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This study aimed to assess the accuracy of predicting pelvic lymph node status using sentinel lymph node (SLN) biopsy with indocyanine green (ICG) and to examine the outcomes of SLN biopsy-guided abdominal radical trachelectomy (ART). Patients with stage IA2–IB2 cervical cancer from January 2009 to January 2021 were included. ICG was injected before ART and SLNs were identified, excised, and assessed intraoperatively using fast-frozen sections. Systemic pelvic lymphadenectomy was subsequently performed. The SLN detection rate, sensitivity, and false-negative rate were determined. Thirty patients desiring fertility preservation were enrolled, of whom 26 successfully completed ART and four underwent radical hysterectomies because of metastatic primary SLNs. Bilateral SLNs were identified in all patients. The sensitivity, false-negative rate, and negative predictive value were 100%, 7.7%, and 92.3%, respectively. Three (12%) patients were lost to follow-up: two relapsed and one died of tumor progression. Of the nine patients who tried to conceive after surgery, four achieved pregnancy and three delivered healthy live infants. In women with early-stage cervical cancer who desired to conserve fertility, SLN mapping with ICG had a very high detection rate, sensitivity, and low false-negative rate. SLN biopsy-guided ART is a feasible and accurate method for assessing pelvic node status.

Peritoneal metastasis is one of the most frequent causes of death in several types of advanced cancers; however, the underlying molecular mechanisms remain largely unknown. In this study, we exploited multicolor fluorescent lineage tracking to investigate the clonality of peritoneal metastasis in mouse xenograft models. When peritoneal metastasis was induced by intraperitoneal or orthotopic injection of multicolored cancer cells, each peritoneally metastasized tumor displayed multicolor fluorescence regardless of metastasis sites, indicating that it consists of multiclonal cancer cell populations. Multicolored cancer cell clusters form within the peritoneal cavity and collectively attach to the peritoneum. In vitro, peritoneal lavage fluid or cleared ascitic fluid derived from cancer patients induces cancer cell clustering, which is inhibited by anticoagulants. Cancer cell clusters formed in vitro and in vivo are associated with fibrin formation. Furthermore, tissue factor knockout in cancer cells abrogates cell clustering, peritoneal attachment, and peritoneal metastasis. Thus, we propose that cancer cells activate the coagulation cascade via tissue factor to form fibrin-mediated cell clusters and promote peritoneal attachment; these factors lead to the development of multiclonal peritoneal metastasis and may be therapeutic targets.

We encountered a case of recurrent fallopian tube carcinoma in situ with para-aortic lymph node metastasis 9 months after the first surgery. The patient presented with genital bleeding, and endometrial cytology revealed extrauterine malignant cells. However, endometrial biopsy and imaging modalities could not detect any abnormalities. We performed a total abdominal hysterectomy and bilateral salpingo-oophorectomy after obtaining the patient’s consent. Histopathological examination revealed atypical cells in the fimbrial portion of the fallopian tube. A diagnosis of fallopian tube carcinoma in situ was made. No further adjuvant treatment was administered. Nine months later, fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography revealed pathologic activity in the para-aortic lymph node and CA125 elevation. A diagnosis of metastatic adenocarcinoma was established on the basis of histological examination of a frozen section. The patient underwent para-aortic and pelvic lymph node dissection and omentectomy. The pathology report revealed metastasis to 3 of 69 lymph nodes; however, peritoneal cytology was negative for cancer. To the best of our knowledge, this is the first reported case of recurrent fallopian tube carcinoma in situ.

ObjectiveTo assess the feasibility and acute toxicity of concurrent chemoradiotherapy (CCRT) with high–dose rate intracavitary brachytherapy (HDR-ICBT) and standard dose delivery of cisplatin for Japanese patients with cervical cancer.Materials and MethodsThe phase 2 study included Japanese patients with International Federation of Gynecology and Obstetrics stage III to IVA uterine cervical cancer who had no para-aortic lymphadenopathy (>10 mm) assessed by computed tomography. Patients were 20 to 70 years of age and had Eastern Cooperative Oncology Group performance status of 0 to 1. The radiotherapy protocol consisted of whole-pelvis external beam radiotherapy and HDR-ICBT. The cumulative linear quadratic equivalent dose (EQD2) was 62 to 65 Gy prescribed at point A. Cisplatin was administered weekly at a dose of 40 mg/m2 for 5 courses.ResultsBetween March 2008 and January 2009, 72 patients from 25 institutions were enrolled, and 71 patients were eligible and evaluable for compliance and severe toxicity. The median age of the patients was 57 years (range, 32–70 years). Sixty-five patients (92%) received the planned 5 courses of chemotherapy. Four patients had cisplatin dose reduction according to the protocol. Radiotherapy was completed per protocol in 68 patients (96%). Median overall treatment time was 50 days (range, 37–66 days). The following grade 3 or 4 acute adverse events were observed: neutropenia in 31 patients (44%), anemia in 10 patients (14%), diarrhea in 4 patients (6%), and anorexia in 3 patients (4%).ConclusionsConcurrent chemoradiotherapy with HDR-ICBT and standard weekly delivery of cisplatin was feasible with acceptable toxicity in Japanese patients with cervical cancer.

Objective A multicenter phase II trial was conducted to assess the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) with high-dose-rate intracavitary brachytherapy (HDR-ICBT) using a low cumulative prescribed dose schedule in patients with locally advanced uterine cervical cancer. Methods The Japanese Gynecologic Oncology Group (JGOG) study JGOG1066 enrolled patients with FIGO stages III–IVA uterine cervical cancer who had no para-aortic lymphadenopathy (>10mm) assessed by CT. Patients received definitive radiotherapy (RT) consisting of external beam whole pelvic RT and HDR-ICBT. The cumulative linear quadratic equivalent dose (EQD2) was 62–65Gy prescribed at point A. Cisplatin 40mg/m 2 weekly was administered concurrently with RT for 5 courses. Results Of the 72 patients registered, 71 were eligible. With a median follow-up of 28months, the 2-year progression-free survival rate and pelvic disease progression-free rate were 66% (95% CI, 54% to 76%) and 73% (95% CI, 61% to 82%), respectively. Progression-free survival decreased significantly with increased central tumor size (P=0.036). The 2-year cumulative late complication rates were 24% for all grades, 9% for grade 1, 12% for grade 2, 3% for grade 3, and 0 for grades 4/5. Conclusions The JGOG1066 demonstrated that CCRT using HDR-ICBT with a low cumulative RT dose schedule achieved comparable outcome as those achieved with global dose schedules (EQD2=85Gy) with a lower incidence of late toxicity for locally advanced uterine cervical cancer in a Japanese population.

Aim: To determine the safety and usefulness of conization with an electrosurgical loop (the loop electrosurgical excision procedure [LEEP]) in young women with carcinoma in situ (CIS) of the uterine cervix. Methods: A retrospective medical chart review of five patients with CIS initially treated with LEEP conization between 2002 and 2010 and who later experienced recurrence in the form of invasive or advanced disease was conducted. Results: The median patient age at initial LEEP conization was 41 years (33–56 years). The margin status in conization specimens was positive in three of the five patients. The median time to detection of tumor progression was 50 months (17–58 months). Magnetic resonance imaging was effective in detecting tumor recurrence in all cases. In four patients, hysterectomy was performed to treat the recurrence; these four patients are currently alive and disease-free. One patient with cervical lymph nodes and bone metastases was treated with chemotherapy alone; however, the patient died. In surgical specimens, tumor progression was observed extending toward the endometrium in all five patients and toward the vagina in two patients. Conclusion: This study indicates that patients with CIS occasionally show unexpected tumor progression after conization and the progression could be life-threatening. Recurrent disease often shows tumor progression toward the endometrium or vagina, leading to difficulties in its detection at periodic pelvic examinations.

Objective To evaluate the effectiveness of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy plus postoperative chemotherapy but no radiotherapy for stage IB2-IIB cervical cancer. Methods Forty-six consecutive patients with stage IB2-IIB cervical cancer were treated with NAC followed by radical hysterectomy plus postoperative chemotherapy. Median (range) body mass index (BMI) of the patients was 20.2 (16.2–26.4). Regimens for NAC and postoperative chemotherapy were irinotecan and cisplatin (CPT-11/CDDP) or CPT-11 and nedaplatin (CPT-11/NDP). A total of six cycles of NAC and postoperative chemotherapy were prescribed. No use of radiotherapy was scheduled, except in the case of a recurrence. Results With a median follow-up period for survivors of 38.8months (range 24–54months), the 2- and 3-year progression-free survival rates were 91.2% and 86.1%, respectively. Overall response rate of NAC was 80.4%. Recurrence was observed in seven patients. In the absence of radiotherapy, pelvic recurrence was observed in only three patients; another two had para-aortic lymph nodes and the remaining two distant metastases. Toxicities due to chemotherapy were generally tolerable. Postoperative complications included urinary fistula (four patients, 8.7%) and bowel obstruction (two patients, 4.3%), all of which required surgical intervention. Conclusion The results indicate that NAC followed by surgery plus postoperative chemotherapy but no radiotherapy offers a viable option in the treatment of stage IB2-IIB cervical cancer. Although a relatively large incidence of postsurgical complications was observed among low-BMI patients, this treatment offers the advantage of minimizing radiation-induced morbidity, allowing radiotherapy to be reserved for the possible event of pelvic recurrence.

Objective A multicenter phase II trial was conducted to assess the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) with weekly cisplatin (CDDP) and paclitaxel (PTX) in patients with locally advanced uterine cervical cancer. Methods Patients with FIGO stage III–IVA uterine cervical cancer without para-aortic lymphadenopathy were enrolled. Patients received definitive radiotherapy (RT) consisting of external beam whole-pelvic RT and high-dose-rate intracavitary brachytherapy. The cumulative linear quadratic equivalent dose was 62–65Gy prescribed at point A. weekly CDDP at 30mg/m 2 and PTX at 50mg/m 2 were administered concurrently with RT for ≥5 courses. Results Sixty-eight of the 70 registered patients were eligible. The complete response rate was 76.5% (95% confidence interval [CI], 66.4–86.6%). With a median follow-up of 27months (range, 7.9–33.5), the 2-year cumulative progression-free survival and the 2-year cumulative overall survival rates were 83.8% (95% CI, 75.1–92.6%) and 92.7% (95% CI, 86.4–98.9%), respectively. The pelvic cumulative disease progression-free and the 2-year cumulative distant metastasis rates were 89.6% (95% CI, 82.3–96.9%) and 13.2% (95% CI, 5.2–21.3%), respectively. The 2-year cumulative late complication rates were 25% for all grades, 13.2% for grade 1, 5.9% for grade 2, 2.9% for grade 3, and 2.9% for grade 4. Conclusions For locally advanced cervical cancer, CCRT with weekly CDDP 30mg/m 2 and PTX at 50mg/m 2 demonstrated favorable antitumor activity, and was feasible and safe with respect to the protocol-specified serious adverse reactions and events. Evaluation of this regimen in phase III trials is warranted.

Objective The aim of this study was to identify the risks and benefits of the stepladder V-Y advancement medial thigh flap for vulvovaginal reconstruction in comparison to direct skin closure. Methods Fifty-four patients with vulvar cancer treated in our hospital between 1992 and 2013 were enrolled in this study. The cohort group (group A) consisted of 25 patients who underwent surgery from August 2006 until April 2013. During this period, we changed our surgical paradigm to incorporate reconstructive plastic surgery immediately following surgery for vulvar cancer performed by gynecologic oncologists. The control group (group B) consisted of 29 patients treated between 1992 and August 2006. During this period, our surgical approach was limited to direct skin closure with no reconstructive plastic surgery. Perioperative findings and clinical outcomes were compared retrospectively. Results Patient characteristics and surgical procedures, other than the reconstructive surgery, were the same for the 2 groups. The mean blood loss and operative times were similar, and there were no major complications in either group; however, the average length of hospital stay was significantly shorter in group A (P = 0.04). Conclusions Stepladder V-Y advancement medial thigh flap lowers posttreatment morbidity and improves quality of life for patients with vulvar cancer. Rapid recovery from surgery is reflected in the short hospital stay, and it enables immediate induction of adjuvant therapy. It may possibly contribute to improved treatment outcome.

We report on a 53-year-old woman with osteosarcoma of the skull who underwent radiation therapy for metastatic brain tumor. She had a history of uterine endometrial cancer treated with chemotherapy and surgery 9 years previously. FDG PET/CT for surveillance showed nodular accumulation at the right suprainguinal region and very avid accumulation at the left side of the occipital bone. Bone scan showed increased accumulation at the same portion of the occipital bone. The occipital tumor was surgically removed and diagnosed as radiation-induced osteosarcoma.

ObjectiveThe prognosis and vaginal disease control rate after treatment with radiotherapy or concurrent chemoradiotherapy (CCRT) are reported to be worse for primary non–squamous cell carcinoma (non-SCC) of the vagina than for squamous cell carcinoma (SCC) of the vagina. Our objective was to examine the clinicopathological characteristics of primary non-SCC of the vagina and suggest an appropriate treatment strategy.Materials and MethodsIn a retrospective chart review, we identified patients with primary vaginal cancer who were treated in our hospital between 1990 and 2013. Twelve patients with histologically diagnosed non-SCC were identified. None of these cases was associated with in utero diethylstilbestrol exposure. Clinical data, including patient characteristics, stage, treatment outcome, and the site of recurrence, were recorded.ResultsThe 12 identified cases included 5 of clear cell carcinoma, 3 of adenocarcinoma, 2 of adenosquamous carcinoma, 1 of carcinosarcoma, and 1 of mucinous adenocarcinoma. The most common location of the tumor was the upper one third of the vagina (56%). Initial treatment involved surgery in 8 patients. Among them, 4 received adjuvant chemotherapy, 3 received adjuvant radiotherapy, and 1 received neither. The initial treatment among the remaining 4 patients was CCRT in 1, neoadjuvant chemotherapy in 2 (followed by CCRT or surgery), and best supportive care in 1. The last 3 patients had lung metastasis. Six patients experienced recurrence, including vaginal recurrence in 2 patients and lymphatic spread in 4 patients. Five of these 6 patients experienced hematogenous metastasis.ConclusionsDespite the absence of in utero diethylstilbestrol exposure in our cases, clear cell adenocarcinoma accounted for 41.7% (5/12) cases. A favorable local control rate was achieved in all 12 cases, but the incidence of distant metastasis, especially to the lung, was high. Prevention of distant metastasis may be the key to treating patients with non-SCC of the vagina.

Objective. To investigate the lymph node sites most susceptible to involvement relative to primary tumor histology in ovarian cancer. Methods. The locations of metastatic lymph nodes were investigated in 208 patients with primary ovarian cancer who underwent systemic lymphadenectomy covering both the pelvic and para-aortic regions. Results. Lymph node metastasis was present in 12.8% (20/156) of patients with stage I (pT1M0), 48.6% (18/37) with stage II (pT2M0), and 60% (9/15) with stage III (pT3M0) disease, thus in 22.6% (47/208) of all study patients. Isolated para-aortic nodal involvement was present in 23.3% (14/60) of patients with serous tumor and 4.1% (6/148) of those with non-serous tumor ( P = 0.00002). In an analysis of 35 positive nodes from 25 patients with up to 3 positive nodes, 86.4% (19/22) of metastatic lymph nodes from patients with serous tumor were found in the para-aortic region, with 14 positive nodes located above the inferior mesenteric artery (IMA) and 5 below it, whereas metastasis to para-aortic lymph nodes accounted for 53.8% (7/13) of metastatic lymph nodes from patients with non-serous tumor ( P = 0.0334). Conclusions. The locations of metastatic lymph nodes in ovarian cancer depend upon the histologic type of the primary cancer. In cases of serous tumor, the para-aortic region, particularly above the IMA, is the prime site for the earliest lymph node metastasis. However, the likelihood of pelvic node involvement is almost equal to that of para-aortic node involvement in cases of non-serous tumor.

Follicular atresia is characterized by apoptosis of granulosa cells, and telomerase plays an important role in the apoptotic process. To study the relationship between follicular atresia and telomerase activity, we investigated changes in telomerase activity and localization in experimentally induced atretic follicles of immature rats. Immature female Sprague-Dawley rats received 15 IU equine CG (eCG) by subcutaneous injection. Rats were killed under ether anesthesia at 2, 3, 4, or 5 days after eCG injection. Telomerase activity in granulosa cells was measured by telomeric repeat amplification protocol (TRAP) assay, and telomerase localization in the ovary was examined by in situ TRAP assay. Telomerase activity was detected at high levels in granulosa cells on day 2 after eCG injection regardless of follicle size, and levels were significantly decreased in large follicles, with atretic changes, on days 4 and 5. No such decrease was observed in granulosa cells of small follicles. In the next experiment, rats received subcutaneous injections of estradiol (1, 10, or 50 microg/rat) to prevent follicular atresia or sesame oil as a control from day 2 to day 4 after eCG injection and were killed under ether anesthesia on day 5 after eCG injection. The changes observed in the large follicles on days 4 and 5 in oil treated rats were not observed with estradiol treatment. These findings suggest that the telomerase in granulosa cells is likely to play an important role for healthy follicle life and that loss of its activity may be associated with follicular atresia.

Background: Ovarian metastasis is rare in cases of early-stage uterine cervical cancer. For the patients with stage 1b cervical cancer, the incidences of ovarian metastasis were 0.22% of squamous cell carcinoma and 3.72% of adenocarcinoma. The safety of ovarian preservation is controversial for young women, although these women may find it important to preserve fertility. Case: A 36-year-old Japanese woman underwent a loop electrosurgical excision procedure for cervical adenosquamous carcinoma with invasion of 0.8 mm in depth and 1 mm in horizontal extent. She wished to preserve her fertility and was therefore followed up without additional treatments. Thirty months after the loop electrosurgical excision procedure, she had 10 cm-diameter ovarian tumors and underwent hysterectomy, bilateral salpingooophorectomy, appendectomy. This ovarian tumor was revealed to metastasis from cervical carcinoma. Conclusion: To our knowledge, this is first reported case of ovarian metastasis with microinvasive adenosquamous cell carcinoma. The pathological characteristics are important for prognosis: frequent small foci of invasion and high atypia.

The aim of this study was to investigate the heat stability of squamous cell carcinoma (SCC) antigen, a tumor-associated serine proteinase inhibitor (serpin), in tumor tissue extract by electrophoretic methods. After heat treatment at 70 degrees C for 2 h, the tumor tissue extract showed a single main protein band of 45 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) which reacted with a monoclonal antibody specific for SCC antigen. The heat-stable SCC antigen was separated by two-dimensional electrophoresis (2-DE) into four spots with pI 6.4-5.9 and Mr 44500-45 000 of SCC antigen-1. Furthermore, the SCC antigen-1 still showed its inhibitory activity against a cysteine proteinase, papain, by gelatin zymography. These results suggest that heat treatment of protein sample at 70 degrees C for 2 h may be a useful method for a partial purification of SCC antigen-1 which can inhibit lysosomal cysteine proteinases such as cathepsin L, S, and K.

Comparative genomic hybridization (CGH) analysis of microscopic tumor samples is allowed by universal DNA amplification using degenerate oligonucleotide primed-PCR (DOP-PCR). To evaluate the reliablity of DOP-PCR CGH, we performed DOP-PCR CGH and standard CGH in parallel using DNAs extracted from 10 malignant tumors of the hepatobiliary tract and pancreas. Similar results were obtained by both methods with a few exceptions, indicating that DOP-PCR CGH provides cytogenetic information equivalent to that obtained from standard CGH. We also investigated the sensitivity of DOP-PCR CGH using sequential dilutions of DNA from microdissected tumor cells. DOP-PCR using 100 to 800 pg of template DNA yielded successful CGH results. However, less than 50 pg of template DNA was not suitable because of the small amount of generated DNA. These findings suggest that DOP-PCR CGH is applicable for CGH analysis of tiny specimens which are too small for standard CGH. Accordingly, DOP-PCR CGH analysis may become a useful method in clinical laboratory examination.

Genetic abnormalities were detected by comparative genomic hybridization (CGH) in 12 ovarian clear cell adenocarcinomas. DNA sequence copy number abnormalities (CNAs) occurring in more than 20% of the cancers included increased copy numbers of 8q11-q13, 8q21-q22, 8q23, 8q24-qter, 17q25-qter, 20q13-qter and 21q22-qter and reduced copy numbers of 19p. Increases in copy numbers of 8q11-q13, 8q21-q22, 8q23 and 8q24-qter occurred more frequently in disease-free patients than in recurrent/non-surviving patients (p < 0.05). However, increases in copy numbers of 17q25-qter and 20q13-qter occurred more frequently in recurrent/non-surviving patients than in disease-free patients (p < 0.05). Furthermore, increases in copy numbers of 17q25-qter and 20q13-qter occurred together (p < 0.05). Additionally, there were negative correlations between increases in copy numbers of 8q21-q22 and 17q25-qter, and between 8q21-q22 and 20q13-qter (p < 0.05). It appears that ovarian clear cell adenocarcinomas can be classified into two subtypes, one being cancer with an increase in copy numbers of 8q and the other being cancer with increases in copy numbers of 17q25-qter and 20q13-qter.

ObjectiveThe purpose of this study was to determine whether the platinum-free interval (PFI) was a predictive indicator in second-line treatment of cervical cancer in patients who had undergone prior platinum-based chemotherapy. The role of the PFI in selecting the second-line regimen in other gynecologic malignancies is also discussed.MethodsIn this retrospective study, we examined the clinical records of patients with recurrent or metastatic cervical cancer who had received platinum-containing combination regimens as second-line chemotherapy. All patients had received prior platinum-containing chemotherapy or concurrent chemoradiotherapy.ResultsThe overall response rate to second-line chemotherapy was 25.8%; 7 patients achieved a complete response and 17 a partial response. The median progression-free survival (PFS) was 5.1 months and median overall survival (OS) was 13.5 months. The response rate was 12.5%, 14.2%, 20.0%, 22.2%, and 55.0%; median PFS was 4.0, 5.1, 4.4, 5.8, and 7.4 months; and median OS was 10.2, 14.4, 11.9, 16.3, and 19.7 months when PFI was within 3, 3 to 5, 6 to 11, 12 to 23, and more than 24 months, respectively. Age (>50 years), size (>3 cm), prior radiotherapy, and PFI (>24 months) were identified as prognostic factors in the multivariate analysis for PFS and OS.ConclusionsThe results indicate that a PFI of more than 24 months is the discriminating point between platinum-sensitive and platinum-resistance cervical cancer. This indicates that PFI offers a useful tool in selecting agents for second-line chemotherapy in a wide range of gynecologic malignancies.

To assess the feasibility and acute toxicity of concurrent chemoradiotherapy (CCRT) with high-dose rate intracavitary brachytherapy (HDR-ICBT) and standard dose delivery of cisplatin for Japanese patients with cervical cancer.The phase 2 study included Japanese patients with International Federation of Gynecology and Obstetrics stage III to IVA uterine cervical cancer who had no para-aortic lymphadenopathy (10 mm) assessed by computed tomography. Patients were 20 to 70 years of age and had Eastern Cooperative Oncology Group performance status of 0 to 1. The radiotherapy protocol consisted of whole-pelvis external beam radiotherapy and HDR-ICBT. The cumulative linear quadratic equivalent dose (EQD2) was 62 to 65 Gy prescribed at point A. Cisplatin was administered weekly at a dose of 40 mg/m(2) for 5 courses.Between March 2008 and January 2009, 72 patients from 25 institutions were enrolled, and 71 patients were eligible and evaluable for compliance and severe toxicity. The median age of the patients was 57 years (range, 32-70 years). Sixty-five patients (92%) received the planned 5 courses of chemotherapy. Four patients had cisplatin dose reduction according to the protocol. Radiotherapy was completed per protocol in 68 patients (96%). Median overall treatment time was 50 days (range, 37-66 days). The following grade 3 or 4 acute adverse events were observed: neutropenia in 31 patients (44%), anemia in 10 patients (14%), diarrhea in 4 patients (6%), and anorexia in 3 patients (4%).Concurrent chemoradiotherapy with HDR-ICBT and standard weekly delivery of cisplatin was feasible with acceptable toxicity in Japanese patients with cervical cancer.

To determine the safety and usefulness of conization with an electrosurgical loop (the loop electrosurgical excision procedure [LEEP]) in young women with carcinoma in situ (CIS) of the uterine cervix.A retrospective medical chart review of five patients with CIS initially treated with LEEP conization between 2002 and 2010 and who later experienced recurrence in the form of invasive or advanced disease was conducted.The median patient age at initial LEEP conization was 41years (33-56years). The margin status in conization specimens was positive in three of the five patients. The median time to detection of tumor progression was 50months (17-58months). Magnetic resonance imaging was effective in detecting tumor recurrence in all cases. In four patients, hysterectomy was performed to treat the recurrence; these four patients are currently alive and disease-free. One patient with cervical lymph nodes and bone metastases was treated with chemotherapy alone; however, the patient died. In surgical specimens, tumor progression was observed extending toward the endometrium in all five patients and toward the vagina in two patients. This study indicates that patients with CIS occasionally show unexpected tumor progression after conization and the progression could be life-threatening. Recurrent disease often shows tumor progression toward the endometrium or vagina, leading to difficulties in its detection at periodic pelvic examinations.

Background:In the surgical treatment for early-stage cervical carcinoma, it is important to identify preoperatively a low-risk group of patients as candidates for less radical surgery to avoid the morbidity associated with radical hysterectomy. The aim of this study was to evaluate the correlation between tumor diameter measured preoperatively using magnetic resonance imaging (MRI) and pathological prognostic factors in International Federation of Gynecology and Obstetrics (FIGO) stage IB1 cervical carcinoma.Methods:A total of 125 patients with FIGO stage IB1 cervical cancer were included in this study. Clinical records, pathology reports, and MRI findings were retrospectively reviewed.Results:Histological diagnosis was squamous cell carcinoma in 57 patients and nonsquamous cell carcinoma in 68 patients. All patients underwent preoperative evaluation by MRI within a median period of 13.5 days before surgery. The tumor diameter measured by MRI ranged from zero (no tumor detected) to 42 mm, with a median of 23 mm. Pathological prognostic factors included parametrial involvement, lymph node metastasis, deep stromal invasion, and lymphovascular space invasion. All these factors were found less frequently in patients with a smaller tumor diameter. Most notably, parametrial involvement was seen in none of the patients with tumors 20 mm or less and was detected only in patients with tumors greater than 20 mm (P= 0.01).Conclusions:In the FIGO stage IB1 cervical carcinoma, the tumor diameter measured preoperatively by MRI correlates well with other pathological prognostic factors, especially with parametrial involvement. This finding suggests that the tumor diameter measured in preoperative MRI may serve as a strong predictor of parametrial involvement in FIGO stage IB1 cervical carcinoma, which can be used to select a candidate population for less radical surgery without the need for a cone biopsy before hysterectomy.

To assess radiotherapy protocol compliance in a multi-institutional phase II study of concurrent chemoradiotherapy for patients with locally advanced cancer of the uterine cervix (JGOG1066).For study protocol development, various radiotherapy parameters were examined and consensus was reached by Japanese radiation oncologists with cervical cancer treatment expertise. Quality assurance (QA) was also discussed and included in the protocol. A credentialing process was used to select institutions for participation in the study. Individual case reviews referring to 18 QA items were undertaken for each patient. Radiotherapy data were submitted to the Japanese Gynecologic Oncology Group (JGOG) data center and reviewed by the members of the radiotherapy committee. The QA evaluation was classed as per protocol, deviation, and violation.Individual case reviews were performed on 69 of 72 patients entered in the study. In 24 patients (35%), there were no deviations for any QA items. There were also no deviations seen for 5 of the 18 items in 69 patients evaluated. Deviations of 64 QA items were seen in 45 cases, and violations were seen in 4 cases (4 items). The most common deviation concerned appropriate application for the external beam radiotherapy (EBRT) boost to involved nodes or parametrium (32 cases). The 4 violations were identified in the QA items regarding high-dose rate intracavitary brachytherapy.Radiotherapy protocol compliance was favorable except for the EBRT boost indications. The results of this study validate the quality of radiotherapy in JGOG1066, and indicate that the final analysis will provide meaningful results.

5587 Background: A multicenter phase II trial was conducted to assess the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) with weekly CDDP/PTX in patients with locally advanced uterine...

Objective. To determine the effectiveness of chemotherapy alone as postoperative adjuvant therapy for intermediate- and high-risk cervical cancer. Methods. The study group comprised of 65 consecutive patients with stage IB or IIA squamous cell or adenosquamous cervical cancer who were initially treated with radical hysterectomy and pelvic lymphadenectomy between 1993 and 2002. Tumors were of intermediate-risk (stromal invasion > 50%, n = 30) or high-risk (positive surgical margin, parametrial invasion, and/or lymph node involvement, n = 35). In all cases, chemotherapy was administered adjuvantly: three courses of bleomycin, vincristine, mitomycin, and cisplatin for intermediate-risk cases and five courses for high-risk cases. Disease-free survival and complications of the combined therapy were investigated. Results. Estimated 5-year disease-free survival was 93.3% for the 30 patients with intermediate-risk tumors (100% for those with squamous cell carcinoma and 71.4% for those with adenosquamous carcinoma) and 85.7% for the 35 patients with high-risk tumors (89.3% for those with squamous cell carcinoma and 71.4% for those with adenosquamous carcinoma). The incidence of locoregional recurrence was 3.3% in the intermediate-risk group and 8.6% in the high-risk group. Side effects of chemotherapy and complications of the combined therapy were within acceptable limits. No patient had severe bleomycin-related pulmonary toxicity. Only 1.5% of patients developed small bowel obstruction, which was cured by conservative therapy. Conclusions. The treatment results suggest the potential role of adjuvant chemotherapy alone for patients with cervical cancer.

Objective To examine the effectiveness of postoperative chemotherapy for para-aortic lymph node (PAN) metastasis in patients with endometrial cancer. Methods Among 350 clinical stage I–II endometrial cancer patients who underwent systemic pelvic and para-aortic lymphadenectomy during the period 1995 through 2002, 26 patients were identified with PAN metastasis. Of these patients, nine had only one positive PAN and 17 had two or more positive PANs (mean 4.9, range 1–22). All patients were treated postoperatively with a single chemotherapy regimen consisting of ifosfamide, epiadriamycin, and cisplatin scheduled for 5 cycles. Median (range) follow-up for surviving patients was 85 (38–119) months. Treatment outcome, including disease-free survival relative to the number of positive PANs, was investigated. Results Among the 26 patients with PAN involvement, four developed recurrence. Three of the four patients had 10 or more positive PANs. Estimated 5-year disease-free survival rates were 89% for patients with one positive PAN, 82% for those with two or more positive PANs, and 85% for all patients. No significant difference was identified between the first two groups (P = 0.6543). Conclusions Postoperative chemotherapy can yield a favorable outcome in endometrial cancer patients with PAN metastasis, even those with multiple positive nodes.

A loss of the DNA copy number at chromosomal region 11q23-24 as detected by comparative genomic hybridization (CGH) is a marker of poor prognosis in patients with endometrial cancer. Malignant tumors display genetic instability, which is classified into two types: microsatellite instability (MIN) and chromosomal instability (CIN). In the present study, we examined whether there is a relation between loss of 11q23-24 and genetic instability in endometrial adenocarcinoma. Loss of 11q23-24 was detected in 4 of 70 endometrial cancers by fluorescence in situ hybridization (FISH), and DNA aneuploidy was detected by laser scanning cytometry (LSC) in 14 tumors. All tumors with 11q23-24 loss were aneuploid, and three of them were considered to have CIN. These findings suggest that 11q23-24 contains gene(s) necessary for normal chromosome replication and cell division.

The aim of this study was to detect the cleaved form of serine proteinase inhibitor (serpin), squamous cell carcinoma (SCC) antigen-1 in normal and malignant squamous epithelial tissues, which implies the presence of its target proteinase. The cleaved SCC antigen-1 in normal squamous epithelium was identified as a single spot with pI 6.35 and M(r) 40,000 by two-dimensional electrophoresis (2-DE) combined with immunoblotting. Interestingly, the cleaved form showed different biochemical properties in heat stability or immunoreactivity with a monoclonal antibody for SCC antigen (Mab 426) compared to intact SCC antigen-1. Furthermore, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of tissue extracts showed an abundant 40 kDa band of cleaved SCC antigen-1 in tumor tissue compared to normal tissue. Among the potential target proteinase of SCC antigen-1, immunoblotting analyses revealed that cathepsin L2 was remarkably overexpressed in tumor tissue, while cathepsin L was expressed in both normal and tumor tissues. These findings indicate that SCC antigen-1 interacts with specific endogenous proteinases such as cathepsins L and L2 in physiological and pathological states of squamous epithelium.

We report here the extremely rare case of a 28-year-old woman with advanced stage uterine sarcoma arising soon after a cesarean section. She underwent an abdominal cesarean section because of a breech presentation. At the time of the procedure, there were no abnormal findings such as leiomyoma of the uterus in the abdominal cavity. One year later, she was referred to our hospital because of a large abdominal tumor. Transabdominal power Doppler ultrasonography and magnetic resonance imaging (MRI) showed a large hypervascular tumor in the abdominal cavity. Her serum levels, for the two tumor markers carbohydrate antigen CA125 and LDH, were elevated, at 219 U/ml (< 35 U/ml) and 862 IU/l (115 U/ml-217 U/ml), respectively. On the basis of a diagnosis of malignant tumor of gynecological origin, exploratory laparotomy was performed, and through biopsy, the tumor was found to be advanced undifferentiated uterine sarcoma. She exhibited a good response to neoadjuvant chemotherapy consisting of cisplatin, epirubicin, and dimethyltriazenoimidazole carboxamide (DTIC) every 28 days, which was successfully followed by a hysterectomy.

Genetic alterations are assumed to be necessary for the development and progression of ovarian cancer. However, the genetic alterations that occur during lymph node metastasis and peritoneal dissemination are poorly understood. In the present study, we used comparative genomic hybridization to detect genetic alterations in 30 tumors from patients with primary ovarian cancers and analyzed the associations of these genetic alterations with clinical stage and surgical pathological factors, such as histological grade, lymph node metastasis, and peritoneal dissemination. The total number of genetic alterations per tumor ranged from 0 to 39, with an average of 17.7 alterations per tumor. Among the genetic alterations in ovarian cancers, gains on chromosomes 8q and 3q and losses on chromosomes 17p, 18q, and 4q were observed frequently. Although the difference in total numbers of genetic alterations between early-stage tumors and advanced-stage tumors was not significant, the difference was significant when high-grade cancers were compared with low-grade cancers. Eight regions on seven chromosomes showed genetic alterations related to lymph node metastasis or peritoneal dissemination. Gain at 11q13-q14 and loss at 17q11.2-q21 were related not only to lymph node metastasis and peritoneal dissemination but also to clinical stage and histological grade.

The development of carcinoma is associated with alterations in the expression of many cell adhesion molecules. Syndecan-1 is a cell surface proteoglycan that binds cells to the extracellular matrix and changes its expression following malignant transformation in some tumors. Our purpose was to examine the pattern of syndecan-1 expression in cancer of the uterine cervix and assess the clinicopathological significance of syndecan-1 expression. A total of 106 tissue specimens (6 normal, 19 cervical intraepithelial neoplasia (CIN) and 81 invasive cancer) were analyzed immunohistochemically. In addition, the corresponding expression of mRNA in tumor tissues was evaluated by reverse transcription-polymerase chain reaction (RT/PCR) in comparison with normal counterparts. Syndecan-1 was positive in normal squamous cells except the basal cell layer. The intensity of syndecan-1 staining was the strongest in normal epithelium, followed by CIN, and invasive squamous cell carcinoma. Syndecan-1 expression in cancer tissue tended to be higher in keratinizing type than non-keratinizing type and not found in adenocarcinoma. Syndecan- 1 expression was markedly decreased at the mRNA level in invasive squamous cell carcinoma as compared with that of normal uterine cervix. Interestingy, there was an inverse correlation between the expression of syndecan-1 in the primary site and lymph node metastasis, although there was no significant correlation between syndecan- 1 expression and the prognosis. The results of the present study suggest that syndecan-1 expression is associated with squamous tissues and plays a key role in the progression of the cancer of the uterine cervix especially in the metastatic process.

The aim of the present study was to evaluate the clinical significance of the serum anti-p53 antibody in patients with uterine and ovarian cancer. Some of the ovarian patients were also evaluated for overexpression of p53 by immunohistochemistry and for cytogenetic alterations by comparative genomic hybridization (CGH). Serum anti-p53 antibodies were determined by an enzyme immunoassay kit. The antibody was detected in 8/30 (27%) of ovarian cancers, in 12/86 (14%) cancers of the uterine cervix, in 5/41 (12%) cancers of the uterine body, and 0/9 (0%) healthy women. The overall survival rate in patients with ovarian cancer was significantly worse in patients with anti-p53 antibody positivity than that in patients with anti-p53-antibody-negative cancers using the log rank test (p = 0.017). There was a significant correlation between the presence of anti-p53 antibody and tissue overexpression of p53 in ovarian cancers. CGH analysis showed that the aberrations in DNA sequence copy number in ovarian cancers were significantly increased in anti-p53-antibody-positive cases compared to antip53-antibody-negative cases including increased copy number on 20q and reduced copy number on 5q and 13q. Although the exact relationship between the presence of serum anti-p53 antibody (specific humoral response) and cytogenetic alterations is still unknown, these findings suggest that the measurement of serum anti-p53 antibody may be useful for the assessment of genetic instability and tumor biological aggressiveness.

Endometrial cancer progression is determined by a complex pattern of multiple genetic aberrations, but how these aberrations affect prognosis is unknown. In this study, we undertook a genome-wide screening to detect genetic changes by comparative genomic hybridization (CGH) in 51 tumors from patients with primary endometrioid carcinoma of the uterine corpus. The observed genetic changes were subsequently correlated with the progression of the disease and the clinical outcome in each case. The average number of genetic aberrations (copy number gains and losses) was significantly greater in non-surviving patients than in disease-free patients (12. 6 vs. 2.7, P < 0.0001). According to multivariate analysis, lymph node metastasis (P = 0.015), cervical involvement (P = 0.007) and one or more copy number losses at 9q32-q34, 11q23, or Xq12-q24 (P = 0.023) were significantly predictive of death from the disease. Interestingly, lymph node metastasis was significantly associated with copy number gains at 8q22-q23 and 8q24-qter (P = 0.003 and P = 0.025, respectively). Moreover, cervical involvement was also correlated significantly not only with gains of 8q22-q23 and 8q24-qter but also with loss of 11q23 (P = 0.04, 0.0003, and P = 0. 009, respectively). These results suggest that analysis of genetic changes may help predict clinical outcome and the presence of metastatic disease as well as assist in therapeutic decision making for patients with endometrioid carcinoma.