Systematic versus sentinel-lymph-node-driven axillary-lymph-node dissection in clinically node-negative patients with operable breast cancer. Results of the GF-GS01 randomized trial.

PURPOSE: Sentinel-lymph-node (SLN) resection seems to minimize systematic axillary-lymph-node dissection (sALND) side effects in operated breast cancer patients. We explored whether SLN resection achieves similar therapeutic outcomes as sALND but with fewer side effects. METHODS: A randomized, controlled, open-label trial with parallel-group design compared sALND restricted to cases with positive SLN biopsy (test arm, n = 774) versus SLN biopsy followed by sALND (control arm, n = 770). RESULTS: The five-year overall survivals in control and test arms were 96.42 and 95.64% (P = 0.2925). The estimated difference was nearly zero (precisely, - 0.79%, one-tailed 95% confidence interval (CI) limit - 2.44%). In a multivariate Cox model, the adjusted hazard ratio in the test arm was HR 0.81 (upper 95% CI limit 1.17). Advanced age (HR 1.05 per additional year, CI [1.03-1.08]), negative progesterone receptor (HR 2.17 [1.35-3.45]), SLN metastasis (HR 1.69 [1.03-2.79]), and only one SLN identification technique (HR 4.14 [1.21-14.18]) were associated with lower survival. Patients with ≥ 1 severe side effect at 1 month in control and test arms were 173/703 = 24.6% [21.5-28.0%] and 91/693 = 13.1% [10.7-15.9%] (P < 0.001). The estimated sensitivity of SLN biopsy (control arm) was 145/178 = 81.5% [74.8-86.7%]. CONCLUSIONS: Restricting ALND to cases with positive SLN biopsy does not affect the overall survival but reduces by 11.5% [7.5-15.6%] (P < 0.001) the risk of severe short-time side effects of sALND.

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.

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.

Total transvaginal mesh (TVM) technique for treatment of pelvic organ prolapse: a 5-year prospective follow-up study.

INTRODUCTION AND HYPOTHESIS: To evaluate clinical effectiveness and complication rates at 5 years following the total Trans Vaginal Mesh (TVM) technique to treat pelvic organ prolapse. METHODS: Prospective, observational, multi-centre study in patients with prolapse of stage II or higher. RESULTS: Of the 90 women enrolled in the study, 82 (91%) were available for the 5-year follow-up period. At the 5-year endpoint, success, defined as no surgical prolapse reintervention and leading edge <-1 (International Continence Society [ICS] criteria) or above the level of the hymen, was 79% and 87% respectively. A composite criterion of success defined as: leading edge above the hymen (<0) and no bulge symptoms and no reintervention for prolapse was met by 90%, 88% and 84% at the 1-, 3-, and 5-year endpoints respectively. Quality of life improvement was sustained over the 5 years. Over the 5-year follow-up period, a total of only 4 patients (5%) required re-intervention for prolapse, while a total of 14 patients (16%) experienced mesh exposure for which 8 resections needed to be performed. Seven exposures were still ongoing at the 5-year endpoint, all asymptomatic. Only 33 out of 61 (54%) sexually active patients at baseline remained so at 5 years. De novo dyspareunia was reported by 10%, but no new cases at the 5-year endpoint. One patient reported de novo unprovoked mild pelvic pain at 5 years, 5 reported pains during pelvic examination only. CONCLUSIONS: Five-year results indicated that TVM provided a stable anatomical repair. Improvements in QOL and associated improvements in prolapse-specific symptoms were sustained. Minimal new morbidity emerged between the 1- and 5-year follow-up.

Anatomy theaters in the history and teaching of surgery.

The study of anatomy has played a large part in the progress of scientific observation throughout the centuries and was pivotal in elevating anatomy from the magical thinking of the Hippocrates era and freeing it from subservience to medicine which was all-powerful in the past. Anatomy theaters appeared in Northern Italy in the 14th century and developed in Western Europe from the early 16th century to the beginning of the 19th century. Anatomy theaters lived their golden age in France during the 18th century when the Royal Academy of Surgery (Académieroyaledechirurgie) was created in 1743. These theaters were open to the public, and therefore offered the double vocation of teaching and public entertainment: they were used to teach anatomy and surgery to students and surgeons and offered distraction for the well-informed public that was fascinated by death, ever-present and familiar to all. Anatomical dissection accomplished a double ritual: the "profane" ritual of valorization of scientific knowledge and the "sacred" ritual, where mankind, obsessed with death, respected the human body considered as a divine image. Anatomy theaters declined as they became overshadowed by progress in anatomical teaching using well-illustrated works in well-equipped medical schools while exhibition of anatomic oddities for public amusement was relegated to fairs and circus sideshows. Nonetheless they opened the way to modern anatomo-clinical methods and surgery.

[TVT Secur: prospective study and follow up at 1 year about 154 patients]. / TVT Secur : étude prospective et suivi à un an de 154 patientes.

OBJECTIVES: To evaluate the efficacy and complications of this new sub-urethral tape procedure with a follow up of 12 months. MATERIALS AND METHODS: Prospective, multicenter study of 154 patients operated for stress urinary incontinence with the TVT Secur. Patients were operated between 24 July 2006 and 18 December 2007 and were all controlled at 2 months and 118 at 1 year. No associated surgical procedure was performed. RESULTS: One hundred five patients had pure stress incontinence with 12 of them presenting an intrinsic sphincter deficient. Forty-nine had a mixed urinary incontinence with 12 of them having ISD. Preoperatively, 69 patients complained of urgency and 12 of micturation disorder. Anaesthesia was local for 97 patients (63%). Per operative complications were five hemorrhages, one bladder injury, one vaginal wound, 21 patients had post-void residual volume (100 to 200ml) and one groin pain. We noted two exposed tapes, one granuloma, one ITU and seven lateral vaginal bands. Among the patients with urge at baseline, 61.2% were cured at 2 months and 75.5% at 1 year. De novo urge appeared in 12.8% at 2 months and 12.3% at 1 year. De novo micturation disorder was found in 9.5% at 2 months and 3.7% at 1 year. The cured patients at 1 year were 70.3%, improved 11% and fails 18.7%. The cured rate remains same between 2 months and 1 year. The improved patients (24%) at 2 months remain 11% at 1 year. The recurrence rate was 12,8% at 1 year. CONCLUSION: The results are inferior to TVT or TVT-O procedures. We probably must selected the patients for this procedure.

[TVT Secur: more and more minimally invasive. Preliminary prospective study of 110 cases]. / TVT Secur: de plus en plus minimal invasif. Etude préliminaire prospective sur 110 cas.

OBJECTIVES: To present a new minimal invasive suburethral tape device derivative of the classic TVT, to describe the technique of laying, to evaluate complications and results to short term. MATERIALS AND METHODS: Prospective multicentric study of 110 patients presenting a stress urinary incontinence and benefiting from the laying of TVT Secur without associated operation. The tape is identical to that old-fashioned retropubic and obturator TVT, smaller, laying in "U" or in "hammock" without orifice of exit, to avoid complications due to crossed spaces of the other techniques. The device and the technique of laying are described by authors. The originality of the TVT Secur resides in the mechanism of insertion of the tape to a metallic divice. All patients have been controlled at two months and complications with notably pains (quotation VAS) as well as objective results have been reported. RESULTS: Pure and isolated stress urinary incontinence for 71 patients, mixed incontinence for 39 and sphincter deficient for 23. Preoperative urgency for 49 patients and dysuria for 10 of them. The method "hammock" has been used in 85.5% of cases. The type of anaesthesia has been pure local for 69.1% (0 to 98.8% for the different centers) with an average operative time of 8'30". Under local anaesthesia, the average per operative pain was quoted 2.8/10, and 0.7 at the end of intervention. Peroperative complications have revealed a wound of bladder, a vaginal wound and four bleeding of more than 100ml. In immediate continuations a total retention yielding to 24h and 13 postmicturition residual between 100 and 200ml have been mentioned. At two months, authors have observed the following: de novo urgency in 19.6%, de novo dysuria in 13.2%, one tape exposition, one granuloma, one urinary infection and seven perceptible lateral cords without pain. Thirteen patients have signalled to have had moderated pains on a duration of four to 30 days. Early objective results are globally 70.4% of dry patients (83% for pure isolated SUI, 72.2% for SUI with deficient sphincter, 50% for mixed incontinence). The pure local anaesthesia was recommended by 98% of patients. CONCLUSION: The diminution of complications ahead not to be made to the detriment of results, it is necessary to envisage multicentric studies with standardized modifications. The indications of this new device will have to be defined.

[TVT-O treatment of stress urinary incontinence: immediate and one-year results]. / Traitement de l'incontinence urinaire d'effort par bandelette TVT-O: résultats immédiats et à un an.

OBJECTIVE: To compare one-year results between the classic retropupubic (TVT) and the in-out transobturator approaches (TVT-O) of tension-free vaginal tape for the treatment of stress urinary incontinence (SUI). PATIENTS AND METHODS: The first 82 patients operated for SUI by TVT-O in our institution were included in the analysis. Patients were evaluated at 1 and 12 months. The global satisfaction rate was assessed at 12 months by a self-reported questionnaire. Results were compared to those of the first 124 patients operated of SUI by TVT in the same institution and by the same surgeons between 1996 and 1999. RESULTS: Except a younger mean age in the TVT-O group (57 versus 60 years), no other preoperative parameter was significantly different between the TVT and the TVT-O groups. The mean operating time was shorter in the TVT-O group (15 versus 30 minutes, P<0.001). No intraoperative complication occurred. The rate of bladder perforation was significantly lower in the TVT-O group (0 versus 8.8%, P=0.004). The rate of post-voiding residual less than 100 ml was higher in the TVT-O group (88 versus 61%, P<0.001). In the TVT-O group, 40% of patients had postoperative inguinal pain (mean=9 days, range 2-15 days). After 12 months from TVT-O, 85% of patients were completely dry, 6% had de novo over bladder activity, and 93.5% of patients were satisfied with the treatment they received. The 12-month results were not significantly different between the TVT and the TVT-O groups. DISCUSSION AND CONCLUSION: With a follow-up of 12 months, TVT-O is as efficient as TVT and has a lower risk of bladder injury, a cut by half operating time, and less postoperative dysuria.

[Intraperitoneal chemotherapy in ovarian cancer]. / Chimiothérapie intrapéritonéale dans le cancer de l'ovaire.

Ovarian cancer represents 4500 new cases a year in France and the prognosis of such tumor is not yet clear, even for the early stages. This is notably owing to the amount and size of peritoneal tumor residual. Recently, five therapeutic trials were published concerning the intra-peritoneal chemotherapy of ovarian cancer stage III in patients to whom an optimal debulking surgery had been done. These studies were variable in there outcome showing on the one hand, either the absence of significant difference or a significant lengthening of both total life duration and life without recurrence during the period of treatment with intra-peritoneal chemotherapy. On the other hand, there was a significant increase in hematological toxicity and temporary impairment of the quality of life during intra-peritoneal treatments. There were also complications linked to the intra-peritoneal catheter, which led to the termination of the treatment protocol in some cases. However, results showed a mattering benefit of survival in spite of a notable rate of incomplete treatment protocols. These results have demonstrated the necessity to consider the intra-peritoneal adjuvant chemotherapy as a treatment option in patients with epithelial ovarian cancer stage III. Patients must be highly selected and well counseled, in order to go for this treatment option after receiving optimal debulking surgeries.

[Urogynecology pelvic organ prolapse French surgical training during and after residency]. / Formation des internes et jeunes assistants de gynécologie-obstétrique en statique pelvienne en France.

OBJECTIVES: For the treatment of prolapse, the vaginal route is less standardized than laparoscopy and seems abandoned by younger doctors. Our objectives were to evaluate the surgical experience of resident and youth gynecology and obstetrics assistants in pelviperineology and the level of confidence and mastery of the different surgical treatment of pelvic. METHODS: An anonymous questionnaire sent via an Internet platform interviewing residents and young assistants of gynecology and obstetrics (promotion 2005 to 2010) in France on their surgical training in pelviperineology. RESULTS: Twenty-nine percent (208/724) of the persons contacted responded with two thirds of residents and one third of young assistants, all regions of France were represented. Sixty-four percent of respondents wanted to favor a surgical career. The laparoscopic sacrocolpopexy was declared to be the best method mastered while residents and young assistants reported being more often leading operator in vaginal techniques during their medical training. CONCLUSION: Surgical practice during medical training of resident and young assistants did not seem associated with declared mastery level of technique. Different clinical surgical practice training techniques such as simulation, cadaveric study, movies on surgical technics may also improve the level of confidence and mastery of young doctors for surgical techniques.

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.

[Endometrial choriocarcinoma in peri-menopausal women]. / Choriocarcinome utérin en péri-ménopause.

We report a case of a primary uterine choriocarcinoma associated with adenocarcinoma occurring during peri-menopausal age, and review the literature. The clinical course and the histopathology of the case were reviewed and a Medline literature search for other cases was performed. BHCG and analysis of uterine curettage provided the diagnosis of choriocarcinoma. Polychemotherapy, started immediately after the patient's clinical condition deteriorated, was successful. Colpohysterectomy and pelvic lymphadenectomy were performed 5 months later. Treatment was completed by vaginal curietherapy. Histopathologic examination of the surgical specimen revealed only adenocarcinoma. The patient was followed for 18 months without evidence of recurrence. The literature search revealed that primary forms are exceptional; the etiology is unknown. Treatment is based on polychemotherapy. Primary choriocarcinomas are rare tumours, associated with other histopathological forms. We document a case occurring during the peri-menopausal period and review the literature on this pathology. The very poor prognosis in the past has changed with early polychemotherapy.

[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.

Generation of high specificity of effect through low-specificity binding of proteins to DNA.

It is proposed that proteins can bind with relatively low-affinity and specificity to multiple sites, defined as sequence motifs, on polynucleotide chains, and that such binding can collectively be turned into high-affinity, high-specificity binding through cooperative effects, especially when the sequence motifs recur periodically. The selection of individual nucleotides has in general been thought to be the condition of the existence and conservation of function in most of the noncoding sequences. This condition seems unnecessary. Calculations are presented as a step in the direction of giving credibility to a model of stable gene repression.

Skin-window-induced inflammation in breast cancer patients: a study of macrophage migration.

A decreased number of macrophages has previously been demonstrated by means of skin-window assays in operable breast cancer patients. However, in this type of cellular inflammatory response, a varying intensity of cellular activation, cellular recruitment and macrophage chemotaxis exists. In this study, we performed skin windows after stimulation by a chemo-attractant (FMLP) and a recall antigen (Candidin-latex). Cellular responses were classified in 19 breast cancer patients according to the presence (A+) or absence (A0) of macrophage activation by comparison to healthy controls. In 13 A0 patients, the admixture of a cytokine (IFN alpha) and an immunomodulator (P40) to one agent or the other or both resulted in the restoration of macrophage functions. Our study shows that uniform cellular responses to chemo-attractants and antigens are observed in healthy and not immunocompromised individuals as assessed by skin-window tests. However, the cellular response recorded in immunodeficient cancer patients is altered. It also shows that the admixture to chemoattractants and antigens of particular cytokines or better still of an immunomodulator displaying a wide spectrum of activity offers a way of restoring macrophage functions. Individual responses to immunotherapy in clinical oncology may be related to such results.