[A Case of Myelodysplastic Syndrome Developed during Chemotherapy for Postoperative Recurrent Ovarian Cancer That Progressed to Acute Myeloid Leukemia].

Recent developments in chemotherapy for gynecologic malignancies have improved treatment results in patients and promoted long-term survival. However, various adverse events caused by long-term chemotherapy are still being observed. Here, we report a case of myelodysplastic syndrome that developed during chemotherapy for recurrent ovarian cancer and progressed to acute myeloid leukemia. However, chemotherapy for ovarian cancer was continued while maintaining the quality of life under certain conditions, such as maintenance of platelet levels in collaboration with a hematologist. A 69- year-old woman(gravida 3, para 2)was diagnosed with stage ⅢC ovarian cancer in our department. After 6 cycles of preoperative chemotherapy with paclitaxel plus carboplatin plus bevacizumab(TC plus Bev), we performed a simple abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, sigmoid colon resection, and low anterior resection. Postoperatively, 3 cycles of TC plus Bev and 6 cycles of Bev monotherapy were completed for stage ⅢC ovarian cancer (ypT3cNXM0, high-grade serous carcinoma). However, the cancer recurred, and the patient received 3 cycles of gemcitabine plus Bev and 3 cycles of doxorubicin plus Bev. Precursor cells and prolonged neutropenia were observed, and myelodysplastic syndrome was diagnosed. One month later, the condition progressed to acute myeloid leukemia. The patient's neutrophil count recovered spontaneously, and subsequently, 7 cycles of weekly paclitaxel plus Bev therapy were completed along with symptomatic treatment. Unfortunately, she died of septic shock against the background of acute myeloid leukemia. It is important to monitor the appearance of blasts for early detection of therapy-related myelodysplastic syndromes occurring during chemotherapy, as in the case in this report. Additionally, it is important to maintain platelet count and continue chemotherapy for the primary disease.

Oncologic outcomes in elderly patients who underwent hysterectomy for endometrial cancer: a multi-institutional survey in Kinki District, Japan.

BACKGROUND: The goal of this study is to assess the oncologic outcomes of elderly patients who underwent hysterectomy for endometrial cancer across three variables: hysterectomy approach, lymph node resection, and adjuvant therapy. METHODS: Hospital records of patients aged ≥ 70 years who underwent hysterectomy for endometrial cancer were obtained from 19 institutions. Patients were categorized into three risk groups: low, intermediate, and high. In each group, disease-free survival and overall survival were compared according to hysterectomy approach, lymph node resection, and adjuvant therapy using Kaplan-Meier method. Cox regression analysis with a 95% confidence interval was performed to estimate relative risk (RR) of death. RESULTS: A total of 1246 patients were included. In the low-risk group, the adjusted RR for death for minimally invasive surgery (MIS) versus laparotomy and lymph node resection versus no lymph node resection were 0.64 (0.24-1.72) and 0.52 (0.24-1.12), respectively. In the intermediate-risk group, the adjusted RR for death for MIS versus laparotomy, lymph node resection versus no lymph node resection, and adjuvant therapy versus no adjuvant therapy were 0.80 (0.36-1.77), 0.60 (0.37-0.98), and 0.89 (0.55-1.46), respectively. In the high-risk group, the adjusted RRs for death for lymph node resection versus no lymph node resection and adjuvant therapy versus no adjuvant therapy were 0.56 (0.37-0.86) and 0.60 (0.38-0.96), respectively. CONCLUSIONS: MIS is not inferior to laparotomy in uterine-confined diseases. Lymph node resection improved the outcome for all disease stages and histological types. In contrast, adjuvant therapy improved the outcomes only in high-risk patients.

Neutrophil-to-lymphocyte ratio is associated with sensitivity to platinum-based chemotherapy and prognosis in patients with advanced serous ovarian carcinoma.

The role of the neutrophil-to-lymphocyte ratio (NLR) in predicting sensitivity to chemotherapy and prognosis has attracted great interest in several types of cancer. In the present study, the correlation between pre-chemotherapy NLR and sensitivity to platinum-based chemotherapy and prognosis in patients with advanced serous ovarian carcinoma was examined by retrospectively reviewing the medical records of 50 patients with stage III-IV serous ovarian carcinoma from 2005 to 2012. Patients were divided into high-NLR (32 patients) and low-NLR (18 patients) groups according to a cutoff value of 2.47. This cutoff was calculated using a receiver operating characteristic (ROC) curve that demonstrated 84% specificity and 60% sensitivity. Patient characteristics, sensitivity to platinum-based chemotherapy and prognosis were subsequently compared. The results revealed no significant difference in patient characteristics between the two groups. In the low-NLR group, 14 of 18 patients (77.8%) were sensitive to platinum-based chemotherapy, whereas 11 of 32 were sensitive in the high-NLR group (34.4%) (P=0.007). Overall and disease-free survival (DFS) were significantly longer in the low-NLR than in the high-NLR group (P=0.013 and P=0.043, respectively). The current results suggested that pre-chemotherapeutical NLR may serve as a biomarker of sensitivity to platinum-based chemotherapy and prognosis in patients with advanced serous ovarian carcinoma.

Age-related differences in prognosis and prognostic factors among patients with epithelial ovarian cancer.

Approximately 40% of all patients with ovarian cancer in Japan are aged ≥65 years. The aim of the present study was to evaluate the differences in prognosis and prognostic factors between elderly and younger patients with epithelial ovarian cancer. A total of 114 patients with International Federation of Gynecology and Obstetrics (FIGO) stage I-IV ovarian cancer who were initiated on primary treatment at the Osaka City University Hospital (Osaka, Japan) were included in this study. Patient characteristics, treatment outcome and prognosis were compared between elderly (aged ≥65 years) and younger patients, and the prognostic factors associated with overall survival were evaluated by univariate and multivariate analyses. The most common histological type in younger patients was clear cell carcinoma (33.8%) vs. serous carcinoma in elderly patients (44.1%), with a significant difference in the distribution of histological type (P=0.006). Complete resection was achieved in 56.2% of younger patients compared with 32.4% of elderly patients (P=0.03). The rates of standard primary treatment were comparable (56.7% of younger vs. 50.0% of elderly patients). Overall and disease-free survival did not differ significantly between the two groups. Multivariate analyses identified FIGO stage and standard primary therapy as prognostic factors in younger patients and performance status in elderly patients. Age was not an independent significant prognostic factor among patients with ovarian cancer. Therefore, performance status, rather than age, should be considered when selecting the optimal treatment for elderly patients based on objective assessment.

Expression of UCP2 is associated with sensitivity to platinum-based chemotherapy for ovarian serous carcinoma.

The standard treatment for ovarian serous carcinoma is maximum debulking surgery and platinum-based chemotherapy. Despite the high response rate for chemotherapy, the majority of patients will be resistant to first-line agents and the prognosis for these patients is particularly poor. Currently there are no reliable methods to determine or predict platinum resistance. Uncoupling protein 2 (UCP2) is widely expressed in cancer cells and regulates the production of mitochondrial reactive oxygen species (ROS). A reduction in ROS is associated with carcinogenesis and chemoresistance. Downregulation of UCP2 significantly causes increased cell death following chemotherapy. The present study investigated the association between UCP2 expression and platinum sensitivity. The study included 54 patients with ovarian serous carcinoma (FIGO stages III and IV) who were treated at Osaka City University Hospital between January 2005 and December 2012. Patients were divided into a platinum-sensitive group (n=27) and platinum-resistant group (n=27) based on the platinum-free interval, which was calculated from the time of last platinum administration to the time of recurrence. UCP2 expression in human ovarian serous carcinoma cells was inhibited by genipin, and changes in carboplatin sensitivity were examined. The UCP2 weighted score was lower in the platinum-sensitive group than in the platinum resistant-group (P=0.005). In addition, patients in the low UCP2 expression group were more sensitive to platinum-based chemotherapy than those in the high UCP2 expression group (P=0.001). Sensitivity to carboplatin was significantly increased when UCP2 was inhibited in human ovarian serous carcinoma cells in vitro. UCP2 expression may be a predictive marker of the efficacy of platinum-based chemotherapy for patients with ovarian serous carcinoma.

XPA expression is a predictive marker of the effectiveness of neoadjuvant chemotherapy for locally advanced uterine cervical cancer.

The standard treatment for locally advanced uterine cervical cancer is concurrent chemoradiotherapy. Successful neoadjuvant chemotherapy (NAC) may reduce tumor size and facilitate a hysterectomy, thereby improving the prognosis for patients with locally advanced cervical cancer. In contrast, unsuccessful NAC may worsen the prognosis because if a hysterectomy is not possible, the change in treatment plan may delay the initiation of core treatment. Therefore, there is a need to identify biomarkers that predict the efficacy of NAC in patients with uterine cervical cancer. The xeroderma pigmentosum complementation group A (XPA) protein serves a major role in nucleotide excision repair, which is a key DNA damage response pathway involved in cisplatin resistance. In the present study, the association between XPA expression in tumor tissue and the efficacy of NAC for locally advanced uterine cervical cancer was investigated. Data from 56 patients aged <70 years with locally advanced uterine cervical cancer (FIGO stages IIIA or IIIB) who were classified into two groups based on effective (n=31) and ineffective (n=25) responses to NAC treatment was evaluated. Tumor tissue samples were obtained by punch biopsy prior to NAC and XPA expression was examined immunohistochemically and scored using a weighted scoring system. In addition, the effects of RNA interference-mediated downregulation of XPA on the cisplatin sensitivity of uterine cervical cancer cells was investigated in vitro. It was revealed that the NAC effective group had significantly lower weighted XPA scores than the NAC ineffective group (P=0.001). Similarly, low tumor expression of XPA was significantly associated with higher sensitivity to NAC (P=0.001). Additionally, the downregulation of XPA expression in cervical cancer cells significantly increased their sensitivity to cisplatin in vitro. The results of the present study suggest that low XPA expression may be a predictive biomarker of NAC efficacy for patients with locally advanced uterine cervical cancer, which may be helpful for improving their prognosis.

TBX2 expression is associated with platinum-sensitivity of ovarian serous carcinoma.

The standard treatment for ovarian serous carcinoma comprises maximum debulking surgery and platinum-based chemotherapy. Despite the high response rate to chemotherapy, the majority of patients will be resistant to first-line agents and the prognosis for these patients is particularly poor. At present there are no reliable methods to determine or predict platinum resistance. T-box 2 (TBX2) is widely expressed in cancer cells and is involved in embryonic development and cell cycle regulation. TBX2 enables cells to bypass senescence through its ability to repress the cell cycle regulators p21 and p14ARF; silencing TBX2 induces senescence. Ectopic expression of TBX2 is associated with conferred resistance to the DNA-damaging chemotherapeutic drugs cisplatin and doxorubicin. In the present study the association between TBX2 expression and platinum sensitivity was investigated. A total of 54 patients with ovarian serous carcinoma (FIGO stages III and IV) were treated at Osaka City University Hospital (Osaka, Japan) from January 2005 to December 2012. Patients were divided into platinum-sensitive (n=27) and resistant (n=27) groups, according to the platinum-free interval calculated from the last platinum administration to the time of recurrence. TBX2 expression in human ovarian serous carcinoma cells was inhibited by a TBX2-specific siRNA and changes in cisplatin and carboplatin sensitivity were determined. The TBX2-weighted score was significantly lower in the platinum-sensitive group than the platinum-resistant group (P=0.005) and the low TBX2 expression group was significantly more sensitive to platinum-based chemotherapy (P=0.004). Sensitivity to cisplatin and carboplatin significantly increased when TBX2 expression was inhibited in human ovarian serous carcinoma cells in vitro (P<0.05). TBX2 expression may serve as a predictive marker of the efficacy of platinum-based chemotherapy for patients with ovarian serous carcinoma.

UCP2 expression may represent a predictive marker of neoadjuvant chemotherapy effectiveness for locally advanced uterine cervical cancer.

Concurrent chemoradiotherapy is the standard treatment for locally advanced uterine cervical cancer. However, effective neoadjuvant chemotherapy (NAC) can reduce tumor size and facilitate hysterectomy for locally advanced uterine cervical cancer. NAC treatment could improve the prognosis of patients with locally advanced cervical cancer. However, if NAC is ineffective, radiotherapy must be pursued. This causes a delay in initiating the core treatment and results in a worse prognosis. Therefore, the identification of predictive markers of whether NAC is likely to be effective for the treatment of locally advanced uterine cervical cancer could improve patient prognosis. Uncoupling protein 2 (UCP2) is broadly expressed in cancer cells, and suppresses mitochondrial reactive oxygen species (ROS) production. UCP2 contributes to both carcinogenesis and chemoresistance by reducing ROS. Downregulation of UCP2 results in significantly increased cell death following chemotherapy. The present study investigated the association between UCP2 expression and NAC effectiveness. A total of 58 patients with locally advanced uterine cervical cancer (stage IIIA or IIIB) treated at Osaka City University Hospital between April 1995 and March 2010 were examined. Tumor tissue samples were obtained by punch biopsy prior to NAC. UCP2 expression was examined immunohistochemically and scored using a weighted scoring system. Patients were divided into NAC effective (n=34) and ineffective (n=24) groups. Furthermore, UCP2 expression in human uterine cervical cancer cells was inhibited by genipin, and changes in cisplatin sensitivity were examined. UCP2 weighted score was higher in the NAC ineffective group than in the NAC effective group (P=0.038). Additionally, the low UCP2 expression group was more sensitive to NAC than the high UCP2 expression group (P=0.041). Sensitivity to cisplatin was significantly increased when UCP2 was inhibited in human uterine cervical cancer cells in vitro. UCP2 expression may become a predictive marker of whether NAC is effective for patients with locally advanced uterine cervical cancer, which could improve patient prognosis.

A retrospective clinical analysis of 5 cases of vaginal melanoma.

Vaginal melanoma is a rare tumor, accounting for <1% of all melanomas and ~1-5% of all vaginal malignant tumors. The prognosis of vaginal melanoma is extremely poor, as it is often resistant to chemotherapy and radiotherapy, and metastases may develop in the early stages of the disease. The present study investigated 5 patients with vaginal melanoma treated at the Department of Gynecology of Osaka City University Hospital (Osaka, Japan) between October, 2000 and April, 2014. All the cases presented with abnormal genital bleeding as the main complaint. Notably, in 3 of the 5 cases the tumors appeared as non-pigmented polyps. Local resection was performed as the primary treatment in all 5 cases. After surgery, dermal injection of interferon ß (feron maintenance therapy) was performed in 3 cases, and dacarbazine, nimustine, vincristine and interferon ß (DAVFeron therapy) was administered in 1 case as adjuvant therapy. All 5 cases recurred within 1 year. The site of recurrence varied, and included the vaginal wall, liver, brain and lung. The median overall survival was 419 days and the median progression-free survival 177 days. In this cohort, all the cases presented with abnormal genital bleeding as the main complaint. Therefore, malignant melanoma of the vagina must be considered along with other gynecological malignancies in patients with abnormal genital bleeding. In this study, over half of the cases had a non-pigmented polypoid lesion of the vagina. Therefore, malignant melanoma of the vagina must be considered when a polypoid lesion is identified on the vaginal wall.

Pharmacokinetic analyses of carboplatin in a patient with cancer of the fallopian tubes undergoing hemodialysis: A case report.

Opportunities for patients undergoing hemodialysis to receive chemotherapy are increasing. A combination of paclitaxel and carboplatin (TC) is first-line chemotherapy in patients with Müllerian cancer. However, the optimal dose and time interval between the end of carboplatin administration and initiation of hemodialysis remains to be elucidated. TC was administered to a patient with fallopian tube cancer undergoing hemodialysis. The paclitaxel regimen was determined to be 135 mg/m2 (total of 210 mg) over 3 h. After paclitaxel administration, 125 mg of carboplatin was administered over 1 h to achieve a target area under the concentration-time curve (AUC) of 5.0 mg•min/ml using the Calvert formula. The time interval between the end of carboplatin administration and hemodialysis initiation was 1 h at the first cycle, 16 h at the second cycle and 20 h at the third cycle, and the AUC obtained was 2.86, 4.16 and 6.0 mg•min/ml, respectively. The desired AUC of free platinum was demonstrated and only mild side effects were observed at the third cycle. Therefore, hemodialysis was initiated 20 h after completion of carboplatin infusion at cycles 4-6. The total chemotherapy planned was completed without severe adverse events. Measurement of the concentration of free platinum subsequent to administration is useful for determination of the optimal dose of carboplatin and time interval following administration to obtain an adequate AUC. The present study suggests that carboplatin can be administered to a patient undergoing hemodialysis, and that an adequate interval between the end of carboplatin administration and hemodialysis initiation may be ~20 h.

Expression of epidermal growth factor-like domain 7 may be a predictive marker of the effect of neoadjuvant chemotherapy for locally advanced uterine cervical cancer.

Neoadjuvant chemotherapy (NAC) followed by hysterectomy may be effective for the treatment of locally advanced uterine cervical cancer and improve patient prognosis. It is important to identify markers that are able to predict whether NAC may be successful. Epidermal growth factor-like domain 7 (EGFL7) regulates vascular sprouting in blood vessel formation. In numerous types of human cancer, EGFL7 is upregulated and inhibits endothelial cell adhesion molecules, decreasing vascular tightness and, thus, increasing vascular permeability. It is considered that the overexpression of EGFL7 is able to inhibit drug delivery, resistance to apoptosis and the epithelial-to-mesenchymal transition. In the current study, 63 patients with locally advanced uterine cervical cancer were reviewed and classified as stage IIIA-IIIB using the International Federation of Gynecology and Obstetrics criteria. These patients (aged <70 years) were treated at Osaka City University Medical School Hospital, Japan, between 1995 and 2010. Tumor tissue samples were obtained by biopsy prior to NAC. The tissue samples were classified as group 1 or 2 depending on the efficacy of NAC. Surgery and radiotherapy were administered in group 1 (n=36), for which NAC was effective. In the patients of group 2 NAC was not effective, and radiotherapy alone was administered (n=27). The expression of EGFL7 and Snail was examined in paraffin-embedded tissue sample sections using the avidin-biotin peroxidase complex method. The results indicated that EGFL7 expression levels were significantly higher in group 2, as compared with group 1 (P<0.001). A similar result was observed for the expression levels of Snail (P=0.001). Group 1 exhibited significantly longer overall survival times compared with group 2 (P=0.001). The patients were also classified into a low EGFL7 expression level group (weighted score of ≤6) and a high EGFL7 expression level group (weighted score of ≥8). NAC was observed to be significantly more effective in the low EGFL7 expression level group (P<0.001), as compared with the high expression level group. The results suggest that the expression levels of EGFL7 may be a potential predictive marker of the efficacy of NAC for the treatment of locally advanced uterine cervical cancer.

Complete recovery from paraneoplastic anti-NMDAR encephalitis associated with a small ovarian teratoma following a laparoscopic salpingo-oophorectomy: A case report.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a severe but treatment-responsive disorder, initially identified in young women with an ovarian teratoma. Symptoms include mood, behavior and personality irregularities that resemble acute psychosis. The present study reports the rare case of a patient with anti-NMDAR encephalitis and severe neurological symptoms, that exhibited a rapid recovery following a laparoscopic salpingo-oophorectomy. The 39-year-old woman was admitted to the Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine (Osaka, Japan) with a 5-day history of fever and stomach ache. One week later, the patient developed hallucinations and emotional lability. Initially, a diagnosis of limbic or herpes encephalitis was considered; thus, the patient was administered acyclovir and received steroid pulse therapy. However, the patient subsequently developed apnea, and in response, a tracheal intubation, mechanical ventilation and plasmapheresis were performed. Anti-NMDAR encephalitis was subsequently considered as a diagnosis and mediastinal and pelvic computed tomography (CT) examinations were conducted to detect for the presence of a teratoma. A 24×24-mm cystic lesion was identified in the pelvis from an abdominal CT scan and the lesion appeared to be an ovarian teratoma. In addition, serum and cerebrospinal fluid samples were collected, and were found to test positive for anti-NMDAR antibodies. A laparoscopic salpingo-oophorectomy was performed, which resulted in rapid improvement of the patients mental symptoms, followed by a complete recovery.

Sirtuin1 expression predicts the efficacy of neoadjuvant chemotherapy for locally advanced uterine cervical cancer.

Cisplatin-based, cyclic balloon-occluded arterial infusion, neoadjuvant chemotherapy (NAC) has previously been reported to enable hysterectomy in patients with locally advanced cervical cancer. Sirtuin1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase that deacetylates a number of proteins and is overexpressed in several human malignancies. Upregulation of SIRT1 has been reported to induce tumorigenesis and chemoresistance. To assess the role of SIRT1 in uterine cervical cancer, the outcomes in 62 patients aged <70 years with locally advanced International Federation of Gynecology and Obstetrics (FIGO) stage IIIA-IIIB uterine cervical cancer were reviewed between 1995 and 2010. Tumor samples were obtained by biopsy prior to NAC. The patients were separated into two groups. One group comprised of the patients in which NAC was effective, surgery and radiotherapy were performed (NAC+OP+R group; n=35), and the second group contained patients in which NAC was ineffective and radiation therapy was performed (NAC+R group; n=27). SIRT1 and p53 expression was assessed immunohistochemically in paraffin-embedded sections. SIRT1 expression was significantly higher in the NAC+R compared to the NAC+OP+R group (P<0.001), as was p53 expression (P=0.001). The overall survival time was significantly longer in the NAC+OP+R compared to the NAC+R group (P=0.001). Following the division of patients into two groups based on SIRT1 level, low (weighted score ≤4, n=30), and high level (weighted score ≥6, n=32) groups, the former group was significantly more sensitive to NAC (P<0.001). Collectively, these results indicate that SIRT1 expression may predict the efficacy of NAC as a treatment for locally advanced uterine cervical cancer.

Comparison of outcomes between squamous cell carcinoma and adenocarcinoma in patients with surgically treated stage I-II cervical cancer.

To improve our understanding of cervical adenocarcinoma (AD) and evaluate the clinical and pathological variables affecting its prognosis, we retrospectively reviewed the medical records of 455 patients with cervical cancer [International Federation of Gynecology and Obstetrics stage I/II; 91 cases with AD and 364 with squamous cell carcinoma (SCC)] who underwent surgery at our hospital between January, 1995 and August, 2012 and compared the characteristics and prognoses between AD and SCC cases, including age, clinical stage, histological type, lymph node metastasis, lymphovascular space invasion (LVSI), cervical stromal invasion, parametrial invasion, vaginal invasion, corpus invasion, ovarian metastasis and tumor diameter. We used Cox regression analysis to determine independent prognostic factors. AD was found to have a significantly poorer prognosis in all the patients (P=0.001), stage I patients (P=0.001) and stage IB patients (P<0.05). The prognosis did not differ in patients who did not require postoperative treatment; however, patients who received postoperative treatment exhibited a significantly poorer prognosis (P<0.05). Patients with AD who received postoperative irradiation alone had a significantly poorer prognosis (P<0.05). The multivariate analysis identified LVSI (P=0.008), stromal invasion (P=0.024) and ovarian metastasis (P=0.032) as independent predictors of shorter survival. AD was associated with a worse prognosis compared to SCC in patients with stage IB disease, particularly in those who required postoperative treatment. Such patients may benefit from individualized postoperative treatments that differ from those applied for SCC.