Unintrusive multi-cancer detection by circulating cell-free DNA methylation sequencing (THUNDER): development and independent validation studies.

BACKGROUND: Early detection of cancer offers the opportunity to identify candidates when curative treatments are achievable. The THUNDER study (THe UNintrusive Detection of EaRly-stage cancers, NCT04820868) aimed to evaluate the performance of enhanced linear-splinter amplification sequencing, a previously described cell-free DNA (cfDNA) methylation-based technology, in the early detection and localization of six types of cancers in the colorectum, esophagus, liver, lung, ovary, and pancreas. PATIENTS AND METHODS: A customized panel of 161 984 CpG sites was constructed and validated by public and in-house (cancer: n = 249; non-cancer: n = 288) methylome data, respectively. The cfDNA samples from 1693 participants (cancer: n = 735; non-cancer: n = 958) were retrospectively collected to train and validate two multi-cancer detection blood test (MCDBT-1/2) models for different clinical scenarios. The models were validated on a prospective and independent cohort of age-matched 1010 participants (cancer: n = 505; non-cancer: n = 505). Simulation using the cancer incidence in China was applied to infer stage shift and survival benefits to demonstrate the potential utility of the models in the real world. RESULTS: MCDBT-1 yielded a sensitivity of 69.1% (64.8%-73.3%), a specificity of 98.9% (97.6%-99.7%), and tissue origin accuracy of 83.2% (78.7%-87.1%) in the independent validation set. For early-stage (I-III) patients, the sensitivity of MCDBT-1 was 59.8% (54.4%-65.0%). In the real-world simulation, MCDBT-1 achieved a sensitivity of 70.6% in detecting the six cancers, thus decreasing late-stage incidence by 38.7%-46.4%, and increasing 5-year survival rate by 33.1%-40.4%, respectively. In parallel, MCDBT-2 was generated at a slightly low specificity of 95.1% (92.8%-96.9%) but a higher sensitivity of 75.1% (71.9%-79.8%) than MCDBT-1 for populations at relatively high risk of cancers, and also had ideal performance. CONCLUSION: In this large-scale clinical validation study, MCDBT-1/2 models showed high sensitivity, specificity, and accuracy of predicted origin in detecting six types of cancers.

Outcomes and patterns of secondary relapse in platinum-sensitive ovarian cancer: implications for tertiary cytoreductive surgery.

AIM: To evaluate the outcomes and patterns of patients with secondary relapsed ovarian cancer. METHODS: A retrospective study was conducted. The cases comprised 83 patients who underwent tertiary cytoreductive surgery (TCS) followed by chemotherapy, whereas the controls consisted of 76 patients who received chemotherapy alone. RESULTS: The median survival was 20 months in 159 patients. Patients with microscopic residual disease after TCS had a median survival of 32.9 months compared with 14.6 months in those with macroscopic residual disease [hazard ratio (HR), 2.82; P = 0.001) and 15.0 months in patients with chemotherapy alone (HR, 2.23; P = 0.001). When stratified by a progression-free interval (PFI) after secondary cytoreduction (SCR), TCS showed no benefit in patients with a PFI ≤12 months or a PFI >12 months compared with those with chemotherapy alone. TCS improved survival in patients with recurrent disease in the pelvis compared with those with recurrent disease in the middle or upper abdomen, with a median survival of 34.9 months and 14.6 months, respectively (HR, 2.94; P = 0.010). However, TCS was not a survival determinant by multivariate analysis. A multivariate analysis identified a PFI after SCR (≤12 mos vs. >12 mos; HR, 2.34; 95% CI, 1.29-4.24; P = 0.005), mesenteric lymph node metastasis at SCR (yes vs. no; HR, 4.18; 95% CI, 1.93-9.03; P < 0.001) and treatment arms at secondary relapse (chemotherapy alone vs. TCS; HR, 1.56; 95% CI, 1.03-2.38; P = 0.037) as independent predictors of survival. CONCLUSIONS: Limited survival benefit from tertiary cytoreductive surgery was observed in patients with platinum-sensitive secondary relapsed ovarian cancer.

Predictors of survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery based on the pooled analysis of an international collaborative cohort.

BACKGROUND: This study aims to identify prognostic factors and to develop a risk model predicting survival in patients undergoing secondary cytoreductive surgery (SCR) for recurrent epithelial ovarian cancer. METHODS: Individual data of 1100 patients with recurrent ovarian cancer of a progression-free interval at least 6 months who underwent SCR were pooled analysed. A simplified scoring system for each independent prognostic factor was developed according to its coefficient. Internal validation was performed to assess the discrimination of the model. RESULTS: Complete SCR was strongly associated with the improvement of survival, with a median survival of 57.7 months, when compared with 27.0 months in those with residual disease of 0.1-1 cm and 15.6 months in those with residual disease of >1 cm, respectively (P<0.0001). Progression-free interval (≤23.1 months vs >23.1 months, hazard ratio (HR): 1.72; score: 2), ascites at recurrence (present vs absent, HR: 1.27; score: 1), extent of recurrence (multiple vs localised disease, HR: 1.38; score: 1) as well as residual disease after SCR (R1 vs R0, HR: 1.90, score: 2; R2 vs R0, HR: 3.0, score: 4) entered into the risk model. CONCLUSION: This prognostic model may provide evidence to predict survival benefit from secondary cytoreduction in patients with recurrent ovarian cancer.

The role of secondary cytoreductive surgery for recurrent mucinous epithelial ovarian cancer (mEOC).

BACKGROUND: Mucinous epithelial ovarian cancer (mEOC) may exhibit a distinct biological behavior in epithelial ovarian cancer (EOC). The role of secondary cytoreductive surgery was evaluated in patients with recurrent mEOC, and the prognosis was assessed. METHODS: Twenty-one patients with stages IIc to IV mEOC who experienced disease recurrence and received secondary cytoreductive surgery at Fudan University Cancer Hospital between Jan. 1997 and Dec. 2005 were retrospectively reviewed. Survival curves were generated using the Kaplan-Meier method and the significant comparison of survival rate was estimated by the log-rank test. RESULTS: The median progression-free interval (PFI) was 14 months (range, 5-46 months) after the first cytoreduction. Seven patients (33%) who received secondary cytoreductive surgery were optimally cytoreduced with residual disease less than or equal 1cm, and the other 14 patients (67%) underwent suboptimal surgical cytoreduction. The overall median survival time was 27 months (range, 8-64 months). The median survival time after recurrence was 10 months (range, 3-32 months). There was no significant statistical difference in median survival between patients with optimal and suboptimal secondary surgical cytoreduction, with an estimated survival of 10 months and 9.8 months, respectively (P>0.05). CONCLUSION: Optimal primary cytoreductive surgery for advanced mEOC was very important. Once it recurs, the prognosis is very poor. Patients with recurrent mEOC should be carefully assessed before performing secondary cytoreductive surgery, as this may have limited impact on the overall survival rates.

Surgical treatment for patients with different origins of Krukenberg tumors: outcomes and prognostic factors.

AIMS: We sought to investigate survival impacts of metastasectomy in women with Krukenberg tumors of the ovary and survival benefits in different origins (gastric cancer, colorectal cancer, or others). METHODS: All patients diagnosed with Krukenberg tumors of the ovary who underwent surgical treatment at a single institution between 1997 and 2003 were retrospectively evaluated. Survival analyses and comparisons were performed using Kaplan-Meier method and log-rank test. RESULTS: A total of 54 patients with Krukenberg tumors of the ovary were identified. The estimated 5-year survival was 12.1%. The median survival in patients with microscopic residual disease after metastasectomy was 29.6 months, compared to 10 months in those with visible residual disease (P<0.01). The median survival among patients with Krukenberg tumors of gastric origin, colon and rectum origin, and other origins were 13 months, 29.6 months, and 48.2 months, respectively (P=0.03). There was a significant difference in survival between patients with metastatic disease confined to the ovaries and those with extensive metastases, with an estimated median survival of 30.7 months and 10 months, respectively (P=0.02). Multivariate analysis suggested that the origin of ovarian metastatic carcinoma (P<0.01), residual disease after metastasectomy (P<0.01), and KPS (Karnofsky performance status) (P=0.03) were independent prognostic factors of survival. CONCLUSIONS: Patients with Krukenberg tumors from colorectal cancer experience a better prognosis than those from gastric cancer and benefit more from metastasectomy. And metastasectomy significantly lengthens overall survival in patients with primary colorectal or breast cancer, higher KPS score, and those with optimal metastasectomy.

Concurrent chemotherapy and adjuvant extended field irradiation after radical surgery for cervical cancer patients with lymph node metastases.

The purpose of this retrospective study was to report our experience with concurrent chemotherapy and adjuvant extended field irradiation after radical surgery for cervical carcinoma patients with common iliac node and/or multiple pelvic lymph nodes metastases. We studied 25 patients with FIGO stage IB-IIB (IB, 3; IIA, 15; and IIB, 7) cervical carcinoma who underwent radical surgery and had histologically confirmed involvement of common iliac nodes and/or multiple (>or=2) pelvic lymph nodes. These patients received the first cycle of systemic chemotherapy 2 weeks after radical surgery. Then, they received pelvic and extended field irradiation (40-45 Gy) with weekly cisplatinum (30 mg/m(2)). They were then given five more cycles of consolidation chemotherapy. Survival curves were generated by the Kaplan-Meier method. The 3-year progression-free survival (PFS) and overall survival rates were 63% and 76%, respectively. The PFS rates with multiple pelvic node and common iliac node metastases were 69% and 61%, respectively. The pelvic recurrence rate was 8% (2/25) and that for distant metastases was 32% (8/25). No patient's treatment failed in the para-aortic region. The median interval from the surgery to the recurrence was 14 months (range, 5-29 months). Nineteen (76%) patients experienced grades 1-2 and four (16%) experienced grades 3-4 neutropenia. Fifteen patients (60%) experienced grades 1-2 and one (4%) experienced grades 3-4 gastrointestinal toxicity. Concurrent chemotherapy and adjuvant extended field irradiation after radical surgery achieved good local control with acceptable toxicity. However, subsequent distant metastasis was still the predominant form of treatment failure even after consolidation chemotherapy.

Surgery and salvage chemotherapy for Chinese women with recurrent advanced epithelial ovarian carcinoma: a retrospective case-control study.

The objective of this paper is to clarify the role of cytoreductive surgery and salvage chemotherapy in the management of recurrent advanced epithelial ovarian carcinoma (RAEOC) and to identify factors affecting disease recurrence. One hundred sixty seven patients with RAEOC treated at the Cancer Hospital of Fudan University between January 1986 and December 1997 were retrospectively reviewed. Survival was calculated by Kaplan-Meier method with difference in survival estimated by the log-rank test. Independent prognostic factors were identified by the Cox stepwise regression model and variants associated with disease recurrence were determined using logistic stepwise regression methods. The median age was 52 (range 27-72) years. Sixty (35.9%) patients underwent re-debulking surgery, 23 of them with residual disease

Adenovirus 5 E1a-mediated gene therapy for human ovarian cancer cells in vitro and in vivo.

The aim of this study was to investigate therapeutic efficacy of adenovirus-mediated E1a gene therapy for ovarian cancer in vitro and in vivo. Recombinant replication-deficient adenoviral vectors were prepared by superinfection of 293 cells, and then purified. The efficacy of the adenovirus vector system to infect ovarian cells was tested using different multiplicity of infection (MOI) and different times (1-4) of Ad.RSVlacZ. SKOV-3 cells (10(3) per well) were infected once with 2 x 10(4) adenovirus. The cells were harvested and counted on different days for 7 days to generate the in vitro growth curve. Tumor-bearing mice were injected intraperitoneally with ovarian cancer cells and treated by intraperitoneal injection of 100 microl (2.5 x 10(8) PFU) viral solution containing either replication-deficient Ad.E1a(+); control virus Ad.E1a(-) which is the same adenovirus as Ad.E1a(+) except for E1a deletion, or just phosphate buffered solution. The transduction efficacy increased with higher MOI and reached a plateau at the 20:1 ratio. When Ad.E1a(+) was used to transduce the HER-2/neu overexpressing human ovarian cancer cell line SKOV-3, tumor cell growth in vitro was greatly inhibited by E1a transduction. Also, Ad.E1a+ greatly inhibited tumor growth of SKOV-3-bearing mice. Immunohistochemistry analysis indicated that Ad.E1a protein was expressed in tumor tissue and expression of HER-2/neu p185 protein was suppressed. Very strong beta-gal staining was detected in tumors, and beta-gal activity in small intestine, lung, heart, stomach, liver, and kidney was detected. No beta-gal activity was detected in the tumor and other organs in control mice injected with Ad.E1a(-) or PBS. Adenovirus-type 5 E1a gene can efficaciously inhibit HER-2/neu-overexpressing ovarian cancer, and this promising procedure could greatly benefit ovarian cancer patients with high expression of HER-2/neu.

Impact of secondary cytoreductive surgery on survival of patients with advanced epithelial ovarian cancer.

AIMS: To investigate the impact on survival of secondary cytoreduction for advanced epithelial ovarian cancer and variables influencing redebulking surgical outcome. METHODS: Between 1986 and 1997, 106 patients who received secondary cytoreductive surgery and consequent second-line chemotherapy for stages III and IV epithelial ovarian cancer were retrospectively reviewed. The optimal residual disease cut-off was 1.0 cm. The Cox proportional regression model and logistic stepwise regression were used in statistical processing of the data. RESULTS: The median age of the patients was 50 years (range, 26-77 years). Optimal secondary cytoreduction was achieved in 46 of 106 patients (43.4%). There was a significant difference in survival between patients who were optimally cytoreduced compared to those suboptimaly cytoreduced, with an estimated median survival in the optimal group of 20 months vs 8 months in the suboptimal group ((2)=42.03, P=0.0000). When factorized, patients had significant survival benefit from optimal secondary cytoreduction for recurrent disease and interval cytoreduction. Survival was adversely influenced by progression-free interval < or =12 months (P=0.0078), residual disease >1 cm (P=0.0001) and presence of refractory ascites (P=0.0001). The probability of successful redebulking surgery was affected by presence of refractory ascites (P=0.0023) in all 106 patients and by the ascites (P=0.0072) and residual disease at initial operation in recurrent disease (P=0.0096). CONCLUSION: Secondary surgical cytoreduction surgery significantly lengthened survival for patients with recurrent epithelial ovarian cancer or those receiving interval cytoreduction. Patients with refractory ascites, however, were not suitable for aggressive secondary surgery, and redebulking surgery for those with residual disease of >1.0 cm after primary operation should be considered prudently in recurrent disease.

Effect of cytoreductive surgery on survival of patients with recurrent epithelial ovarian cancer.

BACKGROUND AND OBJECTIVES: The value of secondary cytoreductive surgery is still controversial, especially in patients with recurrent epithelial ovarian cancer. In this retrospective study, we investigated the effect on survival of secondary cytoreduction for recurrent disease and variables influencing redebulking surgical outcome. METHODS: Between 1986 and 1997, 60 patients who received primary cytoreductive surgery and platinum-based chemotherapy for stage III and IV epithelial ovarian cancer experienced disease recurrence at least 6 months after completion of primary therapy, and secondary surgical cytoreduction was performed. The optimal residual disease cutoff was 1.0 cm. The Cox proportional regression model and Logistic stepwise regression were used in statistical processing of the data. RESULTS: The median progression-free interval between the two operations was 13 months (range, 6-56 months). Optimal secondary cytoreduction was achieved in 23 patients (38.33%). There was a significant difference in survival between patients who were optimally cytoreduced compared to those suboptimally cytoreduced, with an estimated median survival in the optimal group of 19 months vs. 8 months in the suboptimal group (chi(2) = 22.04, P = 0.0000). Prognosis of survival for individuals with progression-free interval >12 months was better than that of those with the interval 1.0 cm after primary operation should be considered prudently.

Epithelial ovarian cancer presenting initially with extraabdominal or intrahepatic metastases: a preliminary report of 25 cases and literature review.

The purpose of this study was to investigate the clinical features of patients with epithelial ovarian cancer (EOC) that are initially categorized as extraabdominal adenocarcinoma of unknown primary. Twenty-five patients with EOC, who were treated in the Cancer Hospital of Shanghai Medical University from January 1986 to December 1997, and manifesting as extraperitoneal or liver parenchyma metastases at the time of presentation without detectable ovarian tumors, were retrospectively studied. Sixteen patients (64%) were optimally surgical debulked. When compared with 52 other women with stage IV EOC, 20 patients who initially sought treatment for extraabdominal metastases experienced a better prognosis, with an estimated median survival of 24 months versus 10 months (p = 0.0427). The median survival was 30 months in patients with pleural effusion or supraclavicular lymph node metastases versus 19 months in those with spread to other sites (p = 0.0264). The prognosis of such cases, mainly for those with supraclavicular lymphadenopathy or malignant pleural effusion, is better than that for other stage IV EOC patients, probably because most of the patients who initially had distant metastases were generally in condition that permitted aggressive surgery or multicycle chemotherapy.

Cytoreductive surgery for stage IV epithelial ovarian cancer.

We tried to determine the role of cytoreductive surgery for stage IV epithelial ovarian cancer and in what conditions this surgical procedure could carry the best benefits. From January 1986 to December 1997, seventy-one of 73 patients with stage IV epithelial ovarian cancer who were treated in Cancer Hospital of Shanghai Medical University were retrospectively reviewed. Clinical information including age, grade, histology, presence of ascites, size of residual disease, site of extra-abdominal metastasis, whether initially presenting as metastatic disease or not, neo-adjuvant chemotherapy, platinum-based chemotherapy and second-line chemotherapy was obtained. Survival was calculated by life-table and survival curves were computed using the Kaplan-Meier method with differences in survival estimated by log-rank test. Independent prognostic factors were identified by Cox's proportional hazards regression model. The median age of the patients' population was 54 years (range 22-82), median follow-up time was 12 months (range 3 to 130) and estimated 5-year survival rate 6.1%. Thirty out of 71 (42.3%) patients were successfully debulked (< or = 1 cm) at the time of initial surgery. There was a significant difference in five-year survival rate between patients optimally (14.1%) vs suboptimally (0%) cytoreduced, with an estimated median survival in the optimal group of 23 months vs 9 months in the suboptimal group (P=0.0001, long-rank test). When the variables were factorized, only in patients with malignant pleural effusion or positive supraclavicular lymph nodes, optimal cytoreduction could get the greatest benefits. Multivariate analysis revealed that the size of residual disease and ascites were independent factors of survival. However, only ascites was the prognostic factor of progression-free survival. Optimal cytoreductive surgery is an important determinant of survival in women with stage IV epithelial ovarian cancer, mainly in those with malignant pleural effusion or positive supraclavicular lymph node pathology.