Prognostic impact of the number of resected pelvic nodes in endometrial cancer: Japanese Gynecologic Oncology Group Study JGOG2043 post hoc analysis.

OBJECTIVE: This study aimed to determine whether the number of resected pelvic lymph nodes (PLNs) affects the prognosis of endometrial cancer (EC) patients at post-operative risk of recurrence. METHODS: JGOG2043 was a randomized controlled trial to assess the efficacy of three chemotherapeutic regimens as adjuvant therapy in EC patients with post-operative recurrent risk. A retrospective analysis was conducted on 250 patients who underwent pelvic lymphadenectomy alone in JGOG2043. The number of resected and positive nodes and other clinicopathologic risk factors for survival were retrieved. RESULTS: There were 83 patients in the group with less than 20 PLNs removed (group A), while 167 patients had 20 or more PLNs removed (group B). There was no significant difference in patients' backgrounds between the two groups, and the rate of lymph node metastasis was not significantly different. There was a trend toward fewer pelvic recurrences in group B compared with group A (3.5% vs. 9.6%; p=0.050). Although Kaplan-Meier analysis showed no statistically significant difference in survival rates between the two groups (5-year overall survival [OS]=90.3% vs. 84.3%; p=0.199), multivariate analysis revealed that resection of 20 or more nodes is one of the independent prognostic factors (hazard ratio=0.49; 95% confidence interval=0.24-0.99; p=0.048), as well as surgical stage, high-risk histology, and advanced age for OS. CONCLUSION: Resection of 20 or more PLNs was associated with improved pelvic control and better survival outcomes in EC patients at risk of recurrence who underwent pelvic lymphadenectomy alone and were treated with adjuvant chemotherapy.

Ovarian serous borderline tumors with recurrent or extraovarian lesions: a Japanese, retrospective, multi-institutional, population-based study.

BACKGROUND: Ovarian serous borderline tumors (SBT) are typically unilateral and are primarily treated using hysterectomy and bilateral salpingooophorectomy (SO). However, most young patients prefer fertility-sparing surgeries (FSS) with tumorectomy or unilateral SO. Micropapillary morphology and invasive implants have been designated as histopathological risk indicators for recurrence or metastasis, but their clinical impact remains controversial because of limitations like diagnostic inconsistency and incomplete surgical staging. METHODS: A nationwide multi-institutional population-based retrospective surveillance was conducted with a thorough central pathology review to reveal the clinical features of SBT. Of 313 SBT patients enrolled in the Japanese Society of Clinical Oncology's Surveillance of Gynecologic Rare Tumors, 289 patient records were reviewed for clinical outcomes. The glass slides of patients at stage II-IV or with recurrence or death were re-evaluated by three gynecological pathologists. RESULT: The 10-year overall and progression-free survival (PFS) rates were 98.6% and 92.3%. The median recurrence period was 40 months and 77.0% was observed in the contralateral ovary within 60 months. Patients aged ≤ 35 years underwent FSS more frequently and relapsed more (p < .001). A clinic-pathological analysis revealed diagnosis during pregnancy, FSS, and treatment at non-university institutes as well as advanced stage and large diameter were independent risk factors of recurrence. Among patients having pathologically confirmed SBTs, PFS was not influenced by the presence of micropapillary pattern or invasive implants. CONCLUSION: The recurrence rate was lower in this cohort than previous reports, but the clinical impacts of incomplete resection and misclassification of the tumor were still significant on the treatment of SBT.

Surgically treated cervical cancer in a high-risk group in the era of the 2018 FIGO staging schema: a nationwide study.

The 2018 International Federation of Gynecology and Obstetrics (FIGO) revision to the staging criteria for uterine cervical cancer adopted pathological staging for patients who underwent surgery. We investigated the correlation between clinicopathological factors and prognosis in patients with high-risk factors in accordance with the FIGO 2018 staging criteria by analyzing a real-world database of 6,192 patients who underwent radical hysterectomy at 116 institutions belonging to the Japan Gynecologic Oncology Group. A total of 1,392 patients were categorized into the high-risk group. Non-squamous cell carcinoma histology, regional lymph node metastasis, pT2 classification, and ovarian metastasis were identified as independent risk factors for mortality. Based on pathological findings, 313, 1003, and 76 patients were re-classified into FIGO 2018 stages IIB, IIIC1p, and IIIC2p, respectively. Patients with stage IIIC2p disease showed worse prognoses than those with stage IIB or IIIC1p disease. In patients with stage IIIC1p disease, overall survival was significantly better if their tumors were localized in the uterine cervix, except for single lymph node metastasis, with a 5-year overall survival rate of 91.8%. This study clarified the heterogeneity of the high-risk group and provided insights into the feasibility of upfront radical hysterectomy for a limited number of patients harboring high-risk factors.

JGOG2046: a feasibility study of neoadjuvant chemotherapy followed by debulking surgery for clinically diagnosed FIGO stage IVb endometrial cancer.

BACKGROUND: We evaluated the feasibility of neoadjuvant chemotherapy, followed by debulking surgery, for clinically diagnosed FIGO stage IVb endometrial cancer (protocol number: JGOG2046). METHODS: The experimental treatment consisted of 3 cycles of paclitaxel (180 mg/m2) plus carboplatin (AUC5) followed by debulking surgery, including total abdominal hysterectomy, bilateral salpingo-oophorectomy, and 3 cycles of adjuvant chemotherapy. Patients were considered as eligible if they were pathologically diagnosed as primary endometrial cancer, and had both endometrial tumor and distant metastasis confirmed by imaging examinations. The primary endpoint was the incidence of patients who completed debulking surgery after the neoadjuvant chemotherapy. RESULTS: While 51 patients were enrolled from 23 hospitals, the final study cohort consisted of 49 patients with a mean age of 59.0 years. Although the response ratio of the neoadjuvant chemotherapy was 65.3% (95% CI 50.4-78.3%), 67.3% (95% confidence interval (CI) 52.5-80.1%) underwent debulking surgery after the neoadjuvant chemotherapy and 59.2% (95% CI 45.2-71.8%) completed the protocol treatment including 3 courses of adjuvant chemotherapy. The median disease-free survival time was 9.1 months (95% CI 6.5-11.9), while the median overall survival time was 23.2 months (95% CI 11.9-27.8). A patient with sigmoid colon cancer and another with cervical cancer were included in this study. CONCLUSIONS: Neoadjuvant chemotherapy followed by debulking surgery was a feasible and acceptable treatment for metastatic endometrial cancer. (225 words).

CXCR4 signaling regulates repair Schwann cell infiltration into the spinal cord after spinal cord injury in mice.

Schwann cells are glial cells that myelinate neuronal axons in the peripheral nervous system (PNS). When the PNS is damaged, Schwann cells de-differentiate into p75-positive "repair Schwann cells," which contribute to neural circuit regeneration. Interestingly, Schwann cells in the dorsal roots are known to be reprogrammed to repair Schwann cells even after spinal cord injury (SCI) and then migrate into the injured spinal cord. However, the molecular mechanism underlying the migration of repair Schwann cells remains unknown. Since a recent in vitro study revealed the importance of CXCR4 signaling in Schwann cell migration, we investigated whether CXCR4 signaling is involved in the PNS-to-central nervous system (CNS) migration of repair Schwann cells after SCI. We revealed that repair Schwann cells express CXCR4, and its ligand CXCL12 is upregulated in the injured spinal cord. We also found that the pharmacological inhibition of CXCR4 signaling decreased the infiltration of repair Schwann cells. Moreover, CXCR4 agonist administration effectively increased the infiltration of repair Schwann cells along with improved motor function. These findings strongly suggest the involvement of CXCR4 signaling in the PNS-to-CNS migration of repair Schwann cells after SCI.

A novel aquaporin-4-associated optic neuritis rat model with severe pathological and functional manifestations.

BACKGROUND: Optic neuritis (ON) is a common manifestation of aquaporin-4 (AQP4) antibody seropositive neuromyelitis optica (NMO). The extent of tissue damage is frequently severe, often leading to loss of visual function, and there is no curative treatment for this condition. To develop a novel therapeutic strategy, elucidating the underlying pathological mechanism using a clinically relevant experimental ON model is necessary. However, previous ON animal models have only resulted in mild lesions with limited functional impairment. In the present study, we attempted to establish a feasible ON model with severe pathological and functional manifestations using a high-affinity anti-AQP4 antibody. Subsequently, we aimed to address whether our model is suitable for potential drug evaluation by testing the effect of minocycline, a well-known microglia/macrophage inhibitor. METHODS: AQP4-immunoglobulin G (IgG)-related ON in rats was induced by direct injection of a high-affinity anti-AQP4 monoclonal antibody, E5415A. Thereafter, the pathological and functional characterizations were performed, and the therapeutic potential of minocycline was investigated. RESULTS: We established an experimental ON model that reproduces the histological characteristics of ON in seropositive NMO, such as loss of AQP4/glial fibrillary acidic protein immunoreactivity, immune cell infiltration, and extensive axonal damage. We also observed that our rat model exhibited severe visual dysfunction. The histological analysis showed prominent accumulation of macrophages/activated microglia in the lesion site in the acute phase. Thus, we investigated the possible effect of the pharmacological inhibition of macrophages/microglia activation by minocycline and revealed that it effectively ameliorated axonal damage and functional outcome. CONCLUSIONS: We established an AQP4-IgG-induced ON rat model with severe functional impairments that reproduce the histological characteristics of patients with NMO. Using this model, we revealed that minocycline treatment ameliorates functional and pathological outcomes, highlighting the usefulness of our model for evaluating potential therapeutic drugs for ON in NMO.

Clinico-pathological characteristics of patients with stage IB1-IB2 (FIGO 2018) uterine cervical cancer: a nationwide study in Japan.

OBJECTIVE: The aim of this retrospective analysis is to reveal clinicopathological findings and clinical outcome of patients with stage IB1/IB2 (FIGO 2018) uterine cervical cancer. METHODS: Based on the database of the Japanese Gynecologic Oncology Group, 2194 patients with stage IB1/IB2 (FIGO 2018), who underwent radical hysterectomy between 1/1/2004-12/31/2008, were identified as eligible for this retrospective study. RESULTS: Patients with squamous cell carcinoma had significantly frequent lympho-vascular space invasion than those with non-squamous cell carcinoma in both stage IB1 and IB2 (stage IB1; 29.1% vs. 17.1%, p < 0.0001, stage IB2; 50.5% vs. 39.7%, p = 0.0009). Among 1262 patients with stage IB1, 61.2% (772/1262) were low-risk group, 29.4% (371/1262) were intermediate-risk group (single risk: 23.3%, double risks: 6.1%). Of 932 patients with stage IB2, 32.1% (299/932) were low-risk group, 59.1% (551/932) were intermediate-risk group (single intermediate-risk: 31.0%, double intermediate-risk: 28.1%). Disease-free survival rate and overall survival rate of stage IB1 patients were significantly better than those with stage IB2 (5-year DFS; 94.7% vs. 88.6%, p < 0.001, 5-yrs OS; 98.5% vs. 95.1%, p < 0.001). Stage IB1 Patients with double intermediate-risk showed significantly worse survival than those with single intermediate-risk (5-yrs DFS: 96.1% vs. 84.6%, p < 0.001, 5-yrs OS: 98.9% vs. 93.0%, p = 0.029). Multivariate analysis revealed that double intermediate-risk was the independent prognostic factor in stage IB1, but non-squamous cell carcinoma and intermediate-risk in stage IB2. CONCLUSION: Non-squamous cell carcinoma and intermediate-risk decreased survival in patients with stage IB2, whereas double intermediate-risk was a negative impact on survival in stage IB1.

Stage III disease of ovarian, tubal and peritoneal cancers can be accurately diagnosed with pre-operative CT. Japan Clinical Oncology Group Study JCOG0602.

PURPOSE: Computed tomography of the abdomen and pelvis is a useful imaging modality for identifying origin and extent of ovarian cancer before primary debulking surgery. However, the International Federation of Gynecology and Obstetrics staging for ovarian cancer is determined based on surgico-pathological findings. The purpose of this study is to determine whether computed tomography staging can be the surrogate for surgico-pathological International Federation of Gynecology and Obstetrics staging in advanced ovarian cancer undergoing neoadjuvant chemotherapy. METHODS: Computed tomography staging was compared with surgico-pathological International Federation of Gynecology and Obstetrics staging in primary debulking surgery arm patients in a randomized controlled trial comparing primary debulking surgery and neoadjuvant chemotherapy (JCOG0602). The cancer of primary debulking surgery arm was identically diagnosed regarding the origin and extent with the cancer of neoadjuvant chemotherapy arm before accrual, using imaging studies (computed tomography and/or magnetic resonance imaging), cytological examination (ascites, pleural effusion or tumor contents fluid) and tumor marker (CA125 > 200 U/mL and CEA < 20 ng/mL). Institutional computed tomography staging was also compared with computed tomography staging by central review. RESULTS: Among 149 primary debulking surgery arm patients, 147 patients who underwent primary debulking surgery immediately were analyzed. Positive predictive values and sensitivity of computed tomography staging for surgical stage III disease (extra-pelvic peritoneal disease and/or retroperitoneal lymph node metastasis) were 99%. Meanwhile, positive predictive values for the presence of small (≤2 cm) extra-pelvic peritoneal disease were low; <20% in omentum. Accuracy of institutional computed tomography staging was comparable with computed tomography staging by central review. CONCLUSIONS: Preoperative computed tomography staging in each institution can be the surrogate for surgico-pathological diagnosis in stage III disease of ovarian cancer patients undergoing neoadjuvant chemotherapy without diagnostic surgery, but reliability of diagnosis of stage IIIB disease is inadequate.Clinical trial registration: UMIN000000523(UMIN-CTR).

Netrin-G1 Regulates Microglial Accumulation along Axons and Supports the Survival of Layer V Neurons in the Postnatal Mouse Brain.

Microglia, the resident immune cells of the central nervous system, accumulate along subcerebral projection axons and support neuronal survival during the early postnatal period. It remains unknown how microglia follow an axon-specific distribution pattern to maintain neural circuits. Here, we investigated the mechanisms of microglial accumulation along subcerebral projection axons that were necessary for microglial accumulation in the internal capsule. Screening of molecules involved in this accumulation of microglia to axons of layer V cortical neurons identified netrin-G1, a member of the netrin family of axon guidance molecules with a glycosyl-phosphatidylinositol anchor. Deletion or knockdown of the netrin-G1 gene Ntng1 reduced microglial accumulation and caused loss of cortical neurons. Netrin-G1 ligand-Ngl1 knockout-mice-derived microglia showed reduced accumulation along the axons compared with wild-type microglia. Thus, microglia accumulate around the subcerebral projection axons via NGL1-netrin-G1 signaling and support neuronal survival. Our observations unveil bidirectional neurotrophic interactions between neurons and microglia.

Comparison of survival between primary debulking surgery and neoadjuvant chemotherapy for stage III/IV ovarian, tubal and peritoneal cancers in phase III randomised trial.

BACKGROUND: Regarding the comparison between primary debulking surgery (PDS) and neoadjuvant chemotherapy (NACT) for stage III/IV ovarian, tubal and peritoneal cancers, EORTC55971 and CHORUS studies demonstrated noninferiority of NACT. Previously, we reported reduced invasiveness of NACT in JCOG0602. This is a final analysis including the primary endpoint of overall survival (OS). METHODS: Patients were randomised to PDS (PDS followed by 8x paclitaxel and carboplatin, i.e. TC regimen) or NACT (4x TC, interval debulking surgery [IDS], 4x TC). The primary endpoint was OS. The noninferiority hazard ratio (HR) margin for NACT compared with PDS was 1·161. The planned sample size was 300. FINDINGS: Between 2006 and 2011, 301 patients were randomised, 149 to PDS and 152 to NACT. The median OS was 49·0 and 44·3 months in the PDS and NACT. HR for NACT was 1·052 [90·8% confidence interval (CI) 0·835-1·326], and one-sided noninferiority p-value was 0·24. Median progression-free survival was 15·1 and 16·4 months in the PDS and NACT (HR: 0·96 [95%CI 0·75-1·23]). In the PDS arm, 147/149 underwent PDS and 49/147 underwent IDS. In the NACT arm 130/152 underwent IDS. Complete resection was achieved in 12% (17/147) of PDS and 31% (45/147) of PDS ± IDS in the PDS arm and in 64% (83/130) of IDS in the NACT arm. Optimal surgery (residual tumour <1 cm) was achieved in 37% (55/147), 63% (92/147), and 82% (107/130 respectively. In the NACT, PS 2/3, serum albumin ≤2·5, CA125 > 2000 an institution with low study activity was advantageous, whereas clear/mucinous histology was disadvantageous for OS. INTERPRETATION: The noninferiority of NACT was not confirmed. NACT may not always be a substitute for PDS. However, as our study had smaller numbers, the noninferiority of the previous studies cannot be denied. FUNDING: Ministry of Health, Labour and Welfare, Japan and the National Cancer Center, Japan. CLINICAL TRIAL INFORMATION: UMIN000000523.

Clinical status and prognostic factors in Japanese patients with uterine leiomyosarcoma.

OBJECTIVE: Uterine leiomyosarcoma (uLMS) is a rare gynecologic malignancy for which the currently available treatments do not consistently provide long-term disease control. This study aimed to reveal the current clinical status of uLMS to support future clinical trials. METHODS: This study enrolled patients with uLMS treated at 53 Japanese institutions from 2000 to 2012. Central pathological review (CPR) was performed. All cases were confirmed by CPR, and epidemiological features, treatment, and prognosis were analyzed statistically. RESULTS: A total of 307 patients were enrolled. A diagnosis of uLMS was confirmed in 266 patients (86.6%) of patients after CPR, of whom data for 259 were analyzed. Of these, 186 (71.8%) patients underwent complete gross resection as primary therapy. Ninety-eight patients received no additional adjuvant therapy, while docetaxel and gemcitabine was the most frequent regimen among 155 patients treated with adjuvant chemotherapy. In all cases, the median overall survival (OS) was 44.2 months. Multivariate analyses of prognostic factors in all cases identified stage III and IV disease, high serum lactate dehydrogenase level, and menopausal status as poor prognostic factors. However, in stage I cases, high serum lactate dehydrogenase level and no adjuvant treatment were identified as poor prognostic factors. The 5-year OS of patients with stage I uLMS treated with adjuvant chemotherapy was significantly better than that of those without adjuvant treatment (67.8% vs 46.7%, P = 0.0461). CONCLUSIONS: Despite complete removal of the primary lesion, the clinical course of patients with uLMS was poor due to recurrence of distant metastasis. The application of a suitable biomarker and effective adjuvant chemotherapy are required to improve the prognosis of patients with uLMS.

Analysis of the relapse patterns and risk factors of endometrial cancer following postoperative adjuvant chemotherapy in a phase III randomized clinical trial.

OBJECTIVE: This study was to analyze patterns and risk factors of relapse after postoperative adjuvant chemotherapy for endometrial cancer. METHODS: Among patients enrolled in a randomized phase III trial (JGOG2043) investigating the efficacy of adjuvant chemotherapy for endometrial cancer at a high risk of progression, the recurrent patients were studied. Clinical information were collected, and correlation between relapse-related factors and clinicopathological factors were analyzed. RESULTS: Among 193 patients analyzed, 50% had local relapse and 63% had distant relapse. Local relapse involved regional lymph nodes in 30%, while distant relapse involved the abdominal cavity in 42%. Imaging was used to confirm relapse in 83%, and the median disease-free interval (DFI) was 11.5 months. Factors showing a significant correlation with DFI ≤12 months were residual tumor at surgery (p < 0.01), Grade 3 histology (p < 0.01), and lymph node metastasis (p = 0.03). In contrast, treatment with paclitaxel and carboplatin showed a significant correlation with DFI >12 months (p = 0.04). The median post-relapse overall survival (RS) was 23.9 months. In multivariate analysis, CA125 ≥ 100 U/mL prior to relapse (p < 0.01), distant metastasis (p < 0.01), DFI ≤ 12 months (p = 0.02), and not performing para-aortic lymphadenectomy (p = 0.01) were independently related to poor RS. CONCLUSIONS: Relapse of endometrial cancer following adjuvant chemotherapy often occurs by 1 year after treatment, with common relapse sites of the abdominal cavity and regional lymph nodes. Among treatment-related factors, RS was correlated with DFI and para-aortic lymphadenectomy.

The usefulness of bevacizumab for relief from symptomatic malignant ascites in patients with heavily treated recurrent ovarian cancer.

AIM: Accumulation of ascites fluid is a major obstacle in the late phase of epithelial ovarian cancer. However, there is no consensus on a specific treatment for malignant ascites. The present study evaluated the clinical benefit of half-dose bevacizumab therapy (7.5 mg/kg every 3-4 weeks). METHODS: This was a single-arm interventional study performed at Aichi Cancer Center Hospital. Four patients with platinum-resistant epithelial ovarian cancer and symptomatic malignant ascites were no longer considered candidates for standard chemotherapy. As a palliative approach, half-dose bevacizumab therapy (7.5 mg/kg every 3-4 weeks) was used with informed consent. The clinical data of these patients were retrospectively reviewed. RESULTS: All patients had been heavily pretreated and showed progressive disease. Thus, standard chemotherapy was no longer feasible, and palliative paracentesis for malignant ascites was clinically needed. Among the four patients, three did not require additional paracentesis after bevacizumab therapy, and there were no adverse events. One patient needed paracentesis owing to lymphorrhea. CONCLUSION: The use of bevacizumab therapy as a palliative approach for malignant ascites might be an option in patients with terminal-stage ovarian cancer. However, further evaluation is needed with regard to the possibility of severe side effects and medical expenses.

Anti-repulsive guidance molecule-a antibody treatment and repetitive transcranial magnetic stimulation have synergistic effects on motor recovery after spinal cord injury.

Damaged axons in the adult central nervous system (CNS) fail to regenerate spontaneously due to several intrinsic and extrinsic factors that inhibit axon elongation. An extrinsic inhibitory factor, repulsive guidance molecule-a (RGMa), is upregulated around spinal cord lesion sites. Inhibition of RGMa using an antibody promotes axon sprouting, regeneration, and motor recovery after spinal cord injury (SCI) in rodents and primates. Repetitive transcranial magnetic stimulation (rTMS) has been used as a form of rehabilitation, and accumulating studies have suggested that rTMS is able to modulate neural plasticity of the cortex. Here, we conducted rTMS with anti-RGMa antibody treatment in mice with SCI to investigate the potential synergistic effects on motor recovery. Although mice treated with anti-RGMa antibody and rTMS concomitantly did not show significant motor recovery, mice treated sequentially with anti-RGMa antibody followed by rTMS showed better motor performance than mice treated with anti-RGMa antibody alone. Moreover, we found that Ca2+/calmodulin-dependent kinase II (CaMKII) was upregulated in mice treated with anti-RGMa antibody and rTMS sequentially compared with mice received a single anti-RGMa antibody treatment. These results suggest that anti-RGMa antibody treatment and rTMS intervention have synergistic effects on motor recovery, and that the timing of rTMS intervention is a critical factor to maximize the effect of anti-RGMa antibody treatment. These interventions may provide new therapeutic strategies for promoting motor recovery after SCI.

Association of Radical Hysterectomy Surgical Volume and Survival for Early-Stage Cervical Cancer.

OBJECTIVE: To examine the association between surgical volume and survival of women with early-stage cervical cancer who underwent radical hysterectomy. METHODS: This is a nationwide multicenter retrospective study examining consecutive women with clinical stage IB1-IIB cervical cancer who underwent radical hysterectomy and pelvic lymphadenectomy from 2004 to 2008 (N=5,964). The surgical volume per site over the 5-year period was defined as low-volume (fewer than 32 surgeries, 46 [39.7%] institutions, n=649 [10.9%]), mid-volume (32-104 surgeries, 60 [51.7%] institutions, n=3,662 [61.4%]), and high-volume (105 surgeries or more, 10 [8.6%] institutions, n=1,653 [27.7%]). Surgical volume-specific survival was examined with multivariable analysis and propensity score matching. RESULTS: The median number of surgeries per site was 44 (interquartile range, 17-65). The 5-year disease-free survival rates among stage IB1-IIB disease were 77.2%, 79.9%, and 84.5% for low-, mid-, and high-volume groups, respectively. On multivariable analysis, women in high-volume centers had a decreased risk of recurrence (adjusted hazard ratio [HR] 0.69, 95% CI 0.58-0.82, P<.001) and all-cause mortality (adjusted HR 0.73, 95% CI 0.59-0.90, P=.003) compared with those in mid-volume centers. Specifically, women in high-volume centers had a decreased risk of local recurrence (adjusted HR 0.62, 95% CI 0.49-0.78, P<.001) but not distant recurrence (adjusted HR 0.85, 95% CI 0.67-1.06, P=.142) compared with those in mid-volume centers. Among 1,700 women with clinical stage IB1 disease treated with surgery alone, surgery at high-volume centers was associated with a decreased risk of recurrence (adjusted HR 0.45, 95% CI 0.25-0.79, P=.006) and all-cause mortality (adjusted HR 0.29, 95% CI 0.11-0.76, P=.013) compared with surgery at mid-volume centers on multivariable analysis. After propensity score matching, surgery at high-volume centers remained an independent prognostic factor for decreased recurrence (adjusted HR 0.69, 95% CI 0.57-0.84, P<.001) and all-cause mortality (adjusted HR 0.75, 95% CI 0.59-0.95, P=.016) compared with surgery at mid- and low-volume centers on multivariable analysis. CONCLUSION: Hospital volume for radical hysterectomy may be a prognostic factor for early-stage cervical cancer. Surgery at high-volume centers is associated with decreased local recurrence risk and improved survival.

Evaluation of objective nutritional indexes as predictors of one-year outcomes after transcatheter aortic valve implantation.

BACKGROUND: Objective nutritional indexes have been shown to predict prognoses in some clinical settings. We aimed to investigate the prognostic values of these indexes in patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: We retrospectively analyzed 95 consecutive patients who underwent TAVI at our institution from December 2013 to February 2017. As objective nutritional indexes, a controlling nutritional status (CONUT) score, prognostic nutritional index (PNI), and geriatric nutritional risk index (GNRI) were calculated at baseline. The optimal cut-off values were determined using receiver operating characteristic curve analysis. According to the cut-off values, we investigated the association of these indexes with 1-year clinical outcomes including all-cause mortality and re-hospitalization due to heart failure. RESULTS: In the Kaplan-Meier analysis, patients with a higher CONUT score and lower PNI had significantly higher incidence rates of 1-year mortality (26.9% vs. 2.9%; p<0.001, 17.4% vs. 2.0%; p=0.011, respectively) and composite outcome of mortality and re-hospitalization due to heart failure (38.5% vs. 13.0%; p=0.006, 39.3% vs. 11.9%; p=0.002, respectively). On Cox hazard analysis, CONUT score and PNI were significantly associated with 1-year mortality [hazard ratio (HR): 1.91; 95% confidence interval (CI): 1.27-2.88; p=0.002, HR: 0.86; 95% CI: 0.75-0.99; p=0.031, respectively] and the composite outcome (HR: 1.49; 95% CI: 1.11-2.00; p=0.007, HR: 0.88; 95% CI: 0.80-0.97; p=0.011, respectively). CONCLUSIONS: The CONUT score and PNI are associated with 1-year clinical outcomes especially with 1-year all-cause mortality in patients undergoing TAVI. Moreover, the CONUT score and PNI might have better predictive values than GNRI.

Effect of Taxane Plus Platinum Regimens vs Doxorubicin Plus Cisplatin as Adjuvant Chemotherapy for Endometrial Cancer at a High Risk of Progression: A Randomized Clinical Trial.

IMPORTANCE: The efficacy of taxane plus platinum regimens has been demonstrated for advanced or recurrent endometrial cancer; however, it has not been assessed in postoperative adjuvant chemotherapy for endometrial cancer. OBJECTIVE: To evaluate the clinical benefit of taxane plus platinum compared with standard doxorubicin plus cisplatin as postoperative adjuvant chemotherapy in endometrial cancer. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter, open-label, phase 3 randomized clinical trial, patients with endometrial cancer at high-risk stage I or II or stage III or IV that did not extend beyond the abdominal cavity and had 2 cm or greater residual tumor were included from 118 institutions in Japan from November 24, 2006, to January 7, 2011. Data was analyzed from March 15, 2017, to June 30, 2017. INTERVENTIONS: Eligible patients were randomly assigned (1:1:1) to receive 6 cycles of doxorubicin, 60 mg/m2, plus cisplatin, 50 mg/m2, on day 1; docetaxel, 70 mg/m2, plus cisplatin, 60 mg/m2, on day 1; or paclitaxel, 180 mg/m2, plus carboplatin (area under the curve, 6.0 mg/mL × min) on day 1 every 3 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival. Secondary end points were overall survival, occurrence of adverse events, tolerability, and status of lymph node dissection. RESULTS: Among 788 eligible patients, the median (SD) age was 59 (22-74) years; 263 patients were assigned to doxorubicin plus cisplatin treatment, 263 patients to docetaxel plus cisplatin treatment, and 262 patients to paclitaxel plus carboplatin treatment. The number of patients who did not complete 6 cycles was 53 (20.1%) for the doxorubicin plus cisplatin group, 45 (17.1%) for the docetaxel plus cisplatin group, and 63 (24.0%) for the paclitaxel plus carboplatin group. Tolerability of these regimens were not statistically different. After a median follow-up period of 7 years, there was no statistical difference of progression-free survival (doxorubicin plus cisplatin, 191; docetaxel plus cisplatin, 208; paclitaxel plus carboplatin, 187; P = .12) or overall survival (doxorubicin plus cisplatin, 217; docetaxel plus cisplatin, 223; paclitaxel plus carboplatin, 215; P = .67) among the 3 groups. The 5-year progression-free survival rate was 73.3% for the doxorubicin plus cisplatin group, 79.0% for the docetaxel plus cisplatin group, and 73.9% for the paclitaxel plus carboplatin group, while the 5-year overall survival rates were 82.7%, 88.1%, and 86.1%, respectively. CONCLUSIONS AND RELEVANCE: There was no significant difference of survival among patients receiving doxorubicin plus cisplatin, docetaxel plus cisplatin, or paclitaxel plus carboplatin as postoperative adjuvant chemotherapy for endometrial cancer. Because each regimen showed adequate tolerability but different toxic effects, taxane plus platinum regimens may be a reasonable alternative to treatment with doxorubicin plus cisplatin. TRIAL REGISTRATION: UMIN-CTR identifier: UMIN000000522.

Neuropilin-1-mediated pruning of corticospinal tract fibers is required for motor recovery after spinal cord injury.

Following incomplete spinal cord injury (SCI), reorganization of the corticospinal tract (CST) contributes to spontaneous motor recovery. Axotomized CST fibers form collaterals and make synapses with interneurons, followed by pruning of excess fibers. Although axonal pruning is involved in refinement of neural circuits, its molecular mechanisms and functional roles remain poorly understood. To address these questions, we performed dorsal hemisections of mouse thoracic spinal cord. We observed that Neuropilin-1 (Nrp1) mRNA was upregulated in layer 5 pyramidal neurons in the motor cortex 14 days after SCI, when the pruning occurred. Nrp1 knockdown using adeno-associated virus (AAV) vector encoding Nrp1 shRNA in the hindlimb motor area impaired the pruning of collaterals after SCI. Nrp1 knockout by injecting AAV vector encoding Cre recombinase into Nrp1 floxed mice also suppressed axonal pruning. Propriospinal neurons, interneurons that connect CST and motoneurons, expressed Semaphorin 3A (Sema3A), the ligand of Nrp1. Furthermore, the genetic deletion of Nrp1 specifically in the hindlimb motor area suppressed the recovery of skilled movement at 21 and 28 days after SCI. The present findings demonstrate that the pruning of collaterals mediated by Nrp1 is required for motor recovery after SCI, and suggest that refinement of the neuronal network facilitates motor recovery.