Lymphatic mapping of the breast: locating the sentinel lymph nodes.

When the concept of sentinel lymph node biopsy was described in patients with melanoma, researchers quickly started to use lymphatic mapping techniques in breast cancer patients in an attempt to locate the sentinel node in the axilla. We have been performing mammary lymphoscintigraphy in this role for 6 years and have now studied 159 patients. Like others, we have found that most breast cancers (93%) have lymphatic drainage that includes the axilla, and we have found an average of 1.4 axillary sentinel nodes in these patients. Surgical biopsy of the axillary sentinel nodes accurately staged the node field in 96% of patients. We have also found, however, that the pattern of lymphatic drainage from the cancer site is unpredictable; and in 49% of patients lymphatic drainage occurred across the center line of the breast to axillary or internal mammary sentinel nodes. In more than half of our patients (56%) lymphatic drainage occurred to lymph nodes outside the axilla including the internal mammary (45%), supraclavicular (13%), and interpectoral and intramammary interval nodes (12%). These nodes are also sentinel nodes, and their presence indicates that a sentinel node biopsy procedure that stages only the status of the axillary lymph nodes has the potential to understage about half the patients with breast cancer. High quality lymphoscintigraphy allows accurate mapping of peritumoral lymphatic drainage in most patients with breast cancer. It is possible that in the future accurate nodal staging in each individual will involve biopsy of all sentinel lymph nodes, regardless of their location.

Purification, crystallization and preliminary X-ray analysis of human recombinant cytosolic serine hydroxymethyltransferase.

As an enzyme of the thymidylate synthase cycle, serine hydroxymethyltransferase (SHMT) has a key role in nucleotide biosynthesis. Elevated activities of SHMT have been correlated with the increased demand for nucleotide biosynthesis in tumors of human and rodent origin, making this enzyme a novel target for cancer chemotherapy. Here the purification and crystallization of recombinant human cytosolic SHMT are reported. Crystals belong to space group P6222 or P6422 with cell parameters a = b = 155.0, c = 235.5 A and diffract to at least 3.0 A resolution.

The crystal structure of human cytosolic serine hydroxymethyltransferase: a target for cancer chemotherapy.

BACKGROUND: Serine hydroxymethyltransferase (SHMT) is a ubiquitous enzyme found in all prokaryotes and eukaryotes. As an enzyme of the thymidylate synthase metabolic cycle, SHMT catalyses the retro-aldol cleavage of serine to glycine, with the resulting hydroxymethyl group being transferred to tetrahydrofolate to form 5, 10-methylene-tetrahydrofolate. The latter is the major source of one-carbon units in metabolism. Elevated SHMT activity has been shown to be coupled to the increased demand for DNA synthesis in rapidly proliferating cells, particularly tumour cells. Consequently, the central role of SHMT in nucleotide biosynthesis makes it an attractive target for cancer chemotherapy. RESULTS: We have solved the crystal structure of human cytosolic SHMT by multiple isomorphous replacement to 2.65 A resolution. The monomer has a fold typical for alpha class pyridoxal 5'-phosphate (PLP) dependent enzymes. The tetramer association is best described as a 'dimer of dimers' where residues from both subunits of one 'tight' dimer contribute to the active site. CONCLUSIONS: The crystal structure shows the evolutionary relationship between SHMT and other alpha class PLP-dependent enzymes, as the fold is highly conserved. Many of the results of site-directed mutagenesis studies can easily be rationalised or re-interpreted in light of the structure presented here. For example, His 151 is not the catalytic base, contrary to the findings of others. A mechanism for the cleavage of serine to glycine and formaldehyde is proposed.

Silicone breast implants: implications for society and surgeons.

In the last two years, scientific studies have confirmed that there is no significant increase in risk of subsequent breast cancer, connective-tissue disease or symptoms in women with silicone gel-filled breast implants. Despite this evidence, a moratorium (in place since 1992) on the use of these prostheses in the United States has been maintained by the pressure of overwhelming litigation. At the same time, Australian authorities also announced a moratorium, restricting the availability of silicone breast implants. Huge damages awarded by United States courts forced Dow Corning, manufacturer of a large percentage of breast prostheses, to file for Chapter 11 bankruptcy in May 1995. This effectively terminated the major source of implantable silicone for medical use. The withdrawal of implantable silicone and other implantable prosthetic material will be a significant loss for surgeons and society. This paper will highlight the consequences if reasoned scientific data are not relied on by Australian courts to assess claims for damages relating to medical devices.

Mammary lymphoscintigraphy in breast cancer.

UNLABELLED: Lymphoscintigraphy has previously been used to define lymph drainage patterns and locate sentinel lymph nodes, prior to surgery, in patients with cutaneous melanoma. The aim of this study was to apply this technique to patients with breast cancer using intramammary injections placed around the primary tumor in the breast. METHODS: Lymphoscintigraphy using 99mTc-labeled antimony sulphide colloid was performed in 34 patients with a suspected primary breast cancer. Images were recorded immediately and at 2.5 hr using a LFOV digital gamma camera. Sentinel lymph node location was marked when possible. RESULTS: Lymphatic drainage patterns were successfully recorded in all but three patients. Lymph drainage was to the axillary, internal mammary, supraclavicular and, in one patient, infraclavicular node fields in various combinations but always on the same side of the body as the breast tumor. There was unexpected drainage across the center line of the breast to axillary or internal mammary nodes in 32% of patients with inner or outer quadrant lesions. Direct drainage to supraclavicular or infraclavicular nodes occurred in 20% of upper quadrant lesions. Drainage to the ipsilateral axilla occurred in 85% of patients, where a single sentinel node was seen in all cases. CONCLUSION: Intramammary lymphoscintigraphy can be used to define the lymphatic drainage patterns of individual breast cancers. The surface location of sentinel lymph nodes in the draining node fields can be marked and in the axilla their depth can be measured. It should therefore be possible to use lymphoscintigraphy, along with a blue dye injection technique or the gamma probe at surgery, to locate sentinel lymph nodes in patients with breast cancer.

Probing the details of the HIV-1 Rev-Rev-responsive element interaction: effects of modified nucleotides on protein affinity and conformational changes during complex formation.

The solution structure of the human immunodeficiency virus type 1 (HIV-1) Rev-responsive element (RRE) has been investigated by enzymic and chemical structural probing of a 71 nt RRE transcript. The minimum sequence information required to maintain recognition by the Rev protein has previously been mapped to a 29 nt stem-loop structure, known as minSLIIB. The key recognition target is a single-stranded RNA bubble at the base of the RNA stem. The fine details of RNA recognition have been probed using chemically synthesized minSLIIBs containing variant base or sugar residues at sites within the bubble. These have been analysed by gel retardation assays and their relative affinities for Rev protein determined. Complex formation between the wild-type minSLIIB RRE and Rev protein was also monitored using CD spectroscopy, which suggests a change in RNA conformation upon Rev binding. The spectral change is consistent with localized melting of RNA, leading to a decrease in the level of base stacking and/or a change in base tilting, during formation of the complex. Deoxynucleotide substitutions on just one side, the 5' side, of the bubble inhibit the conformational change detected by CD. The data are consistent with a dynamic interaction between Rev and its target site. The contact points between Rev and the RRE were probed directly using photo-cross-linking with either ribo-5-bromouridine- or ribo-4-thiouridine-substituted minSLIIBs. The data are consistent with protein-RNA contacts at the bottom of the bubble.

Surgical management of breast cancer. Experience of the Central Sydney Area Health Service Breast X-ray Programme, 1988-1991.

OBJECTIVE: To review the breast cancers detected in the first three years of the Central Sydney Area Health Service Breast X-ray Programme, their histopathology and their surgical management within the program. DESIGN: Between March 1988 and March 1991, women screened in the program who had a suspicious lesion were referred for surgical assessment at the program assessment centre at Rachel Forster Hospital. These women were seen by staff of the assessment centre, including program surgeons, and were then treated at either Rachel Forster Hospital or Royal Prince Alfred Hospital. Features examined include cancer detection, clinical findings, diagnostic techniques, histopathological diagnosis of the lesions and surgical management. RESULTS: One hundred and eight cancers were detected in 105 women, with 59% of the cancers impalpable. The benign to malignant ratio was 1.0:1.5. Twenty-four cancers (22%) were ductal carcinoma-in-situ with or without microinvasion, and 84 (78%) were frankly invasive. Of the 86 axillary dissections, 63 (73%) showed no node involvement on histological examination. At the time of diagnosis, 27% of the women had axillary node involvement proven by axillary dissection. The overall mastectomy rate was 58%. Radiotherapy, chemotherapy and tamoxifen were used in both stage I and stage II disease. CONCLUSION: The surgical management of cancers reflects similar findings reported in other screening programs. There is an increasing trend towards breast conservation surgery and up to 90% of the women in this study present with favourable prognostic factors for long term survival.

Developments in surgical oncology--past, present, and future trends.

The historical development of integrated treatment programs for locally advanced or aggressive cancers, for which the results of surgical excision or radiotherapy are unsatisfactory, is reviewed. Chemotherapy should be used first (induction chemotherapy), while tumour vasculature is intact; intra-arterial infusion gives a greater regional effect. Central residual tumour may be eradicated by subsequent radiotherapy and/or surgery. Regional induction chemotherapy is particularly useful in treating locally advanced stage III breast cancer, locally advanced head and neck cancer, gastric cancer, and locally advanced sarcomas and melanomas of the limbs. A team approach, involving surgical and medical oncologists, radiotherapists, immunologists, and others should improve the results in these patients.

Preliminary results of conservative treatment of early breast cancer with tumourectomy, axillary dissection and postoperative radiotherapy. A retrospective review of 107 patients.

A consecutive series of 107 patients with early breast cancer treated by tumourectomy, axillary dissection and postoperative radiotherapy was retrospectively reviewed. The average age at presentation was 48, range 30-79. Only 23.4% of women were post-menopausal. Average follow-up time was 48 months, range 19-94 months. Eight-three per cent had palpable lesions, the remaining 16.8% had needle localization. Ninety-four patients (88.7%) had lesions less than 2 cm in diameter clinically. One patient had a lesion greater than 3 cm in diameter clinically. Seventy-two per cent had invasive duct carcinoma. Twenty (18.9%) had invasive disease at the margins and fifteen were re-excised. Of the 20 patients who had invasive disease at the margins, three developed local recurrence. True loco-regional recurrence rate (i.e., loco-regional recurrence rate without distant metastasis) was 2.8%. All had level I and II axillary dissections and 26.4% were up-staged from clinical stage 1 to pathological stage II. Five patients died, three with recurrences and two with unrelated disease. Tumourectomy, axillary dissection and postoperative radiotherapy is an acceptable regimen for early carcinoma of the breast.

The possible relationship between mammary dysplasia and breast cancer.

The literature concerning a possible association between benign mammary dysplasia and breast cancer is reviewed. Prospective studies confirm a higher increase in the incidence of breast cancer in patients with clinically and biopsy proven benign mammary dysplasia than in those in whom it has not shown to be present. A plea is made for active follow-up of these patients.