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.

A Dose-Finding Trial for Hyperthermic Intraperitoneal Cisplatin in Gynecological Cancer Patients Receiving Hyperthermic Intraperitoneal Chemotherapy.

Background: To identify the maximum tolerated dose (MTD) of hyperthermic intraperitoneal cisplatin at 43°C among gynecological cancer patients. Methods: In this Phase I dose-finding trial, Bayesian optimal interval (BOIN) design was used. We sought to explore the MTD with a target dose-limiting toxicity (DLT) rate of 20%, 4 prespecified doses (70 mg/m2, 75 mg/m2, 80 mg/m2 and 85 mg/m2), and 30 patients. Results: Between 2019 and 2020, 30 gynecologic cancer patients were enrolled. No patients received bevacizumab in subsequent treatment. The most common adverse events related to cisplatin were nausea and vomiting (100%), followed by tinnitus (26.7%) and kidney injury (23.3%). Of the seven patients with kidney injury, four had persistent renal impairment, and finally progressed into chronic kidney injury. DLTs were noted only in the dose level 4 group (85 mg/m2) and included acute kidney injury, pulmonary embolism, anemia, and neutropenia. When cisplatin was given at dose level four (85 mg/m2), the isotonic estimate of the DLT rate (22%) was closest to the target DLT rate of 20%. Therefore, 85 mg/m2 was selected as the MTD, with a 51% probability that the toxicity probability was greater than the target DLT rate. Conclusions: For gynecological cancer patients who received HIPEC for peritoneal metastases, the MTD of cisplatin in HIPEC at 43°C was 85 mg/m2. Our findings apply to patients who do not receive bevacizumab (ChiCTR1900021555).

Expression and clinical significance of Gal-3 and NFκB pathway-related factors in epithelial ovarian carcinoma.

OBJECTIVE: To explore the expression and clinical significance of Gal-3 and NFκB pathway related factors in epithelial ovarian carcinoma cells. METHODS: 99 histologic specimens of epithelial ovarian cancer and 20 normal ovarian histologic specimens were collected, and the expressions of Gal-3, IκB and p65 were detected by immunohistochemistry. Their relationship with clinical characteristics was analyzed. RESULTS: The expression of Gal-3 and p65 was negatively correlated with the overall survival rate (P<0.05), while the expression of IκB was positively correlated with the overall survival rate (P<0.05). Expression of Gal-3, p65 and IκB were found associated with EOC platinum resistance (P<0.05), and expression of Gal-3 and p65 correlated with pathologic grading (P<0.05). IκB and Gal-3 were associated with the recurrence of EOC (P<0.05). IκB may be related to clinical stage (P<0.05). Multivariate analysis results showed that abnormal expression of Gal-3 may be an independent prognostic risk factors for the drug resistance to platinum-based chemotherapy (95% CI=5.336~34.112, P<0.05). The expression of Gal-3, p65, and IκB can be clinical immunohistochemical indicators that determine the prognosis of EOC, but the amount of Gal-3 expression was related to the epithelial ovarian cancer's pathologic type and overall survival, which suggested that Gal-3 can be used as a prognostic factor in epithelial ovarian cancer. CONCLUSION: Targeted therapy of Gal-3 may become an effective potential new method against epithelial ovarian cancer.

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.

Pretreatment serum lactate dehydrogenase is an independent prognostic factor for patients receiving neoadjuvant chemotherapy for locally advanced cervical cancer.

For locally advanced cervical cancer (LACC), hypoxia is a characteristic property. This study aimed to investigate whether baseline lactic dehydrogenase (LDH) level, which is a marker of hypoxia, had clinical value in determining neoadjuvant chemotherapy (NACT) response and prognosis for LACC patients. The study cohort included 418 patients with a median follow-up of 37.5 months. Cox proportional hazards models were used to assess the prognostic value of baseline LDH levels. Multivariate logistic regression analysis was performed to identify independent predictors of complete response after NACT. Backward stepwise selection with the Akaike information criterion was used to identify factors that could be entered into the multivariate regression model. Compared with patients with LDH levels <252.0 µ/L, patients with LDH levels ≥252.0 µ/L were more likely to have an elevated level of squamous cell carcinoma antigen, lymphatic vascular space involvement, lymph node metastasis, and positive parametrium and achieved lower complete remission rates. Baseline LDH levels ≥252.0 µ/L was an independent prognosticator for recurrence-free survival (adjusted hazard ratio [HR], 3.56; 95% confidence interval [CI] 2.22-5.69; P < 0.0001) and cancer-specific survival (adjusted HR, 3.08; 95% CI, 1.89-5.01; P < 0.0001). The predictive value of baseline LDH value remained significant in the subgroup analysis. LDH level ≥252.0 µ/L was identified as an independent predictor of complete remission after NACT (adjusted odds ratio [OR], 0.29; 95% CI, 0.15-0.58; P < 0.0001). Baseline LDH ≥252.0 µ/L is an independent prognostic predictor for patients receiving neoadjuvant chemotherapy for LACC. It helps distinguish patients with different prognosis and select patients who are more likely to benefit from NACT.

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.

Can radical parametrectomy be omitted in occult cervical cancer after extrafascial hysterectomy?

BACKGROUND: Occult invasive cervical cancer discovered after simple hysterectomy is not common, radical parametrectomy (RP) is a preferred option for young women. However, the morbidity of RP was high. The aim of our study is to assess the incidence of parametrial involvement in patients who underwent radical parametrectomy for occult cervical cancer or radical hysterectomy for early-stage cervical cancer and to suggest an algorithm for the triage of patients with occult cervical cancer to avoid RP. METHODS: A total of 13 patients with occult cervical cancer who had undergone RP with an upper vaginectomy and pelvic lymphadenectomy were included in this retrospective study. Data on the clinicopathologic characteristics of the cases were collected. The published literature was also reviewed, and low risk factors for parametrial involvement in early-stage cervical cancer were analyzed. RESULTS: Of the 13 patients, 9 had a stage IB1 lesion, and 4 had a stage IA2 lesion. There were four patients with grade 1 disease, seven with grade 2 disease, and two with grade 3 disease. The median age of the entire patients was 41 years. The most common indication for extrafascial hysterectomy was cervical intraepithelial neoplasia 3. Three patients had visible lesions measuring 10-30 mm, in diameter and ten patients had cervical stromal invasions with depths ranging from 4 to 9 mm; only one patient had more than 50% stromal invasion, and four patients had lymph-vascular space invasion (LVSI). Perioperative complications included intraoperative bowel injury, blood transfusion, vesico-vaginal fistula, and ileus (1 case for each). Postoperative pathologic examination results did not show residual disease or parametrial involvement. One patient with positive lymph nodes received concurrent radiation therapy. Only one patient experienced recurrence. CONCLUSIONS: Perioperative complications following RP were common, whereas the incidence of parametrial involvement was very low among selected early-stage cervical cancer patients. Based on these results, we thought that patients with very low-risk parametrial involvement(tumor size ≤ 2 cm, no LVSI, less than 50% stromal invasion, negative lymph nodes) may benefit from omitting RP. Further prospective data are warranted.

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.

A modified triple incision technique for women with locally advanced vulvar cancer: a description of the technique and outcomes.

OBJECTIVE: Women with locally advanced vulvar carcinoma have an excellent chance of a cure by undergoing a radical vulvectomy with an "en bloc" inguinofemoral lymphadenectomy, but the morbidity associated this surgical approach is substantial. To achieve an outcome comparable with the traditional radical method in terms of oncologic safety, and an improved post-operative quality of life, we modified the classic triple-incision technique and suggested it as an alternative for these patients. The aim of this study was to report this new technique. STUDY DESIGN: Between January 2004 and November 2009, 24 patients with clinical stage T2 (≥ 4 cm) or T3 invasive vulvar cancer underwent surgical treatment with our modified triple incision technique. Their clinical and surgical complications and follow-up data were retrospectively reviewed. RESULTS: The post-surgical complications were as follows: lymphoedema in 45.8%, wound breakdown in 20.8% and cellulitis in 8.3%. After a median follow-up of 35.5 months, three (12.5%) patients developed a recurrence in the skin bridge (2/24, 8.3%) or lungs (1/24, 4.2%). All patients suffering from skin bridge recurrences were salvaged by local re-resection. Four (16.7%) cases of death were noted: three (12.5%) patients died of non-cancer-related diseases and one (4.2%) died from a multifocal pulmonary metastasis; no evidence of vulvar or groin disease was observed at these patients' last follow-up. CONCLUSION: The modified triple-incision technique described in this preliminary study appears to be safe, feasible and tolerable for patients with a locally advanced vulvar cancer, and offers an acceptable morbidity.

[Prognostic value of preoperative serum high sensitivity C-reactive protein in patients with endometrial cancer].

OBJECTIVE: To evaluate whether high sensitivity C-reactive protein (hs-CRP) is a predictive factor in the patients with endometrial cancer. METHODS: The investigators retrospectively analyzed the clinical records of 110 patient with endometrial carcinoma treated at our institution for their initial serum hs-CRP level at pre-operation. Pearson's chi-square was used to evaluate the association of the level of hs-CRP with variables associated with a poor prognosis. COX proportional hazard model was employed to perform univariate and multivariate analyses. RESULTS: The median serum level of hs-CRP in the patients with endometrial cancer was 5.58 mg/L (range: 0.02 - 140.54 mg/L). The serum level of hs-CRP was significantly associated with advanced tumor stage (P < 0.01), lymph node involvement (P < 0.05) and patient age (P < 0.05). Tumor stage, lymph node involvement, histological grade, post-operative adjuvant therapy and the serum level of hs-CRP were correlated with the overall and disease-free survivals. Tumor stage and the serum level of hs-CRP were independent factors. The rank correlation analysis showed that there was a positive correlation between the serum levels of hs-CRP and CA125 (P < 0.01). CONCLUSION: The serum level of hs-CRP may serve as a prognostic parameter in patients with endometrial cancer. Further studies are warranted to validate its value.

[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.