In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates.

Gene-editing technologies, which include the CRISPR-Cas nucleases1-3 and CRISPR base editors4,5, have the potential to permanently modify disease-causing genes in patients6. The demonstration of durable editing in target organs of nonhuman primates is a key step before in vivo administration of gene editors to patients in clinical trials. Here we demonstrate that CRISPR base editors that are delivered in vivo using lipid nanoparticles can efficiently and precisely modify disease-related genes in living cynomolgus monkeys (Macaca fascicularis). We observed a near-complete knockdown of PCSK9 in the liver after a single infusion of lipid nanoparticles, with concomitant reductions in blood levels of PCSK9 and low-density lipoprotein cholesterol of approximately 90% and about 60%, respectively; all of these changes remained stable for at least 8 months after a single-dose treatment. In addition to supporting a 'once-and-done' approach to the reduction of low-density lipoprotein cholesterol and the treatment of atherosclerotic cardiovascular disease (the leading cause of death worldwide7), our results provide a proof-of-concept for how CRISPR base editors can be productively applied to make precise single-nucleotide changes in therapeutic target genes in the liver, and potentially in other organs.

Impact of lymphadenectomy in patients with locally recurrent or persistent cervical cancer treated with salvage hysterectomy.

AIM: To investigate the role of lymphadenectomy (LND) in locally recurrent or persistent cervical cancer patients treated with salvage hysterectomy. METHODS: Locally recurrent or persistent cervical cancer patients treated with salvage hysterectomy, with or without LND, were identified. Patients were divided into two groups according to the status of radiologic evidence of lymph node metastasis, and the impact of LND was investigated by evaluating postoperative survival. RESULTS: This study included 72 patients; 48 did not show radiological evidence of lymph node metastasis (Group 1) while 24 did (Group 2). Overall, the addition of LND to salvage hysterectomy resulted in increased postoperative complications. In Group 1, salvage hysterectomy plus LND resulted in the identification of five cases with false-negative lymph nodes (19.2%), but showed no advantage over salvage hysterectomy alone in terms of postoperative survival. In Group 2, all patients underwent LND, which resulted in the identification of eight cases with false-positive nodes (33.3%), and reasonably long postoperative survival. The estimated 3-year postoperative survival rate in this group was 39.7%. CONCLUSION: Including LND in salvage hysterectomy allows for precise lymph node staging but increases risk of postoperative complications. However, considering the inability to improve survival, LND should not be performed during salvage hysterectomy in patients without radiological evidence of lymph node metastasis. In patients with radiological evidence of lymph node metastasis, salvage hysterectomy plus LND can only be performed in those who understand the risk of postoperative complications and the limited evidence supporting its survival advantage.

[Safety and Efficacy of Robot-Assisted Surgery for Early Uterine Cancer in Our Institution over Five Years Since Its Introduction].

Lacking experience of laparoscopic surgery against gynecologic malignancies, we started performing robot-assisted surgery for uterine cancer in September 2017. Here we compared the safety and efficacy of robot-assisted surgery with those of open surgery in early-stage uterine cancer patients. The surgical time was significantly longer and the blood loss and hospital stay were significantly shorter for robot-assisted versus open surgery. No recurrence was observed after robot-assisted surgery. Robot-assisted surgery can be safely performed even in general hospitals and is an effective treatment option for early-stage uterine cancer patients.

Significance of Pretreatment C-Reactive Protein, Albumin, and C-Reactive Protein to Albumin Ratio in Predicting Poor Prognosis in Epithelial Ovarian Cancer Patients.

To investigate the prognostic significance of pretreatment C-reactive protein (CRP), albumin, and the CRP to albumin ratio (CRP/Alb) in epithelial ovarian cancer (EOC) patients. Clinical data from 308 EOC patients between April 2007 and March 2016 were collected and retrospectively reviewed. The cutoff values for CRP, albumin, and CRP/Alb were defined by receiver operating characteristics (ROC) analyses. Univariate or multivariate analysis was conducted to evaluate the prognostic significance of these factors for disease-specific survival. The cutoff values for CRP, albumin, and CRP/Alb were 0.76, 3.8, and 0.048 by ROC analysis, respectively. Cox regression analyses demonstrated that an elevated CRP/Alb is an independent predictor of short disease-specific survival irrespective of clinical stage or optimal surgery rate. When examined according to clinical stage, elevated CRP/Alb was associated with short disease-specific survival in both early-stage and advanced-stage patients. Cox regression analyses demonstrated that an elevated CRP, but not lower albumin, is also an independent predictor of short disease-specific survival. When two prognosticators were compared, CRP/Alb was found to be superior to CRP for predicting disease-specific survival in EOC patients. Pretreatment elevated CRP/Alb is a predictor of shorter survival in EOC patients regardless of clinical stage.

The role of myeloid-derived suppressor cells in increasing cancer stem-like cells and promoting PD-L1 expression in epithelial ovarian cancer.

The aim of this study was to investigate the role of myeloid-derived suppressor cells (MDSC) in the induction of cancer stem-like cells (CSC) and programmed death ligand 1 (PD-L1) expression in ovarian cancer. CSC were defined as tumor cells expressing high levels of aldehyde dehydrogenase 1 (ALDH 1). We inoculated G-CSF-expressing or Mock-expressing ovarian cancer cells into mice, and the frequencies of MDSC and CSC in tumors of these models were compared by flow cytometry. To directly demonstrate the role of MDSC in the induction of CSC and the increase in PD-L1 expression, we performed in vitro co-culture. MDSC and CSC (ALDH-high cells) were more frequently observed in G-CSF-expressing cell-derived tumors than in Mock-expressing cell-derived tumors. Co-culture experiments revealed that MDSC increased the number of CSC via the production of PGE2. Moreover, PGE2 produced by MDSC increased tumor PD-L1 expression via the mammalian target of rapamycin (mTOR) pathway in ovarian cancer cells. In an in vitro experiment in which ovarian cancer cells were co-cultured with MDSC, higher expression of PD-L1 was observed in CSC than in non-CSC (ALDH-low cells). Furthermore, by immunofluorescence staining, we found that PD-L1 was co-expressed with ALDH1 in in vivo mouse models. In conclusion, PGE2 produced by MDSC increases the stem cell-like properties and tumor PD-L1 expression in epithelial ovarian cancer. Depleting MDSC may be therapeutically effective against ovarian cancer by reducing the number of CSC and tumor PD-L1 expression.

Impact of a reduction in follow-up frequency on life expectancy in uterine cervical cancer patients.

BACKGROUND: The appropriate interval of post-treatment follow-up appointments for uterine cervical cancer is unclear. The aim of this study was to investigate the impact of reducing the frequency of post-treatment follow-up examinations on life expectancy and medical expenses in cervical cancer patients. METHODS: Cervical cancer patients who were treated with radiotherapy between 2008 and 2017, underwent a less frequent follow-up program, and subsequently developed recurrent disease were included in consecutive group (CG). Non-randomized groups of cervical cancer patients who underwent a frequent follow-up program after radiotherapy between 1997 and 2007, and subsequently developed recurrent disease were also identified through a chart review and served as a comparison group (primary group [PG]). Clinical data regarding the primary disease, follow-up, recurrence, and survival were collected. Univariate and multivariate analyses of predictors of survival were performed. RESULTS: A total of 263 recurrent cervical cancer patients (PG: 154, CG: 109) were included in the current study. A reduction in follow-up frequency of up to 40% did not increase the frequency of symptomatic recurrence (PG: vs. CG: 31.2% vs. 35.8%, p = 0.43) or reduce the median overall survival periods of recurrent cervical cancer patients (PG vs. CG: 32 months vs. 36 months, p = 0.15). However, the reduction in the follow-up frequency significantly reduced follow-up costs. CONCLUSION: Reducing the frequency of follow-up by up to 40% did not result in shorter overall survival compared with a conventional follow-up program. The results of this study provide a rationale for future studies investigating the optimal follow-up schedule for patients with cervical cancer.

Aneurysm-type plexiform lesions form in supernumerary arteries in pulmonary arterial hypertension: potential therapeutic implications.

Histological observations in human pulmonary arterial hypertension (PAH) suggest a link between plexiform lesions and pulmonary supernumerary arteries. Pulmonary microvascular endothelial cells are characterized as hyperproliferative and progenitor-like. This study investigates the hypothesis that aneurysm-type plexiform lesions form in pulmonary supernumerary arteries because of their anatomical properties and endothelial characteristics similar to pulmonary microvascular endothelial cells. To induce PAH, rats were injected with Sugen5416, and exposed to hypoxia (10% O2) for 3 days (early stage) or 3 wk (mid-stage), or 3 wk of hypoxia with an additional 10 wk of normoxia (late-stage PAH). We examined morphology of pulmonary vasculature and vascular remodeling in lung serial sections from PAH and normal rats. Aneurysm-type plexiform lesions formed in small side branches of pulmonary arteries with morphological characteristics similar to supernumerary arteries. Over the course of PAH development, the number of Ki67-positive cells increased in small pulmonary arteries, including supernumerary arteries, whereas the number stayed consistently low in large pulmonary arteries. The increase in Ki67-positive cells was delayed in supernumerary arteries compared with small pulmonary arteries. In late-stage PAH, ~90% of small unconventional side branches that were likely to be supernumerary arteries were nearly closed. These results support our hypothesis that supernumerary arteries are the predominant site for aneurysm-type plexiform lesions in Sugen5416/hypoxia/normoxia-exposed PAH rats partly because of the combination of their unique anatomical properties and the hyperproliferative potential of endothelial cells. We propose that the delayed and extensive occlusive lesion formation in supernumerary arteries could be a preventive therapeutic target in patients with PAH.

Lurbinectedin (PM01183), a selective inhibitor of active transcription, effectively eliminates both cancer cells and cancer stem cells in preclinical models of uterine cervical cancer.

Objective The objective of this study was to evaluate the antitumor effects of lurbinectedin on cervical cancer with a special focus on its effects on cancer stem cells (CSCs). Methods Using two cervical cell lines (ME180 and CaSki cells), the antitumor effects of lurbinectedin were assessed in vitro using the MTS assay and colony formation assay. The growth inhibitory effects of paclitaxel and cisplatin were also evaluated as controls. By employing ALDH1 activity as a marker of CSCs, the antitumor effects of lurbinectedin on cervical CSCs and non-CSCs were individually evaluated. Finally, we investigated the mechanisms by which lurbinectedin eliminated cervical CSCs. Results Lurbinectedin had significant antitumor activity toward cervical cancer cells at low nanomolar concentrations in vitro. Mouse xenografts of cervical cancer revealed that lurbinectedin significantly inhibits tumor growth. The growth-inhibitory effect of lurbinectedin was greater than that of cisplatin and paclitaxel. ALDH-high CSCs were observed in both cervical cancer cell lines (4.4% and 2.4% in ME180 and CaSki cells, respectively). Lurbinectedin downregulated stem cell-related gene expression (Oct4, Nanog, and SOX2), inhibited HDAC1 activity, and effectively eliminated ALDH-high CSCs. Conclusions Lurbinectedin is highly effective on uterine cervical cancer because it eliminates CSCs, and lurbinectedin is a promising agent to overcome platinum resistance in cervical cancer.

Pre-treatment prognostic nutritional index is superior to platelet count in predicting disease-specific survival in patients with epithelial ovarian cancer.

OBJECTIVE: Both pre-treatment prognostic nutritional index and platelet count were reported to be independent prognostic factors in epithelial ovarian cancer patients. However, their relationship has not been investigated. The aim of this study was to investigate the association between the pre-treatment prognostic nutritional index and platelet count, and to compare their utility as prognostic indicators for patients with epithelial ovarian cancer. METHODS: Clinical data from epithelial ovarian cancer patients treated between April 2007 and March 2016 were collected and retrospectively reviewed. The association between the pre-treatment prognostic nutritional index and platelet count was evaluated using Spearman's rank correlation coefficient. After determining the cut-off values for the pre-treatment platelet count and prognostic nutritional index for predicting disease-specific survival by time-dependent receiver operating characteristic (ROC) curve analysis, we compared the clinical utility of platelet counts and the prognostic nutritional index. RESULTS: A total of 308 patients were included in the analysis. Median age was 57 (range 16-81) years. The International Federation of Gynecology and Obstetrics (FIGO) clinical stage at initial diagnosis was stage I in 137 patients (44.5%), stage II in 27 patients (8.8%), stage III in 96 patients (31.2%), and stage IV in 48 patients (15.6%). Most patients (37.7%) had serous adenocarcinoma. Of the 295 patients who underwent primary or interval debulking surgery, optimal debulking was performed in 240 patients (77.9%). Decresed pre-treatment prognostic nutritional index was correlated with increased pre-treatment platelet count (p<0.0001), and when compared, the prognostic nutritional index had a significantly greater area under the ROC curve value than the platelet count for predicting disease-specific survival (0.8348 vs 0.6413, p=0.0007). An elevated platelet count was significantly associated with a shorter disease-specific survival in epithelial ovarian cancer patients (p<0.0001). However, when the prognostic nutritional index was adjusted, an elevated platelet count did not provide any prognostic information (lower prognostic nutritional index, p=0.45; higher prognostic nutritional index, p=0.77). CONCLUSIONS: The pre-treatment prognostic nutritional index was superior to the platelet count for predicting disease-specific survival for epithelial ovarian cancer patients. Although pre-treatment thrombocytosis was reported to be an independent poor prognostic factor in epithelial ovarian cancer patients, it generally reflects a lower prognostic nutritional index, and did not provide any prognostic information when the prognostic nutritional index was adjusted.

A phase II study of irinotecan combined with S-1 in patients with advanced or recurrent cervical cancer previously treated with platinum based chemotherapy.

OBJECTIVES: We conducted a phase II study to investigate the efficacy and toxicities of irinotecan plus oral S-1 in patients with advanced or recurrent uterine cervical cancer. METHODS: Patients with advanced or recurrent cervical cancer previously treated with platinum based chemotherapy were enrolled. Irinotecan (150 mg/m2) was administered intravenously over the course of 90 min on day 1, and S-1 (80 mg/m2) was given orally in two divided doses from days 1 to 14 of a 21 day cycle. The primary endpoint of this phase II study was response rate. Secondary endpoints included safety, progression free survival, and overall survival. RESULTS: A total of 19 patients were enrolled and treated. The response rate was 29.4%. Grade 3-4 hematologic toxicities were observed in three patients (15.7%). The only grade 3-4 non-hematologic toxicity observed was grade 3 diarrhea. The median progression free survival and overall survival were 3 months and 9 months, respectively. CONCLUSION: S-1 plus irinotecan in a 3 weekly setting is safe and active in women with advanced or recurrent cervical cancer previously treated with platinum based chemotherapy. Future corroborative clinical studies are warranted.

Radiotherapy for isolated recurrent epithelial ovarian cancer: A single institutional experience.

AIM: To evaluate the efficacy and toxicity of external beam radiotherapy (RT) for isolated recurrent epithelial ovarian cancer (EOC). METHODS: Twenty-four isolated recurrent EOC patients treated with RT at Osaka University Hospital between January 2000 and January 2017 were included in the current study. Data regarding the primary or recurrent diseases, follow-up findings, and efficacy or toxicities of RT were collected and retrospectively analyzed. Survival rates were calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Their median age was 59 years. Most patients had International Federation of Gynecology and Obstetrics stage III-IV diseases at the initial diagnosis. Histologically, serous adenocarcinoma was predominant, followed by clear cell adenocarcinoma. All patients had received at least one regimen of platinum-based chemotherapy; 8 were platinum-sensitive relapse and the others were platinum-resistant. Lymph nodes were the most common sites of recurrence, and the median tumor size was 25.5 mm. The median total dose of RT administered was 54 Gy, with a median daily dose of 2 Gy. RT was well-tolerated, and no patients experienced Grade 3/4 toxicities. The in-field overall response rate was 58.3% (14/24), the median regression rate was -40.2% (range: -100 to 0) and the median survival period after RT was 17 months. The 1-year survival and local progression-free survival rates after RT were 66.7% and 45.8%, respectively. CONCLUSION: RT showed significant antitumor effect against isolated recurrent EOC without causing severe toxicities. Prospective studies with sufficient statistical power are warranted to further evaluate the role of RT in this patient population.

Exosomal miR-99a-5p is elevated in sera of ovarian cancer patients and promotes cancer cell invasion by increasing fibronectin and vitronectin expression in neighboring peritoneal mesothelial cells.

BACKGROUND: microRNAs (miRNAs) stably exist in circulating blood and are encapsulated in extracellular vesicles such as exosomes. The aims of this study were to identify which exosomal miRNAs are highly produced from epithelial ovarian cancer (EOC) cells, to analyze whether serum miRNA can be used to discriminate patients with EOC from healthy volunteers, and to investigate the functional role of exosomal miRNAs in ovarian cancer progression. METHODS: Exosomes were collected from the culture media of serous ovarian cancer cell lines, namely TYK-nu and HeyA8 cells. An exosomal miRNA microarray revealed that several miRNAs including miR-99a-5p were specifically elevated in EOC-derived exosomes. Expression levels of serum miR-99a-5p in 62 patients with EOC, 26 patients with benign ovarian tumors, and 20 healthy volunteers were determined by miRNA quantitative reverse transcription-polymerase chain reaction. To investigate the role of exosomal miR-99a-5p in peritoneal dissemination, neighboring human peritoneal mesothelial cells (HPMCs) were treated with EOC-derived exosomes and then expression levels of miR-99a-5p were examined. Furthermore, mimics of miR-99a-5p were transfected into HPMCs and the effect of miR-99a-5p on cancer invasion was analyzed using a 3D culture model. Proteomic analysis with the tandem mass tag method was performed on HPMCs transfected with miR-99a-5p and then potential target genes of miR-99a-5p were examined. RESULTS: The serum miR-99a-5p levels were significantly increased in patients with EOC, compared with those in benign tumor patients and healthy volunteers (1.7-fold and 2.8-fold, respectively). A receiver operating characteristic curve analysis showed with a cut-off of 1.41 showed sensitivity and specificity of 0.85 and 0.75, respectively, for detecting EOC (area under the curve = 0.88). Serum miR-99a-5p expression levels were significantly decreased after EOC surgeries (1.8 to 1.3, p = 0.002), indicating that miR-99a-5p reflects tumor burden. Treatment with EOC-derived exosomes significantly increased miR-99a-5p expression in HPMCs. HPMCs transfected with miR-99a-5p promoted ovarian cancer invasion and exhibited increased expression levels of fibronectin and vitronectin. CONCLUSIONS: Serum miR-99a-5p is significantly elevated in ovarian cancer patients. Exosomal miR-99a-5p from EOC cells promotes cell invasion by affecting HPMCs through fibronectin and vitronectin upregulation and may serve as a target for inhibiting ovarian cancer progression.

Comparison of clinical utility between neutrophil count and neutrophil-lymphocyte ratio in patients with ovarian cancer: a single institutional experience and a literature review.

OBJECTIVE: We retrospectively investigated the prognostic significance and clinical utility of pretreatment neutrophilia and elevated neutrophil-lymphocyte ratio (NLR) in patients with epithelial ovarian cancer. METHODS: Clinical data were collected from 344 surgically staged ovarian cancer patients between April 2007 and March 2016 and retrospectively reviewed. Neutrophilia and elevated NLR were defined as a neutrophil count ≥ 8,000/µl and an NLR ≥ 4.0, respectively. Univariate or multivariate analysis was conducted to evaluate the association between pretreatment neutrophilia or elevated NLR and clinicopathological characteristics, optimal surgery rate, progression-free survival (PFS) and disease-specific survival (DSS). Finally, we compared the clinical utility between neutrophil count and NLR by receiver operating characteristic (ROC) analysis. RESULTS: Pretreatment neutrophilia and elevated NLR were observed in 24 (7.0%) and 142 (41.3%) patients, respectively. In univariate analysis, both neutrophilia and elevated NLR were found to be associated with short PFS and DSS (p < 0.005). Multivariate analysis showed that neutrophilia and elevated NLR were predictors for shorter survival. In ROC analysis, the NLR tended to have a greater area under the ROC curve (AUC) value than the neutrophil count in predicting recurrence (0.7011 vs 0.6516, p = 0.0546) and had a significantly greater AUC value in predicting DSS (0.7249 vs 0.6379, p = 0.0182). Finally, based on the neutrophil count and NLR, we divided the patients into 3 prognostic groups-high-risk group (elevated NLR with neutrophilia), intermediate-risk group (elevated NLR without neutrophilia), and low-risk group (normal NLR), which allows for individualized and accurate survival estimates. CONCLUSIONS: Pretreatment neutrophilia and elevated NLR are independent poor prognostic factors in epithelial ovarian cancer patients. The NLR was superior to neutrophil count in predicting the survival of epithelial ovarian cancer patients.

The significance of tumor-associated neutrophil density in uterine cervical cancer treated with definitive radiotherapy.

OBJECTIVE: The aim of this study was to investigate the prognostic significance of tumor-associated neutrophil (TAN) density in cervical cancer patients that were treated with definitive radiotherapy. METHODS: The baseline characteristics and outcome data of FIGO stages IB-IVA cervical cancer patients who were treated with definitive radiotherapy between January 1996 and December 2011 were collected. Using biopsy samples obtained at the time of the initial diagnosis, the expression levels of CD66b in the patients' cervical tumors were evaluated by immunohistochemistry. Univariate and multivariate analyses were performed to evaluate the relationships between intratumoral TAN density and various clinicopathological features as well as progression-free survival (PFS) in these patients. RESULTS: The CD66b-positive cells (TAN) were observed in 209 (83.6%) of 250 cervical cancer specimens. The TAN density was significantly associated with shorter PFS. Multivariate analysis identified an increased number of TAN (hazard ratio [HR]: 4.95; 95% confidence interval [CI]: 2.51-10.7; p<0.0001), FIGO stage IVB disease (HR: 2.64; 95% CI: 1.38-5.01; p=0.01), non-squamous cell carcinoma (SCC) histology (HR: 2.50; 95% CI: 1.23-4.64; p=0.01), larger tumors (HR: 1.58; 95% CI: 1.03-2.40; p=0.04), and pelvic lymph node metastasis (HR: 2.24; 95% CI: 1.48-3.38; p=0.0001) as independent prognostic factors for short PFS. CONCLUSION: Intratumoral TAN density is an independent prognostic factor for short PFS in cervical cancer patients treated with definitive radiotherapy.

The Significance of Pretreatment Thrombocytosis and Its Association With Neutrophilia in Patients With Surgically Treated Endometrial Cancer.

OBJECTIVE: The aim of this study was to investigate the prognostic significance of a pretreatment thrombocytosis and its association with neutrophilia in patients with surgically treated endometrial cancer. METHODS: The baseline characteristics and outcome data of 508 patients with surgically treated endometrial cancer between January 2000 and December 2010 were collected and retrospectively reviewed. The patients were separated into 4 groups according to their platelet counts and the neutrophil counts, and the progression-free and overall survival rates of the 4 groups were compared. A Cox proportional hazards regression model was used to explore the independent prognostic factors. RESULTS: Pretreatment thrombocytosis was found to be associated with advanced stage (P = 0.0186), nonendometrioid histology (P = 0.0139), a deeper myometrial invasion (P = 0.0103), lymphovascular space involvement (P = 0.0404), cervical involvement (P = 0.004), positive peritoneal cytology (P = 0.0198), lymph node metastasis (P = 0.0301), and more frequent treatment failure (P = 0.0006). Multivariate analysis demonstrated that an older age (hazard ratio [HR], 2.54; 95% confidence interval [CI], 1.46-4.51; P = 0.0009), advanced clinical stage (HR, 5.27; 95% CI, 2.94-9.86; P < 0.0001), lymphovascular space involvement (HR, 3.37; 95% CI, 1.74-7.07; P = 0.0002), and pretreatment thrombocytosis (HR, 4.99; 95% CI, 2.47-9.39; P < 0.0001) were significant predictors of survival. When examined according to clinical stage, pretreatment thrombocytosis was prognostically significant only in patients with stage III-IV disease. The neutrophil count in patients who display thrombocytosis was significantly greater than that observed in patients without thrombocytosis (median, 6702 vs 4406/µL; P < 0.0001). Moreover, patients who displayed both thrombocytosis and neutrophilia had significantly shorter survival than that in those with either thrombocytosis or neutrophilia alone. CONCLUSIONS: Presence of thrombocytosis at the time of the initial diagnosis is an independent predictor of shorter survival in patients with advanced-stage (stages III-IV) endometrial cancer. Moreover, pretreatment thrombocytosis and concurrent neutrophilia are an independent predictor of shorter survival regardless of clinical stage.

The efficacy of surgical treatment of recurrent or persistent cervical cancer that develops in a previously irradiated field: a monoinstitutional experience.

BACKGROUND: There are no guidelines about the selection of recurrent cervical cancer patients for salvage surgery. METHODS: Patients who developed recurrent or persistent cervical cancer in a previously irradiated field and were subsequently treated with salvage surgery (the surgery group) or palliative care alone (the palliative group) were identified. Patient characteristics, treatment-related complications, and survival were retrospectively compared between the two groups. RESULTS: A total of 79 patients (surgery group, n = 51; palliative group, n = 28) were identified. In the surgery group, no intraoperative complications or treatment-related deaths occurred. Eleven patients (21.6%) experienced severe postoperative complications. After a median follow-up period of 41.5 months, 23 patients (45.1%) had developed recurrent disease, predominantly at distant sites, and 19 patients (37.3%) had died of disease progression. The estimated 3-year progression-free survival (PFS) and overall survival rates of the surgery group were 50.4 and 56.5%, respectively. In the palliative group, all of the patients died of disease progression. Positive surgical margins and lymph node metastasis were found to be independent prognostic factors for PFS in the surgery group. Among the patients with no or one poor prognostic factor, the patients in the surgery group survived significantly longer than those in the palliative group. However, among the patients with 2 poor prognostic factors, the surgery group and palliative group displayed similar survival periods. CONCLUSIONS: Salvage surgery is a curative treatment in recurrent or persistent cervical cancer patients. However, considering its high surgical complication rate, salvage surgery should only be offered to carefully selected patients.

High-Performance Ferrite Nanoparticles through Nonaqueous Redox Phase Tuning.

From magnetic resonance imaging to cancer hyperthermia and wireless control of cell signaling, ferrite nanoparticles produced by thermal decomposition methods are ubiquitous across biomedical applications. While well-established synthetic protocols allow for precise control over the size and shape of the magnetic nanoparticles, structural defects within seemingly single-crystalline materials contribute to variability in the reported magnetic properties. We found that stabilization of metastable wüstite in commonly used hydrocarbon solvents contributed to significant cation disorder, leading to nanoparticles with poor hyperthermic efficiencies and transverse relaxivities. By introducing aromatic ethers that undergo radical decomposition upon thermolysis, the electrochemical potential of the solvent environment was tuned to favor the ferrimagnetic phase. Structural and magnetic characterization identified hallmark features of nearly defect-free ferrite nanoparticles that could not be demonstrated through postsynthesis oxidation with nearly 500% increase in the specific loss powers and transverse relaxivity times compared to similarly sized nanoparticles containing defects. The improved crystallinity of the nanoparticles enabled rapid wireless control of intracellular calcium. Our work demonstrates that redox tuning during solvent thermolysis can generate potent theranostic agents through selective phase control in ferrites and can be extended to other transition metal oxides relevant to memory and electrochemical storage devices.

Prognostic significance of systemic neutrophil and leukocyte alterations in surgically treated endometrial cancer patients: a monoinstitutional study.

OBJECTIVE: The aim of this study was to investigate the prognostic significance of an elevated neutrophil count at the time of the initial diagnosis in patients with surgically treated endometrial cancer. METHODS: The baseline characteristics and outcome data of patients who were diagnosed with endometrial cancer between January 2000 and December 2010 were collected and retrospectively reviewed. The patients were separated into two groups according to their neutrophil counts. The clinicopathological characteristics and overall survival rates of the two groups were compared. A Cox proportional hazard regression model was used to investigate the prognostic significance of an elevated neutrophil count among patients with surgically treated endometrial cancer. RESULTS: An elevated neutrophil count was found to be associated with an advanced clinical stage (P<0.0001), lymphovascular space involvement (P=0.0003), cervical involvement (P=0.0049), the proportion of patients that received adjuvant therapy (P=0.0020), elevated NLR (P<0.0001), and treatment failure (P<0.0001). Multivariate analyses demonstrated that age (hazard ratio (HR)=2.23, 95% confidence interval (95% CI)=1.30 to 3.91; P=0.0035), clinical stage (HR=4.72, 95% CI=2.61 to 8.90; P<0.0001), lymphovascular space involvement (HR=3.15, 95% CI=1.60 to 6.68; P=0.0007), an elevated neutrophil count (HR=2.76, 95% CI=1.43 to 5.03; P=0.0033), and an elevated white blood cell count (HR=2.79, 95% CI=1.50 to 4.96; P=0.0017) were significant predictors of survival. CONCLUSION: The elevated neutrophil or leukocyte counts at the time of the initial diagnosis are independent prognostic factors in patients with surgically treated endometrial cancer.

Prognostic Significance of Pretreatment Thrombocytosis in Cervical Cancer Patients Treated With Definitive Radiotherapy.

OBJECTIVE: The aim of this study was to investigate the prevalence and prognostic significance of an elevated platelet count at the time of the initial diagnosis in patients with cervical cancer who are treated with definitive radiotherapy. METHODS: The baseline characteristics and outcome data of cervical cancer patients who were treated with definitive radiotherapy between November 1993 and December 2011 were collected and retrospectively reviewed. The patients were separated into 2 groups according to their platelet counts. The clinicopathological characteristics and overall survival rates of the 2 groups were compared. A Cox proportional hazards regression model was used to investigate the prognostic significance of an elevated platelet count. RESULTS: An elevated platelet count was found to be associated with younger age (P = 0.0003), an advanced clinical stage (P < 0.0001), larger tumors (P = 0.0025), lower hemoglobin levels (P < 0.0001), and more frequent treatment failure (P = 0.0015). Multivariate analysis demonstrated that an advanced clinical stage (hazards ratio [HR], 2.93; 95% confidence interval [CI], 1.47-6.70; P = 0.0015), nonsquamous cell carcinoma histology (HR, 2.67; 95% CI, 1.52-4.42; P = 0.0011), larger tumors (HR, 3.86; 95% CI, 2.18-7.03; P < 0.0001), lower hemoglobin levels (HR, 1.99; 95% CI, 1.34-2.93; P = 0.0008), and an elevated platelet count (HR, 1.65; 95% CI, 1.03-2.56; P = 0.0395) were significant predictors of survival. CONCLUSIONS: An elevated platelet count at the time of the initial diagnosis is an independent prognostic factor in cervical cancer patients who are treated with definitive radiotherapy.

Temporal hemodynamic and histological progression in Sugen5416/hypoxia/normoxia-exposed pulmonary arterial hypertensive rats.

We have investigated the temporal relationship between the hemodynamic and histological/morphological progression in a rat model of pulmonary arterial hypertension that develops pulmonary arterial lesions morphologically indistinguishable from those in human pulmonary arterial hypertension. Adult male rats were injected with Sugen5416 and exposed to hypoxia for 3 wk followed by a return to normoxia for various additional weeks. At 1, 3, 5, 8, and 13 wk after the Sugen5416 injection, hemodynamic and histological examinations were performed. Right ventricular systolic pressure reached its maximum 5 wk after Sugen5416 injection and plateaued thereafter. Cardiac index decreased at the 3∼5-wk time point, and tended to further decline at later time points. Reflecting these changes, calculated total pulmonary resistance showed a pattern of progressive worsening. Acute intravenous fasudil markedly reduced the elevated pressure and resistance at all time points tested. The percentage of severely occluded small pulmonary arteries showed a similar pattern of progression to that of right ventricular systolic pressure. These small vessels were occluded predominantly with nonplexiform-type neointimal formation except for the 13-wk time point. There was no severe occlusion in larger arteries until the 13-wk time point, when significant numbers of vessels were occluded with plexiform-type neointima. The Sugen5416/hypoxia/normoxia-exposed rat shows a pattern of chronic hemodynamic progression similar to that observed in pulmonary arterial hypertension patients. In addition to vasoconstriction, nonplexiform-type neointimal occlusion of small arteries appears to contribute significantly to the early phase of pulmonary arterial hypertension development, and plexiform-type larger vessel occlusion may play a role in the late deterioration.