Outcome in early cervical cancer following pre-operative low dose rate brachytherapy: a ten-year follow up of 257 patients treated at a single institution.

OBJECTIVE: To report the outcome of preoperative low dose rate uterovaginal brachytherapy (LDR-UVBT) followed by radical surgery in the treatment of early cervical carcinoma. METHODS: 257 patients treated at Institut Curie from 1985 to 2008 for cervical carcinoma less than 4cm (FIGO stages Ib1, IIA and IIB) were studied. Patients received preoperative LDR-UVBT followed by hysterectomy Piver II type, with pelvic lymph nodes dissection (PLND). Predictive factors for pathological response to brachytherapy were analyzed with logistic regression, as well as survival rates. RESULTS: 44% of patients had residual tumor, 4.3% of patients had parametrial invasion and 17.9% of patients had lymph node involvement. Predictive factors for an incomplete pathological response were: initial clinical tumor size 20mm (OR 2.1), pN1 (OR 2.77), glandular carcinoma (OR 2.51) and lymphovascular invasion (OR 4.35). 7.4% and 2.7% of patients had respectively grade 2 and grade 3 post-therapeutic late complications. Median follow up was 122 months [1-282]. Five-year actuarial overall survival and disease free survival were respectively 83% CI [78.3-87.5] and 80.9% CI [76.3-85.7]. In multivariate analysis, factors affecting significantly the overall survival and disease free survival rates were: lymph node involvement (RR 4.53 and 8.96 respectively), parametrial involvement (RR 5.69 and 5.62 respectively), smoking (RR 3.07 and 2.63 respectively). CONCLUSIONS: Preoperative LDR-UVBT results in good disease control with a low complications rate. Its accuracy could be improved by a better selection of patients. Lymph nodes and parametrial evaluation remains a challenging issue that should be achieved with imaging and minimal invasive surgery.

Lateral mammaplasty reconstruction after surgery for breast cancer.

BACKGROUND: Up to 60 per cent of cancers develop laterally in the breast and breast-conserving surgery frequently produces superolateral nipple-areolar complex (NAC) distortion aggravated by postoperative irradiation. Correction is technically demanding and the outcomes are variable. Lateral mammaplasty may allow wider excision margins and prevent such deformities. METHODS: This was a review of 86 consecutive patients who had lateral mammaplasty: combined wide tumour excision with NAC repositioning on a reliable dermoglandular pedicle. Simultaneous axillary surgery was performed via a separate or combined incision. Aesthetic outcomes were assessed. RESULTS: The median age of the women was 54 (range 29-75) years; 55 (64 per cent) had palpable tumours and 73 (85 per cent) underwent simultaneous axillary surgery. Median radiological and histological tumour sizes were 29.8 and 33.6 mm, respectively, and median weight of excised tumour was 150 g. Two patients required haematoma evacuation. Eleven women required revisional surgery for involved or close margins. Aesthetic outcomes were excellent or good in 93 per cent. CONCLUSION: Lateral mammaplasty produced clear margins in 87 per cent of women. It is an option when a deformity is anticipated after breast-conserving surgery, and is particularly valuable when neoadjuvant chemotherapy has downgraded a large tumour.

[Secondary breast reconstruction using exclusive lipofilling]. / Reconstruction mammaire secondaire par lipomodelage exclusif.

Lipofilling is usually performed in breast surgery for treatment of aesthetics sequelae after breast conserving surgery or correction after breast reconstruction by prothesis or musculocutaneous flaps. We present a case of a patient where exclusive lipofilling breast reconstruction has been successfully performed. Aesthetic result is assessed by the patient and the surgeon as very satisfactory after one year of follow-up. This technology not much used in this present indication have important advantages in terms of tolerance or morbidness but the long-term results depend on not controlled factors such as volumetric cast iron or fatty resorption. Further studies are necessary to define the patients will be able to benefit from this technology and to assess the modalities of follow-up but also to measure evenly practicability, stability of reconstruction and its evolution in time. However, aesthetic result and contentment of the patient allow us to envisage the broadcasting of this technology of mammary reconstruction for selected patients.

Abdominoperineal resection for anal cancer.

PURPOSE: Following initial radiotherapy or chemoradiotherapy for the treatment of anal cancer, patients who present with either persistent or locally recurrent disease are treated by abdominoperineal resection. The aim of this retrospective study was to review the long-term survival and prognostic factors after such surgery in a single institution. METHODS: Over a 34-year period (1969-2003), 422 patients with nonmetastatic anal cancer were treated with a curative intent. Of these, 83 (median age 61 years; 74 women) underwent abdominoperineal resection. RESULTS: Forty-one patients underwent abdominoperineal resection for persistent disease and 42 for locally recurrent disease. Postoperative mortality was 4.8 percent and morbidity was 35 percent with 18 percent having perineal wound infections. Median follow-up was 104 months (range, 3-299). The 3-year and 5-year actuarial survival was 62.8 and 56.5 percent respectively. Using univariate analysis, patients below 55 years, females, T1-2 tumors, N0-N1 lymphadenopathy and the absence of locally advanced tumor were associated with significantly improved survival. Surgery, whether for persistent or locally recurrent disease, did not affect the 5-year survival rate. CONCLUSIONS: Abdominoperineal resection for nonmetastatic anal cancer is associated with a high morbidity rate but may result in long-term survival regardless of the indication.

[Nipple and areola reconstruction by tattooing, "F" and "Z" flaps]. / La reconstruction de la plaque aréolo-mamelonnaire par tatouage, lambeaux << F >> et << Z >>

Nipple and areola reconstruction is very important in the evaluation of the quality of breast reconstruction. It can be done during the primary or secondary breast reconstruction or later. We have performed the techniques of nipple reconstruction routinely since 1992. Under local anesthesia during a second operative time or general anesthesia during breast reconstruction, the local "F" and "Z" skin flaps and tattooing grant a quality result in the wound and the long-term projection. They are easily reproduced, rapid and as there is no graft the choice of the incisions grants a good tolerance. Complications are rare and it is always possible to use other techniques in case of poor result. We also present the main techniques of nipple and areola reconstruction with their advantages and limits.

[Breast cancer surgery: use of mammaplasty. Results. Series of 298 cases]. / Résultats carcinologiques et esthétiques du traitement du cancer du sein par plastie mammaire. 298 cas.

Breast cancer surgery has long consisted in the sole use of mastectomy. Then, it was proved that, in terms of global survival, conservative treatments associated with radiotherapies could give the same results. But breast deformations due to classic conservative treatments led some authors to use plastic surgery procedures: breast plastic surgery. Some breast plastic surgery procedures are well-known, others have been adapted to breast cancer treatment and more particularly in case of tumor of superior and internal quadrants. After the retrospective analysis of a series of 298 cases from the Institute Curie, the aim of this survey is to find whether there is a difference between: breast plastic surgery and usual treatments like mastectomy and classic conservative treatments. For most cases, the tumors were invasive ductal carcinoma and T2N0M0 carcinoma. This survey showed, among these cases, 94.56% of global survival, 86.81% of survival without metastasis and a five-year 93.47% without local recurrence, which is comparable to the results for mastectomies and classic conservative treatments. In selected cases, the use of mammaplasty could be interesting for breast cancer surgery treatment.

[Preoperative location of microcalcifications after macrobiopsy: failure of lipiodol]. / Repérage du site de prélèvement de microcalcifications par mammotome: échec du lipiodol.

Accurate mark of macrobiopsy site, carried out borderline or malignant lesions, is very important for surgeons. We report a woman case, 68 year's old, who presents intraductal carcinoma diagnoses on macrobiopsy. On postbiopsy X-ray, we can note lipiodol used instead of clip to reaper macrobiopsy site. Our observation shows how lipiodol use is not adapted into this indication.

BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell lines.

Instability of microsatellites is a hallmark of the DNA replication error phenotype (RER+) due to the inactivation of mismatch repair genes. In humans, microsatellite instability has first been described in colorectal tumors developing in either hereditary nonpolyposis colorectal cancer or sporadic patients. Colorectal tumorigenesis in RER+ and RER- tumors is probably due to distinct mechanisms, and RER+ tumors have a better prognosis than RER- tumors. The study of the RER status of a tumor may thus be important in the future to determine biological prognosis factors and investigate therapeutical strategies. The RER status of 134 primary tumors and 26 cell lines derived from colorectal cancers was established by PCR amplification and analysis of a minimum of 32 microsatellite loci. This characterization allowed us to unambiguously classify 35 primary tumors and 7 cell lines as RER+. Typing of a single poly(A) tract, BAT-26, was sufficient to confirm the RER status of 159 of these 160 tumors and cell lines. Moreover, in DNA from unaffected individuals, normal tissues of a subset of the RER+ patients, and all RER- tumors or cell lines, BAT-26 was quasi-monomorphic, showing only minor size variations. BAT-26 alleles showing shortening from 4 to 15 bp were observed in all but 1 of the RER+ tumors and cell lines. The size difference between the range of normal large alleles and unstable small alleles was sufficient to be detected by electrophoresis on conventional polyacrylamide gels stained with ethidium bromide. We thus propose a simple, low-cost, and rapid method to screen for the RER status of colorectal cancer primary tumors and cell lines, even in the absence of matching normal DNA and, in most cases, without the need for radioactivity. This method could easily be set up in routine laboratories.

Frequently elevated content of immunochemically defined wild-type p53 protein in colorectal adenomas.

Mutations of the p53 tumour-suppressor gene are considered to be rare in human colorectal adenomas, a premalignant state of the digestive tract. We have analysed a series of 32 exophytic tumours of the colon and rectum for the presence of p53 protein. In 26 of the 28 pure adenomas, the presence of significant levels of p53 proteins was established by a sensitive two-point enzyme-linked immunosorbent assay. The detectability of p53 protein was frequently limited to PAb 1801, recognizing an N-terminal epitope. Immunoblotting of the fractions captured by the monoclonal antibodies revealed that PAb 421 reacted exclusively with a 53-kDa species, whereas an additional 48-kDa band was detected after incubation with PAb 1801. In the adenomas, the mutant conformation-specific PAb 240 was always negative and no mutations were detected on exons 5-8 in three large and highly dysplastic lesions, selected for their high p53 protein content. The remaining four of the 32 tumours presented foci of cancer. Three of these were shown to contain 'mutant' PAb 240-reactive p53, and gene mutations were identified in two by denaturing gradient gel electrophoresis and sequencing of the amplified products. Intense p53 nuclear immunohistochemical staining was associated with the malignant areas. We conclude that a novel mechanism affecting the regulation of p53 protein could occur in colorectal adenomas.

Polymorphisms and probable lack of mutation in the WAF1-CIP1 gene in colorectal cancer.

WAF1/CIP1, a gene up-regulated by p53 encodes an inhibitor of cyclin-dependent kinases. Induction of WAF1/CIP1 in cells with intact p53 is believed to be instrumental in cell cycle arrest and apoptosis caused by DNA damage. In a model system, WAF1/CIP1 has been shown to have tumor suppressive activity. It is not known however whether WAF1/CIP1 is mutated in human primary tumors. Cells from colorectal cancer have been shown to acquire a series of genetic alterations, including frequent p53 mutations. Thus colorectal tumors, particularly those without identified p53 mutations, are good candidate to search for putative WAF1/CIP1 mutations. DNA extracted from 45 tumors, (including 28 tumors for which p53 mutations had previously been searched for and not found) were PCR amplified for exon 2 of WAF1/CIP1. A search for point mutations was performed in each amplified product using a denaturing gradient gel electrophoresis (DGGE) technique which enables the efficient screening of codons 9 to 139 (i.e. 80% of the WAF1/CIP1 coding sequence). Two different DNA variants were identified and shown to be present in constitutional DNAs of the corresponding patients. The first variant, a C to A transversion at codon 31, changes a serine for an arginine and was detected in eight tumors (18% of the cases). The second variant, detected in a single case (2%) is a silent A to T transversion at the third base of codon 91. DNA extracted from 70 unrelated members from the Centre d'Etude du Polymorphisme Humain (CEPH) was screened for these polymorphisms. The ser/arg polymorphism of codon 31 was detected in seven cases (10%) thus suggesting that it is not associated with a marked colorectal cancer predisposition. The polymorphism on codon 91 was not detected. Two additional variants (arginine to histidine at position 67 and threonine to methionine at position 80) were observed once each in the CEPH family members. Somatic mutation of the WAF1/CIP1 gene was not observed, indicating that, unless there are hot spots for mutations outside the screened region, this gene is not a frequent site of point mutation in colorectal cancer.

Sentinel node biopsy or limited oriented axillary dissection (LOAD) in early breast cancer.

AIMS: The value of the sentinel node biopsy technique is recognised by the majority of surgical teams as an alternative to conventional axillary lymph node dissection for the treatment of small breast cancers. Secondary procedures are necessary when lymph node invasion not detected by frozen section examination is discovered post-operatively. In order to avoid or limit these reoperations, our sentinel node biopsy technique has gradually been transformed into limited oriented axillary dissection (LOAD), which avoids secondary procedures in the majority of patients. PATIENTS AND METHODS: Three hundred and eighty two patients were operated on by the same surgeon, using the patent blue sentinel node identification technique. This technique failed in nine patients, seven of whom were obese. Only one lymph node was removed in 75 patients, two in 88 patients, 3-5 in 174 patients and more than five lymph nodes were removed in the remaining patients. Eighty-eight percent of patients had no lymph node invasion on intraoperative and post-operative examination. RESULTS: Only seven patients were reoperated by secondary conventional lymph node dissection and there was residual cancer in only one patient. CONCLUSION: The oriented limited axillary dissection technique, combined with frozen section histological examination, avoids the usually unnecessary secondary operations in small breast cancers, in which axillary lymph node invasion rarely exceeds more than two nodes. This technique requires surgeons experienced in axillary surgery and conventional sentinel lymph node biopsy. It needs to be validated on a larger scale by a multicentre randomized prospective trial comparing LOAD to conventional axillary lymph node dissection.

Effect of taurocholic acid feeding on methyl-nitro-N-nitroso-guanidine induced gastric tumors.

Bile reflux is generally accepted as a causative factor of gastric cancer after partial gastrectomy. The present study was designed to evaluate the promotion, by the per oral administration of taurocholic acid, of methyl-N-nitro-N'-nitrosoguanidine (MNNG)-induced gastric carcinogenesis. MNNG (83 mg/l) was given in the drinking water to half the male Wistar rats during 12 weeks while the other half served as controls. After this treatment half of the MNNG-treated animals and half of the controls were placed under a diet containing 0.2% of taurocholic acid while the other animals received the standard diet. At the 40th week after initiation of MNNG, surviving animals were killed. Their stomachs and their duodenums were observed for macro and microscopic examination. Macroscopically there were 7 animals bearing gastric tumors in the MNNG group and 15 in the MNNG + bile group (P less than 0.05). Microscopically there were 7 animals with severe antral dysplasia in the MNNG group, 7 rats with fundic dysplasia and 18 with severe antral dysplasia in the MNNG + bile group. Both groups developed an identical number of duodenal tumors which were invasive adenocarcinomas or angiosarcomas. In this experiment taurocholic acid significantly promoted gastric carcinogenesis. It is postulated that surgical techniques inducing duodenal reflux in the stomach may produced a 'high risk' group of patients in which a long and careful follow-up is required.

A morphologic and kinetic basis for the more invasive character of N-methyl-N'-nitro-N-nitrosoguanidine induced duodenal tumors following pyloroplasty.

Pyloroplasty increased the invasiveness of duodenal tumors in Wistar rats receiving N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 12 weeks (83 mg/l in drinking water) (Arch. Surg., 117, 768-771). To assess morphologic and kinetic alterations, analyses of tritiated thymidine (3HTdR) pulse-labeled fundic, antral and duodenal mucosa were carried out. The normal appearance of MNNG-treated antral and duodenal mucosa was characterized by the appearance of elongated hyperactive columns exhibiting elevated levels of DNA synthesis. Pyloroplasty in carcinogen-treated rats induced both a 3-fold enhancement in the number of these elongated columns and an elevation in the number of proliferating cells within them (P less than 0.001). In the MNNG and pyloroplasty treated duodenal mucosa 26% of columns contained over 130 cells/column rather than an average of 100 cells in normal appearing MNNG-treated mucosa. DNA synthesis was increased by 23% within these hyperactive glands (11.3 proliferative cells/column vs. 9.4/column in normal appearing mucosa). Pyloroplasty creates both an increase of gastric bile reflux and an increase of the gastric evacuation rate, conditions which influence cell proliferation. Such alterations in antro-pyloro-duodenal physiology contribute to the increased cellular activity observed, promote malignant transformation and foster the expression of invasiveness.

Comparison of the carcinogenic effects of two 2-nitro-naphthofurans injected sub-cutaneously in rats.

7-Methoxy-2-nitro-naphtho[2,1-b]furan (R 7000) and its methylated homolog in position 1 (R 7372) are among the most mutagenic agents presently known, as shown by the results obtained both in the Ames test and in the SOS Chromotest. Their carcinogenic effects were tested in rats. We were able to confirm the carcinogenic effects of these nitro-naphthofurans, the presence of a methyl group--while increasing the mutagenic effect of R 7000 10 times--induces a significant decrease of the carcinogenic effects in R 7372. The discrepancy between the mutagenic effects in bacterial assays and the carcinogenic effects of these two 2-nitro-naphthofurans remains to be explained.

Positron emission tomography detection of breast cancer metastasis to the uterus.

BACKGROUND: We report the case of a patient presenting with moderate elevation of the tumor marker cancer antigen 15.3 during breast cancer follow-up. CASE: After a negative standard metastatic work-up, a positron emission tomography scan identified a localized central pelvic zone of uptake. Hysterectomy was performed, and pathology revealed a breast cancer metastasis within a previously known uterine leiomyoma. Positron emission tomography allowed assessment of soft tissues. CONCLUSION: With high sensitivity and specificity, positron emission tomography can be used to localize breast cancer metastases suspected by the presence of elevated serum tumor marker but not detected on standard metastatic workup.

Cancer induction after pyloroplasty in rats: treatment with N-methyl-N'-nitro-N-nitrosoguanidine.

Nineteen male Wistar rats received N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in drinking water (83 mg/L) to initiate glandular adenocarcinoma of the stomach; eight control rats received tap water. After 12 weeks a pyloroplasty was performed on nine rats receiving MNNG and three control rats. Ten MNNG-treated rats and five control rats had no operation. All were observed for 38 weeks before being killed. No difference in the incidence of antral adenocarcinomas was found between the MNNG-treated groups; however, those without operation showed in situ changes in the duodenum and those treated with pyloroplasty showed five invasive adenocarcinomas. In this model pyloroplasty alone did not increase the risk of gastric cancer but increased the risk of duodenal tumors. Pyloroplasty apparently accelerated the gastric evacuation rate, resulting in greater insult to the duodenal mucosa. Such a condition may require a higher proliferative rate in the duodenum and may increase subsequent formation of malignant tumors.

Existence of two distinct processes of chromosomal evolution in near-diploid colorectal tumors.

The comparison of all the karyotypes established in each of 18 near-diploid colorectal tumors made it possible to reconstruct a clonal evolution and to distinguish between early and late chromosomal aberrations. Because no abnormalities were observed in all tumors, and as even the most frequent changes, i.e., monosomy 17p and monosomy 18, may be present in mosaic, no chromosomal change can be regarded as a common primary event in the carcinogenetic process. However, the repeated occurrence of several changes favors the hypothesis of two karyotypic evolutionary processes. In most tumors, monosomy 17p and 18 were found, and the karyotypic evolution involved mainly several additional monosomies due to unbalanced rearrangements or losses that affect, by order of decreasing frequency, chromosomes 1p, 4, 14, 5q, 6q, 2p, and 11q, as well as gains of chromosomes 20, 8q, 13, 17q, and X. In this group of tumors, the mean number of chromosomes remains close to 46. In the other tumors, either only a monosomy 17p or a monosomy 18 was found and the karyotypic evolution involved essentially trisomies, resulting from gains with, by order of decreasing frequency, a preferential involvement of chromosomes 7, 8q, 13, 17q, 20, X, 2p, 5, and 16, the only additional recurrent deletion affecting chromosome 1p. In these tumors, the mean chromosome number is close to 51. Ten out of 11 polyploid sidelines emerged from monosomic-type tumors.

Cytogenetics of colorectal adenocarcinomas.

The occurrence of nonrandom chromosomal anomalies in colorectal adenocarcinomas could be demonstrated from the cytogenetic study of 100 cases. The most frequent changes are a rearrangement of chromosome 17, leading to the loss of its short arm and a loss of one chromosome 18. Three types of tumors with abnormal karyotypes can be defined. First are the monosomic-type near-diploid tumors (MD), characterized by a monosomy of both 17p and chromosome 18 mostly associated with other recurrent monosomies. In two of three cases, one or several minor derived polyploid subclones are also observed. Second are the monosomic-type polyploid tumors (MP), which have a pattern of chromosome imbalance very similar to that of MD tumors. They derive from MD tumors by endoreduplication followed by complete disappearance of the original MD clone. Third are the trisomic-type tumors (TT), which lose either 17p or chromosome 18 or none, most of the anomalies being gains of entire chromosomes. These TT tumors never undergo endoreduplication. In addition, seven tumors with normal karyotypes were found and may constitute another category (NT). A nonrandom distribution of these tumor types in relation to tumor site was observed, since in the distal colon, TT and NT tumors are underrepresented and endoreduplications are significantly more frequent. The level of chromosomal mutagenesis is two- to threefold higher in MD and MP than in TT tumors. More than 95% of the rearrangements are unbalanced, and most of them result from breakpoints located in juxtacentromeric heterochromatin. A good correlation is found between our results and the available molecular data on allelic losses. The involvement of recessive tumor suppressor genes in colorectal tumorigenesis and the possible relationship between chromosomal imbalances and deviations in metabolic pathways is described.

Chromosome imbalance in endometrial adenocarcinoma.

The results of karyotypic analysis by R-banding after short-term culture of eight new cases of endometrial adenocarcinomas are presented and compared to previously published data. Among a total of 25 cases reported that had a diploid or near-diploid chromosome number, 72% contained a trisomy or tetrasomy 1q, often as the only abnormality. An excess of the long arm of chromosome 1 is, therefore, shown to be the predominant feature of endometrial adenocarcinoma. Trisomies 10, 2, 7, and 12 were, in decreasing order, the most frequently associated abnormalities, but trisomy 10, found in 40% of the cases, can also exist as the only imbalance. Because breakpoints in chromosome 1 are generally centromeric, a position effect with oncogene activation seems unlikely. It is suggested that the observed chromosome imbalances are secondary and are the result of the adaptation of the cancer cell to disturbed metabolic pathways.