R.J. Salmon

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.

Surgical management of liver metastases from uveal melanoma: 16 years' experience at the Institut Curie

BACKGROUND Uveal melanoma is characterised by a high prevalence of liver metastases and a poor prognosis. AIM To review the evolving surgical management of this challenging condition at a single institution over a 16-year period. PATIENTS AND METHODS Between January 1991 and June 2007, among 3873 patients with uveal melanoma, 798 patients had liver metastases. We undertook a detailed retrospective review of their clinical records and surgical procedures. The data was evaluated with both uni- and multivariate statistical analysis for predictive survival indicators. RESULTS 255 patients underwent surgical resection. The median interval between ocular tumour diagnosis and liver surgery was 68 months (range 19-81). Liver surgery was either microscopically complete (R0; n = 76), microscopically incomplete (R1; n = 22) or macroscopically incomplete (R2; n = 157). The median overall postoperative survival was 14 months, but increased to 27 months when R0 resection was possible. With multivariate analysis, four variables were found to independently correlate with prolonged survival: an interval from primary tumour diagnosis to liver metastases >24 months, comprehensiveness of surgical resection (R0), number of metastases resected (< or = 4) and absence of miliary disease. CONCLUSIONS Surgical resection, when possible, is able to almost double the survival and appears at present the optimal way of improving the prognosis in metastatic uveal melanoma. Advances in medical treatments will be required to further improve survival.

Characteristic chromosomal imbalances in 18 near-diploid colorectal tumors

The cytogenetic study of 18 near-diploid colorectal tumors shows that the observed numerical and structural abnormalities resulted in recurrent chromosomal losses and gains. By order of decreasing frequencies, they are: monosomy 17p (16/18), partial or more frequently complete monosomy 18 (14/18), trisomy 20q (11/18), trisomy or tetrasomy 13 (10/18), monosomy lp and trisomies X and 8q (9/18). The absence of recurrent breakpoints in euchromatin contrasts with the high preponderance of breakage at various places of heterochromatic region. Because these tumors are characterized by very recurrent chromosomal imbalances, it is assumed that the observed chromosomal changes may be related to a recessive genetic determinism and to gene dosage imbalances.

Résections hépatiques pour métastases de cancer du sein : résultats et facteurs pronostiques (65 cas)

Study aim: To report results of liver resections for breast cancer liver metastasis (BCLM) and to evaluate the rate of survival and the prognostic factors. Patients and method: Between 1988 and 1999, 69 patients were operated on for BCLM and 65 who had liver resection were analyzed. The selection criteria for surgery were: normal performance status and liver function test; radiological objective response to chemotherapy (and/or hormonotherapy); in cases of non-isolated BCLM, complete response of associated metastatic site (usually bone) and no brain metastases. The mean age of the 65 patients was 47 (30–70) years. BCLM was diagnosed an average of 60 (0–205) months after the initial cancer. The BCLM was more frequently solitary (n = 44). The mean diameter was 3.8 (0–12) cm. The mean number of cycles of chemotherapy before surgery was 7.5 (3–24). Liver resections included major hepatectomy (n = 31) : right n = 19, extended left n = 4, left n = 8, minor hepatectomy (n = 25) and limited resection (n = 9). Results: There was no postoperative mortality. The 18% morbidity rate included a majority of pleural effusions with two reoperations. The median follow-up was 41 months (6–100 months). The survival rate after surgery was 90% at 1 year, 71% at 3 and 46% at 4 years. Thirteen patients are alive at 4 years. The 36-month survival rate differed according to the time to onset of BCLM: 55% before versus 86% after 48 months (p = 0.01). The other studied factors were not statistically associated with survival. The recurrence rate in the remaining liver at 36 months differed according to the lymph node status of the initial breast cancer: 40% for N0-N1 versus 81% for N1b-N2 (p = 0.01) and according to the type of liver resection: 45% for minor liver resection versus 73% for major (p = 0.02). Conclusion: Adjuvant liver surgery should be included in multicenter treatment protocols for medically-controlled breast cancer liver metastasis.

Oncoplastic breast surgery: A review and systematic approach

Oncoplastic breast surgery (OBS) is relatively new, but has made rapid progress from its tentative steps of infancy in the 1990s. The recent Milanese Consensus Conference on Breast Conservation concluded that, firstly, oncoplastic techniques are warranted to allow wide excision and clear margins without compromising cosmesis. Secondly, such surgery is ideally performed at the same time as oncological excision. Whilst technically more challenging than standard breast conserving therapy (BCT), OBS is well proven, if not yet widely practised, both oncologically and aesthetically and a review of the available techniques is perhaps timely. The roots of breast conserving therapy can be traced to the 1930s, actually due to advances made in radiotherapy, and the last 20 years have seen it become firmly established. This review aims to summarise the key historical developments and latest innovations in OBS. Not only are our patients, who expect not only safe cancer treatment but a satisfactory aesthetic outcome, increasingly informed and demanding, but longer follow up has stimulated surgeons to improve outcomes. In many cases, particularly with ptosis and macromastia, the cancer can be treated, usually with wider excision margins, simultaneously improving the aesthetic appearance. Present at the birth of OBS, the Institut Curie has continued to introduce innovative techniques over the last two decades and a systematic approach, comprising nine basic techniques, has evolved to allow high quality treatment of any and all breast cancers suitable for OBS.

Prognosis of cloacogenic and squamous cancers of the anal canal

From 1968 to 1982, 195 patients with invasive cancer of the anal canal were treated (average age, 67±11 years; range, 38 to 85 years; sex ratio [women/men]:5/1). Histology revealed: cloacogenic cancer, 20 cases; squamous cancer, poorly differentiated, 30; moderately differentiated, 68; well differentiated, 77. The initial size of the cloacogenic cancers was smaller than the squamous cancers. Invasion less than half the circumference of the canal was 90 and 74 percent, respectively. No patients with cloacogenic cancer presented with positive inguinal nodes; however, there were 22 unilateral and five bilateral positive nodes in the squamous cancers. All 195 patients received radiotherapy as the first treatment. There were no differences among the patients operated on with respect to sterilized operative specimens, postradiotherapy sequelae, perineal recurrences, and/or visceral metastases in the cloacogenic and squamous cancers. Five-year survival was better in cloacogenic (62 percent) than in squamous cancers (56 percent); this diffeernce was not significant, and was related to the initial size of the tumor. The number of patients with no evidence of disease and good anal function was significantly related to the initial size of the tumor, and was independent of the histologic findings.

Cytogenetic and molecular approaches of polyploidization in colorectal adenocarcinomas.

We present the cytogenetic analysis of 23 cases of polyploid colorectal adenocarcinomas. We took advantage of the high intratumoral heterogeneity of the karyotypes to identify clones, subclones, and cell-to-cell variations. This allowed us to reconstruct the chromosomal evolution of each tumor and to propose a schema of the chromosomal changes in relation to the endoreduplication process. All but one case were characterized by a relative deficiency of chromosomes 17p and 18. Other deficiencies affecting the late-replicating X, and to a lesser degree, 1p, 5q, 14, 15, 8p, 10, 21, and 4, and excesses affecting the early-replicating X, 8q, 13, 16, 17q, and 11 were frequently associated. This pattern of imbalances is very similar to that of the monosomic type previously described in near-diploid tumors. The pattern of the 23rd tumor corresponded to those of the trisomic type tumors. These data largely confirm the existence of two distinct processes of chromosomal evolution in colorectal adenocarcinomas, with a strong tendency to undergo endoreduplication for the monosomic type near-diploid tumors. To correlate cytogenetic and molecular data, allelic losses analyses were investigated for probes of chromosomes 17p and 18. In all 12 informative tumors, a loss of heterozygosity for probes of the short arm of chromosome 17 indicated the occurrence of a rearrangement of chromosome 17 before the endoreduplication. The same was true for allelic losses for probes of chromosome 18 found in 11 of 12 informative tumors. The correlation between cytogenetic and molecular data is thus excellent and indicates that losses of 17p and 18 are early events in the tumor process.

Preoperative staging of liver metastases from uveal melanoma by magnetic resonance imaging (MRI) and fluorodeoxyglucose-positron emission tomography (FDG-PET)

BACKGROUND Microscopically complete (R0) resection of metastases from uveal melanoma prolongs median overall survival compared to incomplete surgery. The aim of this study was to compare the sensitivity of dynamic-enhanced magnetic resonance imaging (MRI) with fluorodeoxyglucose-positron emission tomography (FDG-PET) in the preoperative diagnosis of liver metastases from uveal melanoma. PATIENTS AND METHODS Fifteen consecutive patients (mean age: 56 years) underwent FDG-PET and liver MRI. Extrahepatic metastatic disease was excluded by whole body computed tomography and bone scintigraphy. MRI and FDG-PET were performed with a mean of 19 days (range: 1-30) before surgery. Imaging findings were compared with surgical (including intraoperative ultrasonography) and histological findings on a lesion by lesion analysis. RESULTS R0 resection was performed in 12 patients. A total of 28 lesions were resected with 27 histologically proven metastases. Nine lesions were smaller than 5mm, 7 measured 5-10mm and 11 were larger than 10mm. Sensitivity and positive predictive value were 67% and 95% for MRI compared to 41% and 100% for FDG-PET. The difference between the two modalities was statistically significant (p=0.01; McNemar test). In remaining 3 patients, diffuse miliary disease (>10 capsular lesions) was discovered intraoperatively, and was suspected on preoperative MRI in 2 cases. Only one extrahepatic lesion identified by FDG-PET was falsely positive. CONCLUSIONS In this preliminary study, MRI was superior to FDG-PET for staging of liver metastases from uveal melanoma. Although miliary disease was suggested by MRI in some cases, preoperative confirmation remains imperfect.

Deletion Mapping of the Tumor Suppressor Locus Involved in Colorectal Cancer on Chromosome Band 8p21

Several somatic genetic alterations have been described in colorectal carcinoma (CRC). Recurrent chromosomal deletions have suggested the presence of tumor suppressor genes (TSG) specifically involved in colorectal carcinogenesis. For one of them, two non‐overlapping regions have been proposed on the short arm of chromosome 8, encompassing the LPL and NEFL genes. The short arm of chromosome 8 has been extensively studied in colorectal cancer and in other cancer types. Both regions have been reported as candidate loci for a TSG. In order to delineate a reliable region of deletional overlap on chromosome arm 8p in CRC, a series of 365 CRC samples was selected for the absence of microsatellite instability (RER, replication error); tumor and normal matched DNAs were studied for 54 microsatellite polymorphisms distributed on 8p using multiplex‐PCR amplification. After purification of tumor nuclei by flow cytometry based on either the abnormal DNA index or the presence of a high expression of cytokeratin, complete allelic losses on 8p were observed in 48% of cases. Measurement of the DNA index showed that 88% of RER tumors were hyperploid. Complete allelic losses of only part of the short arm were observed on 26 occasions. These data allowed us to define a 1 cM interval of common deletion, flanked by the loci D8S1771 and NEFL, where a putative TSG may be localized. Genes Chromosomes Cancer 25:147–153, 1999.

Cytogenetic study of 30 colorectal adenomas

The cytogenetic analysis of 30 colorectal adenomas obtained from 24 patients is reported. Only normal karyotypes were observed in eight cases. Among the 22 adenomas with abnormal karyotypes, 15 showed clonal anomalies. Chromosome gains involving chromosomes 13, 20, 7, 9, and 12 were recurrently observed. Chromosome 18 was frequently lost or involved in translocations at bands q21-q22. More chromosome alterations were observed in the cases in which histologic examination revealed severe dysplasia or a carcinomatous component. These anomalies are discussed in relation to those described in colorectal adenocarcinoma.