Biomarker-driven targeted therapy in patients with recurrent platinum-resistant epithelial ovarian cancer (BRIGHT): protocol for an open-label, multicenter, umbrella study.

BACKGROUND: Platinum-resistant, recurrent ovarian cancer has an abysmal prognosis with limited treatment options. Poly-(ADP-ribose)-polymerase (PARP), angiogenesis, and immune checkpoint inhibitors might improve the outcomes of platinum-resistant, recurrent ovarian cancer, but accurate patient selections for those therapies remain a significant clinical challenge. PRIMARY OBJECTIVE: To evaluate the efficacy and safety of biomarker-driven combinatorial therapies of pamiparib, tislelizumab, bevacizumab, and nab-paclitaxel in platinum-resistant, recurrent ovarian cancer. STUDY HYPOTHESIS: A precision medicine combination of PARP inhibitors, anti-angiogenic therapy, immunotherapy, and chemotherapy will improve disease outcomes of platinum-resistant, recurrent ovarian cancer by accounting for genomic and immunologic features. TRIAL DESIGN: The BRIGHT Trial is a prospective, open-label, multicenter, phase II, umbrella study planning to enroll 160 patients with serous, endometrioid, or clear cell platinum-resistant, recurrent ovarian cancer from 11 clinical centers in China. Patients are assigned to one of three experimental arms based on biomarkers. Patients with BRCA1/2 mutations will receive pamiparib plus bevacizumab (arm 1, n=40) regardless of CD8+ tumor-infiltrating lymphocytes count. Patients with wild-type BRCA1/2 (BRCAwt) and ≥3 CD8+ tumor-infiltrating lymphocytes count will receive the combination of tislelizumab, bevacizumab, and nab-paclitaxel (arm 2, n=50), while BRCAwt patients with <3 CD8+ tumor-infiltrating lymphocytes count will receive bevacizumab plus dose-dense nab-paclitaxel (arm 3, n=50). After completing patient enrollment in arm 2, another 20 BRCAwt patients with ≥3 CD8+ tumor-infiltrating lymphocytes count will be included as an arm 2 expansion. Treatment will continue until disease progression or intolerable toxicity, and all adverse events will be recorded. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients include those aged ≥18 with serous, endometrioid, or clear cell ovarian cancer, platinum-resistant recurrence, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. PRIMARY ENDPOINT: Objective response rate (ORR) assessed by the investigators by the RECIST 1.1 criteria. SAMPLE SIZE: 160 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Recruitment is estimated to be completed by 2024 and results may be published by 2027. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05044871.

Timing of interval debulking surgery and postoperative chemotherapy after neoadjuvant chemotherapy in advanced epithelial ovarian cancer: a multicenter real-world study.

BACKGROUND: To investigate the prognostic relevance of the time to interval debulking surgery (TTS) and the time to postoperative adjuvant chemotherapy (TTC) after the completion of neoadjuvant chemotherapy (NACT). METHODS: A retrospective real-word study included 658 patients with histologically confirmed advanced epithelial ovarian cancer who received NACT at seven tertiary hospitals in China from June 2008 to June 2020. TTS was defined as the time interval from the completion of NACT to the time of interval debulking surgery (IDS). TTC was defined as the time interval from the completion of NACT to the initiation of postoperative adjuvant chemotherapy (PACT). RESULTS: The median TTS and TTC were 25 (IQR, 20-29) and 40 (IQR, 33-49) days, respectively. Patients with TTS > 25 days were older (55 vs. 53 years, P = 0.012) and received more NACT cycles (median, 3 vs. 2, P = 0.002). Similar results were observed in patients with TTC > 40 days. In the multivariate analyses, TTS and TTC were not associated with PFS when stratified by median, quartile, or integrated as continuous variables (all P > 0.05). However, TTS and TTC were significantly associated with worse OS when stratified by median (P = 0.018 and 0.018, respectively), quartile (P = 0.169, 0.014, 0.027 and 0.012, 0.001, 0.033, respectively), or integrated as continuous variables (P = 0.018 and 0.011, respectively). Similarly, increasing TTS and TTC intervals were associated with a higher risk of death (Ptrend = 0.016 and 0.031, respectively) but not with recurrence (Ptrend = 0.103 and 0.381, respectively). CONCLUSION: The delays of IDS and PACT after the completion of NACT have adverse impacts on OS but no impacts on PFS, which indicates that reducing delays of IDS and PACT might ameliorate the outcomes of ovarian cancer patients treated with NACT.

Development and validation of a nomogram to predict cancer-specific survival of mucinous epithelial ovarian cancer after cytoreductive surgery.

BACKGROUND: Mucinous epithelial ovarian cancer (mEOC) is a relatively uncommon subtype of ovarian cancer with special prognostic features, but there is insufficient research in this area. This study aimed to develop a nomogram for the cancer-specific survival (CSS) of mEOC based on Surveillance, Epidemiology, and End Results (SEER) database and externally validate it in National Union of Real World Gynecological Oncology Research and Patient Management (NUWA) platform from China. METHODS: Patients screened from SEER database were allocated into training and internal validation cohort in a ratio of 7: 3, with those from NUWA platform as an external validation cohort. Significant factors selected by Cox proportional hazard regression were applied to establish a nomogram for 3-year and 5-year CSS. The performance of nomogram was assessed by concordance index, calibration curves and Kaplan-Meier (K-M) curves. RESULTS: The training cohort (n = 572) and internal validation cohort (n = 246) were filtered out from SEER database. The external validation cohort contained 186 patients. Baseline age, tumor stage, histopathological grade, lymph node metastasis and residual disease after primary surgery were significant risk factors (p < 0.05) and were included to develop the nomogram. The C-index of nomogram in training, internal validation and external validation cohort were 0.869 (95% confidence interval [CI], 0.838-0.900), 0.839 (95% CI, 0.787-0.891) and 0.800 (95% CI, 0.738-0.862), respectively. The calibration curves of 3-year and 5-year CSS in each cohort showed favorable agreement between prediction and observation. K-M curves of different risk groups displayed great discrimination. CONCLUSION: The discrimination and goodness of fit of the nomogram indicated its satisfactory predictive value for the CSS of mEOC in SEER database and external validation in China, which implies its potential application in different populations.

Does the primary treatment sequence affect post-relapse survival in recurrent epithelial ovarian cancer? A real-world multicentre retrospective study.

OBJECTIVE: To explore the impact of the primary treatment sequence (primary debulking surgery, PDS, versus neoadjuvant chemotherapy and interval debulking surgery, NACT-IDS) on post-relapse survival (PRS) and recurrence characteristics of recurrent epithelial ovarian cancer (REOC). DESIGN: Real-world retrospective study. SETTING: Tertiary hospitals in China. POPULATION: A total of 853 patients with REOC at International Federation of Gynaecology and Obstetrics stages IIIC-IV from September 2007 to June 2020. Overall, 377 and 476 patients received NACT-IDS and PDS, respectively. METHODS: Propensity score-based inverse probability of treatment weighting (IPTW) was performed to balance the between-group differences. MAIN OUTCOME MEASURES: Clinicopathological factors related to PRS. RESULTS: The overall median PRS was 29.3 months (95% CI 27.0-31.5 months). Multivariate analysis before and after IPTW adjustment showed that NACT-IDS and residual R1/R2 disease were independent risk factors for PRS (p < 0.05). Patients with diffuse carcinomatosis and platinum-free interval (PFI) ≤ 12 months had a significantly worse PRS (p < 0.001). Logistic regression analysis revealed that NACT-IDS was an independent risk factor for diffuse carcinomatosis (OR 1.36, 95% CI 1.01-1.82, p = 0.040) and PFI ≤ 12 months (OR 1.59, 95% CI 1.08-2.35, p = 0.019). In IPTW analysis, NACT-IDS was still significantly associated with diffuse carcinomatosis (OR 1.29, 95% CI 1.05-1.58, p = 0.015) and PFI ≤ 12 months (OR 1.90, 95% CI 1.52-2.38, p < 0.001). CONCLUSIONS: The primary treatment sequence may affect the PRS of patients with REOC by altering the recurrence pattern and PFI duration.

The first Chinese National Union of Real-world Gynaecological Oncology Research and Patient Management Platform: A retrospective study.

OBJECTIVE: To produce high-quality, real-world evidence for oncologists by collating scattered gynaecologic oncology (GO) medical records in China. DESIGN: Retrospective study. SETTING: The National Union of Real-world Gynaecological Oncology Research and Patient Management Platform (NUWA platform). SAMPLE: Patient-centred data pool. METHODS: The NUWA platform integrated inpatient/outpatient clinical, gene and follow-up data. Data of 11 456 patients with ovarian cancer (OC) were collected and processed using 91 345 electronic medical records. Structured and unstructured data were de-identified and re-collated into a patient-centred data pool using a predefined GO data model by technology-aided abstraction. MAIN OUTCOME MEASURES: Recent treatment pattern shifts towards precision medicine for OC in China. RESULTS: Thirteen first-tier hospitals across China participated in the NUWA platform up to 7 December 2021. In total, 3504 (30.59%) patients were followed up by a stand-alone patient management centre. The percentage of patients undergoing breast cancer gene (BRCA) mutation tests increased by approximately six-fold between 2017 and 2018. A similar trend was observed in the administration rate of poly(ADP-ribose) polymerase inhibitors as first-line treatment and second-line treatment after September 2018, when olaparib was approved for clinical use in China. CONCLUSION: The NUWA platform has great potential to facilitate clinical studies and support drug development, regulatory reviews and healthcare decision-making.

Fuzuloparib Maintenance Therapy in Patients With Platinum-Sensitive, Recurrent Ovarian Carcinoma (FZOCUS-2): A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Trial.

PURPOSE: This phase III trial aimed to explore the efficacy and safety of fuzuloparib (formerly fluzoparib) versus placebo as a maintenance treatment after response to second- or later-line platinum-based chemotherapy in patients with high-grade, platinum-sensitive, recurrent ovarian cancer. PATIENTS AND METHODS: Patients with platinum-sensitive, recurrent ovarian cancer previously treated with at least two platinum-based regimens were assigned (2:1) to receive fuzuloparib (150 mg, twice daily) or matching placebo for 28-day cycles. The primary end points were progression-free survival (PFS) assessed by blinded independent review committee (BIRC) in the overall population and PFS by BIRC in the subpopulation with germline BRCA 1/2 mutation. RESULTS: Between April 30, 2019, and January 10, 2020, 252 patients were randomly assigned to the fuzuloparib (n = 167) or placebo (n = 85). As of July 1, 2020, the median PFS per BIRC assessment in the overall population was significantly improved with fuzuloparib treatment (hazard ratio [HR], 0.25; 95% CI, 0.17 to 0.36; one-sided P < .0001) compared with that with placebo. The HR derived from a prespecified subgroup analysis showed a consistent trend of benefit in patients with germline BRCA 1/2 mutations (HR, 0.14; 95% CI, 0.07 to 0.28) or in those without mutations (HR, 0.46; 95% CI, 0.29 to 0.74). The most common grade ≥ 3 treatment-emergent adverse events reported in the fuzuloparib group were anemia (25.1%), decreased platelet count (16.8%), and decreased neutrophil count (12.6%). Only one patient (0.6%) discontinued fuzuloparib because of treatment-related toxicity (concurrent decreased white blood cell count and neutrophil count). CONCLUSION: Fuzuloparib as maintenance therapy achieved a statistically significant and clinically meaningful improvement in PFS for patients with platinum-sensitive, recurrent ovarian cancer versus placebo, regardless of germline BRCA 1/2 mutation, and showed a manageable safety profile.

Real-world Experience of Olaparib Treatment in Patients with Ovarian Cancer: A Chinese Multicenter Study.

The objective of this study was to evaluate the real-world application, efficacy, and safety data of olaparib for maintenance therapy and active treatment in patients with ovarian cancer in China. Patients with ovarian cancer from 17 institutions in China treated with olaparib as maintenance or active therapy from January 2018 to March 2020 were included in this study. The medical records were reviewed, and follow-up information was collected for analysis of the patients' clinicopathologic characteristics as well as the effectiveness and safety of olaparib. A total of 251 patients receiving olaparib were included, with 84 as maintenance therapy after first-line chemotherapy (FL-M), 97 as maintenance therapy after platinum-sensitive recurrence (PSR-M), and 70 as active treatment (AT). The probability of progression-free survival (PFS) at 12 months was 87.6% in the FL-M group and 63.8% in the PSR-M group. According to the multivariate analysis, complete response (CR) to chemotherapy for the PSR-M patients was the only factor affecting the PFS (HR = 0.414, P = 0.014), and platinum sensitivity was the only factor affecting PFS improvement in the AT group (HR = 0.317, P = 0.009). In the AT group, the objective response rate was 37.1%, the CR rate was 7.1%, and 30% of the patients had stable disease. Eight (3.2%) patients discontinued olaparib due to toxicity. Anemia was the most common adverse event. In conclusion, olaparib is effective and well tolerated in the real-world setting of ovarian cancer treatment. Platinum sensitivity is positively correlated to the effectiveness of olaparib in both maintenance and active treatment.

Pegylated liposomal doxorubicin in patients with epithelial ovarian cancer.

OBJECTIVE: To evaluate the efficacy and safety of PLD in treating of in patients who experience epithelial ovarian, fallopian tubal, and peritoneal cancer progression within 12 months after the first-line platinum-based therapy. METHODS: This was an open-label, single-arm and multicenter clinical trial. The ORR was the interim primary objective, and the DCR, AEs and QOL were the secondary objectives. The impact of factors on efficacy outcomes, the change trend of CA125 and the artificial platinum-free interval were exploratory endpoints. RESULTS: Totally, 115 patients were enrolled in this study and included in the ITT population. Moreover, 101 patients were included in the safety population. The median follow-up time was 4 months (IQR 2-6). In the ITT population, the confirmed ORR was 37.4% (95% CI, 28.4-46.4%), and the DCR was 65.2% (95% CI, 56.4-74.1%). The previous response status to platinum-based chemotherapy and baseline CA125 levels were significantly correlated with the ORR. The ORR was significantly higher in patients with a CA125 decrease after the first cycle than in the patients with a CA125 increase. The most common grade 3 or higher AE was hand-foot syndrome (3 [3.0%] of 101 patients). No statistically significant differences existed between the baseline and the postbaseline questionnaires. CONCLUSIONS: For patients who experience platinum-resistant and platinum-refractory relapse, the use of PLD may be acceptable because of the associated satisfactory efficacy, low frequency of AEs and high patient QOL. Moreover, a low CA125 level at baseline and a reduction in CA125 after the first cycle are predictive factors for satisfactory efficacy.

Primary anorectal malignant melanoma: a case report.

Anorectal melanoma (ARM) is rare and lethal. We report a case of a 48-year-old woman with 9 months of rectal swelling and bleeding. Physical examination revealed a mass about 5 × 6 cm on the anterior wall of the rectum, 3 cm from the anal verge, and the patient underwent abdominoperineal resection (APR). After hematoxylin-eosin staining and immunohistochemical staining, it was considered an ARM, which is an aggressive disease with a poor survival. Immunohistochemical staining showed the tumor to be positive for S-100, Melan A, Ki67 proliferative index of 70%, and negative for HMB45. The melanoma had infiltrated the adventitia and metastasized to the (intestinal) 16/16 lymph nodes with cancerous nodule formation. There were multiple organs with metastasis (liver, spleen, pancreas, lung and subcutaneous soft tissue) three months after operation. Overall, pre-operative biopsy may be insufficient to make a definite diagnosis, and immunohistochemistry is necessary. Therefore, the gold standard treatment for ARM is oncological radical surgical resection.

BRCA mutation frequency and clinical features of ovarian cancer patients: A report from a Chinese study group.

AIM: Subjects with germline BRCA1/2 mutations (gBRCAm) have an increased risk of developing breast cancer and ovarian cancer. At present, knowledge of BRCA1/2 mutation frequency in Chinese patients with ovarian cancer is still insufficient, and the detailed clinical information of these patients is poorly understood. METHODS: A total of 547 unselected ovarian cancer patients were enrolled, and their gBRCAm status was detected. Clinical characteristics including age, personal and family history, histopathologic diagnosis, carbohydrate antigen 125 (CA-125) level, ascites, Federation International of Gynecology and Obstetrics (FIGO) stage, residual lesions, platinum sensitivity, recurrence interval and survival information were collected. Accurate assessments of disease response were based on the RECIST standard or CA-125 level. RESULTS: In 547 patients with ovarian cancer, we detected 129 (23.6%) patients with pathogenic mutations, 84 patients with BRCA1 mutations (15.4%) and 45 patients with BRCA2 mutations (8.2%). Twenty-five novel mutations were identified, and the mutation of BRCA1, c.5470_5477del8, was the most common mutation in this study. BRCA1/2 mutations were significantly associated with age; personal and family history; FIGO stage; secondary recurrence interval; sensitivity to platinum in 1st, 2nd and 3rd line treatment; and response to doxorubicin liposomes. Patients with BRCA1/2 mutations showed significant advantages in 3- and 5-year survival rates but no advantage in long-term survival. CONCLUSION: BRCA1/2 mutation prevalence in Chinese ovarian cancer patients is higher than the international rate. We recommend BRCA1/2 testing for patients with family histories and personal histories of malignancy and genetic counseling for cancer in healthy people with high-risk family histories.

Radiosensitivity of human ovarian cancer cells is enhanced by pseudolaric acid B due to the inhibition of the Ras/Raf/ERK signaling pathway.

Ovarian cancer has the highest mortality rate among gynecological cancers; the most effective therapy for this cancer is a combination of radiation treatment and chemotherapy. However, radiation resistance is the leading factor associated with treatment failure. The present study aimed to investigate pseudolaric acid B (PAB) as a potential radiosensitizer for the treatment of ovarian cancer. The present study performed MTT and clonogenic assays, and demonstrated that PAB could induce a radiosensitizing effect on SKOV-3 cells. An Annexin V/propidium iodide staining assay revealed that PAB exerted a radiosensitizing effect by inducing SKOV-3 cell apoptosis. In addition, western blot analysis demonstrated that the activity of the Ras/RAF proto-oncogene serine/threonine-protein kinase/extracellular signal-regulated kinase signaling pathway was reduced by combination therapy with PAB and irradiation. In conclusion, the present study establishes PAB as a radiosensitizer, and provides a rational basis for the use of PAB and irradiation as a combination therapy to treat ovarian cancer.

Overexpression of tissue microRNA10b may help predict glioma prognosis.

We investigated the relationship between microRNA-10b (miR-10b) expression and prognosis in human glioma patients. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was used to characterize the expression patterns of miR-10b in 128 glioma and 20 normal brain tissues. Clinical information - age, sex, Karnofsky Performance Status (KPS) and World Health Organization (WHO) grade - were also collected. The associations between miR-10b expression and the clinicopathological factors and outcome of glioma patients were statistically analyzed. Expression levels of miR-10b in glioma tissue were significantly higher than in normal brain tissue (P<0.001). High-grade glioma (WHO grade III and IV) had much higher miR-10b expression levels than low-grade tumors (WHO grade I and II). Additionally, the increased miR-10b expression in the glioma tissues was significantly associated with a low KPS (P=0.03). Kaplan-Meier survival curves and Cox regression analyses showed that overexpression of miR-10b (P=0.01) and high grade (P=0.02) were independent factors predicting poor outcome for glioma patients. Furthermore, subgroup analyses showed that the miR-10b expression level was significantly associated with poor overall survival in glioma patients with high grades (P<0.001). Up-regulation of miR-10b may have value in predicting clinical outcome in glioma patients, particularly for those with high pathological grades.

[Isolation, purification and characterization of endothelial cells from endometrial cancer and normal endometrial tissue].

OBJECTIVE: To immunopurify human endometrial endothelial cells (HEEC) from fresh surgical specimens of endometrial cancers and normal endometrial tissues, and investigate their biological characteristics. METHODS: Endothelial cells of endometrial cancers and normal endometrial tissues were isolated using anti-CD31 conjugated magnetic microbeads. The isolated endothelial cells were cultured in vitro and their origins were identified. Their angiogenic characteristics were observed by MTT, wound healing, Transwell cell invasion and tube formation assays. RESULTS: Flow cytometry revealed that the immunopurification technique yielded endothelial cell purity of > 95% in all samples. All purified HEEC were characterized as endothelial cells on the basis of expression of the classical endothelial markers vWF and CD31 as shown by immunofluorescence examination. Although the tumor-associated HEEC didn't show more rapid proliferation than normal HEEC, they exhibited enhanced migration ability (P = 0.006), potent invasiveness (P = 0.033), and elevated tube formation in vitro (P = 0.029). CONCLUSIONS: Human endometrial endothelial cells can be efficiently isolated from endometrial cancer and normal endometrial tissues by immunomagnetic methods. Tumor-associated HEEC exhibit enhanced migratory ability, potent invasiveness, and elevated tube formation in vitro.

PET/CT scanning guided intensity-modulated radiotherapy in treatment of recurrent ovarian cancer.

OBJECTIVE: This study was undertaken to evaluate the clinical contribution of positron emission tomography using (18)F-fluorodeoxyglucose and integrated computer tomography (FDG-PET/CT) guided intensity-modulated radiotherapy (IMRT) for treatment of recurrent ovarian cancer. MATERIALS AND METHODS: Fifty-eight patients with recurrent ovarian cancer from 2003 to 2008 were retrospectively studied. In these patients, 28 received PET/CT guided IMRT (PET/CT-IMRT group), and 30 received CT guided IMRT (CT-IMRT group). Treatment plans, tumor response, toxicities and survival were evaluated. RESULTS: Changes in GTV delineation were found in 10 (35.7%) patients based on PET-CT information compared with CT data, due to the incorporation of additional lymph node metastases and extension of the metastasis tumor. PET/CT guided IMRT improved tumor response compared to CT-IMRT group (CR: 64.3% vs. 46.7%, P=0.021; PR: 25.0% vs. 13.3%, P=0.036). The 3-year overall survival was significantly higher in the PET-CT/IMRT group than control (34.1% vs. 13.2%, P=0.014). CONCLUSIONS: PET/CT guided IMRT in recurrent ovarian cancer patients improved the delineation of GTV and reduce the likelihood of geographic misses and therefore improve the clinical outcome.

[Angiogenesis related gene expression profiles of human endometrial endothelial cells isolated from tissue of endometrial cancer].

OBJECTIVE: To identify and verify the different genes expression pattern between human endometrial endothelial cells (HEEC) isolated from endometrial cancer and normal endometrium. METHODS: Endothelial cells were isolated from 5 patients with endometrial cancer (endometrial cancer group 1) and 5 patients with normal endometria tissue (control group 1) admitted from June to November 2007 in Shandong Cancer Hospital. Global expression patterns of endothelial cells were examined using oligonucleotide microarrays. Tissues from 36 patients with endometrial cancer (endometrial cancer group 2) and 10 normal endometrial tissues (control group 2) admitted from January 2007 to April 2008 were selected to verify the expression of different genes, in which up-regulated genes including ESM1, MMP-10, SPP1 and HMGB1 were tested by quantitative real-time PCR and immunohistochemistry. RESULTS: Microarray analyses revealed 317 genes that exhibited > 2-fold or < 0.5 differences were identified (including 191 genes up-regulated and 126 down-regulated). Pathway analysis showed that these genes involved cell cycle, cell adhesion molecules, and extracellular matrix-receptor interaction were obviously predominant. Of them, 97 up-regulated genes and 44 down-regulated genes were related to angiogenesis. The mRNA expression of ESM1, MMP-10, SPP1 and HMGB1 in endometrial cancer group 2 were 0.898, 3.890, 1.433 and 1.881, respectively. Positive expression of SPP1, MMP-10, ESM1 and HMGB1 was observed in endometrial cancer group 2. However, the SPP1, ESM1 and HMGB1 was negative expressed in control group 2. CONCLUSION: It shows that there are the different angiogenesis related genes between endometrial cancer and normal endothelium, which will provide insights into the anti-angiogenesis therapy for endometrial cancers.

Intensity-modulated radiation therapy for advanced cervical cancer: a comparison of dosimetric and clinical outcomes with conventional radiotherapy.

OBJECTIVE: The aim of this study is to evaluate the dosimetry, efficacy and toxicity of reduced field intensity-modulated radiation therapy (RF-IMRT) for patients with advanced cervical cancer. METHODS: From August 2005 to August 2010, 60 patients with stage IIB-IIIB cervical cancer underwent reduced field IMRT (RF-IMRT group) and 62 patients treated with conventional radiotherapy (c-RT group) were enrolled. The RF-IMRT plans were as follows: whole pelvic IMRT plan was performed to deliver a dose of 30Gy firstly, then the irradiated volume was reduced to lymphatic drainage region as well as paracervix and parametrium for an additional 30Gy boost. Intracavitary brachytherapy and concurrent chemotherapy were performed during external irradiation. The tumor coverage and normal tissue avoidance were evaluated. Treatment response, toxicities and survival were assessed. RESULTS: The mean dose delivered to the planning target volume was significantly higher in RF-IMRT group than in c-RT group (61.5 vs. 50.8Gy, P=0.046). IMRT plans yielded better dose conformity to the target and better sparing of the rectal, bladder and small intestine. The RF-IMRT patients experienced significantly lower acute and chronic toxicities with comparable short-term effects than did those treated with conventional RT (CR: 87.7% vs. 88.3%, P=0.496; PR: 7.0% vs. 6.7%, P=0.440). No significant differences were found between treatment groups for 1year, 3year, and 5year overall survival (OS) levels, although the latter approached statistical significance in favor of IMRT, while a significantly higher progression-free survival (PFS; P=0.031) was seen for IMRT. CONCLUSIONS: RF-IMRT yields improved dose distributions, with lower toxicities, while providing comparable clinical outcomes. The increased PFS may be an advantage.

Sentinel lymph node biopsy as guidance for radical trachelectomy in young patients with early stage cervical cancer.

BACKGROUND: The purpose of this study was to assess the feasibility and accuracy of sentinel lymph nodes (SLNs) detection using 99mTc phytate in predicting pelvic lymph nodes status for radical abdominal trachelectomy (RAT) in patients with early stage cervical cancer. METHODS: Sixty-eight women with stage IA2-IB1 cervical cancer and scheduled to undergo fertility-sparing surgery enrolled in this study. 99mTc-labeled phytate was injected before surgery. Intraoperatively, SLNs were identified, excised, and submitted to fast frozen section. Systematic bilateral pelvic lymphadenectomy and/or para-aortic lymph node dissection was performed. Then RAT was performed in patients with negative SLNs. All nodes were sent for routine pathological examination and immunostained with anti-cytokeratin antibody to detect micrometastases. Outcomes of follow up and fertility were observed. RESULTS: SLNs were identified in 64 of 68 patients (94.1%). Of these, SLNs of 8 patients (11.8%) were positive on frozen sections and proved to be metastasis by final pathologic examination. The sensitivity, accuracy, and false negative rates were 100%, 100%, and 0%, respectively. All 60 patients with negative SLN underwent RAT successfully. Two relapses occurred and no one died of tumor progression during follow-up. Five of the 15 patients with procreative desire conceived 8 pregnancies (3 term delivery, 2 premature birth, 1 spontaneous abortion, and 2 were still in the duration of pregnancy) after surgery. CONCLUSIONS: The identification of SLN using 99mTc-labeled phytate is accurate and safe to assess pelvic nodes status in patients with early cervical cancer. SLNs biopsy guided RAT is feasible for patients who desire to have fertility preservation.

Intensity-modulated radiation therapy versus para-aortic field radiotherapy to treat para-aortic lymph node metastasis in cervical cancer: prospective study.

AIM: To compare dosimetry, efficacy, and toxicity of intensity-modulated radiation therapy (IMRT) with para-aortic field radiotherapy in patients with para-aortic lymph node (PALN) metastasis of cervical cancer. METHODS: This prospective study examined 60 patients with cervical cancer with PALN metastasis who underwent whole-pelvis radiotherapy followed by brachytherapy between November 1, 2004 and May 31, 2008. After 3 cycles of chemotherapy, patients were serially allocated into two groups and treated with IMRT or para-aortic field RT at doses of 58-68 Gy and 45-50 Gy, respectively. Treatment response was evaluated and toxicities were assessed. Patients in the IMRT group were treated with both para-aortic field RT and IMRT in order to compare the exposure dose of organs at risk. RESULTS: In the IMRT group, the mean dose delivered to the planning target volume was 67.5 Gy. At least 99% of the gross tumor volume received effective coverage and radical dose (median, 63.5 Gy; range, 54.5-66) during treatment. IMRT plans yielded better dose conformity to the target and better sparing of the spinal cord and small intestine than para-aortic field RT. The IMRT patients experienced less acute and chronic toxicities. The IMRT group also had higher 2- and 3-year survival rates than the para-aortic RT group (2-year, 58.8% vs 25.0%, P = 0.019; 3-year, 36.4% vs 15.6%, P = 0.016). However, no significant difference was found in 1-year survival (67.7% vs 51.3%, P =0.201). The median survival in the IMRT group was 25 months (range, 3 to 37 months). The actuarial overall survival, disease-free survival, and locoregional control rates at 2 years were 67%, 77%, and 88%, respectively, in the IMRT group. CONCLUSIONS: IMRT provides better clinical outcomes than para-aortic field radiotherapy in patients with PALN metastasis. However, cervical local and distal recurrence remain a problem. Long-term follow-up and studies involving more patients are needed to confirm our results.

Inhibition of osteopontin suppresses in vitro and in vivo angiogenesis in endometrial cancer.

OBJECTIVE: Osteopontin (OPN) has been found to play an important role in tumor angiogenesis in recent years. Our previous studies have shown that OPN is overexpressed in tumor-associated human endometrial endothelial cells (HEECs) isolated from tissue samples of patients with endometrial cancer. In the present study, we aimed to further determine the role of OPN in endometrial cancer-associated angiogenesis. METHODS: We knock down OPN expression in HEECs and human endometrial cancer Ishikawa (ISK) cells using the small interference RNA method, and then evaluate the effects of OPN on endometrial cancer-associated angiogenesis by in vivo mouse studies and in vitro assays. RESULTS: Our results revealed that proliferative activity of HEECs and ISK cells in vitro was not affected by transfection with the siOPN-RNA (P>0.05). Inhibition of OPN expression in HEECs reduced the cell migration, with the percentage of repaired area of 36.32+/-2.88 vs. 8.54+/-1.13 (P=0.007). HEEC/siOPN and ISK/siOPN demonstrated 67.4% and 51.2% decreased invasiveness compared with controls, respectively (P<0.05). The number of branched points per well was obviously lower in HEEC/siOPN than that in HEEC/Control (32.46+/-17.10 vs. 53.15+/-15.44, P=0.021). Furthermore, ISK cells transfected with OPN siRNA formed smaller tumor in mice and led to a lower microvessel density, i.e., angiogenesis, in transplanted tumors of mice than scrambled siRNA controls (12.88+/-7.14 vs. 28.42+/-9.69 vessels per HPF, P=0.019). CONCLUSION: These data confirm the positive role of OPN in endometrial cancer-associated angiogenesis and might be of great benefit for finding rational approach in endometrial cancer therapy.

Differential expression profiling of gene response to ionizing radiation in two endometrial cancer cell lines with distinct radiosensitivities.

Although radiotherapy is routinely administered to high-risk endometrial carcinoma and offer a significant disease-free survival advantage, the therapeutic effect is sometimes limited by the occurrence of radioresistance. To determine the patterns of gene expression responsible for the radioresistance and to search for potential target genes for radiotherapy, we selected two cell lines with distinct radiosensitivities using colony-formation assay from four endometrial cancer cell lines. The cell cycle distribution showed higher fractions of G2/M phase cells in the radiosensitive cell line KLE after radiation compared with the radioresistant cell line ISK. Apoptosis assessment also showed significant elevation in the percentage of early apoptosis cells in KLE cells. Subsequently, gene expression changes after X-ray exposure were analyzed by using oligonucleotide microarrays. We identified, respectively, in ISK and KLE, 227 and 354 genes that exhibited > or =2-fold difference. However, only 53 genes showing differences more than double the median expression value between the two groups were defined as radiosensitivity (or radioresistance)-related genes. Among these, genes associated with DNA-repair, apoptosis, growth factor, signal transduction, cell cycle and cell adhesion were predominant. The validity of the expression level of 10 randomly selected genes was confirmed by real-time PCR and/or Western blotting. In conclusion, the differential gene expression changes that occur after radiation in the two cell lines will provide insight into molecular mechanisms of radioresistance in endometrial carcinoma, and also the means to find potential targets to achieve further gains in therapeutic benefit.