Determining the maximum tolerated dose of paclitaxel combined with fixed dose of cisplatin for hyperthermic intraperitoneal chemotherapy in ovarian cancer: A multicenter phase I trial.

OBJECTIVE: To determine the maximum tolerated dose (MTD) of paclitaxel combined with a fixed dose of cisplatin (75 mg/m2) delivered via hyperthermic intraperitoneal chemotherapy (HIPEC) to patients with ovarian cancer. METHODS: This multicenter Phase I trial employed a Bayesian Optimal Interval (BOIN) design. The MTD was determined to have a target dose-limiting toxicity (DLT) rate of 25%. The starting dose was 175 mg/m2. The Data and Safety Monitoring Board made decisions regarding dose escalation or de-escalation in increments of 25 mg/m2 for subsequent patient cohorts, up to a maximum sample size of 30 or 12 patients treated at a given dose. RESULTS: Twenty-one patients participated in this study. Among the three evaluable patients who received 150 mg/m2 paclitaxel, no DLTs were observed. Among the 12 evaluable patients who received 175 mg/m2 paclitaxel, two reported DLTs: one had grade 4 neutropenia and one had grade 4 anemia, neutropenia, and leukopenia. Four of the six evaluable patients who received 200 mg/m2 paclitaxel reported DLTs: one patient had grade 4 diarrhea, one had grade 3 kidney injury, and two had grade 4 anemia. The isotonic estimate of the DLT rate in the 175 mg/m2 dose group was 0.17 (95% confidence interval, 0.02-0.42), and this dose was selected as the MTD. CONCLUSION: Paclitaxel, when combined with a fixed dose of cisplatin (75 mg/m2), can be safely administered intraperitoneally at a dose of 175 mg/m2 in patients with ovarian cancer who received HIPEC (43 °C, 90 min) following cytoreductive surgery.

Effects of neoadjuvant hyperthermic intraperitoneal chemotherapy on chemotherapy response score and recurrence in high-grade serous ovarian cancer patients with advanced disease: A multicentre retrospective cohort study.

OBJECTIVE: To investigate whether the combination of neoadjuvant hyperthermic intraperitoneal chemotherapy (NHIPEC) plus intravenous neoadjuvant chemotherapy (IV NACT) has superior efficacy to IV NACT alone. DESIGN: Retrospective cohort study. SETTING: Two tertiary referral university hospitals. POPULATION: Patients with ovarian cancer who received NACT-interval debulking surgery (IDS) between 2012 and 2020. METHODS: The tumour response to NACT was evaluated with the chemotherapy response score (CRS) system. Survival outcomes were compared. MAIN OUTCOME MEASURES: CRS 3, progression-free survival (PFS), and overall survival (OS). RESULTS: In total, 127 patients were included, and 46 received NHIPEC plus IV NACT. The addition of NHIPEC was independently associated with an increased likelihood of CRS 3 (p = 0.033). Patients who received NHIPEC + IV NACT had significantly improved PFS compared with those who received IV NACT alone (median PFS: 22 versus 16 months, p < 0.001). The use of NHIPEC was identified as an independent predictor of PFS (p < 0.0001). OS did not differ significantly between treatment groups (p = 0.062), although a trend favouring NHIPEC was noted. Incidence of grade 3-4 adverse events and the surgical complexity score of IDS were similar between the two groups. CONCLUSIONS: Compared with IV NACT alone, the combination of NHIPEC and IV NACT resulted in improved tumour response and longer PFS. The addition of NHIPEC did not increase the risk of adverse effects or affect the complexity of IDS.

Efficacy of neoadjuvant hyperthermic intraperitoneal chemotherapy in advanced high-grade serous ovarian cancer (the NHIPEC trial): study protocol for a randomised controlled trial.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is an important treatment option for patients with ovarian cancer. Although intravenous NACT can improve optimal resection rates and decrease surgical morbidity and mortality, these advantages do not translate into a survival benefit. Ovarian carcinoma is mainly confined to the peritoneal cavity, which makes it a potential target for hyperthermic intraperitoneal chemotherapy (HIPEC). Our previous study showed that HIPEC could be used in the neoadjuvant setting, which was named neoadjuvant HIPEC (NHIPEC). Since hyperthermia is an excellent chemosensitiser, we hypothesised that the combination of NHIPEC and intravenous NACT could show superior efficacy to intravenous NACT alone. METHODS: This study is a single-centre, open-label, randomised (1:1 allocation ratio) phase 2 trial. A total of 80 patients will be randomly assigned into an experimental group (NHIPEC+intravenous NACT) or a control group (intravenous NACT). Patients in the experimental group will receive NHIPEC following laparoscopic evaluation, and four tubes will be placed via the laparoscopic ports, which will be used to administer NHIPEC. Then, perfusion with docetaxel (60-75 mg/m2) will be performed (43°C for 60 min, Day 0) followed by cisplatin (75 mg/m2, Day 1) infusion (43°C for 60 min) 24 hours later. After NHIPEC, two cycles of intravenous NACT will be given. Patients in the control group will receive three cycles of intravenous NACT. The primary endpoint is the proportion of patients who achieve a Chemotherapy Response Score (CRS) of 3 according to the CRS system. The secondary endpoints include progression-free survival, overall survival and the rates of complete resection and NHIPEC-related adverse events. ETHICS APPROVAL AND DISSEMINATION: This study was approved by the Ethics Committee of Sun Yat-sen Memorial Hospital (approval number: 2020-ky-050). Results will be submitted to peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2000038173.

Impact of Hyperglycemia on Outcomes among Patients Receiving Neoadjuvant Chemotherapy for Bulky Early Stage Cervical Cancer.

BACKGROUND: The impact of hyperglycemia on survival of patients undergoing neoadjuvant chemotherapy (NACT) for bulky early stage cervical cancer (BESCC) has not been explored. METHOD: Records of patients who received NACT and radical hysterectomy in our institution between January 2005 and June 2010 were reviewed. RESULTS: In total, 347 patients were included. The median follow-up time was 37 months (range: 4-65). Patients with hyperglycemia (fasting blood glucose ≥ 100 mg/dl) had shorter recurrence-free survival (RFS) (univariate hazard ratio [HR] = 1.95, 95% confidence interval [CI] [1.16, 3.28], P = 0.010) and cancer-specific survival (CSS) (univariate HR = 2.24, 95% CI [1.33, 3.78], P = 0.002) compared with those with euglycemia (fasting blood glucose <100 mg/dl). In multivariate analysis, positive surgical margins, parametrium invasion, node metastasis, hyperglycemia and complete response to NACT independently predicted recurrence and cancer-specific death. To further validate the prognostic value of hyperglycemia, we conducted a subgroup analysis based on patient baseline characteristics and prognostic effect of hyperglycemia remained significant in all subgroups. On multivariable logistic regression analysis, euglycemia before NACT, squamous cell tumor and pre-treatment squamous cell carcinoma antigen levels < 3.5 ng/ml were identified as independent predictors of complete response after NACT. CONCLUSIONS: FBG ≥100 mg/dl is a negative prognostic predictor for cervical cancer patients receiving NACT for BESCC. Patients with hyperglycemia are less likely to achieve complete response after NACT. Our findings underscore the clinical utility of hyperglycemia screening of for cervical cancer patients.

Impact of the care provided by gynecologic oncologists on outcomes of cervical cancer patients treated with radical hysterectomy.

For many malignant diseases, specialized care has been reported to be associated with better outcomes. The purpose of this study is to investigate the influence of gynecologic oncologists on treatment outcomes for cervical cancer patients treated by radical hysterectomy. Records of patients who received radical hysterectomy between January 2005 and June 2010 were reviewed. Perioperative morbidity, recurrence-free survival, and cancer-specific survival were assessed. Cox regression model was used to evaluate gynecologic oncologists as an independent predictor of survival. A total of 839 patients were included. Of these patients, 553 were treated by gynecologic oncologists, while 286 were treated by other subspecialties. With regard to operative outcomes, significant differences in favor of operation by gynecologic oncologists were found in number of patients receiving para-aortic node sampling and dissection (P=0.038), compliance with surgical guidelines (P=0.003), operative time (P<0.0001), estimated blood loss (P<0.0001), transfusion rate (P=0.046), number of removed nodes (P=0.033), and incidences of ureteric injury (P=0.027), cystotomy (P=0.038), and fistula formation (P=0.002). Patients who were operated on by gynecologic oncologists had longer recurrence-free survival (P=0.001; hazard ratio [HR] =0.64; 95% confidence interval [CI] [0.48, 0.84]) and cancer-specific survival (P=0.005; HR=0.64; 95% CI [0.47, 0.87]), and this association remained significant in patients with locally advanced disease. Care by gynecologic oncologists was an independent predictor for improved recurrence-free survival (P<0.0001; HR=0.57; 95% CI [0.42, 0.76]) and cancer-specific survival (P=0.001; HR=0.58; 95% CI [0.42, 0.81]), which was still significant among patients with locally advanced cancer. Given the results, we believe for cervical cancer patients receiving radical hysterectomy, operation by gynecologic oncologists results in significantly improved surgical and survival outcomes. The importance of the subspecialty of a gynecologist for cervical cancer patients should be addressed in clinical practice, especially for those in developing countries.

Expression and functional role of ALDH1 in cervical carcinoma cells.

Tumor formation and growth is dictated by a very small number of tumor cells, called cancer stem cells, which are capable of self-renewal. The genesis of cancer stem cells and their resistance to conventional chemotherapy and radiotherapy via mechanisms such as multidrug resistance, quiescence, enhanced DNA repair abilities and anti-apoptotic mechanisms, make it imperative to develop methods to identify and use these cells as diagnostic or therapeutic targets. Aldehyde dehydrogenase 1 (ALDH1) is used as a cancer stem cell marker. In this study, we evaluated ALDH1 expression in CaSki, HeLa and SiHa cervical cancer cells using the Aldefluor method to isolate ALDH1-positive cells. We showed that higher ALDH1 expression correlated with significantly higher rates of cell proliferation, microsphere formation and migration. We also could demonstrate that SiHa-ALDH1- positive cells were significantly more tumorigenic compared to SiHa-ALDH1-negative cells. Similarly, SiHa cells overexpressing ALDH1 were significantly more tumorigenic and showed higher rates of cell proliferation and migration compared to SiHa cells where ALDH1 expression was knocked down using a lentivirus vector. Our data suggested that ALDH1 is a marker of cervical cancer stem cells and expand our understanding of its functional role.

Neoadjuvant chemotherapy with paclitaxel plus platinum for invasive cervical cancer in pregnancy: two case report and literature review.

BACKGROUND: Cervical cancer (including carcinoma in situ) is the most common malignancy during pregnancy. Neoadjuvant chemotherapy (NACT) with paclitaxel plus cisplatin has been used in patients with cervical cancer successfully, but experience of its prenatal treatment is limited. CASE REPORT: We report two pregnant women with locally advanced cervical cancer. They were treated with cisplatin plus paclitaxel NACT until fetal pulmonary maturity was achieved, and then accepted cesarean section followed by radical hysterectomy. To minimize the chemo-resistant/radio-resistant tumor cell clones and increase the potencies of NACT, we modified the dose of the chemotherapeutic agents and the treatment interval using cisplatin (50 mg/m(2)) and paclitaxel (75 mg/m(2)) every 2 weeks. Evaluation for clinical response to chemotherapy displayed a partial and complete response, respectively. Both patients had not had any evidence of recurrence for 21 and 13 months. Their children did not have any evidence of malformations and showed normal development at 21 and 13 months of follow-up, respectively. CONCLUSION: Neoadjuvant chemotherapy with paclitaxel plus cisplatin appears to be feasible and safe for pregnant patients with invasive cervical cancer and infants.

[Influences of lymphatic vessel ligation in pelvic lymphadenectomy on postoperative lymphocyst formation--a randomized controlled trial].

BACKGROUND AND OBJECTIVE: Pelvic lymphocysts are the most common postoperative complications of pelvic lymphadenectomy. Prevention of this disease is more important than treatment. This randomized study was to evaluate the preventive effect of lymph vessel ligation during pelvic lymphadenectomy on pelvic lymphocyst formation. METHODS: A total of 39 patients with gynecologic malignancy, who had pelvic lymphadenectomy in the Second Affiliated Hospital of Sun Yat-sen University from July 2006 to January 2007, were randomized into the ligation group (19 patients) and the non-ligation group (20 patients). All patients had no heart disease, hepatopathy, nephronia, pneumonopathy, hypoproteinemia and no history of radiotherapy. All the patients were followed-up with sonographic evaluation and physical examination for lymphocysts and other postoperative complications at 1, 4, 12, and 24 weeks after operation. RESULTS: No significant differences were observed between the two groups in pathlogic type, age, height, weight, body surface area, body mass index (BMI), operation duration, estimated blood loss, time to the passage of flatus, total drainage volume, duration of drainage, and duration of hospital stay (P>0.05). The occurrence rate of lymphocysts was significantly lower in the ligation group than in the non-ligation group at one week after operation (26.3% vs. 60.0%, P<0.05). The rates were slightly lower in the ligation group than in the non-ligation group without significant differences after then (31.6% vs. 55.0% at the 4th week), (16.7% vs. 45.0% at the 12th week), (20.0% vs. 27.8% at the 24th week). No significant differences were observed in the occurrence of other postoperative complications between the two groups (P<0.05). CONCLUSION: Ligations of the deep inguinal lymph vessels, obturator lymph vessels, common iliac lymph vessels, and the lymph vessels at the crossing of the external iliac and the inter iliac vein can decrease the occurrence of postoperative lymphocysts in short-term period, and will not increase the occurrence of postoperative complications.

[Primary clear cell carcinoma of the cervix: report of five cases and review of the literature].

OBJECTIVE: To explore the clinical diagnostic and therapeutic characteristics, prognostic factors of patients with primary clear cell carcinoma of the cervix. METHODS: The clinical, pathologic and follow-up data of patients with primary clear cell carcinoma of the cervix treated in our hospital from Jan 2003 to Dec 2006 were collected and analyzed retrospectively. The relative literature was reviewed. RESULTS: Five patients with primary clear cell carcinoma of the cervix were treated (1 case stage I b1, 2 of stage I b2, 1 of stage IIa, 1 of stage IVa). The mean age was 40.2 years (32 to 50 years). The primary symptom was mostly irregularly vaginal bleeding (3/5) and clinical type was predominantly (4/5) endophytic growth. The positive rate of cervical cytologic examination was 2/4, the negative rate of cervical human papillomavirus (HPV) DNA examination was 4/4. Serum CA125 level was abnormal (62.5 to 592.1 kU/L) before operation and when relapse occurred, and returned to normal after operation. All of five patients underwent operation, pathologic examination showed that three patients with infiltration in deep 1/2 myometrium of cervix, and two patients with infiltration in cervix-corpus juncture. Four patients underwent radical abdominal hysterectomy with systematic pelvic lymphadenectomy. All of four patients underwent four courses of chemotherapy with fluorouracil (5-FU) and carboplatin, one patient (stage II a) was added with intracavitary brachytherapy. None of the four patients had relapse or metastasis after a follow-up of 10 to 44 months. The patient with stage IV a underwent firstly hysterectomy and prerectum mass removal. Pelvic relapse occurred three months after operation and the patient then underwent the second operation, external beam radiotherapy and intracavitary brachytherapy and 8 courses of chemotherapy with paclitaxel (taxol) and carboplatin. There was no relapse or metastasis after a follow-up of 26 months. CONCLUSIONS: Primary clear cell carcinoma of the cervix may be unrelated to HPV infection. It shows predominantly endophytic growth and tends toward deep infiltration in cervix and extending to uterine corpus. Operation combined with chemotherapy with carboplatin and 5-FU or taxol may lead to relatively perfect short-term therapeutical effect. Serum CA125 can help to monitor prognosis.

[Construction of adeno-associated virus vector containing human papilloma virus 16 E7 gene and its expression in eukaryotic cells].

OBJECTIVE: To construct recombinant adeno-associated virus vector containing human papilloma virus (HPV) 16E7 gene and identify its effectiveness of expression in eukaryotic cell. METHODS: Recombinant adeno-associated virus particles containing HPV16E7 gene were generated by co-transfection of plasmids pAAV-MCS-E7, pAAV-RC and pAAV-helper into HEK293 cells. The viral particles were collected and purified. The vector titer was measured by southern blot. After the eukaryotic cells were transfected by virus particles, RT-PCR and western blot analysis were performed to identify rAAV expression. RESULTS: The recombinant adeno-associated virus vector containing HPV16E7 gene was correctly constructed. The vector titer measured by southern blot was approximately 1 x 10(11)/ml. After the eukaryotic cells were transfected by the recombinant adeno-associated virus vector, the expression of HPV16E7 gene was identified by RT-PCR and western blot. CONCLUSIONS: Recombinant adeno-associated virus HPV16E7 vector is successfully constructed and can stably express in eukaryotic cells.