an absolute 9.8%, but this was not statistically significant ( P =.089). There was a significant improvement in disease-specific survival in the CCRT group for HPV18-positive (60.9% vs 30.4%, P =.019) and HPV58-positive (69.3% vs 48.9%, P =.026) patients compared with the RT alone group. In contrast, the differences in survival with CCRT compared with RT alone in the HPV16-positive and HPV-33 positive subgroups were not statistically significant ( P =.86 and P =.53, respectively). An improved disease-specific survival was observed for CCRT treated patients infected with both HPV16 and HPV18, but these differenced also were not statistically significant. Conclusions The HPV genotype may be a useful predictive factor for the effect of CCRT in patients with advanced squamous cell carcinoma of the cervix. Verifying these results in prospective trials could have an impact on tailoring future treatment based on HPV genotype.

Uterine sarcomas are uncommon tumours from mesenchymal elements. They are thought to arise primarily from endometrial stroma and uterine muscle, respectively. When endometrial stroma undergoes malignant transformation, it might be accompanied by a malignant epithelial component. Thus, malignant mesenchymal uterine tumours comprise leiomyosarcoma, endometrial stromal sarcoma, undifferentiated uterine sarcoma and carcinosarcoma. In this chapter, we discusses preoperative presentation, diagnosis and current progress in different imaging modalities, including ultrasonography, computed tomography, magnetic resonance image and positron emission tomography scan. We summarise advances in new technology, which might improve preoperative detection and enhance referral to gynaecologic oncologists for optimal staging surgery and treatment.

Patients with cervical cancer and supraclavicular lymph nodes (SLN) recurrence have a poor but heterogeneous prognosis. The aim of this study was to identify potential prognostic factors - including FDG-PET results - that may affect survival and treatment outcomes in patients with this group of patients.Between January 2001 and December 2008, we identified a total of 31 consecutive patients with cervical cancer who had evidence of SLN recurrence. All participants underwent FDG-PET. Survival was measured from the date of documented SLN recurrence. The latency period was defined as the length of time from the date of first diagnosis to the date of SLN recurrence.The median follow-up time was 22.8 months (range: 4.7-105.1). The 3- and 5-year survival rates were 41% and 27.3%, respectively. Patients with intermediate SUV values (between 4.3 and 8) had a significantly better prognosis than subjects with both high (8) or low (4.3) SUV values (p=0.004). Latency period2 years, SCC-Ag levels ≥ 4ng/mL, recurrence extend beyond SLN, and SUV of4.38 were significant adverse prognostic factors by multivariate analysis. The 3-year overall survival (OS) rate of patients carrying 0-1 adverse prognostic factors was 90% (low-risk group), while 3-year OS rates for intermediate-risk group (2 factors) and high-risk group (3-4 factors) were 30% and 0%, respectively (p=0.001).Our results justify the use of PET (accurate extent of relapse and SUV) as a prognostic tool in patients with cervical cancer and SLN recurrence.

Purpose To study the outcomes of patients with adenocarcinoma/adenosquamous carcinoma (AC/ASC) of the cervix primarily treated with radiotherapy (RT), identify the prognostic factors, and evaluate the efficacy of concurrent chemoradiotherapy (CCRT) or salvage surgery. Methods and Materials A total of 148 patients with Stage I-IVA AC/ASC of cervix after full-course definitive RT were included. Of the 148 patients, 77% had advanced stage disease. Treatment failure was categorized as either distant or local failure. Local failure was further separated into persistent tumor or local relapse after complete remission. The effectiveness of CCRT with cisplatin and/or paclitaxel was examined, and the surgical salvage rate for local failure was reviewed. Results The 5-year relapse-free survival rate was 68%, 38%, 49%, 30%, and 0% for those with Stage IB/IIA nonbulky, IB/IIA bulky, IIB, III, and IVA disease, respectively, and appeared inferior to that of those with squamous cell carcinoma of the cervix treated using the same RT protocol. Incomplete tumor regression after RT, a low hemoglobin level, and positive lymph node metastasis were independent poor prognostic factors for relapse-free survival. CCRT with weekly cisplatinum did not improve the outcome for our AC/ASC patients. Salvage surgery rescued 30% of patients with persistent disease. Conclusion Patients with AC/ASC of the cervix primarily treated with RT had inferior outcomes compared to those with squamous cell carcinoma. Incomplete tumor regression after RT was the most important prognostic factor for local failure. Salvage surgery for patients with persistent tumor should be encouraged for selected patients. Our results did not demonstrate a benefit of CCRT with cisplatin for this disease.

Objective: To evaluate the pregnancy courses and obstetric outcomes in patients conceived after conservative treatment of endometrial cancer. Materials and Methods: Case series and systemic review of pregnancy women after fertility-sparing treatment of endometrial cancer. Patients with early stage endometrial cancer were identified through Tumor Registry in Chang Gung Memorial Hospital between 1990 and 2005 and MEDLINE search. Diagnosed cases were managed by fertility-sparing therapies. Pregnancies followed by assisted reproductive technology and spontaneous or ovulation with intrauterine insemination were designated as Group 1 and Group 2, respectively. Results: Five livebirths in three patients with two sets of twin pregnancy were delivered. Adding 47 women in the MEDLINE search literature, there were 65 deliveries with 77 livebirths. Groups 1 and 2 had 15 and 50 deliveries, respectively. Group 1 had 23 livebirths including four sets of twins and two sets of triplets, whereas 54 livebirths consisted of two sets of twins and one set of triplets were noted in Group 2 (p = 0.003). Seven preterm deliveries were noted in Group 1 and three in Group 2 (p = 0.001). Cesarean rate was 93.3% versus 22.0% (p

Cervical carcinoma is the second most common cause of death from gynecological cancers worldwide. Knowledge of the molecular mechanisms underlying the tumorigenesis of cervical cancer cell, except human papilloma virus infection, is limited.A microarray was used to study the differential expression of genes in cancerous tissues to identify new molecular markers for diagnosis and prognosis. Their differential expression was confirmed with Western blotting and immunohistochemical analyses. The clinical correlations and prognostic significance of the aberrantly expressed proteins were evaluated to identify novel biomarkers of cervical cancer.The expression of gelsolin was significantly upregulated in 78% of patients with cervical cancer, and gelsolin was selected for further study. Gelsolin expression was stronger in cervical tumor tissues than in the surrounding noncancerous tissues (P0.001). Gelsolin expression in the plasma of cervical cancer patients was increased 2.2-fold compared with that of healthy control subjects (P0.001). The levels of plasma gelsolin in the early and late stages were significantly different (P=0.006). According to immunohistochemical analysis, increased gelsolin expression was associated with histological type and FIGO stage II. The 5-year overall survival and recurrence-free survival rates for the low-expression group (cut-off=115) were significantly higher than those of the high-expression group. Cancer cells with reduced gelsolin expression exhibited reduced migration and proliferation.These results provide strong evidence that gelsolin plays an important role in cellular proliferation and migration in cervical cancer and suggest that gelsolin is a promising marker for cervical cancer screening and prognosis.

Objective Previous studies have shown that SPF1/GP6+ PCR followed by HPV Blot has high sensitivity and high reproducibility for the detection of human papillomavirus (HPV). However, there have been reports of false-negative results. In the present study we endeavoured to improve the diagnostic performance of HPV DNA testing in cervical swab specimens. We also aimed to identify viral load thresholds. Methods We examined DNA from cervical swabs of 7 women with a cervical intraepithelial neoplasia grade 2 or worse (CIN2+) who were negative by HPV DNA testing. For control purposes, 106 cytology negative/HPV-negative samples were included. PCR was performed with either 1μL of DNA solution or different amounts of input DNA (25, 50, and 100ng). We tested two different commercial alkaline phosphatases (ALPs) at two distinct reaction times. The overall conclusions were based on HPV Blot, type-specific PCR, direct sequencing, and real-time quantitative PCR (qPCR). Results All seven patients with CIN2+ disease turned HPV-positive when 100ng of input DNA and E6 type-specific PCR were used. Discrepant and false-negative results were obtained using different amounts of input DNA. Different commercial ALPs showed a significant impact on detection performance. Analysis of viral load indicated that the detection threshold for HPV infection using SPF1/GP6+ PCR plus HPV Blot was approximately 10 2 –10 3 copies. Conclusions Reliable determination of HPV status is crucially dependent on the amount of input genomic DNA.

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. PETor PET/CTadded benefit to primary treatment planning in cervical cancer with MRI-defined suspected distant nodal metastasis.

Background Type-specific persistence of human papillomavirus (HPV) infection can cause invasive cervical cancer. Objectives To evaluate the efficacy of HPV detection and typing with a general polymerase chain reaction (PCR)-based genotyping array and to compare it with a type-specific PCR assay. Study design Four hundred and thirty-three cervical samples were tested with a modified MY11/GP6+ PCR-based reverse-blot assay (EasyChip ® HPV Blot; King Car, Taiwan [hereafter HPV Blot]) and with 20 genotypes of L1-type-specific PCR (HPV-6, -11, -16, -18, -31, -33, -35, -39, -45, -51, -52, -53, -56, -58, -59, -62, -66, -68, -70, and -71 [CP8061]). Results The concordance of the two tests in determining HPV positivity was 96.8% (419/433), with a Cohen's κ = 0.93 (95% CI: 0.90–0.97) and McNemar's test of P = 1.0, which indicates excellent agreement. The overall concordance of the two tests in the identification of type-specific HPV was 91.0% (394/433). Sensitivity (90–100%), specificity (99.2–100%), and accuracy (98.6–100%) rates of HPV Blot against the gold standard were satisfactory for HPV-16, -18, -58, -33, -52, -39, -45, -31, -51, -70 while HPV-71 (63.6%) had suboptimal sensitivity. Though the κ values between the two tests for many individual genotypes could not be reliably calculated because of low positivity, the κ values for HPV-16, -52, and -58 were excellent (0.93, 0.96, and 0.95, respectively). Conclusion The modified MY11/GP6+ PCR-based HPV Blot assay is accurate and sensitive for detection and genotyping of HPV in cervical swab samples.

Cervical cancer is one of the leading female cancers in Taiwan and ranks as the fifth cause of cancer death in the female population. Human papillomavirus has been established as the causative agent for cervical neoplasia and cervical cancer. However, the tumor biology involved in the prognoses of different cell types in early cancers and tumor responses to radiation in advanced cancers remain largely unknown. The introduction of microarray technologies in the 1990s has provided genome-wide strategies for searching tens of thousands of genes simultaneously. In this review, we first summarize the two types of microarrays: oligonucleotides microarray and cDNA microarray. Then, we review the studies of functional genomics in cervical cancer. Gene expression studies that involved cervical cancer cell lines, cervical cells of cancer versus normal ectocervix, cancer tissues of different histology, radioresistant versus radiosensitive patients, and the combinatorial gene expression associated with chromosomal amplifications are discussed. In particular, CEACAM5 , TACSTD1 , S100P , and MSLN have shown to be upregulated in adenocarcinoma, and increased expression levels of CEACAM5 and TACSTD1 were significantly correlated with poorer patient outcomes. On the other hand, 35 genes, including apoptotic genes (e.g. BIK , TEGT , SSI-3 ), hypoxia-inducible genes (e.g. HIF1A , CA12 ), and tumor cell invasion and metastasis genes (e.g. CTSL , CTSB , PLAU , CD44 ), have been noted to echo the hypothesis that increased tumor hypoxia leads to radiation resistance in cervical cancer during radiation.

DNA vaccination has emerged as a promising strategy for cancer immunotherapy. However, since DNA vaccines have low immunogenicity, various strategies have been developed to enhance the potency of DNA vaccines. In the current study, we aim to determine whether the potency of the DNA vaccine encoding human papillomavirus type 16 (HPV-16) E7 antigen can be enhanced by IL-2. We have generated a DNA vaccine encoding IL-2 linked to HPV-16 E7 antigen. Our results indicate that the DNA vaccine encoding a fusion of IL-2 and E7 proteins generated the highest frequency of E7-specific CD8(+) T cells. We also found that the DNA vaccine encoding a fusion of IL-2 and E7 proteins generated the strongest protective as well as therapeutic anti-tumor effect against E7-expressing tumors. In addition, it was observed that CD8(+) T cells were mainly responsible for the antitumor effect generated by the DNA vaccine encoding a fusion of IL-2 and E7 proteins. Thus, we conclude that the linkage of IL-2 to HPV-16 E7 antigen significantly enhances the DNA vaccine potency against E7-expressing tumors. Our strategy may potentially be used in other antigenic systems to control infectious diseases and/or cancer.

Objectives. To evaluate the efficacy and safety of a distearoylphosphatidylcholine pegylated liposomal doxorubicin, Lipo-Dox®, in platinum-resistant or refractory epithelial ovarian cancer. Methods. A multicenter phase II trial enrolled women with platinum-resistant or refractory epithelial ovarian carcinoma and naive to anthracycline. Eligible patients had either measurable tumor(s) or elevated serum CA 125 titer. Lipodox was initiated with a dose of 45 mg/m2 at a 4-week interval with subsequent escalation or reduction. A total of six cycles were scheduled. Results. 29 patients, 20 with platinum-resistant and 9 with platinum refractory tumors, were enrolled. Lipo-Dox was given for an average of 4.6 cycles per patient with a total of 134 cycles. Among the 26 evaluable patients, one achieved CR, 5 PR and 9 SD. The overall response rate was 23.1% (95% CI, 6.8%–39.3%) with a median response duration of 11.6 weeks. 5 of the 6 responses were in patients with resistant disease. The median progression-free duration in the SD patients was 25.7 weeks. With a median follow-up of 13.8 months, the median progression-free and median overall survivals in the 26 patients were 5.4 months and 13.8 months, respectively. Hand–foot skin reaction occurred in 4.5% and skin pigmentation in 11.2% of all treatment cycles, all were Grade 1/2. Nausea and vomiting occurred in 14.2%, while anemia, leukopenia and thrombocytopenia occurred in 20.9%, 32.8% and 9% of cycle, respectively, and were mostly Grade 1 or 2. Conclusion. Lipo-Dox, the third liposome encapsulated doxorubicin, at 45 mg/m2 every 4 weeks, is effective against recurrent, platinum-resistant epithelial ovarian cancers.

Most positron emission tomography (PET) imaging studies in gynecologic cancer are performed using (18)F-fluorodeoxyglucose (FDG). It contributes valuable information in primary staging of untreated advanced cervical cancer, in the post-treatment surveillance with unexplained tumor marker (such as squamous cell carcinoma antigen [SCC-Ag]) elevation or suspicious of recurrence, and restaging of potentially curable recurrent cervical cancer. Its value in early-stage resectable cervical cancer is questionable. In ovarian cancer, FDG-PET provides benefits for those with plateaued or increasing abnormal serum CA 125 (35 U/mL), computed tomography and/or magnetic resonance imaging (CT-MRI) defined localized recurrence feasible for local destructive procedures (such as surgery, radiotherapy, or radiofrequency ablation), and clinically suspected recurrent or persistent cancer for which CT-guide biopsy cannot be performed. The role of FDG-PET in endometrial cancer is relatively less defined because of the lack of data in the literature. In our prospective study, FDG-PET coupled with MRI-CT may facilitate optimal management of endometrial cancer in well-selected cases. The clinical impact was positive in 29 (48.3%) of the 60 scans, 22.2% for primary staging, 73.1% for post-therapy surveillance, and 57.1% after salvage therapy, respectively. Scant studies have been reported in the management of vulvar cancer using FDG-PET. More data are needed. Gestational trophoblastic neoplasia is quite unique in biological behavior and clinical management. Our preliminary results suggest that FDG-PET is potentially useful in selected gestational trophoblastic neoplasia by providing a precise metastatic mapping of tumor extent up front, monitoring response, and localizing viable tumors after chemotherapy. The evaluation of a diagnostic tool, such as PET, is usually via comparing the diagnostic efficacy (sensitivity, specificity, etc), by using a more sophisticated receiver operating curve method, or the proportion of treatment been modified. Evaluating PET by clinical benefit is specific to the individual tumor and an attractive new endpoint.

Objective To investigate the interleukin-1 (IL-1) system mRNA and protein expression in human fallopian tubes with ectopic pregnancies. Design A controlled study. Setting Clinical and academic research setting in a university medical center. Patient(s) Women undergoing salpingectomy for fallopian tube with ectopic pregnancy and women undergoing tubal ligation. Intervention(s) Paired segments of human fallopian tubes containing an ectopic pregnancy and parafallopian tube segments adjacent to the ectopic pregnancy were collected from five women undergoing laparoscopic salpingectomy. Segments of fallopian tubes from four women undergoing tubal ligation were used as control tissues. Quantitative competitive polymerase chain reaction (QC-PCR) and immunohistochemistry were performed. Main Outcome Measure(s) The differences of IL-1 system mRNA and the ratio of IL-1β to IL-1 receptor antagonist (IL-1ra) in both fallopian tubes with ectopic pregnancies and normal controls were analyzed. Result(s) A complete IL-1 system mRNA and protein expression was identified in both fallopian tubes with ectopic pregnancies and normal controls. As QC-PCR demonstrated, IL-1β mRNA expression was decreased, and IL-1ra and IL-1 receptor type 1 were increased in fallopian tubes with ectopic pregnancies in comparison with normal control tubes. In para-ectopic tubes, IL-1 receptor type 1 mRNA was statistically significantly increased in comparison with normal controls. There was a lower ratio of IL-1β to IL-1ra at mRNA in fallopian tubes with ectopic pregnancies. Conclusion(s) These results suggest that an inappropriate ratio of IL-1β to IL-1ra and a higher expression of its receptor in fallopian tubes may possibly be implicated to the implantation of an ectopic pregnancy in the oviduct.

Introduction . Ovarian malignant mixed mullerian tumor (MMMT) is a rare, highly aggressive, fatal disease. Patients have a median survival of 18 months and a 5-year survival rate of only 8%. Optimal cytoreduction surgery plus platinum-based combination chemotherapy are associated with better outcomes. Case Report . A 65-year-old patient of stage IIIc ovarian MMMT having obtained a 41-month remission after four courses of aggressive surgical debulking procedures, platinum-containing chemotherapy, and intraoperative radiotherapy suffered from multi-focal recurrences and obtained another 22-month progression-free survival after treatment with monthly liposomal doxorubicin (Lipo-Dox) for 14 courses and Lipo-Dox/carboplatin for subsequent 6 courses without obvious toxicity. Discussion . Liposomal doxorubicin might be useful as salvage chemotherapy for heavily pretreated, recurrent ovarian MMMT. A prospective trial is needed for more proof.

Purpose To evaluate, in a prospective study, the effects of 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) on the detection of extrapelvic lesions, the design of whole pelvis or extended field radiotherapy, and subsequent failure patterns for patients with cervical cancer and enlarged pelvic lymph nodes (LNs) shown on MRI or CT. Methods and materials Between April and December 2001, 19 consecutive patients underwent an additional FDG-PET examination before concurrent chemoradiotherapy. The inclusion criteria for the study were at least one enlarged pelvic LN ≥10 mm in its maximal dimension as shown on radiologic images and no extrapelvic tumors detected by conventional examination. The PET findings of the primary tumor, pelvic LNs, and extrapelvic lesions were investigated and compared with the MRI/CT findings. Tumor FDG uptake was quantitated with the maximal pixel standardized uptake value. Results Except for 1 patient with diabetes mellitus who was excluded from analysis, 18 cervical tumors had significant FDG uptake (maximal pixel standardized uptake value >8). A total of 39 pelvic LNs were reported, and the agreement of positive pelvic LNs between MRI/CT and PET was 79.5%. Five patients (28%) had positive paraaortic LNs on FDG-PET, and their treatment fields were extended to include the paraaortic region. In addition to the paraaortic LNs, 1 patient also had metastasis at the left supraclavicular node. After a minimum follow-up of 12 months (median 15.9), 4 patients (22.2%) developed new extrapelvic metastases. The disease-free survival rate was 78% at 12 months. Conclusion FDG-PET is a useful tool to detect paraaortic LN metastasis and determine the appropriate treatment field for cervical cancer with enlarged pelvic LNs on MRI/CT. The preliminary data suggest that pretreatment FDG-PET can supplement conventional imaging studies, but still has limitations in the detection of microscopic disease.

Radical trachelectomy by vaginal approach is an alternative for young women with early-stage cervical cancer. We modified this procedure to treat two patients with stage Ib1 cervical cancer. With 100% laparoscopic pelvic lymphadenectomy and 80% laparoscopic approach, the technique is laparoscopic radical trachelectomy (LRT). Under direct enhanced vision of the laparoscope, it is easy to identify and preserve ascending branches of the uterine arteries and to divide ligaments surrounding the cervix and vagina. Vaginal procedures require only colpotomy, amputation of cervix, dividing caudal paracolpium, and corpus-vagina anastomosis. Short-term follow-up results of our first patients are satisfactory. Thus, LRT could be a useful alternative for women with early cervical cancer who want to preserve fertility.

Purpose: To retrospectively investigate whether postoperative low-pelvic radiotherapy (RT) is an appropriate treatment for node-negative, high-risk Stage I–IIA cervical cancer patients. Methods and Materials: A total of 228 Stage I–IIA cervical cancer patients treated by radical surgery and postoperative RT were included in this study. All patients had histopathologically negative pelvic node metastasis, but at least one of the following risk factors: parametrial involvement, positive or close resection margins, invasion depth two-thirds or greater cervical stromal thickness. Seventy-nine patients (35%) received 30–50 Gy (median 44) to whole pelvis and a boost dose to the low pelvis (whole-pelvic RT group); the other 149 patients (65%) received low-pelvic RT only (low-pelvic RT group). For both groups, the total external RT dose to the low pelvis ranged from 40 to 60 Gy (median 50). The potential factors associated with survival, small bowel (gastrointestinal) complications, and leg lymphedema were analyzed, and patients who had a relapse in the upper pelvis were identified. Results: The 5-year overall and disease-specific survival rate was 84% and 86%, respectively. After multivariate analysis, only bulky tumor (≥4 cm) and non-squamous cell carcinoma were significantly associated with survival. Parametrial involvement, lymph-vascular invasion, ≤50.4 Gy to the low pelvis, positive or close margins, and low-pelvic RT alone did not significantly affect survival. Grade I–V small bowel complications occurred in 33 patients (15%). Whole pelvic RT and >50.4 Gy to the low pelvis, but not old age and treatment technique (AP-PA vs. box), were significantly associated with gastrointestinal complications. Three patients (2%) in the low-pelvic RT group and 6 patients (8%) in the whole-pelvic RT group were found to have Grade III or higher small bowel complications ( p = 0.023). Thirty-one percent of patients developed lymphedema of the leg. A dose to the low pelvis >50.4 Gy and an AP-PA field, but not whole-pelvic RT, old age, or the number of sampled lymph nodes, were associated with lymphedema of the leg. Five patients (3.6%) of the low-pelvic RT group and none of the whole-pelvic RT group developed upper pelvis relapse. Three of these 5 patients had upper pelvic relapse alone. Conclusion: Compared with whole-pelvic RT plus low-pelvic boost, low-pelvic RT alone significantly reduces the small bowel complications in node-negative, high-risk, Stage I–IIA cervical cancer patients. Although low-pelvic RT alone increases the incidence of upper pelvic relapse, its effect on survival is not substantial. Low-pelvic RT alone appears to be an appropriate treatment method for this group of patients.

Purpose: To evaluate the clinical features of isolated paraaortic lymph node (PALN) recurrence after definitive radiotherapy, and analyze the prognostic factors and effect of salvage treatment. Methods and Materials: Of a total 876 patients who received pelvic radiotherapy after the diagnosis of primary cervical carcinoma, 26 were found to have isolated PALN recurrence as the first recurrent site, and these patients enrolled in this study. Only those with primary-site carcinoma controlled and who were free of other distant metastases were eligible. Nineteen of the 26 patients accepted salvage therapy. Fourteen patients accepted concurrent chemoradiation (CCRT), 1 accepted radiation to the paraaortic region, and 4 accepted chemotherapy alone. Clinical parameters evaluated included tumor markers (SCC and CEA) and image studies. Results: Seven of the 26 patients were alive and disease-free. All 7 survivors had salvage treatment with radiation to the paraaortic region and concurrent cisplatin-based chemotherapy. None of the patients receiving chemotherapy or radiation alone enjoyed long-term, disease-free survival. The 5-year survival rate for isolated PALN recurrence of the 14 patients who accepted salvage concurrent chemoradiation (CCRT) was 51.2%. The presence of a clinical symptom at the time of PALN recurrence was analyzed. Seven of the 12 asymptomatic patients and none of the 14 symptomatic patients survived without disease after salvage treatment. The SCC levels at recurrence showed a statistically significant relationship to disease-free survival. Conclusions: An SCC level of ≤ 4 ng/ml and a lack of symptoms at the time of recurrence were good prognostic factors in isolated PALN recurrence after primary radiation therapy. In addition to concurrent CCRT, periodical surveillance with tumor markers and imaging studies allowed early detection and salvage of those patients.

Background. Recurrent vulvar cancer involving the femoral artery after groin radiation is usually considered inoperable. A patient with such recurrent vulvar cancer successfully treated by femoral vascular graft and rectus abdominis myocutaneous flap reconstruction with limb salvage is described. Case. A 51-year-old woman had recurrent vulvar cancer involving the right femoral vessels 6 months after a radical vulvectomy plus inguinal lymphadenectomy and postoperative pelvic and groin radiation. Radical en bloc excision of tumor along with the involved femoral artery and vein followed by Gore-Tex vascular graft and rectus abdominis myocutaneous flap reconstruction led to a complete remission. However, occlusion of the grafted vessels occurred 21 months following bypass surgery. Since the compensatory collaterals were established, debridement and removal of the occluded graft were carried out. The patient has been clinically free of disease for more than 48 months since graft reconstruction surgery. Conclusion. It is highlighted that aggressive tumor resection with limb salvage is feasible even for patients with vulvar cancer of the groin recurrence involving the femoral artery after primary surgery and groin radiation.

Objective: This study was undertaken to investigate prognostic factors in patients with recurrent cervical carcinoma who had undergone a primary radical hysterectomy and pelvic lymphadenectomy. Study Design: A retrospective analysis of 177 patients with recurrent cervical carcinoma after radical hysterectomy and pelvic lymphadenectomy for stage IB to II disease at a single institution was performed to evaluate clinicopathologic parameters, time to recurrence, pattern of failure, use of salvage therapy, and survival after recurrence. Results: The 5-year survival rate from diagnosis of recurrence in this series was 10.1%. Survival after recurrence was significantly decreased in patients with pelvic lymph node metastasis at primary surgery and adenocarcinoma–adenosquamous carcinoma histologic type. Patients with extravaginal recurrences receiving chemoradiation for recurrent cervical carcinoma had significantly better outcomes than those receiving radiation alone. Six patients who had a distant relapse at a sole site had prolonged survival after salvage therapy, which was accomplished by chemoradiation, surgery plus radiotherapy, or surgery alone. Conclusions: Our results demonstrate the benefit of adding chemotherapy to radiotherapy in the treatment of recurrent cervical carcinoma. Salvage multimodality treatment should be offered to selected patients who have isolated relapse at a single distant site. (Am J Obstet Gynecol 1999;181:518-24.)

Bilateral simultaneous tubal pregnancy is a rare event. Conservative treatment is the standard method to preserve fertility. This report describes the use of a combination of laparoscopic salpingostomy and postoperative prophylactic methotrexate (MTX) in a woman with bilateral tubal pregnancy in order to preserve fertility successfully. A 25-year-old woman, gravida 1, para 0, abortus 1, suffered from secondary amenorrhea combined with intermittent vaginal bleeding and dull lower abdominal pain 1 week before she was referred to our medical center. Her gynecologic history showed secondary infertility of more than 1 year. There was no history of pelvic inflammatory disease, intrauterine contraceptive device use, or major pelvic surgery. Urinary pregnancy test was positive after the second course of clomiphene citrate (Clomid; YunHsin, Taichung, Taiwan), with 100 mg administered orally, from days 5–9 of the menstrual cycle at a private clinic. However, no intrauterine pregnancy was revealed on serial ultrasonography. Serum human chorionic gonadotropin (hCG) level showed an abnormal rise (11,000 IU/L initially vs. 17,000 IU/L 4 days after initial measurement). She was then transferred to our tertiary center. Vaginal ultrasound scan was performed, confirming the absence of a gestational sac in the uterus and showing the presence of abdominal fluid and a right adnexal mass measuring 3.2 × 2.8 cm. Laparoscopic surgery was arranged under the impression of extrauterine pregnancy. In the operating room, about 200 mL of blood was found in the cul-de-sac. Both tubes had an ampullary pregnancy (Figure).

The purpose of our study was to determine whether the chemoradiation is better than radiotherapy alone with respect to survival and treatment toxicity in patients with advanced carcinoma of the cervix. From October 1990 to April 1995, a total of 122 patients with advanced cervical carcinoma were included in this study and randomly assigned to either radiotherapy or concurrent chemotherapy and radiotherapy. The patients in the concurrent group received cisplatin, vincristine, and bleomycin every 3 weeks for a total of four courses, in combination with radiotherapy concurrently. Sixty patients were randomized to the concurrent chemoradiotherapy, and 62 were randomized to the radiotherapy alone. A tumor response was observed in 88.3% of the patients in concurrent group and in 74.2% of the patients in radiotherapy group (P = 0.04). After a median follow-up of 46.8 months, the overall disease-free survival and actuarial survival rate at 3 years were 51.7 and 61.7% in the concurrent group, and 53.2 and 64.5% in the radiotherapy group, respectively. Treatment-related toxicity appears to be higher with the combination of radiotherapy and chemotherapy compared with radiotherapy alone (36.7% versus 17.7%, P = 0.02). However, analysis by Kaplan-Meier method showed that the actuarial survival was not statistically different between the chemoradiotherapy and radiotherapy groups (mean survival time: 38.1 months versus 41.5 months, P = 0.27). In conclusion, this study showed that concurrent multiagent chemoradiotherapy did not prove to be a superior definitive therapy over radiotherapy alone for patients with advanced cervical carcinoma.

A 39-year-old woman having a pure gonadal choriocarcinoma with lung metastasis was referred to our hospital after hysterectomy and bilateral salpingo-oophorectomy. She was found to have a 45XO/46XY karyotype and gonadal dysgenesis. The patient's serum β-hCG was normalized after six courses of chemotherapy with cisplatin and etoposide of conventional dose (100 mg/m 2 , 100 mg/m 2 × 3 days), but began to fluctuate. Thoracoscopic resection of a remaining pleural lesion was negative for malignancy. However, the disease relapsed as multiple metastatic nodules in bilateral lung fields and the mediastinum. After one course of priming chemotherapy with conventional dose (1 g/m 2 cyclophosphamide, 400 mg/m 2 carboplatin, and 500 mg/m 2 etoposide), high-dose chemotherapy with a total dose of 1500 mg/m 2 carboplatin, 1200 mg/m 2 etoposide, and 5 g/m 2 ifosfamide followed by autologous bone marrow transplantation and peripheral stem cell support was given. Thoracoscopic surgery was performed to resect two residual solitary metastatic lung lesions. With these salvage treatments, the patient obtained complete remission and remained disease free at last follow-up (17 months). Our result suggests that high-dose chemotherapy may be effective in chemosensitive nongestational choriocarcinoma when first chemotherapy has failed.

All patients with bulky (> or =4 cm) Stage Ib or IIa cervical carcinoma treated at Chang Gung Memorial Hospital between August 1988 and December 1991 using a strategy of neoadjuvant chemotherapy with cisplatin, vincristine, and bleomycin and radical hysterectomy were reviewed. Fifty-nine evaluable patients received 1 to 3 courses of chemotherapy, and 51 underwent subsequent hysterectomy. The remaining 8 patients, not completing planned surgery, were treated with definitive radiotherapy. The overall clinical response rate was 81.4% (48/59) with 18.6% complete response. Clinical response to chemotherapy was not different by stage, histologic type, tumor size, level of squamous cell carcinoma antigen, or DNA ploidy. However, tumors with DNA indices (DI) greater than 1.3 were associated with higher clinical response rates than tumors with DI < or = 1.3 (P = 0.043). Histologically proven pelvic node metastases was noted in 18.5% (10/54) who had laparotomy. Concomitant pregnancy and more than one node metastases had significant adverse influence on recurrence and death. The 5-year survival rate of those patients who received hysterectomy was 80.3%, while only 1 of the 8 patients without hysterectomy survived. Of the 7 patients received hysterectomy despite clinical poor response, only 2 had node metastases and 3 died, whereas all the 4 patients deterred hysterectomy for poor response died. This study demonstrates the value of DNA flow cytometry in predicting chemosensitivity. However, with a DI cutoff at 1.3, only 29.2% patients could be selected. Further studies are necessary to find additional indicators that predict histological response to select better candidates for this approach and to determine optimal adjunctive treatment in case that poor prognostic features are found.