Long Term Prognostic Implications of Expression of Glucose Transporter-1 and Hexokinase II in Patients with Stage I Uterine Leiomyosarcoma.

Many malignant epithelial tumors show increased expression of glucose transporter-1 (GLUT-1) and hexokinase II (HK-II), both of which are involved in glucose metabolism. GLUT-1 levels are often correlated with prognosis in these tumors. The current retrospective study was conducted to evaluate the importance of GLUT-1 and HK-II expression in leiomyosarcoma (LMS), a malignant uterine non-epithelial tumor with a poor prognosis. The subjects were 23 patients with stage I LMS. Expression of GLUT-1 and HK-II was evaluated immunohistochemically in samples removed surgically, and the MIB-1 index was evaluated as a measure of cell proliferation. The association of these results with prognosis was examined. Twenty samples of leiomyoma (LOM), a benign non-epithelial tumor, were used as controls. Immunohistochemical expression was defined as negative staining (-), weak to sporadic staining (1+), and strong staining (2+) per microscopic field, respectively. Malignancy was evaluated in 2000 cells and the MIB-1 index was calculated. Overall survival for LMS was estimated using the Kaplan-Meier method. Of the LMS cases, 12 were GLUT-1-positive (52.2%; 2+: 2, 1+: 10) and 15 were HK-II-positive (65.2%; 2+: 1, 1+: 14). GLUT-1 expression in LMS was significantly correlated with the MIB1 index. The 10-year survival rates were 90.9% and 58.3% in GLUT-1-negative and GLUT-1-positive cases, respectively, and 75.0% and 73.3% in HK-II-positive and HK-II-negative cases, respectively. GLUT-1 expression was significantly correlated with prognosis. Cases of stage I LMS showed a significant correlation between the expression level of GLUT-1 and the MIB-1 index, an indicator of malignancy. GLUT-1-negative cases had a better prognosis than GLUT-1-positive cases, suggesting that GLUT-1 expression is an effective prognostic marker.

Pyogenic Spondylitis in Multidisciplinary Therapies of Gynecologic Malignancies: Three Cases Reports.

Both during and after cancer treatment, pyogenic spondylitis is an uncommon but serious complication. Because pyogenic spondylitis is often recognized as a complication of a distant process causing bacteremia, it initially may be misdiagnosed the primary infection such as urinary tract infection. Consequently, a considerable delay in diagnosis frequently occurs. In addition, estrogen deprivation caused by cancer treatments including RT/CCRT, CT and surgical therapy promotes changes of the immune system. We report two cases of pyogenic spondylitis in a patient with vaginal cancer that occurred delay of the diagnosis, and in a patient with endometrial cancer that had chronic steroid use, and one case of suppurative osteomyelitis in a patient with vulvar cancer that had diabetes mellitus with obesity. Gynecologic oncologists must consider the diagnosis of pyogenic spondylitis based on clinical symptoms such as localized lumbago and medical history. Estrogen deprivation, repeated cancer treatment, diabetes mellitus with obesity, immunosuppression by chronic steroid use are risk factors of pyogenic spondylitis. To prevent delay in diagnosis of pyogenic spondylitis, it is necessary that we must have careful management and follow-up considering all of information such as clinical features and medical history on patients during and after treating for gynecologic malignancies.

Small Cell Neuroendocrine Carcinoma of the Endometrium with Difficulty Identifying the Original Site in the Uterus.

Diagnosis of malignant uterine tumor with continuous lesions from the uterine body to the cervix, i.e., endometrial or cervical cancer, depends on the main site of the lesions. However, it may be difficult to differentiate advanced cancer that is widespread in the uterus. We experienced a patient who was diagnosed with small cell neuroendocrine carcinoma (SCNEC) based on histopathological characteristics of SCNEC in the endometrium. This tumor frequently coexists with endometrioid carcinoma, but we had difficulty finding the original site of SCNEC in the endometrium. The patient was a 59-year-old, two-parous woman who underwent hysterectomy after diagnosis of malignant uterine tumor. Preoperative cervical and endometrial histology permitted diagnosis of SCNEC. Imaging showed that most of the anterior uterine wall from the uterine body to cervix was replaced by tumors. Histopathologic findings for the resected uterus showed that most of these tumors were SCNEC, but components of endometrioid carcinoma had developed from the endometrium just beneath the fundus to the lower uterine body. The growth pattern of endometrioid carcinoma was endophytic. Based on this finding, the patient was diagnosed with endometrial SCNEC associated with endometrioid carcinoma. The patient initially responded well after postoperative chemotherapy, but early recurrence led to death at three months after the first treatment. This case shows that SCNEC in the uterine body is likely to coexist with endometrioid carcinoma. These findings are useful to determine the original site in postoperative pathological diagnosis of highly advanced tumors. SCNEC is a rapidly progressive and aggressive tumor in clinical practice, but some cases have a relatively good initial response to chemotherapy and it is important to start treatment early.

A Case of Uterine Cervical Adenocarcinoma in Which Initial Total Laparoscopic Hysterectomy Was Performed for Suspected Atypical Endometrial Hyperplasia.

The patient was a 69-year-old multiparous female (gravida/para, 3/3) who had hypertension and arrhythmia. Her history included cerebral infarction treated with conservative therapy. She visited our hospital for atypical genital bleeding. She was diagnosed with atypical glandular cells (AGC) based on cervical cytology, atypical cells in endometrial cytology, and atypical endometrial hyperplasia on preoperative endometrial biopsy, and underwent total laparoscopic hysterectomy. However, in a postoperative pathologic examination, she was diagnosed with stage IB1 cervical adenocarcinoma without endometrial abnormality. AGC appeared in cervical cytology before surgery, but a surgical plan was not made with consideration of cervical adenocarcinoma.

Recurrent Cervical Cancer with Intestinal Perforation That Was Related to Bevacizumab after Long-term NSAIDs Administration and Was Treated with Laparoscopy-assisted Anastomosis.

Bevacizumab is an effective drug for recurrent/advanced cervical cancer. A 59-year-old patient diagnosed with FIGO stage I B2 squamous cell carcinoma of the cervix at our hospital was treated with concurrent chemoradiotherapy as initial treatment. The outcome was judged as close to CR. Local recurrence in the irradiation field and paraaortic lymph node metastasis were noted 2 months after completion of this treatment. Chemotherapy of bevacizumab combined with paclitaxel plus carboplatin (TC) was initiated for recurrent cervical cancer. At 17 days after the 4th cycle, abdominal pain suddenly developed, and a close examination detected free air on abdominal CT, based on which intestinal perforation was diagnosed. Laparoscopic surgery performed to investigate the intraabdominal cavity showed that the small intestine was perforated at 2 sites. These were treated with laparoscopy-assisted partial resection of the small intestine and functional end-to-end anastomosis. Drug therapy for the recurrent cervical cancer was considered, but the primary disease rapidly aggravated and the patient died of the primary disease 11 months after completion of the initial treatment.

A Case of Recurrent Peritoneal Cancer in Which an Antitumor Effect Was Obtained Using a Combination of Etoposide and a Chinese Herbal Medicine with Maintenance of Daily Life.

The patient was a 50-year-old multiparous female (gravida/para 4/2) who had divorced. She was followed up for 1 year and 5 months after completion of initial treatment for peritoneal cancer (preoperative chemotherapy + optimal surgery + chemotherapy). A gradual increase in the tumor marker CA125 occurred, and computed tomography and ultrasonography showed bilateral neck, left supraclavicular and right axillary lymphadenopathy. The patient wanted to continue her job. Therefore, she was treated with etoposide (25 mg) daily for 3 weeks and TJ-48 (juzen-taihoto, 7.5 g) daily for 4 weeks, and then followed up. After two weeks, swelling of lymph nodes had been reduced or eliminated and tumor marker CA125 was negative. The only adverse reaction was slight numbness and the patient continued to work while receiving the same drugs orally for 2 years and 8 months without any symptoms or recurrence. This case shows that a combination of etoposide and TJ-48 has an antitumor effect on recurrent progressive peritoneal cancer while allowing a patient to work and have a normal daily life.

Expression of hypoxia inducible factor-1alpha (HIF-1alpha) and glucose transporter-1 (GLUT-1) in ovarian adenocarcinomas: difference in hypoxic status depending on histological character.

The expression of hypoxia inducible factor-1alpha (HIF-1alpha) and glucose transporter-1 (GLUT-1) was immunohistochemically analyzed in ovarian adenocarcinomas with the aim of elucidating whether hypoxic status is associated with histological type or structural character. The following ovarian adenocarcinomas were used: serous adenocarcinoma (SEA), 21 cases; mucinous adenocarcinoma (MUA), 19 cases; endometrioid adenocarcinoma (ENA), 16 cases; clear cell adenocarcinoma (CLA), 19 cases. High-level expression (3+) of HIF-1alpha was observed in 100% of SEAs, 58% of MUAs, 100% of ENAs and 89% of CLAs, and high-level expression of GLUT-1 in 76% of SEAs, 26% of MUAs, 50% of ENAs and 67% of CLAs. Heterogeneous or localized staining was relatively evident for GLUT-1. Immunohistochemical profiles were in accord with the immunoblotting and mRNA levels of both markers. ELISA for the detection of active HIF-1 demonstrated that HIF-1 is strongly activated in SEAs, ENAs and CLAs as compared to MUAs. Our results show that GLUT-1 overexpression is to some extent regulated by HIF-1alpha and is also strongly associated with histological features, i.e., papillary or stratified structure accompanied by little or no vascular stroma. In conclusion, hypoxic status differs according to the histological type of ovarian adenocarcinoma and the micro-environmental conditions of each type.

Impact of Adding Bevacizumab to Paclitaxel + Carboplatin for Platinum-Sensitive Recurrent Epithelial Ovarian Cancer: A Propensity Score Matching Analysis.

PURPOSE: We evaluated whether adding bevacizumab (Bev) to paclitaxel+carboplatin (TC) could improve outcomes, especially progression-free survival (PFS), in patients with platinum-sensitive recurrent ovarian cancer. PATIENTS AND METHODS: Among patients with platinum-sensitive recurrent ovarian cancer treated at our hospital from May 2008 to March 2017, PFS was compared between those receiving platinum-based chemotherapy or TC+Bev therapy by propensity score matching analysis. RESULTS: Nineteen patients received platinum-based chemotherapy and 13 patients received TC+Bev therapy. PFS (the primary endpoint) was 6.31 months in the platinum-based chemotherapy group versus 14.71 months in the TC+Bev group (hazard ratio: 0.304; 95% confidence interval: 0.114-0.8121; p=0.01752). The safety profile was similar to that expected. CONCLUSION: Adding Bev to TC prolonged PFS in patients with platinum-sensitive recurrent ovarian cancer and adverse effects were tolerable.

Recurrent Small Cell Carcinoma of the Uterine Cervix Responding to Combined Therapy with Paclitaxel, Cisplatin, and Bevacizumab: A Case Report.

We report a patient with recurrent refractory small cell carcinoma of the uterine cervix, in whom combined therapy with paclitaxel, cisplatin, and bevacizumab (TP+Bev) was effective. Small cell cervical carcinoma is a rare malignancy and its outcome is reported to be poor. The patient was a 45-year-old woman who visited a local hospital with the chief complaint of irregular vaginal bleeding and was referred to our department. The results of a smear test and examination of a tissue biopsy specimen suggested small cell carcinoma. FIGO stage II A disease was diagnosed by MRI and CT. She underwent radical hysterectomy with bilateral adnexectomy, and pelvic and para-aortic lymph node dissection. Although postoperative adjuvant chemotherapy was performed, local recurrence was found at three years after surgery. She received radiation therapy to the whole pelvis, bilateral inguinal regions, and site of recurrence. However, multiple liver metastases were detected and the tumor was considered to be refractory. Subsequently, she received TP+Bev as systemic chemotherapy, after which the local recurrence disappeared and the liver metastases became smaller.

The concept of platinum sensitivity could be applied to recurrent cervical cancer: a multi-institutional retrospective study from the Japanese Gynecologic Oncology Group.

PURPOSE: This study aimed at evaluating the applicability of the concept of platinum sensitivity to recurrent cervical cancer. METHODS: The clinical information of patients with recurrent cervical cancer, who were initially treated with platinum-based chemotherapy and received second-line platinum-based chemotherapy at the time of recurrence between January 2008 and December 2012, was retrospectively reviewed. RESULTS: A total of 677 patients from 71 medical centers were analyzed. The median overall survival (OS) for patients with platinum-free interval (PFI) of <6, 6-11, 12-17, and ≥18 months was 12.1 (95% CI 11.0-14.1) months, 17.4 (15.5-20.4) months, 20.2 (17.9-27.6) months, and 29.9 (26.7-36.0) months, respectively (P < 0.0001, log-rank). The best cut-off value of PFI that affected OS was 7 months, analyzed by the minimum P value method. The median progression-free survival (PFS) for patients with less than and more than PFI of 7 months was 6.2 months (95% CI 4.8-9.3) and 21.0 months (18.9-24.8) (P < 0.0001, log-rank), respectively, and the median OS for patients with less than and more than PFI of 7 months was 12.3 months (11.2-14.1) and 24.2 months (20.8-25.8) (P < 0.0001, log-rank). Multivariate analysis revealed that PFI (P < 0.0001, HR 0.449, 95% CI 0.369-0.548) alone had a statistically significant association with OS. CONCLUSIONS: This study showed that the concept of platinum sensitivity could be applied to recurrent cervical cancer and PFI could be one of the independent prognostic factors for patients with recurrent cervical cancer who have previously been treated with platinum-based chemotherapy.

Glucose transporter-1 expression in the thyroid gland: clinicopathological significance for papillary carcinoma.

Glucose transporter-1 (GLUT-1) expression was immunohistochemically analysed in a total of 268 cases of thyroid gland disease, including 129 cases of papillary carcinoma (PC), 60 cases of follicular carcinoma (FC), 57 cases of follicular adenoma, and 22 cases of adenomatous goitre. Seventy-one percent (91/129) of PC cases showed GLUT-1 expression, semi-quantitatively evaluated as: +, 21 cases (16%); 2+, 37 cases (29%); 3+, 33 cases (26%); and negative, 38 cases (29%). These positive cases were divided into two groups: 'membrane-like' pattern in 24 cases (19%), and 'cytoplasm-predominance' pattern in 67 cases (52%). GLUT-1 expression was observed in 5% (3/60) of FC cases, but all follicular adenomas and adenomatous goitres were negative for GLUT-1 (PC vs. FC, p<0.0001). Membrane-like expression was observed more frequently in non-organ-confined PCs (pT4) than in organ-confined PCs (pT1, 2, and 3) (p=0.0056). Seventy-five percent (18/24) of PC cases showing membrane-like expression were non-organ-confined. The membrane-like pattern was observed more frequently in PCs with lymph node (LN) metastasis compared to those without (p=0.0036). Ninety-two percent (22/24) of PC cases showing the membrane-like pattern were not organ-confined. Semi-quantitative analysis of glut-1 mRNA by RT-PCR showed a tendency toward higher expression in PCs compared to FCs, follicular adenomas and adenomatous goitres, and the mRNA expression in PCs with a membrane-like pattern was higher than those showing cytoplasm-predominance. We concluded that: 1) GLUT-1 is immunohistochemically useful in distinguishing PC from FC and benign diseases; 2) GLUT-1 may play an important role in the advancement of PC and LN metastasis, and its membrane-like expression is of more clinical significance than the cytoplasm-predominance pattern; and 3) glut-1 mRNA expression corresponds with the immunohistochemical expression profile.

Hypoxic status in ovarian serous and mucinous tumors: relationship between histological characteristics and HIF-1alpha/GLUT-1 expression.

MATERIAL AND METHODS: We analyzed the expression of hypoxia inducible factor-1alpha (HIF-1alpha) and glucose transporter-1 (GLUT-1) by immunohistochemistry in ovarian serous and mucinous tumors from the point view of the histological characteristics and acquisition of malignancy. A total of 102 ovarian tumors were examined, composed of 31 adenomas (serous 17 and mucinous 14), 32 borderline tumors (serous 13 and mucinous 19), and 39 adenocarcinomas (serous 21 and mucinous 18). RESULTS: The overall positive ratios were as follows: HIF-1alpha, 74% of adenomas, 91% of borderline tumors, and 100% of adenocarcinomas; and GLUT-1, 68% of adenomas, 95% of borderline tumors, and 100% of adenocarcinomas. Comparing serous tumors and mucinous tumors, there was no significant difference in the positive ratios of HIF-1alpha and GLUT-1 of adenomas, borderline tumors, and adenocarcinomas. However, both markers were more strongly expressed in serous adenocarcinomas (HIF-1alpha, 3 + 100%; GLUT-1, 3+76%) than in mucinous adenocarcinomas (HIF-1alpha, 3 + 61%; GLUT-1, 3 + 28%). The results of immunoblotting and mRNA expression level analyses corresponded with those of immunohistochemical expression profiles. DNA binding assay also demonstrated that HIF-1 is more commonly activated in serous adenocarcinomas than in mucinous adenocarcinomas. CONCLUSION: HIF-1alpha and GLUT-1 expressions seemed to be coordinated to adapt ovarian tumor cells into hypoxic conditions in close association with the acquisition of malignancy. We consider that the relatively strong expression of both markers in serous tumors compared with mucinous tumors is related to the difference in their histological characteristics.

An up-to-date anti-cancer treatment strategy focusing on HIF-1alpha suppression: its application for refractory ovarian cancer.

Hypoxia inducible factor-1alpha (HIF-1alpha) predominantly determines the transcriptional activity of HIF-1, which induces the certain genetic expressions to participate in the proliferation and progression of the tumor. It is supposed that HIF-1alpha is also an extremely important factor in cancer treatment. Based on the results of our recent analyses using ovarian tumors, which indicated the close association of HIF-1alpha expression with the acquisition of malignancy and the characterization of histology, we further investigated the possibility of a new strategy of cancer therapy that targeted HIF-1alpha inhibition in the ovarian carcinoma. The cell line HUOCA-II, which originates from the refractory ovarian clear cell adenocarcinoma, was treated with rapamycin. The inhibitory effect of HIF-1alpha was analyzed by immunohistochemistry and western blotting. It was demonstrated that inhibition of HIF-1alpha and vascular endothelial growth factor (VEGF) expressions would lead to the down-regulation of tumor cell proliferation. Interestingly, there was little or no change in GLUT-1 expression by rapamycin administration. Thus, the inhibition of GLUT-1 may also be a key for the new strategy of cancer therapy as well as HIF-1alpha and VEGF.

A resectable case of gastrointestinal stromal tumor derived from the rectal wall after oral targeted molecular therapy with imatinib mesylate.

We performed targeted molecular therapy in a patient with a non-resectable pelvic gastrointestinal stromal tumor (GIST). Imatinib mesylate was administered at 400-600 mg/day for 6 months, and the tumor became resectable. The patient was a 58-year-old female who visited a gynecologic hospital with the chief complaint of a swollen feeling in the lower abdomen. A pelvic tumor was found by imaging, and the patient was referred to our hospital. Laparotomy was performed, but it was found that the tumor arose from the intestinal serous membrane, rather than from the uterus, and complete excision was difficult. A portion of the tumor tissue was excised, and the abdomen was closed. GIST was diagnosed on postoperative pathological examination, and the tissue was positive for c-kit protein on immunostaining. The tumor had markedly shrunk after oral administration of imatinib mesylate for 6 months, and excision by laparotomy became possible.

Progression of 189 women diagnosed with uterine cervical dysplasia based on abnormal results in mass screening.

During the five-year period from January 1997 to December 2001, cytological abnormalities in the uterine cervix were confirmed in 189 women (class IIIa: 172, class IIIb: 9, class IV: 7, and class V: 1) who underwent cytology screening of the uterine cervix at the Tokai University Health Evaluation and Promotion Center. Biopsy samples from the uterine cervix showed that the 172 women categorized into class IIIa based on cytology included 28 with no atypical lesions, 53 with mild dysplasia, 24 with moderate dysplasia, 3 with severe dysplasia; and the 9 women in class IIIb included 2 with mild dysplasia, 5 with moderate dysplasia, 1 with carcinoma in situ, and 1 with invasive carcinoma. The conformity rates between the cytology data and the biopsy samples were 71.3% and 11.1% in class IIIa and class IIIb, respectively. A three-year followup survey of the class IIIa and class IIIb subjects confirmed progression (PRO) in 8 (4.7%), continuous (CON) symptoms in 48 (27.9%), and regression (REG) in 116 (67.4%) in class IIIa, and PRO, CON and REG in 3 (33.3%), 4 (44.4%), and 2 (22.2%), respectively, in class IIIb; the percentage of subjects in the CON+REG group was significantly higher than in the PRO group (p = 0.0052). Twelve subjects underwent resection because uterine carcinoma was suspected in the punch biopsy; these subjects have remained under observation and have now made a complete recovery. Our results suggest that patients with uterine abnormal cells should undergo regular cytology and colposcopy for detection of high-risk patients and to allow treatment at an early stage.

Evaluation of 25 years of Uterine Cervical Cancer Screening at Tokai University Hospital Health Evaluation and Promotion Center.

The total number of persons who underwent uterine cervical cancer screening at the Tokai University Hospital Health Evaluation and Promotion Center during the 25-year period from January 1976 to March 2001 was 30,173 (gross number: 111,181). Since 1995, more than 6,500 females have visited the center annually, and more than 70% were 40-59 years of age. Among these females, 849 exhibited atypical changes higher than class IIIa in the cytological examination (class IIIa: 779, IIIb: 43. IV: 14 and V: 13), and the detection rate was 0.76%. In examining the relationship between the age and number of visits to the center and the detection rate of atypical changes observed in the cytological examination, patients in their 40s exhibited the highest detection rate (1.31%), and the rate at the first screening was 1.19%. Analysis of the age distribution for the detection rate of atypical changes in the cytological examination before 1989 and after 1990 showed that persons in their 40s and 50s had high rates (1.62% and 1.69%, respectively) before 1989, but since 1990 persons in their 20s, 30s and 40s exhibited high rates (2.86%, 2.16% and 2.61%, respectively) (p ＜ 0.001). This suggests a lowering of the age at which atypical changes are observed in the cytological examination.

Case of uterine cervical carcinosarcoma.

Carcinosarcoma (CS) is a rare neoplasm that is called a mixed epithelial and mesenchymal malignancy. CS of the uterine cervix is much less common than its counterparts in the uterine corpus. A 61-year-old, gravida 2, para 2 woman, who had undergone menopause 16 years prior to the presentation, was diagnosed with CS of the uterine cervix. A semiradical hysterectomy was carried out on the diagnosis of stage Ib1 cervical cancer. The patient underwent whole pelvic 45 Gy radiation as a postoperative additional treatment, but she died from multiple organ failure by metastasis 17 months after the operation. The tumor protruded from the cervix to the vagina and measured 4.5 x 3.0 cm. Histologically, the tumor was characterized as a squamous cell carcinoma and mesenchymal malignancy, represented by osteosarcomatous components. The stroma was largely composed of atypical spindle-shaped cells, which were immunohistochemically demonstrated to be of epithelial origin. Uterine cervical CS is one of the aggressive malignancies, and squamous cell carcinomas are common epithelial counterparts of cervical CS as well as adenocarcinomas.

Isomerization and Peroxidizing Phytotoxicity of Thiadiazolidine-thione Compounds.

Eight 5-arylimino-3,4-tetramethylene-1,3,4-thiadiazolidine-2-thiones and eight 4-aryl-1,2- tetramethylene-1,2,4-triazolidine-3,5-dithiones were synthesized and their phytotoxic activities were investigated using sawa millet (Echinochloa utilis), green microalgae (Scenedesmus acutus) and protoporphyrinogen-IX oxidase isolated from etiolated corn (Zea mays) seedlings. 5-Arylimino-3,4-tetramethylene-1,3,4-thiadiazolidine-2-thiones showed strong phytotoxic activities and the same herbicidal mode of action as known for peroxidizing herbicides. 5-Arylimino-3,4-tetramethylene-1,3,4-thiadiazolidine-2-thiones were not or very little converted into 4-aryl-1,2-tetram ethylene-1,2,4-triazolidine-3,5-dithiones either with E. utilis seedlings present for 7 days, with S. acutus cells, or using glutathione 5-transferase (GST) and glutathione (GSH). The phytotoxic activities of 4-aryl-1,2-tetram ethylene-1,2,4-triazolidine- 3,5-dithiones were stronger than those of 5-arylimino-3,4-tetram ethylene-1,3,4-thiadiazolidine- 2-thiones [cf. Sato, Y., et al., Z. Naturforsch. 49c, 49-56 (1994)].