Incidental Finding of an Accessory Ovary at Laparoscopic Surgery.

An accessory ovary is one of the rare gynecologic abnormalities of the female genital tract. The etiology of accessory ovary has been reported to be acquired origin, such as postsurgical or postinflammatory implants, and true embryologic origin. However, as in the present case with unremarkable medical history and no urogenital abnormalities, there are accessory ovaries that cannot be explained by these etiologies. In such cases, the etiology of accessory ovary might possibly be torsion of functional ovarian cyst during the fetal period or asymptomatic torsion of the functional ovarian cyst at some time after birth.

Laparoscopic posterior pelvic exenteration for primary adenocarcinoma of the rectovaginal septum without associated endometriosis: A case report.

The present report describes a case of laparoscopic posterior pelvic exenteration of a primary adenocarcinoma of the rectovaginal septum (PARS) without associated endometriosis. A 49-year-old woman was admitted to hospital for rectal bleeding. Imaging studies showed a 7-cm solid tumor located in the rectovaginal septum, presenting with invasion to the posterior aspect of the uterine cervix and the anterior rectal wall. The patient received laparoscopic posterior exenteration and rectosigmoid anastomosis followed by chemotherapy. There were no intra- or post-operative complications. Histopathological examination of the neoplastic tissue revealed moderate to severe cytological atypia with bizarre multinucleated cells and prominent mitotic figures. Histopathologically, R0 resection was achieved. No endometriotic lesions were confirmed in the primary tumor or other removed tissues. Immunohistochemistry showed positive staining for cytokeratin (CK)7, cancer antigen 125, vimentin, estrogen receptor and p53, but negative staining for CK20, progesterone receptor, p40 and thyroid transcription factor 1. Based on these findings and on the location of the tumor, the neoplasm was diagnosed as PARS without associated endometriosis, which may have arisen from metaplasia of the embryological Müllerian-duct remnants.

Comparison of the primary cesarean hysterotomy scars after single- and double-layer interrupted closure.

INTRODUCTION: It is unclear whether hysterotomy closure techniques can affect niche development. Therefore, this study aimed to analyze the effect of single-layer and double-layer interrupted closures of hysterotomy incisions during primary cesarean section on the formation of uterine niches. MATERIAL AND METHODS: A prospective cohort study of women undergoing primary cesarean section was performed between June 2011 and July 2014. Saline contrast sonohysterography was used to measure the niche depth and residual myometrium. The ratio of the niche depth to the sum of the niche depth and residual myometrium thickness (niche ratio) was calculated. RESULTS: Niches were identified in 14/58 (24.1%) women with single-layer sutures and 55/209 (26.3%) women with double-layer sutures (p = 0.74). Single-layer closure was associated with more than a five-fold increase in the odds of a niche ratio ≥0.4 (odds ratio 5.59; 95% CI 1.71-18.28). CONCLUSION: Single-layer closure may be associated with an increased risk of larger niches (niche ratio ≥0.4), although it may not increase the overall frequency of niche formation.

Paclitaxel-carboplatin for advanced or recurrent carcinosarcoma of the uterus: the Japan Uterine Sarcoma Group and Tohoku Gynecologic Cancer Unit Study.

BACKGROUND: Paclitaxel and carboplatin (PC) have shown antitumor activity in carcinosarcoma of the uterus (CS). The purpose of this prospective multi-institutional study was to determine the response rate (RR), progression-free survival (PFS) and overall survival (OS) and to assess the toxicity of paclitaxel and carboplatin in patients with CS. METHODS: We conducted a phase II study in which patients were administered paclitaxel 175 mg/m(2) over a 3-h period followed by carboplatin (area under the serum concentration-time curve = 6) intravenously over a 30-min period on day 1 of each treatment cycle (3 weeks) until disease progression or adverse effects prohibited further therapy. Eligible patients had histologically confirmed, advanced stage (III or IV), persistent or recurrent measurable disease, and no prior chemotherapy. RESULTS: Six patients were enrolled between February 2006 and April 2009. The median age of the patients was 61 (range 48-77) years; one patient was stage IIIC (17 %) and five were stage IVB (83 %). Three patients (50 %) (1 at stage IIIC and 2 at stage IVB) received total abdominal hysterectomy plus bilateral salpingo-oophorectomy as part of the initial treatment; five (83 %) had homologous tumors and one (17 %) had a heterologous tumor. The median cycle number administered was 4.8 (range 2-7). The RR was 66.7 % (complete response, 2; partial response, 2); the PFS was 9.1 months and OS was not reached. The frequently observed Grade 4 toxicities were neutropenia (3 patients, 50 %). Manageable neutropenic sepsis developed in one patient. CONCLUSION: This is the first prospective multi-institutional study in Asia showing that PC may be effective and tolerable for the treatment of advanced or recurrent CS.

Investigation of the clinicopathological features of fallopian tube malignancy.

The present study investigated the clinico-pathological features of fallopian tube malignancy (FTM) and elucidated the biological behavior of this disorder. Data were compiled concerning FTM from 68 patients from 7 institutes. The patients included 60 cases with fallopian tube carcinoma and 8 cases with fallopian tube carcinosarcoma. The clinical stage was stage III or higher in 72% of the cases. A complete response or partial response was achieved in 56 and 10 of the 68 patients with FTM, respectively, indicating a response rate of 97.1%. The median observation period for FTM was 41 months (3 to 126 months). Three of the 19 patients with stage I/II disease (16%) and 31 of the 49 patients with stage III/IV disease (63%) experienced recurrence, with a median progression-free survival of 17.5 months, and a 3-year overall survival of 77.2%. Regarding the site of recurrence, local intraperitoneal recurrence (26.2%) and solitary recurrences in lymph nodes (19.0%) and in the liver (16.7%) were relatively frequent. Secondary debulking surgery (SDS) was performed in 15 patients (44%) out of the 34 recurrent FTMs. Conversely, recurrence was associated with ascites (carcinomatous peritonitis) in 4 of the 34 recurrent patients, but all 4 patients died. The median survival period after recurrence was 28 months: 7.5 and 30 months with and without ascites, respectively (P<0.001). A univariate analysis showed that prognosis was significantly correlated only with whether SDS could be performed. These results suggest that since FTM frequently results in solitary recurrence, aggressive recurrence treatment including SDS could improve prognosis.

Inhibition of uterine sarcoma cell growth through suppression of endogenous tyrosine kinase B signaling.

Uterine leiomyosarcoma is an aggressive tumor typically found at advanced stages due to difficulties with early diagnosis. Because uterine leiomyosarcoma is resistant to conventional radiation and chemotherapy, the development of more potent medical therapeutics is anticipated. Using quantitative real-time RT-PCR and immunostaining, we found the expression of brain-derived neurotrophic factor (BDNF) and neurotropin-4/5, together with their receptor, tyrosine kinase B (TrkB), in different uterine sarcoma cell lines and primary tumor samples from uterine leiomyosarcoma patients. We noted that levels of BDNF were more abundant than those of neurotropin-4/5. Moreover, the expression of TrkB and its ligands was elevated in a multidrug-resistant cell line and samples obtained from patients with leiomyosarcoma. In cultured uterine sarcoma cells, inhibition of endogenous TrkB signaling by treatment with either the soluble TrkB ectodomain or the Trk receptor inhibitor, K252a, suppressed cell proliferation and increased apoptosis based on cell viability and proliferation, in situ terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end-labeling and caspase-3/7 assays, whereas an inactive plasma membrane nonpermeable K252b was ineffective. Correspondingly, treatment with exogenous BDNF increased cell proliferation. In in vivo studies in athymic nude mice bearing multidrug-resistant uterine sarcoma cell tumors, we demonstrate suppression of tumor growth by treatment with K252a, but not K252b, as reflected by decreased cell proliferation and increased levels of apoptosis and caspase-3/7 activities without obvious side effects. Our findings indicated that endogenous signaling of the TrkB pathway contributed to uterine sarcoma cell growth, and inhibition of TrkB signaling in these tumors could provide a novel medical therapy for patients with uterine sarcomas.

Suppression of hydatidiform molar growth by inhibiting endogenous brain-derived neurotrophic factor/tyrosine kinase B signaling.

Brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) receptor signaling promotes trophoblast growth in normal and abnormal pregnancy. It also regulates the growth of malignant trophoblastic, choriocarcinoma cells. However, possible involvement of this signaling system in hydatidiform mole, another major gestational trophoblastic disease, has not been determined. Here, we found the expression of BDNF in syncytiotrophoblasts and its receptor, TrkB, in cytotrophoblasts of hydatidiform mole using real-time RT-PCR and immunoassays. In molar explant cultures, treatment with soluble TrkB ectodomain or a Trk receptor inhibitor K252a inhibited trophoblast outgrowth as well as decreased cytotrophoblast proliferation and cellular viability based on histopathological analyses and glucose metabolism monitoring. These inhibitors also increased apoptosis and caspase-3/7 activities. In an in vivo model of hydatidiform molar growth based on xenotransplantation of molar tissues into kidney capsules of SCID mice, treatment with K252a suppressed molar growth as reflected by decreased trophoblast proliferation and their invasion into mouse kidney, reduced tissue levels of chorionic gonadotropin-ß, and increased apoptosis. Based on PCR array analyses to identify changes in expression profiles of cell cycle- and apoptosis-related genes in cultured molar explants, suppression of endogenous TrkB signaling led to decreases in key cell cycle-stimulatory and checkpoint genes together with the down-regulation of different antiapoptotic genes. Our findings demonstrate the importance of paracrine signaling by the BDNF/TrkB system in the proliferation and survival of molar trophoblasts. Inhibition of BDNF/TrkB signaling could provide a novel medical treatment for hydatidiform mole.

Phase II clinical study of the combination chemotherapy regimen of irinotecan plus oral etoposide for the treatment of recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 101 Group Study).

OBJECTIVE: To evaluate the efficacy and safety of the combination chemotherapy regimen of irinotecan plus oral etoposide for the treatment of patients with recurrent ovarian cancer after previous treatment with platinum and taxane agents. PATIENTS AND METHODS: A total of 42 patients with recurrent ovarian cancer who had an evaluable lesion and provided informed consent for participation in the present study were analyzed. Irinotecan was administered intravenously at a dose of 60 mg/m on days 1 and 15. Etoposide was administered orally at a daily dose of 50 mg/body weight from days 1 to 21. A 28-day period comprised one cycle. The tumor response, adverse events, progression-free survival, and overall survival were examined. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors and the serum CA125 levels (Gynecologic Cancer Intergroup criteria). Adverse events were assessed according to the NCI-CTCAE (version 3.0). RESULTS: Partial response was observed in 21 patients, stable disease in 14 patients, and progressive disease in 7 patients. The response rate was 50.0%, and the clinical benefit (partial response + stable disease) rate was 83.3%. Hematological toxicities of at least grade 3 severity included leukopenia in 21 patients (50.0%), neutropenia in 22 patients (52.4%), thrombocytopenia in 1 patient (2.4%), anemia in 9 patients (21.4%), and febrile neutropenia in 3 patients (7.1%). Nonhematological toxicities of at least grade 3 severity included queasy feeling in 5 patients (11.9%), vomiting in 3 patients (7.1%), and diarrhea in 2 patients (4.8%). Acute myeloid leukemia occurred in one patient (2.4%). CONCLUSIONS: It is suggested that combination chemotherapy with irinotecan plus oral etoposide offers significant clinical benefit to patients with recurrent ovarian cancer previously treated with platinum and taxane agents.

Brain-derived neurotrophic factor/tyrosine kinase B signaling regulates human trophoblast growth in an in vivo animal model of ectopic pregnancy.

Although medical treatment of unruptured ectopic pregnancy using methotrexate has been established, development of more potent and safer medical treatment is needed due to limited indications and side effects of methotrexate. Brain-derived neurotrophic factor (BDNF) signals through its receptor tyrosine kinase B (TrkB) to regulate the growth of malignant trophoblastic, choriocarcinoma cell. We investigated possible involvement of this signaling system in nonmalignant human trophoblast growth in both ectopic and intrauterine pregnancy. Here, we demonstrated the expression of BDNF in syncytiotrophoblasts and extravillous trophoblasts (EVTs) together with TrkB in cytotrophoblasts and EVTs in human placental villi during both normal and ectopic pregnancies. Treatment of cultured villous explants with soluble TrkB ectodomain or a Trk receptor inhibitor K252a suppressed cytotrophoblast differentiation by inhibiting EVT outgrowth reflected by decreased levels of an EVT marker, human leukocyte antigen-G. These inhibitors also decreased cytotrophoblast proliferation and cellular viability based on histopathological analyses and monitoring glucose metabolism, together with increased apoptosis in cytotrophoblasts based on in situ terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end-labeling and caspase-3/7 assays. After xenotransplantation of human placental villi into SCID mice as an in vivo model of ectopic pregnancy, treatment with K252a suppressed transplanted villi growth as reflected by decreased cytotrophoblast differentiation and proliferation, reduced tissue levels of chorionic gonadotropin-ß, and increased apoptosis and caspase-3/7 activities. Thus, paracrine signaling by the BDNF/TrkB system is important for human cytotrophoblast differentiation, proliferation, and survival, and inhibition of BDNF/TrkB signaling in cytotrophoblasts could provide a novel medical treatment for ectopic pregnancy.

The efficacy and safety of gemcitabine plus paclitaxel combination first-line therapy for Japanese patients with metastatic breast cancer including triple-negative phenotype.

PURPOSE: Gemcitabine (GEM)-paclitaxel combination therapy has been confirmed as a standard therapy for metastatic/recurrent breast cancer (MBC) in Western countries. This study was conducted to assess the efficacy and safety of GEM-paclitaxel combination therapy in Japanese MBC patients. METHODS: Patients were administered paclitaxel 175 mg/m(2) on day 1, and GEM 1,000 or 1,250 mg/m(2) on days 1 and 8 of 21-day cycle. The primary endpoint of this study was overall response rate; secondary endpoints were duration of response, time to progression, survival time and rate. RESULTS: Paclitaxel 175 mg/m(2) plus GEM 1,250 mg/m(2) was determined as the recommended dose. A total of 56 patients received 506 cycles of treatment (median: 7.5 cycles) with a relative dose intensity of 79.6% for GEM and 85.8% for paclitaxel. The response rate was 44.6% (25/56 patients), median time to progression 8.6 months and median survival time 27.1 months. In triple-negative patients, the response rate was 35.7% (5/14 patients), and the median time to progression was 6.0 months. The most frequent grade ≥ 3 toxicities were neutropenia (82.1%), leukopenia (62.5%) and ALT increase (14.3%). CONCLUSIONS: This study confirmed the efficacy and safety of GEM-paclitaxel combination therapy in Japanese MBC patients.

Scleroderma-like cutaneous lesions induced by paclitaxel and carboplatin for ovarian carcinoma, not a single course of carboplatin, but re-induced and worsened by previously administrated paclitaxel.

Scleroderma-like cutaneous lesion as an adverse event from paclitaxel and carboplatin has been reported. No report shows the occurrence of scleroderma-like cutaneous lesions from a single course of carboplatin. The patient is a 67-year-old female, administered paclitaxel and carboplatin as neoadjuvant chemotherapy. Following four courses, scleroderma-like cutaneous lesions were demonstrated. Skin biopsy corresponded to histopathological findings of scleroderma. Immunological investigation shows only antinuclear antibodies are positive. The characteristic Raynaud's phenomenon of scleroderma and hemorrhagic spots on the cuticles were not found. Postoperatively, a single course of carboplatin treatment was given. Scleroderma-like cutaneous lesions re-induced and worsened. This is the first report detailing scleroderma-like cutaneous lesions induced by previously administrated paclitaxel that worsened by carboplatin.

Histopathological prognostic factors predicting para-aortic lymph node metastasis in patients with endometrioid uterine cancer.

INTRODUCTION: The purpose of this study was to determine histopathological factors for para-aortic lymph node (PALN) metastasis in patients with endometrioid uterine cancer. METHODS: A total of 355 patients (Stage I, n=269; II, n=24; and III, n=62) (FIGO 2009) underwent primary radical surgery including complete systematic pelvic lymph node (PLN) and PALN dissection in Tohoku Gynecologic Cancer Unit (TGCU) between 1993 and 2004. Logistic regression analysis was used to determine the independent prognostic factors for PALN metastasis. RESULTS: Multivariate analysis revealed that PLN metastasis (p<0.0001) and ovarian metastasis (p=0.0080) related with PALN metastasis. Moreover, among the sites of PLN metastases, obturator lymph node (LN) [risk ratio (RR): 16.9, 95% confidence interval (CI): 4.3-66.4, p<0.0001] and common iliac LN (RR: 7.1, 95% CI: 1.1-44.5, p=0.0375) related with PALN metastases. In detection of PALN metastasis, combination of obturator LN and/or common iliac LN and/or ovarian metastasis (A) revealed 75.9% sensitivity (22/29) and 97.8% negative predictive value (NPV) (304/311). However, by combination of obturator LN metastasis and/or common iliac LN metastasis and/or grade 3 and/or deep myometrial invasion (B), the detection of PALN metastasis was 100.0% sensitivity (29/29) and 100.0% NPV (198/198). Also, 55.8% (198/355) of patients could have avoided PALN dissection by combination B. CONCLUSIONS: These results suggest that PALN dissection is necessary when combination B is positive by pre- and intra-operative assessments. Further prospective randomized controlled studies need to be conducted in a larger patient population to establish the strategy for detecting PALN metastasis utilizing pre-/intra-operative assessments.

Mayer-Rokitansky-Kustner Hauser syndrome complicated by either uterine leiomyoma or ovarian tumor.

A 50-year-old Japanese woman with Mayer-Rokitansky-Kustner-Hauser syndrome and two pelvic tumors underwent laparotomy. Laparotomy revealed that no torsion of the right ovarian tumor had occurred, with uterine leiomyoma originating from the right side of a rudimentary uterus. Histopathological examination demonstrated leiomyoma of the rudimentary uterus with positive staining for estrogen and progesterone receptors, and mucinous cyst adenoma of the right ovary. Uterine leiomyoma is rare in this syndrome and the present report represents the first published case complicated by ovarian tumor.

[Drug interactions in medical oncology].

Cytotoxic anti-neoplastic drugs are some of the strongest acting drugs. They have a complex pharmacological profile, narrow therapeutic window, steep dose-toxicity curve, and many pharmacokinetic and pharmacodynamic differences both within and between patients. This makes it difficult to avoid adverse effects. These drugs are approved for usage based on their clinical benefit to risk ratio. The recommended dose is usually close to the maximally-tolerated dose in order to achieve maximum therapeutic effect. Therefore, there is more concern about drug interactions affecting the pharmacokinetics of anti-neoplastic drugs than drugs in general. Any physician taking care of oncology patients must understand not only the pharmacokinetic profile(absorption, protein binding, metabolism and excretion)of the anti-neoplastic drugs their using, but also the many factors that affect the pharmacokinetic profile such as hepatic and renal function, and co-administered drugs. Expertise to achieve a good balance between safety and efficacy in medical treatment with proper knowledge in supportive care as well as an understanding of pharmacokinetics, pharmacodynamics and pharmacogenomics is essential for medical oncologists. In this review, we have summarized the drug-drug interactions important for the management of cancer patients. The types of interactions covered are pharmaceutical interactions and interactions at the level of absorption, protein binding, metabolism and excretion.

A landmark point analysis with cytotoxic agents for advanced NSCLC.

INTRODUCTION: As a result of recent publications, we hypothesized that period of 8 weeks after initiation of treatment is a useful landmark point for cytotoxic agents for advanced non-small cell lung cancer (NSCLC). To test this hypothesis, we conducted landmark analyses with clinical trials employing cytotoxic agents. Our goal was to assess the proper design of clinical trials with cytotoxic agents for NSCLC for maximizing patients' benefit. METHODS: We conducted landmark analyses of a phase II study of pemetrexed in locally advanced or metastatic NSCLC and a phase III study of Four-Arm Cooperative Study for advanced NSCLC. A total of 806 patients who received chemotherapy (pemetrexed, cisplatin and irinotecan, paclitaxel and carboplatin, cisplatin and gemcitabine, cisplatin and vinorelbine) were included in this assessment. RESULTS: Tumor-shrinkage rate at 8 weeks was significantly associated with longer survival in the study with pemetrexed (p = 0.043), whereas tumor-shrinkage rate at 4 weeks did not correlated with survival (p = 0.139). Similarly, using the Four-Arm Cooperative Study data, the optimal landmark point was 8 weeks (p = 0.002), not 4 weeks (p = 0.190). CONCLUSION: The landmark point for NSCLC was 8 weeks with all cytotoxic agents in our analysis when the therapy was given as a frontline or subsequent therapy. Our result suggests the concept of a disease-specific landmark point, which may lead to a change of phase II/III clinical study design to evaluate cytotoxic agents and clinical investigators, and their sponsors may consider an early look to assess the efficacy of cytotoxic agents for NSCLC.

Role of complete para-aortic lymphadenectomy in endometrial cancer.

PURPOSE OF REVIEW: Many reports suggest the significance of pelvic lymph-node (PLN) adenectomy in patients with endometrial cancer. However, among these, there is controversy regarding not only what type of patients should have lymphadenectomy performed, but also what extent lymphadenectomy should be performed. RECENT FINDINGS: It has been reported that PLN adenectomy has therapeutic significance in stage I grade 3 and more advanced endometrioid uterine cancer. However, the effects of para-aortic lymph-node adenectomy on its prognostic benefit have not been discussed. SUMMARY: Patients with low-risk disease might not benefit from PLN adenectomy. However, PLN adenectomy might still have merit in low-risk patients, as there are inaccuracies of preoperative and intraoperative assessments. A complete lymphadenectomy is safe with minimum complications. At this point, hysterectomy and bilateral salpingo-oophorectomy with complete PLN adenectomy as the standard surgical procedure for endometrial cancer is thought to be reasonable. At present, the addition of p-aortic lymph-node adenectomy is regarded as an investigated protocol for endometrial cancer. However, p-aortic lymph-node adenectomy may have a therapeutic role for stage IIIC patients. Prospective randomized controlled trial composed of intermediate/high-risk patients should be conducted to clearly demonstrate prognostic improvement by p-aortic lymph-node adenectomy itself.

Endometrioid uterine cancer: histopathological risk factors of local and distant recurrence.

OBJECTIVES: To determine the relationship between histopathological prognostic factors and sites of initial recurrence in endometrioid uterine cancer. METHODS: A total of 355 patients (Stage I, n=227; II, n=38; III, n=90) underwent primary radical surgery including complete systematic pelvic lymph node (PLN) and para-aortic lymph node (PALN) adenectomy followed by adjuvant chemotherapy who were at risk for recurrence. Relapse-free survival (RFS) and disease-related survival (DRS) were analyzed using the log-rank testing. Multivariate Cox regression analysis and logistic regression analysis were used to determine and estimate independent prognostic factors. RESULTS: Lymph-vascular space invasion (LVSI), architectural grade (AG), myometrial invasion, and PLN metastasis (PLNM) were identified as independent prognostic factors for RFS. AG (p=0.0043) related with local recurrence. Among patients who received adjuvant chemotherapy, patients with G3 tumor had higher ratio of recurrence (16/45) compared with G1/2 tumor (11/102) (p=0.0004). Meanwhile, PLNM related with distant recurrence (p=0.0008). There was a statistically significant difference in RFS according to the number of positive PLN sites (group 0: n=313, 1: n=16, > or =2: n=26), five-year RFS in each group was 91.9%, 81.3%, and 41.2%, respectively. CONCLUSIONS: Sites of initial recurrence were related with AG and PLNM in patients with endometrioid uterine cancer. Current chemotherapy alone may not be an effective adjuvant therapy to prevent recurrence in patients with G3 tumor and > or =2 positive PLN sites. Prospective clinical trial needs to be conducted to establish the strategy of adjuvant therapy with these patients.

Efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in previously treated patients with non-small cell lung cancer.

PURPOSE: The objective of this study was to evaluate the efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B(12) in pretreated Japanese patients with advanced non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Patients with an Eastern Cooperative Oncology Group performance status 0 to 2, stage III or IV, and who received previously one or two chemotherapy regimens were randomized to receive 500 mg/m(2) pemetrexed (P500) or 1,000 mg/m(2) pemetrexed (P1000) on day 1 every 3 weeks. The primary endpoint was response rate. RESULTS: Of the 216 patients evaluable for efficacy (108 in each arm), response rates were 18.5% (90% confidence interval, 12.6-25.8%) and 14.8% (90% confidence interval, 9.5-21.6%), median survival times were 16.0 and 12.6 months, 1-year survival rates were 59.2% and 53.7%, and median progression-free survival were 3.0 and 2.5 months for the P500 and P1000, respectively. Cox multiple regression analysis indicated that pemetrexed dose was not a significant prognostic factor. Drug-related toxicity was generally tolerable for both doses; however, the safety profile of P500 showed generally milder toxicity. Main adverse drug reactions of severity grade 3 or 4 were neutrophil count decreased (20.2%) and alanine aminotransferase (glutamine pyruvic transaminase) increased (15.8%) in P500 and neutrophil count decreased (24.3%), WBC count decreased (20.7%), and lymphocyte count decreased (18.0%) in P1000. One drug-related death from interstitial lung disease occurred in the P500. CONCLUSION: P500 and P1000 are similarly active with promising efficacy and acceptable safety outcomes in pretreated patients with NSCLC. These results support the use of P500 as a second- and third-line treatment of NSCLC.

[Influence of oral appliances for obstructive sleep apnea syndrome on stomatognathic system part 1. Occlusion].

PURPOSE: Little information is available on the mandibular protrusion with oral appliances (OA) for the treatment of obstructive sleep apnea syndrome (OSAS) to have no negative effect on the stomatognathic system. The purpose of the current study was to assess the influence of mandibular protrusion on occlusion to fabricate the appropriate OA. METHODS: Twelve healthy adults were selected. With the OA in position, the mandible was advanced 0, 45, 60, 75% of maximum protrusion capacity; bite raising distance between the first molars was 5mm (OA5-0, 45, 60 and 75). The occlusal force, occlusal contact area and occlusal load center following maximum voluntary clenching for 5 seconds were investigated as follows: after wearing the OA for 1, 3 and 6 hours (Stage A1, A3 and A6) and 1 hour after removal (Stage R1). These data were compared with before wearing (Stage B). RESULTS: Occlusal force has significant decrement at Stages A1, A3 and A6 after wearing OA5-75, at Stages A3 and A6 after wearing OA5-60, and at Stage A6 after wearing OA5-0. Occlusal contact area has significant decrement at Stages A1, A3 and A6 after wearing OA5-75, and at Stage A6 after wearing OA5-60. Occlusal load center has significant forward displacement at Stages A3 and A6 after wearing OA5-75, and at Stage A6 after wearing OA5-60. CONCLUSION: To fabricate the appropriate OA in occlusal perspective, it is preferable to set the mandibular position at 45% advancement of maximum protrusion capacity of condyle head in terms of the mandibular positions used in this study.