Jean-Luc Brun

External validation of a laparoscopic-based score to evaluate resectability of advanced ovarian cancers : Clues for a simplified score

BACKGROUND The relevance of laparoscopy-based score in identifying patients with advanced ovarian cancer for optimal cytoreductive surgery has been evaluated. METHODS 55 patients with stage III-IV ovarian cancer, having undergone both laparoscopy and laparotomy for cytoreductive surgery, were retrospectively analyzed. Seven parameters were assessed: omental cake, peritoneal carcinosis, diaphragmatic carcinosis, mesenteric retraction, bowel infiltration, stomach infiltration, liver metastases. Each parameter was assigned 2 points if present and 0 if not (Fagotti score). Sensitivity, specificity, positive (PPV) and negative (NPV) predictive values, and accuracy were calculated for each parameter. Receiver Operating Characteristic (ROC) curve analysis was used to predict the surgical outcome. RESULTS A laparoscopy-based score of >or=8 was associated with suboptimal cytoreduction with sensitivity, specificity, PPV, NPV, and accuracy of 46%, 89%, 89%, 44%, and 60% respectively. ROC curve analysis gave an Area Under the Curve (AUC) of 0.74. A modified score was set up by selecting 4 of the 7 parameters which satisfied the inclusion criteria in our population: diaphragmatic carcinosis, mesenteric retraction, stomach infiltration, liver metastases. Thirteen patients (12%) had a modified score of >or=4 and 42 patients (88%) had a score of <4 with an optimal cytoreduction rate of 0% and 43% respectively (P=0.002). A modified score of >or=4 was associated with suboptimal cytoreduction with sensitivity, specificity, PPV, NPV, and accuracy of 35%, 100%, 100%, 43%, and 56% respectively. ROC curve analysis gave an AUC of 0.68. CONCLUSION This simplified laparoscopy-based score was at least as accurate as the Fagotti score to predict resectability.

Regression of high-grade cervical intraepithelial neoplasia with TG4001 targeted immunotherapy

OBJECTIVE We sought to evaluate the safety and efficacy of TG4001 in patients with human papillomavirus (HPV) 16-related cervical intraepithelial neoplasia (CIN) 2/3 at 6 and 12 months. STUDY DESIGN In all, 21 patients with HPV 16-related CIN 2/3 received 3 weekly subcutaneous injections of TG4001. Regression of the CIN 2/3 lesion and the clearance of HPV 16 infection were monitored by cytology, colposcopy, and HPV DNA/messenger RNA (mRNA) detection. A clinical response was defined by no CIN 2/3 found on conization, or no conization performed because not suspected at cytology or colposcopy. RESULTS Ten patients (48%) were evaluated as clinical responders at month 6. Nine patients experienced an improvement of their HPV 16 infection, by mRNA ± DNA eradication. HPV 16 mRNA clearance was associated with CIN 2/3 cytologic and colposcopic regression in 7 of 10 patients. At month 12, 7 of 8 patients without conization reported neither suspicion of CIN 2/3 relapse nor HPV 16 infection. The remaining patient was lost to follow-up. CONCLUSION These promising data warrant further development of TG4001 in CIN 2/3 treatment.

Factors influencing the use and accuracy of frozen section diagnosis of epithelial ovarian tumors

OBJECTIVE The objective of the study was to study factors influencing the use and accuracy of frozen section diagnosis (FSD) of ovarian tumors. STUDY DESIGN Surgery was performed in 414 patients with epithelial ovarian tumors between 2001 and 2006. Factors were identified by univariate and multivariate analysis. RESULTS FSD was requested in 274 patients: 152 benign, 55 borderline, and 67 malignant tumors. Age 50 years or older, tumor size 10 cm or greater, and preoperative evidence of malignancy were associated with FSD request. The sensitivity and specificity of FSD for benign, borderline, and malignant tumors were 97% and 81%, 62% and 96%, and 88% and 99%, respectively. The histologic type (mucinous), tumor size (less than 10 cm), the borderline component (less than 10%), and the pathologists experience predicted misdiagnosis of borderline tumors. Spread outside the ovary was the only significant predictor of accurate FSD of malignant tumors. CONCLUSION FSD is less accurate for borderline than benign and malignant ovarian tumors. The pathologists experience is a major determinant of diagnostic accuracy.

Expression of MMP-2, -7, -9, MT1-MMP and TIMP-1 and -2 has no prognostic relevance in patients with advanced epithelial ovarian cancer

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in tumor invasion, but their prognostic significance is still under discussion. We set out to analyze the epithelial and stromal expression of MMP-2, MMP-7, MMP-9, MT1-MMP, TIMP-1 and TIMP-2 in advanced epithelial ovarian cancers and to assess their prognostic value. A tissue microarray of malignant ovarian tumors from 69 patients was constructed. Immunostaining results were scored using the HSCORE and assessed by univariate analysis with Bonferroni correction and classical multidimensional scaling (CMDS). Kaplan-Meier survival curves calculated with regard to patient and tumor characteristics were compared by the log-rank test. Patients treated by primary surgery (n=43) had a higher tumor size and a trend toward higher epithelial MMP and TIMP expression than those treated by interval surgery (n=26). Optimal cytoreduction (residue ≤1 cm) was obtained in 27 and 18 patients, respectively. Clinical and histological characteristics were not different in patients with optimal cytoreduction and those with suboptimal cytoreduction. The expression of epithelial MMP-9 (P=0.002) and TIMP-2 (P=0.026) were higher in the latter group. CMDS failed to demonstrate any influence of MMP and TIMP expression with regard to cytoreduction outcome. MMP and TIMP expression did not influence survival. Their prognostic values were outweighed by histological type, lymph node involvement and cytoreduction. Standard statistical analysis adjusted after Bonferroni correction and CMDS reduced the relevance of MMPs and TIMPs in the prognosis of patients with advanced ovarian cancer.

Neoadjuvant chemotherapy or primary surgery for stage III/IV ovarian cancer: contribution of diagnostic laparoscopy.

BackgroundThe aims of this retrospective study were to evaluate laparoscopic triage of patients with advanced ovarian cancer towards primary surgery or neoadjuvant chemotherapy, and to analyze outcome according to the treatment.MethodsBetween January 2001 and December 2006, 55 patients with stage III – IV ovarian cancer underwent diagnostic laparoscopy. Primary surgery was performed when complete cytoreduction was considered feasible, while the other patients received neoadjuvant chemotherapy (platinum-based combination with taxanes) and interval surgery. All the patients received adjuvant chemotherapy.ResultsPatients treated with neoadjuvant chemotherapy (n = 29) had a higher mean body mass index (P = 0.048), higher serum CA 125 levels (P = 0.026), and more metastases (P = 0.045) than patients treated with primary surgery (n = 26). In patients treated with primary surgery, complete cytoreduction and a residual tumour size ≤ 2 cm were obtained in respectively 54% and 77% of cases. Complete cytoreduction was achieved in respectively 100% and 33% of cases when primary surgery was performed by an oncologic gynaecologist and by a non-oncologic gynaecologist (P = 0.002). Interval surgery yielded complete cytoreduction and a residual tumour size ≤ 2 cm in respectively 73% and 85% of cases. With a median follow-up of 24 months (range 7 – 78 months), the survival rates after primary surgery and interval surgery were 61% and 66% respectively.ConclusionDiagnostic laparoscopy is useful for identifying patients with stage III/IV ovarian cancer who qualify for primary cytoreduction. Surgeon experience was a determining factor for the success of complete cytoreduction.

Benefits of Direct Colposcopic Vision for Optimal LLETZ Procedure: A Prospective Multicenter Study

Objective The aim of the study was to assess whether direct colposcopic vision (DCV) of the cervix during large loop excision of the transformation zone (LLETZ) is associated with a decrease in the volume and dimensions of specimens or affects margin status at histology. Materials and Methods A prospective multicenter observational study of 216 women who underwent LLETZ for grades 2 and 3 cervical intraepithelial neoplasia was conducted. The volume and dimensions (circumference, length, and thickness) of the surgical specimens were measured before fixation. Data were compared according to the use of colposcopy during LLETZ. The following 3 groups were considered: LLETZ performed without colposcopy (n = 91), LLETZ performed immediately after colposcopy (n = 51), and LLETZ performed under DCV (n = 74). Results Patient characteristics were comparable with regard to age, parity, history of excision, indication of the procedure, and the size of the cervix. We found a significant decrease in all dimensions of the specimens obtained under DCV (p < .001). Margin status was not affected. After adjusting for confounders, the mean volumes were significantly lower in the DCV group (adjusted mean difference = −0.66 mL; 95% CI = −1.17 to −0.14). The probability that negative margins would be achieved together with the attainment of a volume less than 5 mL and a thickness less than 10 mm was the highest in the DCV group (adjusted OR = 2.80; 95% CI = 1.13 to 6.90). Conclusions Direct colposcopic vision is associated with a significant decrease in the volume and in all dimensions of LLETZ specimens with no compromise in the margin status.

Surgery is not superior to dilation for the management of vaginal agenesis in Mayer-Rokitansky-Küster-Hauser syndrome: a multicenter comparative observational study in 131 patients

BACKGROUND: Vaginal agenesis in Mayer‐Rokitansky‐Küster‐Hauser syndrome can be managed either by various surgeries or dilation. The choice still depends on surgeon’s preferences rather than on quality comparative studies and validated protocols. OBJECTIVE: We sought to compare dilation and surgical management of vaginal agenesis in Mayer‐Rokitansky‐Küster‐Hauser syndrome, in terms of quality of life, anatomical results, and complications in a large multicenter population. STUDY DESIGN: Our multicenter study included 131 patients >18 years, at least 1 year after completing vaginal agenesis management. All had an independent gynecological evaluation including a standardized pelvic exam, and completed the World Health Organization Quality of Life instrument (general quality of life) as well as the Female Sexual Function Index and Female Sexual Distress Scale‐Revised (sexual quality of life) scales. Groups were: surgery (N = 84), dilation therapy (N = 26), and intercourse (N = 20). One patient was secondarily excluded because of incomplete surgical data. For statistics, data were compared using analysis of variance, Student, Kruskal‐Wallis, Wilcoxon, and Student exact test. RESULTS: Mean age was 26.5 ± 5.5 years at inclusion. In all groups, World Health Organization Quality of Life scores were not different between patients and the general population except for lower psychosocial health and social relationship scores (which were not different between groups). Global Female Sexual Function Index scores were significantly lower in the surgery and dilation therapy groups (median 26 range [2.8–34.8] and 24.7 [2.6–34.4], respectively) than the intercourse group (30.2 [7.8–34.8], P = .044), which had a higher score only in the satisfaction dimension (P = .004). However, the scores in the other dimensions of Female Sexual Function Index were not different between groups. The Female Sexual Distress Scale‐Revised median scores were, respectively, 17 [0–52], 20 [0–47], and 10 [10–40] in the surgery, dilation therapy, and intercourse groups (P = .38), with sexual distress in 71% of patients. Median vaginal depth was shorter in dilatation therapy group (9.6 cm [5.5–12]) compared to surgery group (11 cm [6–15]) and intercourse group (11 cm [6–12.5]) (P = .039), but remained within normal ranges. One bias in the surgery group was the high number of sigmoid vaginoplasties (57/84, 68%), but no differences were observed between surgeries. Only 4 patients achieved vaginas <6.5 cm. Delay between management and first intercourse was 6 months (not significant). Seventy patients (53%) had dyspareunia (not significant), and 17 patients all from the surgery group had an abnormal pelvic exam. In the surgery group, 34 patients (40.5%) had complications, requiring 20 secondary surgeries in 17 patients, and 35 (42%) needed postoperative dilation. In the dilation therapy group, 13 (50%) needed maintenance dilation. CONCLUSION: Surgery is not superior to therapeutic or intercourse dilation, bears complications, and should therefore be only a second‐line treatment. Psychological counseling is mandatory at diagnosis and during therapeutic management.

The Accuracy of Large Loop Excision of the Transformation Zone Specimen Dimensions in Determining Volume: A Multicentric Prospective Observational Study.

Objective The aim of the study was to determine which mathematical formula of specimen dimensions is the most accurate method of determining volume of the excised specimen at loop excision of the transformation zone. Materials and Methods A multicenter prospective observational study was conducted. A total of 258 patients who had a loop excision of the transformation zone performed as treatment of cervical intraepithelial neoplasia 2–3 were included. The dimensions and the volume of the specimen were measured at the time of the procedure, before formaldehyde fixation. The volume was measured by immersing the specimen in a graduated cylinder using Archimedes fluid displacement technique. The measured volume was compared with the calculated volume using different volume formulas, that is, a cone, a cylinder, a parallelepiped, and a hemiellipsoid. The main outcome measure was the relationship between calculated volume (using the dimensions of thickness, length, and circumference) and the measured volume of the specimen. Results The mean (SD) thickness, length, and circumference of specimens were 8.8 mm (3.8), 12.7 mm (5.9), and 45.7 mm (16.8), respectively. The mean (SD) measured volume was 2.53 (1.49) mL. Using the formula for the volume of a cone, a cylinder, a parallelepiped and a hemiellipsoid, estimated volumes were 1.03 mL (1.22), 3.10 mL (3.65), 6.20 mL (7.31), and 2.07 mL (2.44), respectively. The highest intraclass correlation coefficient between measured and calculated volume was observed when using the formula for the volume of a hemiellipsoid specimen (0.47, 95% CI = 0.36–0.56). Conclusions The hemiellipsoid formula is the most accurate determinant of the excised volume. Other formulas do not allow for an accurate estimation of the excised volume.

Le point sur le vaccin HPV

Les deux vaccins HPV (Human papillomavirus) developpes a ce jour reposent sur le principe de la vaccination prophylactique a base de particules pseudo-virales L1 (VLP [Virus Like Particles]). Ils ont montre une efficacite superieure a 90 % et significative par rapport au placebo, avec un recul de plus de cinq ans sur la prevention des infections persistantes (95 %) et des dysplasies cervicales (100 %) induites par les genotypes d’HPV concernes par la vaccination. Ces vaccins induisent une immunite humorale stable et durable, avec plus de quatre ans de recul. Elle est superieure a celle qui est obtenue apres infection naturelle, mais le maintien de cette immunite et de son efficacite au-dela de cinq ans doit etre confirme. La necessite d’un rappel ne peut etre precisee a ce jour, mais une reponse anamnestique de qualite a ete obtenue apres une injection vaccinale quadrivalente, cinq ans apres primovaccination. La tolerance des vaccins a court et moyen termes est tres satisfaisante. Les effets indesirables sont frequents sur le site d’injection (> 80 %) et peuvent s’accompagner d’effets systemiques transitoires dans plus de 50 % des cas. Ces effets sont de faible intensite et n’ont quasiment aucune influence sur le deroulement du protocole vaccinal. Le vaccin n’a pas montre d’effet deletere sur l’issue des grossesses. Des etudes de pharmacovigilance sont planifiees afin de detecter d’eventuels effets indesirables rares et confirmer la securite des vaccins a long terme chez les femmes et leurs futurs enfants. Une protection croisee est possible sur HPV 31 et 45, voire 52, en termes de reaction immunitaire pour le vaccin quadrivalent ou d’infection virale pour le vaccin bivalent. Elle doit etre confirmee et evaluee sur la prevention des dysplasies cervicales specifiquement induites par ces genotypes. Par rapport a la population de reference (15 a 26 ans), la reponse immunitaire humorale postvaccinale est augmentee chez les filles de 10 a 15 ans (vaccin quadrivalent) et diminuee chez les femmes de 26 a 55 ans (vaccin bivalent). Elle reste cependant superieure a l’immunite naturelle. Les variations de tolerance observees sont acceptables. Les vaccins HPV sont inefficaces pour augmenter la clairance virale des femmes deja infectees par HPV 16 et/ou 18 (ADN positif) et prevenir les dysplasies cervicales viro-induites. Par contre, la vaccination semble etre efficace chez les femmes seropositives pour HPV 16 ou 18 et ADN negatif. Chez les femmes infectees par des HPV a haut risque autres que 16 et 18, la vaccination n’augmente pas les chances de disparition de l’infection par ces HPV et n’apparait pas efficace pour prevenir les dysplasies cervicales induites par ces virus. La vaccination prophylactique contre l’HPV est tres efficace et bien toleree ; les benefices sont tels qu’elle devrait largement couvrir la population cible. Toutefois, et dans tous les cas, elle doit s’associer au depistage pour une prevention optimale des cancers du col uterin.