Rationale and study design of the CHIPPI-1808 trial: a phase III randomized clinical trial evaluating hyperthermic intraperitoneal chemotherapy (HIPEC) for stage III ovarian cancer patients treated with primary or interval cytoreductive surgery.

BACKGROUND: Ovarian cancer remains the most lethal gynecologic malignancy with high recurrence rates. Because recurrence involves primarily the peritoneum, intraperitoneal chemotherapy is being evaluated as a new approach to treat microscopic peritoneal disease. One trial showed that cisplatin-paclitaxel intraperitoneal chemotherapy with intravenous paclitaxel improved survival but increased morbidity. Another trial reported a significant improvement in overall survival (OS) and disease-free survival (DFS) without increasing the morbidity (P = 0.76) or mortality rates (hazard ratio 0.67, P = 0.02) after adding hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreduction. The current trial aims to evaluate the impact of adding HIPEC to primary or interval cytoreductive surgery for epithelial ovarian cancer (EOC) on the efficacy, safety, treatment feasibility, and quality of life. PATIENTS AND METHODS: This is an international, multicenter, open-label, randomized (1 : 1), two-arm, phase III clinical trial that will enroll 432 patients with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage III EOC. Patients are randomized to receive or not HIPEC with the standard of care. Inclusion criteria include patients with FIGO stage III EOC, Fallopian tube carcinoma or primary peritoneal cancer who undergo complete primary or interval cytoreduction. The primary objective is to assess DFS of the addition of HIPEC. Secondary objectives are the assessment of OS, safety, return to intended oncologic treatment, quality of life and the trade-off between efficacy and morbidity. CONCLUSIONS: The results might help extend the indications of HIPEC to include patients undergoing primary cytoreduction, providing a standardized protocol for HIPEC in EOC management and reliable information on the quality of life after adding HIPEC.

Lomboaortic Lymphadenectomy in Gynecological Oncology: Laparotomy, Laparoscopy or Robot-Assisted Laparoscopy?

BACKGROUND: The outcomes of paraaortic lymphadenectomy were compared for the treatment of gynecological malignancies to identify the most appropriate surgical approach. METHODS: Our retrospective, multicentric study included 1304 patients who underwent paraaortic lymphadenectomy for gynecological malignancies. The patients were categorized into the following five groups based on treatment type: transperitoneal laparoscopy (group A, n = 198), extraperitoneal laparoscopy (group B, n = 681), robot-assisted transperitoneal laparoscopy (group C, n = 135), robot-assisted extraperitoneal laparoscopy (group D, n = 44), and laparotomy (group E, n = 246). RESULTS: The prevalence of cancer types differed according to the surgical approach: there were more ovarian cancers in group E and more cervical cancers in groups B and D (p < 0.001). Estimated blood loss was higher in group E (844.2 mL) than in groups treated with minimally invasive interventions (115.8-141.5 mL, p < 0.005). For infrarenal dissection, fewer nodes were removed in group C compared with the other approaches (16 vs. 21 nodes, respectively, p < 0.05). The average operative time ranged from 169 min for group A to 247 min for group E (p < 0.001). Length of hospital stay was 14 days for group E versus 3.5 days for minimally invasive procedures (p < 0.05). The early postoperative grade 3 and superior Dindo-Clavien complications occurred in 9-10% of the patients in groups B-D, 15% of the patients in group E, and only 3% and 4% for groups A and C, respectively. The most common complication was lymphocele. CONCLUSIONS: Laparotomy increases preoperative and postoperative morbidity. The robot-assisted transperitoneal approach demonstrated a poorer lymph node yield than laparotomy and extraperitoneal approaches.

Adjuvant management of operated uterine sarcomas: A single institution experience.

PURPOSE: The purpose of this study was to describe the adjuvant management of high grade uterine sarcoma and highlight prognostic factors for overall survival and progression-free survival. MATERIAL AND METHODS: Between 01/2000 and 01/2015, 91 patients undergoing surgery were presented at the multidisciplinary team meeting of our institution. The type of surgery, the anatomopathological features, adjuvant treatments, dates and sites of recurrence were collected. The prognostic value of the various factors was evaluated with the multivariate Cox model. RESULTS: A total of 50 women with uterine sarcoma were identified and lesions included 43 leiomyosarcomas (86%) and seven high grade sarcomas (14%). Eighteen patients received adjuvant pelvic radiotherapy (36%) and six adjuvant systemic therapy (12%). The median follow-up time was 63 months. Thirty-nine patients (78%) had a recurrence: 22 had only metastatic recurrence (58%), two had isolated pelvic recurrence (5%) and 15 had pelvic and metastatic recurrence (38%). Adjuvant radiotherapy was associated with survival without pelvic recurrence in univariate analysis (P=0.005, hazard ratio [HR]=0.15); age greater than 55 years and adjuvant radiotherapy were associated with metastatic free survival in multivariate analysis (P=0.015, HR=2.37, and P=0.013, HR=0.41 respectively) CONCLUSION: According to the results of our series, there is a benefit of radiotherapy after surgery in terms of local control of uterine sarcoma. It is necessary to identify the subgroup of patients who will benefit from an adjuvant radiotherapy in order to provide them with more optimal care.

Ultrathin Y2O3:Eu3+nanodiscs: spectroscopic investigations and evidence for reduced concentration quenching.

Here, we report the synthesis and spectral properties of ultrathin nanodiscs (NDs) of Y2O3:Eu3+. It was found that the NDs of Y2O3:Eu3+ with a thickness of about 1 nm can be fabricated in a reproducible, facile and self-assembling process, which does not depend on the Eu3+ concentration. The thickness and morphology of these NDs were determined with small angle x-ray scattering and transmission electron microscopy. We found that the crystal field in these nanoparticles deviates from both the cubic and monoclinic characteristics, albeit the shape of the 5D0 â†’ 7F J (J = 0, 1, 2) transitions shows some similarity with the transitions in the monoclinic material. The Raman spectra of the non-annealed NDs manifest various vibration modes of the oleic acid molecules, which are used to stabilise the NDs. The annealed NDs show two very weak Raman lines, which may be assigned to vibrational modes of Y2O3 NDs. The concentration quenching of the Eu3+ luminescence of the NDs before annealing is largely suppressed and might be explained in terms of a reduction of the phonon density of states.

Complication-related removal of totally implantable venous access port systems: Does the interval between placement and first use and the neutropenia-inducing potential of chemotherapy regimens influence their incidence? A four-year prospective study of 4045 patients.

BACKGROUND: Totally implantable venous access port systems are widely used in oncology, with frequent complications that sometimes necessitate device removal. The aim of this study is to investigate the impact of the time interval between port placement and initiation of chemotherapy and the neutropenia-inducing potential of the chemotherapy administered upon complication-related port removal. PATIENTS AND METHODS: Between January 2010 and December 2013, 4045 consecutive patients were included in this observational, single-center prospective study. The chemotherapy regimens were classified as having a low (<10%), intermediate (10-20%), or high (>20%) risk for inducing neutropenia. RESULTS: The overall removal rate due to complications was 7.2%. Among them, port-related infection (2.5%) and port expulsion (1%) were the most frequent. The interval between port insertion and its first use was shown to be a predictive factor for complication-related removal rates. A cut-off of 6 days was statistically significant (p = 0.008), as the removal rate for complications was 9.4% when this interval was 0-5 days and 5.7% when it was ≥6 days. Another factor associated with port complication rate was the neutropenia-inducing potential of the chemotherapy regimens used, with removal for complications involved in 5.5% of low-risk regimens versus 9.4% for the intermediate- and high-risk regimens (p = 0.003). CONCLUSION: An interval of 6 days between placement and first use of the port reduces the removal rate from complications. The intermediate- and high-risk for neutropenia chemotherapy regimens are related to higher port removal rates from complications than low-risk regimens.

Impact of completion axillary lymph node dissection in patients with breast cancer and isolated tumour cells or micrometastases in sentinel nodes.

BACKGROUND: Omission of completion axillary lymph node dissection (ALND) is a standard practice in patients with breast cancer (BC) and negative sentinel nodes (SNs) but has shown insufficient evidence to be recommended in those with SN invasion. METHODS: A retrospective analysis of a cohort of patients with BC and micrometastases (Mic) or isolated tumour cells (ITCs) in SN. Factors associated with ALND were identified, and patients with ALND were matched to patients without ALND. Overall survival (OS) and recurrence-free survival (RFS) were estimated in the overall population, in Mic and in ITC cohorts. FINDINGS: Among 2009 patients analysed, 1390 and 619 had Mic and ITC in SN, respectively. Factors significantly associated with ALND were SN status, histological type, age, number of SN harvested and absence of adjuvant chemotherapy. After a median follow-up of 60.4 months, ALND omission was independently associated with reduced OS (hazard ratio [HR] 2.41, 90 confidence interval [CI] 1.36-4.27, p = 0.0102), but not with increased RFS (HR 1.21, 90 CI 0.74-2.0, p = 0.52) in the overall population. In matched patients, the increased risk of death in case of ALND omission was found only in the Mic cohort (HR 2.88, 90 CI 1.46-5.69), not in the ITC cohort. The risk of recurrence was also significantly increased in the subgroup of matched Mic patients (HR 1.56, 90 CI 0.90-2.73). INTERPRETATION: A separate analysis of Mic and ITC groups, matched for the determinants of ALND, suggested that patients with Mic had increased recurrence rates and shorter OS when ALND was not performed. Our results are consistent with those of previous studies for patients with ITC but not for those with Mic. Randomised controlled clinical trials are still warranted to show with a high level of evidence if ALND can be safely omitted in patients with micrometastatic disease in SN.

Axillary lymph node micrometastases decrease triple-negative early breast cancer survival.

BACKGROUND: Triple-negative breast cancers (TNBCs) are the most deadly form of breast cancer (BC) subtypes. Axillary lymph node involvement (ALNI) has been described to be prognostic in BC taken as a whole, but its prognostic value in each subtype is unclear. We explored the prognostic impact of ALNI and especially of small size axillary metastases in early TNBCs. METHODS: We analysed in this multicentre study all patients treated for early TNBC in 12 French cancer centres. We explored the correlation between clinicopathological data and ALNI, with a specific focus on the dichotomisation between macrometastases and occult metastases, which is defined as the presence of isolated tumour cells or micrometastases. The prognostic value of ALNI both in terms of disease-free survival (DFS) and overall survival (OS) was also explored. RESULTS: We included 1237 TNBC patients. Five-year DFS and OS were 83.7% and 88.5%, respectively. The identified independent prognostic features for DFS were tumour size >20 mm (hazard ratio (HR)=1.86; 95% CI: 1.11-3.10, P=0.018), lymphovascular invasion (HR=1.69; 95% CI: 1.21-2.34, P=0.002) and ALNI both in case of macrometastases (HR=1.97; 95% CI: 1.38-2.81, P<0.0001) and occult metastases (HR=1.72; 95% CI: 1.1-2.71, P=0.019). DFS and OS were similar between tumours with occult metastases and macrometastases. Tumours presenting at least two pejorative features (out of ALNI, lymphovascular invasion and large tumour size) displayed a significantly poorer DFS in both the training set and validation set, independently of chemotherapy administration. Tumours with no more than one of the above-cited pejorative features had a 5-year OS of ⩾90% vs 70% for other cases (P<0.0001). CONCLUSIONS: Axillary lymph node involvement is a key prognostic feature for early TNBC when isolated tumour cells were identified in lymph nodes. This impact is independent of chemotherapy use.

[Lobular invasive breast cancer prognostic factors: About 940 patients]. / Facteurs pronostiques des carcinomes lobulaires infiltrants du sein : à propos de 940 cas.

OBJECTIVES: To assess the prognostic factors of T1 and T2 infiltrating lobular breast cancers, and to investigate predictive factors of axillary lymph node involvement. METHODS: This is a retrospective multicentric study, conducted from 1999 to 2008, among 13 french centers. All data concerning patients with breast cancer who underwent a primary surgical treatment including a sentinel lymph node procedure have been collected (tumors was stage T1 or T2). Patients underwent partial or radical mastectomy. Axillary lymph node dissection was done systematically (at the time of sentinel procedure evaluation), or in case of sentinel lymph node involvement. Among all the 8100 patients, 940 cases of lobular infiltrating tumors were extracted. Univariate analysis was done to identify significant prognosis factors, and then a Cox regression was applied. Analysis interested factors that improved disease free survival, overall survival and factors that influenced the chemotherapy indication. Different factors that may be related with lymph node involvement have been tested with univariate than multivariate analysis, to highlight predictive factors of axillary involvement. RESULTS: Median age was 60 years (27-89). Most of patients had tumours with a size superior to 10mm (n=676, 72%), with a minority of high SBR grade (n=38, 4%), and a majority of positive hormonal status (n = 880, 93, 6%). The median duration of follow-up was 59 months (1-131). Factors significantly associated with decreased disease free survival was histological grade 3 (hazard ratio [HR]: 3,85, IC 1,21-12,21), tumour size superior to 2cm (HR: 2,85, IC: 1,43-5,68) and macrometastatic lymph node status (HR: 3,11, IC: 1,47-6,58). Concerning overall survival, multivariate analysis demonstrated a significant impact of age less than 50 years (HR: 5,2, IC: 1,39-19,49), histological grade 3 (HR: 5,03, IC: 1,19-21,25), tumour size superior to 2cm (HR: 2,53, IC: 1,13-5,69). Analysis concerning macrometastatic lymph node status nearly reached significance (HR: 2,43, IC: 0,99-5,93). There was no detectable effect of chemotherapy regarding disease free survival (odds ratio [OR] 0,8, IC: 0,35-1,80) and overall survival (OR: 0,72, IC: 0,28-1,82). Disease free survival was similar between no axillary invasion (pN0) and isolated tumor cells (pNi+), or micrometastatic lymph nodes (pNmic). There were no difference neither between one or more than one macromatastatic lymph node. But disease free survival was statistically worse for pN1 compared to other lymph node status (pN0, pNi+ or pNmic). Factors associated with lymph node involvement after logistic regression was: age from 51 to 65 years (OR: 2,1, IC 1,45-3,04), age inferior to 50 years (OR 3,2, IC: 2,05-5,03), Tumour size superior to 2cm (OR 4,4, IC: 3,2-6,14), SBR grading 2 (OR 1,9, IC: 1,30-2,90) and SBR grade 3 (OR 3,5, IC: 1,61-7,75). CONCLUSION: The analysis of this series of 940 T1 and T2 lobular invasive breast carcinomas offers several information: factors associated with axillary lymph node involvement are age under 65 years, tumor size greater than 20mm, and a SBR grade 2 or 3. The same factors were significantly associated with the OS and DFS. The macrometastatic lymph node involvement has a significant impact on DFS and OS, which is not true for isolated cells and micrometastases, which seem to have the same prognosis as pN0.

Evaluation of axillary involvement by ultrasound-guided lymph node biopsy: A prospective study.

OBJECTIVES: The primary aim of this prospective study was to evaluate the accuracy of pre-operative ultrasound (US) alone and associated with a fine needle aspiration cytology (FNAC) or a core needle biopsy (CNB) in the diagnosis of axillary node involvement in patient with breast cancer. The secondary study objective was to determine if this US±FNAC or CNB can lead to the adequate axillary surgery in cN0 and cN1 patient. METHODS: A total of 121 consecutive women with stage cT1 to cT2, cN0/cN1, invasive breast cancer were prospectively identified at our institution between February 2, 2013 and August 30, 2013. The sensitivity, specificity, VPP, NPV were calculated, with confidence intervals, using the definitive histological result of the sentinel node biopsy (SLNB) or axillary lymph node dissection (ALND) as the baseline. RESULTS: Twenty-seven CNB and 2 FNAC were performed. For the whole series, the sensitivity and the specificity of US alone were 48.7% [36-59%] and 89% [83-94%]. For US±FNAC or CNB, the sensitivity and the specificity were 35.9% [26-38%] and 98.8% [94-100%]. Seven women with cN1 clinical examination had SLNB, which permit to decrease the number of ALND of 16.3%. It would have avoided unnecessary SLNB, prompting immediate ALND in 9 patients with cN0 axillae, which means a reduction of SLNB of 8.6%. US±FNAC or CNB lead to the adequate surgery in 72.7% of cases. CONCLUSION: US±CNB or FNAC is also a relatively efficient and safe test and should be considered routinely. It allowed triaging patients to the well axillary surgery (SLNB or ALND).

Just how accurate are the major risk stratification systems for early-stage endometrial cancer?

BACKGROUND: To compare the accuracy of five major risk stratification systems (RSS) in classifying the risk of recurrence and nodal metastases in early-stage endometrial cancer (EC). METHODS: Data of 553 patients with early-stage EC were abstracted from a prospective multicentre database between January 2001 and December 2012. The following RSS were identified in a PubMed literature search and included the Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC-1), the Gynecologic Oncology Group (GOG)-99, the Survival effect of para-aortic lymphadenectomy (SEPAL), the ESMO and the ESMO-modified classifications. The accuracy of each RSS was evaluated in terms of recurrence-free survival (RFS) and nodal metastases according to discrimination. RESULTS: Overall, the ESMO -modified RSS provided the highest discrimination for both RFS and for nodal metastases with a concordance index (C-index) of 0.73 (95% CI, 0.70-0.76) and an area under the curve (AUC) of 0.80 (0.78-0.72), respectively. The other RSS performed as follows: the PORTEC1, GOG-99, SEPAL, ESMO classifications gave a C-index of 0.68 (0.66-0.70), 0.65 (0.63-0.67), 0.66 (0.63-0.69), 0.71 (0.68-0.74), respectively, for RFS and an AUC of 0.69 (0.66-0.72), 0.69 (0.67-0.71), 0.68 (0.66-0.70), 0.70 (0.68-0.72), respectively, for node metastases. CONCLUSIONS: None of the five major RSS showed high accuracy in stratifying the risk of recurrence or nodal metastases in patients with early-stage EC, although the ESMO-modified classification emerged as having the highest power of discrimination for both parameters. Therefore, there is a need to revisit existing RSS using additional tools such as biological markers to better stratify risk for these patients.

A clue towards improving the European Society of Medical Oncology risk group classification in apparent early stage endometrial cancer? Impact of lymphovascular space invasion.

BACKGROUND: Lymphovascular space invasion (LVSI) is one of the most important predictors of nodal involvement and recurrence in early stage endometrial cancer (EC). Despite its demonstrated prognostic value, LVSI has not been incorporated into the European Society of Medical Oncology (ESMO) classification. The aim of this prospective multicentre database study is to investigate whether it may improve the accuracy of the ESMO classification in predicting the recurrence risk. METHODS: Data of 496 patients with apparent early-stage EC who received primary surgical treatment between January 2001 and December 2012 were abstracted from prospective multicentre database. A modified ESMO classification including six risk groups was created after inclusion of the LVSI status in the ESMO classification. The primary end point was the recurrence accuracy comparison between the ESMO and the modified ESMO classifications with respect to the area under the receiver operating characteristic curve (AUC). RESULTS: The recurrence rate in the whole population was 16.1%. The median follow-up and recurrence time were 31 (range: 1-152) and 27 (range: 1-134) months, respectively. Considering the ESMO modified classification, the recurrence rates were 8.2% (8 out of 98), 23.1% (15 out of 65), 25.9% (15 out of 58), and 45.1% (28 out of 62) for intermediate risk/LVSI-, intermediate risk/LVSI+, high risk/LVSI-, and high risk/LVSI+, respectively (P<0.001). In the low risk group, LVSI status was not discriminant as only 7.0% (14 out of 213) had LVSI+. The staging accuracy according to AUC criteria for ESMO and ESMO modified classifications were of 0.71 (95% CI: 0.68-0.74) and 0.74 (95% CI: 0.71-0.77), respectively. CONCLUSIONS: The current modified classification could be helpful to better define indications for nodal staging and adjuvant therapy, especially for patients with intermediate risk EC.

[Impact of a training workshop on residents and senior registrar skill in diagnosis and repair of anal sphincter and rectal mucosae obstetrical injuries]. / Impact d'un atelier de formation au diagnostic et à la réparation des lésions obstétricales du sphincter anal et de la muqueuse rectale sur les compétences des internes et chefs de clinique.

OBJECTIVE: To evaluate the impact of a training workshop on residents and senior registrar skill in repair of anal sphincter and rectal mucosae obstetrical injury. MATERIAL AND METHODS: Residents and senior registrar practical and theoretical knowledge were evaluated by a questionnaire sent, using AGOF (association des gynécologues-obstétriciens en formation) mailing list. This questionnaire includes questions about epidemiology, risk factors and sutures types. Scores were compared according to the participation or not at the workshop. RESULTS: There were 106 residents or senior registrar (48.4%) in the workshop group and 113 (51.6%) in the control group. Scores were significantly higher in the workshop group than in the control group for theoretical knowledge (4.1 vs. 3.7), practical knowledge (17.6 vs. 15.9) and global scores (21.7 vs. 19.7). There was no difference according to the participation before or after the third residency semester. Residents global scores were statistically higher in the workshop group compared to the control group (21.8 vs. 19.5) but there was no significant difference between the senior registrar of the two group. Participants in the workshop group estimate themselves significantly more efficient than in the control group concerning anal sphincter injury repair and rectal mucosae repair. CONCLUSION: A training workshop seems to improve the theoretical and practical skill. LEVEL OF EVIDENCE: 4.

Characteristics and clinical outcome of T1 breast cancer: a multicenter retrospective cohort study.

BACKGROUND: A subgroup of T1N0M0 breast cancer (BC) carries a high potential of relapse, and thus may require adjuvant systemic therapy (AST). PATIENTS AND METHODS: Retrospective analysis of all patients with T1 BC, who underwent surgery from January 1999 to December 2009 at 13 French sites. AST was not standardized. RESULTS: Among 8100 women operated, 5423 had T1 tumors (708 T1a, 2208 T1b and 2508 T1c 11-15 mm). T1a differed significantly from T1b tumors with respect to several parameters (lower age, more frequent negative hormonal status and positive HER2 status, less frequent lymphovascular invasion), exhibiting a mix of favorable and poor prognosis factors. Overall survival was not different between T1a, b or c tumors but recurrence-free survival was significantly higher in T1b than in T1a tumors (P = 0.001). In multivariate analysis, tumor grade, hormone therapy and lymphovascular invasion were independent prognostic factors. CONCLUSION: Relatively poor outcome of patients with T1a tumors might be explained by a high frequency of risk factors in this subgroup (frequent negative hormone receptors and HER2 overexpression) and by a less frequent administration of AST (endocrine treatment and chemotherapy). Tumor size might not be the main determinant of prognosis in T1 BC.

[Demography and training of residents in gynaecology and obstetrics: results of a national survey]. / Démographie et formation des internes en gynécologie et obstétrique : résultats d'une enquête nationale.

OBJECTIVE: To survey French trainees in obstetrics and gynaecology on the general demographic evolution and the quality of training. MATERIAL AND METHODS: A questionnaire was sent to the 919 trainees in obstetrics and gynaecology during the academic year 2010-2011. RESULTS: Answer rate was 38.5%. Almost all trainees (99.4%) wish to have a two-year hospital position before applying for consultant or beginning a private practice; 60.4% of these trainees declare this option realistic. Trainees demography is marked by an increasing number of young doctors to train and a feminization. DISCUSSION AND CONCLUSION: The need of a debate is crucial to assure quality of training after the recent increase in the number of residents and trainees reforms.