Prevention of symptomatic pulmonary embolism for gynecologic malignancies with preoperative asymptomatic venous thromboembolism: GOTIC-VTE trial.

OBJECTIVE: In Japan, perioperative prophylaxis of pulmonary embolism (PE) in gynecologic cancer patients with preoperative asymptomatic venous thromboembolism (VTE) has not been well established yet. The GOTIC-VTE trial was a prospective, multi-center, single-arm clinical trial to investigate the prevention of postoperative symptomatic PE onset by seamless anticoagulant therapy from the preoperative period to 4 weeks after surgery instead of using intermittent pneumatic compression. METHODS: Anticoagulant therapy was started immediately after asymptomatic VTE diagnosis and stopped preoperatively according to the rules of each institution. Unfractionated heparin administration was resumed within 12 hours postoperatively, and this was followed by the switch to low-molecular-weight heparin and subsequently, edoxaban; this cycle was continued for 28 days. Primary outcome was the occurrence of symptomatic PE in 28 days postoperatively. Secondary outcomes were the incidence of VTE-related events in 28 days and 6 months postoperatively and protocol-related adverse events. RESULTS: Between February 2018 and September 2020, 99 patients were enrolled; of these, 82 patients were assessed as the full analysis set, including 58 for ovarian cancer, fallopian tube, or peritoneal cancer; 21 for endometrial cancer; and 3 for cervical cancer. No symptomatic PE was observed within 28 days postoperatively; two patients had bleeding events (major bleeding and clinically relevant nonmajor bleeding) and three had grade 3 adverse events (increased alanine transaminase, aspartate aminotransferase, or gamma-glutamyl transferase). CONCLUSION: The multifaceted perioperative management for gynecologic malignancies with asymptomatic VTE effectively prevented postoperative symptomatic PE. TRIAL REGISTRATION: JRCT Identifier: jRCTs031180124.

Primary vomerine osteotomy with gingivoperiosteoplasty for bilateral cleft lip and palate patients with protrusion and/or torsion of the premaxilla.

In patients with bilateral cleft lip and palate (BCLP) with protrusion and/or torsion of the premaxilla, achieving a favorable outcome with adequate facial and maxillary development remains challenging. In the present study, we report a retrospective cohort of patients with complete BCLP who were treated between 2017 and 2020 at a single center in Japan. We investigated the effects and complications of primary vomerine osteotomy (PVO) with gingivoperiosteoplasty (GPP) following pre-surgical orthodontics (PSO) for premaxillary protrusion and/or torsion. For patients with residual premaxillary protrusion and/or torsion after PSO, PVO, and GPP were performed. The distances and angles of the premaxilla were measured on dental casts before PSO, on the day of PVO, after PVO, and on the day of palatoplasty after cheiloplasty. We further assessed postoperative complications. From a total of 36 patients with complete BCLP after PSO, seven patients underwent PVO with GPP. Proper positioning of the premaxilla was achieved in all seven patients. The distance between the anterior edge of the premaxilla and the anterior edge of the lateral segment and the length of the premaxillary-lateral segment on both sides continued to decrease over time. Loosening of GPP sutures occurred in two cases, although no major complications such as necrosis of the premaxilla or fistula formation occurred. Vomerine osteotomy with GPP before primary cheiloplasty is a potential treatment option in BCLP when the premaxilla still protrudes despite PSO or because PSO cannot be applied.

Revised Cut-Off Value of Human Epididymis Protein 4 Enhances Its Use as an Ovarian Tumor Marker.

OBJECTIVES: Human epididymis protein 4 (HE4), a protein secreted by ovarian tumors, has been used as an ovarian tumor marker. This study aimed to improve the usefulness of HE4 to detect malignant ovarian tumors by reviewing the cut-off values. DESIGN: A retrospective study without intervention was conducted. PARTICIPANTS: One hundred forty-nine healthy women (premenopausal, 126; postmenopausal, 23) and 24 patients with ovarian tumors (malignant, 12; benign, 12) participated in the study. SETTING: The study used the Department of Obstetrics and Gynecology of a university hospital in Japan and the university hospital as a workplace from 2016 to 2018. METHODS: The basic performance of the HE4 assay was evaluated, and the serum HE4 levels of participants were measured. Receiver operating characteristic analysis was performed using the HE4 data of the patients. RESULTS: There were no significant differences in HE4 levels between the pre- and postmenopausal groups of healthy women. When the global cut-off values (premenopausal, 70 pmol/L; postmenopausal, 140 pmol/L) were adopted, the clinical sensitivity, specificity, positive predictive value, and negative predictive value were 41.7%, 91.7%, 83.3%, and 61.1%, respectively. Based on the results of the receiver operating characteristic analysis, we set the HE4 cut-off level at 60 pmol/L, regardless of the menopausal status. With the newly set cut-off value, the clinical sensitivity, specificity, positive predictive value, and negative predictive value were 66.7%, 91.7%, 88.9%, and 73.3%, respectively. That is, the clinical sensitivity of HE4 was improved without lowering specificity. LIMITATIONS: The small number of subjects and the fact that the health status of the healthy women was evaluated based on questionnaires were limitations to the study. CONCLUSION: A clinically useful cut-off value for HE4 as an ovarian tumor marker was established regardless of the menopausal status of the women, with improved clinical sensitivity, positive predictive value, and negative predictive value without lowering specificity. Currently, different cut-off values for HE4 in pre- and postmenopausal women are used globally. The cut-off value for CA125 was the same between pre- and postmenopausal women. Therefore, with the newly established cut-off value, HE4 can be used more conveniently in a non-specialized setting, especially when it is used in combination with CA125.

Clinicopathological features and programmed death-ligand 1 immunohistochemical expression in a multicenter cohort of uterine and ovarian melanomas: a retrospective study in Japan (KCOG-G1701s).

The objective of this study was to propose prognostic factors and optimal treatment strategies by analyzing the clinicopathological features and programmed death-ligand 1 (PD-L1) expression. We analyzed 31 patients diagnosed with uterine or ovarian melanoma between 1997 and 2017 in the Kansai Clinical Oncology Group/Intergroup. Twenty-four and seven patients with cervical and ovarian melanomas were included, respectively. Immune checkpoint inhibitors were used in seven patients, and the objective response rate was 40%. Notably, two patients with objective responses had a high PD-L1 expression. Ten and four patients with cervical and ovarian melanomas, respectively, had high PD-L1 immunohistochemical expressions. Multivariate analysis revealed that tumor stage was an independent prognostic factor for progression-free survival in patients with cervical melanomas. In patients with ovarian melanomas, the 1-year cumulative progression-free and overall survival rates were 0 and 29%, respectively. Kaplan-Meier analyses revealed that age <60 years was associated with poorer progression-free and overall survivals in patients with ovarian melanomas. In patients with cervical melanomas, the 1-, 3-, and 5-year cumulative overall survival rates were 53, 32, and 16%, respectively. Histological atypia was associated with a poorer progression-free survival, but there was no difference in survival between patients who underwent radical hysterectomy and those who did not. The present study is a large cohort study of uterine and ovarian melanomas, which are aggressive tumors with a significantly poor prognosis, even after standard surgery and adjuvant therapy. The use of immune checkpoint inhibitors is a promising and effective treatment option.

A predictor of a postoperative fistula after double-opposing Z-plasty in bilateral cleft lip and palate patients.

Furlow double-opposing Z-plasty (FDOZ) as primary palatoplasty for the bilateral cleft lip and palate (BCLP) closure often leads to a palatal fistula formation in cases with wide clefts. We examined the utility of the calculated maximum closable cleft width to determine the feasibility of a direct palatal closure without lateral incisions. In this retrospective study, we analyzed consecutive patients with a BCLP who were treated for 5 years from 2009. In sixty-three BCLP patients, the following dimensions were measured preoperatively: an actual distance between maxillary tuberosities (Actual X); actual cleft height, calculated from the line joining the maxillary tuberosities to the cleft edge (Actual Y); and actual cleft width at the hard-soft palate junction (Actual Z) and calculated maximum cleft width requiring a direct closure (CMZ). Six months postoperatively, the relationships between the fistula occurrence and actual Z/CMZ were examined. Median values (interquartile range) of Actual X, Y, and Z and CMZ were 35.0 (33.0-39.0) mm, 7.0 (6.0-8.0) mm, 10.0 (8.0-11.0) mm, and 4.6 (2.7-5.7) mm, respectively. The median age at operation was 8.0 (7.0-17.0) months. Fistulae at the hard-soft palate junction developed postoperatively in three cases with more than a 10-mm cleft width (4.76%). A receiver operating characteristic (ROC) curve analysis indicated that actual Z was a better predictor of a postoperative fistula formation than CMZ. An actual cleft width was a better predictor of the fistula occurrence than a calculated maximum cleft width after FDOZ for a BCLP repair. The low fistula rate of FDOZ suggested that FDOZ could be used to close the palate with less than a 10-mm cleft width.

Posterior pharyngeal wall augmentation using autologous tiered costal cartilage for velopharyngeal insufficiency.

The aim of this study was to retrospectively estimate intervention outcomes and to establish suitable indications for autogenous tiered cartilage augmentation (ATCA) of the posterior pharyngeal wall for velopharyngeal insufficiency (VPI). The sample cohort comprised 17 consecutive patients with VPI (10 boys, 7 girls), excluding syndromic cases. Pre- and postoperative findings were comprehensively evaluated using a combination of speech assessment and lateral pharyngography (LPG). Hypernasality and consonant distortion were scored (normal: 0; mild: 1; moderate: 2; severe: 3). Velopharyngeal gap size at rest (AC) and at maximum closure (BC) were measured on LPG. All patients displayed improvements in velopharyngeal function and speech score, and no patients required re-operation. Pre- and postoperative hypernasality scores were 1.9 ± 0.5 and 0.6 ± 0.5, respectively (P < .001). Pre- and postoperative consonant distortion scores were 1.9 ± 0.6 and 0.6 ± 0.5, respectively (P < .001). Pre- and postoperative AC distances were 8.2 ± 3.4 mm and 5.9 ± 2.6 mm, respectively (P < .001). Pre- and postoperative BC distances were 3.9 ± 2.4 mm and 0.3 ± 0.8 mm, respectively (P < .001). Conclusions: ATCA appears effective for surgical treatment of VPI patients with a gap less than 10 mm.

A retrospective study of small-pelvis radiotherapy plus image-guided brachytherapy in stage I-II non-bulky cervical squamous cell carcinoma.

We herein report a retrospective analysis of the efficacy of a combination therapy of pelvic irradiation that excluded the common iliac lymph nodes region and image-guided brachytherapy (IGBT) for non-bulky (≤4 cm) cervical cancer. Thirty-three patients with stage I-II cervical squamous cell carcinoma (≤4 cm) and without pelvic/para-aortic lymphadenopathy who were treated with definitive radiotherapy alone between February 2009 and September 2016 were included. The radiotherapy consisted of CT-based small-pelvis irradiation (whole pelvis minus common iliac lymph node area) of 20 Gy/10 fractions followed by pelvic irradiation with a midline block of 30 Gy/15 fractions and IGBT of 24 Gy/4 fractions (6 Gy/fraction for high-risk [HR] clinical target volume [CTV] D90%). In-room computed tomography (CT) imaging with applicator insertion was used for brachytherapy planning, with physical examinations and diagnostic magnetic resonance imaging (MRI) also being referred to for determination of HR CTV. Over a median follow-up of 60.5 months (range, 7-89), two patients developed distant recurrence and one developed local and distant recurrence. Two patients died from cervical cancer, one from hepatocellular carcinoma and one from non-cancerous disease. The 2/5-year local control (LC), progression-free survival (PFS) and overall survival (OS) rates were 100%/96.7%, 93.8%/90.6% and 93.9%/93.9%, respectively. No pelvic/para-aortic lymph node recurrence was observed. There were no late complications of grade 3 or higher in the small bowel, large bowel/rectum, or bladder. Our results suggest that a combination therapy of IGBT plus small-pelvis irradiation excluding common iliac lymph nodes provides reasonable clinical outcomes and can be a treatment option in non-bulky (≤4 cm) cervical squamous cell carcinoma.

Treatment of congenital short palate using bilateral buccal musculomucosal flaps.

A case of congenital short palate was treated by bilateral buccal musculomucosal flaps. The levator veli palatini muscle formed a continuous sling, but the anterior portion was attached to the posterior border of the hard palate. The speech outcome improved from severe to normal.

FGFR Signaling as a Candidate Therapeutic Target for Cancers Resistant to Carbon Ion Radiotherapy.

Radiotherapy is an essential component of cancer therapy. Carbon ion radiotherapy (CIRT) promises to improve outcomes compared with standard of care in many cancers. Nevertheless, clinicians often observe in-field recurrence after CIRT. This indicates the presence of a subset of cancers that harbor intrinsic resistance to CIRT. Thus, the development of methods to identify and sensitize CIRT-resistant cancers is needed. To address this issue, we analyzed a unique donor-matched pair of clinical specimens: a treatment-naïve tumor, and the tumor that recurred locally after CIRT in the same patient. Exon sequencing of 409 cancer-related genes identified enrichment of somatic mutations in FGFR3 and FGFR4 in the recurrent tumor compared with the treatment-naïve tumor, indicating a pivotal role for FGFR signaling in cancer cell survival through CIRT. Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient. The sensitizer enhancement ratio was 1.66 ± 0.17, 1.27 ± 0.09, and 1.20 ± 0.18 in A549, H1299, and H1703 cells, respectively. Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts.

Orthodontic premaxillary setback versus premaxillary osteotomy with gingivoperiosteoplasty for Bilateral cleft lip and palate patients: 4-year observation outcomes.

Patients with bilateral cleft lip and palate (BCLP) generally require several stages of treatment, and adequate maxillary development without orthognathic surgery is not easy to achieve. The purpose of this study was to determine short-term outcomes of orthodontic premaxillary setback (OPS) and premaxillary osteotomy (PO) for complete BCLP treatment. PATIENTS AND METHODS: Twenty-six patients with BCLP were consecutively treated for 4 years by a single surgeon. All patients were categorized by three indications for the first operation: OPS1, cheiloplasty + gingivoperiosteoplasty (GPP) + palatoplasty; OPS2, cheiloplasty + GPP; and PO, cheiloplasty + GPP + PO. Cephalograms for maxillary growth and velopharyngeal function (VPF) were judged at 4 years old, before orthodontic treatment. RESULTS: OPS1 was performed in 14 cases, OPS2 in 8 cases, and PO in 4 cases. As for cephalometric analysis at 4 years old, no significant differences between groups were seen in any cephalometric measurements. As for speech outcomes, assessment of VPF at 80.8±14.8 months was good in 17 cases, slightly impaired in 8 cases, and marginally impaired in 1 case, with no severely impaired cases. DISCUSSION: No significant differences in maxillary growth or speech outcomes were seen between OPS1, OPS2, and PO groups at 4 years old, possibly because all groups showed the same position of the premaxilla after the first operation. CONCLUSIONS: No significant differences in maxillary growth or speech outcomes were seen for 26 patients with BCLP between OPS1, OPS2, and PO groups at 4 years old. However, the long-term growth characteristics remain unclear.

An electrical scalpel conization versus Shimodaira-Taniguchi conization procedure for cervical intraepithelial neoplasia.

The incidence of cervical intraepithelial neoplasia(CIN) among reproductive-aged women has increased in Japan. Cervical conization is commonly applied for local cervical treatment to preserve fertility. The Shimodaira-Taniguchi (S-T) conization procedure is widely used in Japan. S-T conization uses a high-frequency current and a triangular probe with a linear excision electrode to remove cervical tissue as a single informative specimen. However, alternative of an electrosurgical scalpel (ES) has the advantage of adjusting the surgical margin to the transformation zone in order to preserve the maximum amount of healthy cervical tissue with good hemostasis. The aim of this study is to retrospectively analyze data regarding surgical margin status, perioperative adverse events, cervical stenosis, and preterm birth between S-T and ES.Between January 2009 and December 2014, the medical records of 1166 patients who were diagnosed as CIN II, III, or stage 1a1 cervical cancer and who were treated with conization in 7 hospitals in Gunma Prefecture, Japan were enrolled for this retrospective study. The clinicopathological data was analyzed to statistically compare outcome between S-T and ES conization.There was no difference for age or post-operative follow-up period between ES and S-T treatments. However, positive surgical margins were significantly less frequent in patients who were treated with S-T than in those treated with ES, resulting in a reduced incidence of re-treatment for S-T in comparison with ES patients. In perioperative adverse events, S-T had more patients who were administered antibiotics. The incidence of preterm delivery and cervical stenosis did not differ significantly between the groups.We demonstrate here that S-T is an alternative procedure for cervical conization with a low risk of recurrence and acceptably low rate of adverse events such as cervical stenosis and preterm delivery. The results of this study can provide useful information for future management of patient with cervical intraepithelial neoplasia.

Phase I Study of Carbon Ion Radiotherapy and Image-Guided Brachytherapy for Locally Advanced Cervical Cancer.

A phase I study was performed to determine the recommended dose of carbon ion radiotherapy and 3D image-guided brachytherapy for histologically confirmed stage II (≥4 cm), III, or IVA cervical cancer. Dose-limiting toxicities (treatment-related toxicities occurring within three months from the start of carbon ion radiotherapy) included Grade 3 non-hematological toxicity, Grade 4 hematological toxicity, or interruption of treatment for more than two weeks due to treatment-related toxicities. Carbon ion radiotherapy consisted of whole-pelvic irradiation with 36.0 Gy (relative biological effectiveness) in 12 fractions and local boost with 19.2 Gy in four fractions for the primary site, and for positive lymph nodes. Three sessions of three-dimensional (3D) image-guided brachytherapy were administered after completion of carbon ion radiotherapy. Weekly cisplatin at a dose of 40 mg/m² was given concurrently. At a dose level of one, a total rectosigmoid D2cc dose between 67.2 Gy and 71.3 Gy at a biological equivalent dose of 2 Gy per fraction from carbon ion radiotherapy and 3D image-guided brachytherapy was prescribed. Six patients were enrolled into this dose level. No patients developed the pre-defined dose-limiting toxicities. For late toxicities, however, one patient developed Grade 3 rectal hemorrhage requiring transfusion at 10 months after treatment. The median survival time was 50.0 months for the five surviving patients. No further dose escalation was performed, and we determined the dose of level one as the recommended rectosigmoid dose. Although our results are preliminary, the study regimen encourages further investigation (registration: UMIN000013340).

High Expression of Ubiquitin C-terminal Hydrolase L1 Is Associated With Poor Prognosis in Endometrial Cancer Patients.

OBJECTIVE: The ubiquitin C-terminal hydrolase L1 (UCHL1) plays a key role in tumor invasion and metastasis. Ubiquitin C-terminal hydrolase L1 is overexpressed in various cancers and reported to be correlated with a poor prognosis. The objective of this study was to determine the prognostic significance of UCHL1 in endometrial cancer. METHODS: The expression of UCHL1 in endometrial cancer was assessed using quantitative reverse transcription polymerase chain reaction and immunohistochemistry in 56 and 215 resected tumor specimens, respectively. RESULTS: The 4-year survival rates of the high UCHL1 messenger RNA expression group and high UCHL1 protein expression group were 78% and 71%, respectively, compared with 96% and 95% for the low UCHL1 messenger RNA expression group and low UCHL1 protein expression group, respectively. Kaplan-Meier and log-rank tests indicated a significant correlation between expression of UCHL1 and disease-free survival and overall survival. Moreover, multivariate stepwise Cox proportional hazard regression model analysis showed that UCHL1 was a significant independent marker for predicting a poor disease-free survival and overall survival. In 43 patients with metastatic lesions, immunohistochemical analysis of metastatic lesions revealed that the recurrence rate and mortality rate were 62% and 41%, respectively, in 29 UCHL1-positive patients and 36% and 29%, respectively, in 14 UCHL1-negative patients. CONCLUSIONS: The results of this study suggest that high UCHL1 expression is a strong marker of poor prognosis of endometrial cancer. Furthermore, we suggest that UCHL1 may be involved in the development of distant metastasis in endometrial cancer.

Synchronous Premaxillary Osteotomy with Primary Cheiloplasty for BCLP Patients with Protrusion of the Premaxillae.

BACKGROUND: In bilateral cleft lip and palate (BCLP) patients with protrusion and/or torsion of the premaxillae, it is difficult to achieve a good outcome. We have developed a series of procedures of premaxillary osteotomy with primary cheiloplasty for BCLP patients who did not respond well to presurgical orthodontics (PSO). METHODS: A total of 27 BCLP patients with protrusion and/or torsion of the premaxillae underwent PSO. For 3 BCLP patients in whom the protruded premaxillae could not be returned to a good position, a primary premaxillary osteotomy and gingivoperiosteoplasty (GPP) with cheiloplasty were performed simultaneously. Subsequently, Furlow palatoplasty was performed by one and a half years of age. Maxillary growth was evaluated by dental occlusion at 4 years of age. RESULTS: A premaxillary osteotomy and GPP with cheiloplasty were performed at 6 months. The patients' facial structures improved, their premaxillae were positioned more superiorly, and normal inclination of the incisors was achieved. They had edge-to-edge occlusions or cross bites at 4 years of age. CONCLUSIONS: As advantages, the patients' facial structures improved, and the alveolar bones were formed by GPP. As a disadvantage, premaxillary necrosis might occur because of poor blood circulation. It is important to secure the following 2 blood supplies: from the periosteum and soft-tissue of the anterior premaxillae and from the periosteum and mucosa of the nasal septum. Synchronous premaxillary osteotomy and GPP with primary cheiloplasty are appropriate when the premaxillae cannot be properly repositioned by PSO or PSO cannot be done.

Corrected Cephalometric Analysis to Determine the Distance and Vector of Distraction Osteogenesis for Syndromic Craniosynostosis.

BACKGROUND: The purpose of this study was to confirm the utility of a corrected cephalometric analysis to facilitate the planning of distraction osteogenesis with Le Fort III osteotomy for syndromic craniosynostosis. METHODS: This prospective study involved 4 male and 2 female patients (mean patient age, 8 years 9 months; age range, 4 years 6 months to 13 years 2 months) with Crouzon syndrome who were treated with Le Fort III maxillary distraction using our previously described system of analysis of a corrected cephalogram and who underwent clinical follow-up. Lateral cephalograms were obtained immediately after device removal. RESULTS: Distraction of orbitale moved the vector downward to the adult profile, but there was slightly less elongation than the adult profile for the distraction distance. The desired and real mean angles after distraction of point A were 29.2 ± 7.9° and 6.1 ± 8.5°, respectively, and the desired and the real mean distances after distraction of point A were 30.6 ± 12.7 mm and 29.4 ± 4.1 mm, respectively. CONCLUSIONS: Using the corrected cephalometric analysis, the distance and vector of distraction osteogenesis with Le Fort III osteotomy could be determined in patients with syndromic craniosynostosis. The distraction system brought the patients' facial bones to the planned position using controlling devices.

Transmaxillary Sinus Approach for Le Fort II Osteotomy.

The Le Fort II osteotomy is a relatively rare operation. The posterior wall osteotomy of the maxillary sinus (MS) is often difficult for Le Fort III. We developed the transmaxillary sinus approach (TSA) for the Le Fort II osteotomy that cuts the posterior wall of the MS directly. This report illustrates this easy-to-use procedure for the Le Fort II osteotomy in syndromic craniosynostosis. This procedure was performed in an 18-year-old patient with Apert syndrome and a 15-year-old patient with Pfeiffer syndrome. The thin anterior walls of the MS were removed through an intraoral approach to look inside the MS. Then, the posterior walls were cut by chisel under direct vision using light. The other osteotomy was performed as usual. Distraction osteogenesis with internal and external devices was used in combination. The advantages of TSA are the direct posterior wall osteotomy of the MS with no down fracture and minimal invasiveness to the mucosa of the MS under direct vision. However, the disadvantage is that TSA becomes a blind procedure in a case with no MS or hypoplasia. We developed the TSA for the Le Fort II osteotomy, which could provide direct observation and perform the posterior wall osteotomy of the MS without down fracture. We believe that TSA is an effective surgical procedure for the Le Fort II osteotomy.

Leptomeningeal metastasis of uterine cervical cancer 17 years after primary tumor treatment.

Leptomeningeal metastasis (LM) of uterine cervical cancer is extremely rare. A 54-year-old woman with uterine cervical cancer treated with surgery and radiotherapy developed LM manifesting as ptosis 17 years later. Although rare, LM should be considered in patients with a history of uterine cervical cancer presenting with cranial nerve symptoms.

Prognostic significance of L-type amino acid transporter 1 (LAT1) expression in patients with ovarian tumors.

AIM: Amino acid transporters are essential for the growth, progression and the pathogenesis of various cancers. However, it remains obscure about the clinicopathological significance of L-type amino acid transporter 1 (LAT1) and system ASC amino acid transporter 2 (ASCT2) for patients with human ovarian tumors. The aim of this study is to elucidate the prognostic role of these amino acid transporters in ovarian tumor. METHODS: One-hundred forty-two patients with surgically resected ovarian tumors were analyzed by immunohistochemistry. Expression of LAT1, ASCT2, CD98, Ki-67 and microvessel density (MVD) determined by CD34 were evaluated using specimens of the resected tumors. RESULTS: LAT1 and ASCT2 were positively expressed in 39% and 53%, respectively, of ovarian tumors (n=142) and 50% and 57%, respectively, of epidermal ovarian cancers (n=107). A positive LAT1 expression was closely correlated with the expression for ASCT2 and CD98, and cell proliferation (Ki-67) in ovarian cancer. By multivariate analysis, LAT1 was clarified as a significant independent marker for predicting a poor overall survival (OS). The expression of LAT1 could clearly discriminate between epidermal ovarian cancer and borderline malignancy. The expression level of LAT1 within ovarian cancer cells varied among serous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma and mucinous adenocarcinoma and we found LAT1 expression was higher in clear cell adenocarcinoma than other histological types. CONCLUSIONS: LAT1 is highly expressed in various ovarian tumors and a positive LAT1 expression can serve as a significant independent factor for predicting a poor OS in patients with epidermal ovarian cancer.

TNF-α Suppressed FSH-Induced LH Receptor Expression Through Transcriptional Regulation in Rat Granulosa Cells.

Several inflammatory cytokines regulate ovarian function. TNF-α is produced in granulosa cells under physiological conditions and has a reciprocal action on follicle development. In contrast, in pelvic inflammatory diseases, TNF-α is excessively produced in the pelvic cavity and has an adverse effect on reproductive functions. The objective of this study was to elucidate the mechanism of action of TNF-α on the expression of LH receptor (LHR) in immature rat granulosa cells. TNF-α suppressed FSH-induced LHR mRNA and protein expression and was not associated with cAMP accumulation. By using a luciferase assay, the construct containing base pairs -1389 to -1 of the rat Lhcgr promoter revealed that TNF-α decreased FSH-induced promoter activity. In response to TNF-α, nuclear factor (NF)-κB p65 was translocated to the nucleus, and the suppressive effect of TNF-α on LHR mRNA expression was abrogated by an NF-κB inhibitor. In a chromatin immunoprecipitation assay, TNF-α induced the association of NF-κB p65 with the rat Lhcgr transcriptional promoter region. NF-κB p65 and histone deacetylase (HDAC) interact to mediate expression of several genes at a transcriptional level. HDAC activity is thought to induce tight connections within local chromatin structures and repress gene transcription. Furthermore, the TNF-α-induced suppression of LHR mRNA expression was blocked by an HDAC inhibitor. Taken together, these results suggest that the interaction of NF-κB p65 with HDAC in the promoter region of rat Lhcgr might be responsible for TNF-α action on the regulation of LHR.

Primary Palatoplasty for Unilateral Cleft Lip and Palate Using Mucosal Grafts and Flaps.

The mucosal graft and flaps method (MG method) is a palatoplasty technique that was developed for the purpose of improving maxillary growth in patients with cleft palate. In the MG method, full-thickness buccal mucosa is grafted onto the raw surface created by pushback palatoplasty. The method is unlikely to result in severe scarring and has a favorable effect on maxillary growth. In addition, it is unlikely to result in oronasal fistula and provides good speech results. Overall, postive long-term treatment results have been obtained. Although the MG method is technically difficult and requires a lengthy surgery, the technique is considered to be effective for palate closure in terms of speech and maxillary growth.