Biomedical subjects
J K MacFarlane
Publications and source records attributed to J K MacFarlane.
Retention sutures: are they really necessary?
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Detection of micrometastases from primary breast cancer.
The monoclonal antibody LICR-LON-M8 was used in a series of experiments to determine how an immunohistochemical technique could be used as a diagnostic test for micrometastatic disease in patients with operable, primary breast carcinoma. Optimal tissue and antigen preservation was obtained with fixatives containing either picric acid or a heavy metal such as mercury to allow staining with the monoclonal antibody diluted to 1:12,000 to 1:16,000 from unpurified mouse ascites. Tissue affected by primary and metastatic disease stains in a characteristic fashion, which is distinct from benign breast tissue. All the ductal tumours stained positively for malignant cells with the monoclonal antibody preparation. Within the bone marrow, occasional granulocytes and granulocyte precursors stained positively if the endogenous peroxidase activity was incompletely blocked. These cells were readily differentiated from tumour cells on cytologic examination. With these monoclonal antibody and immunohistochemical staining techniques it may now be possible to detect early micrometastatic disease in the bone marrow of patients with primary breast cancer.
Monoclonal antibody LICR-LON-M8 does not predict the outcome of operable breast cancer.
The prognostic value of the monoclonal antibody LICR-LON-M8, which has been shown to detect micrometastatic disease, was evaluated in a prospective, double-blind, clinical study of bone-marrow specimens from patients with operable breast cancer. Four bone-marrow specimens, obtained from each of 50 patients at the time of excision of the primary breast tumour, were examined immunohistochemically, with LICR-LON-M8 as the primary antibody. All of the primary tumour specimens demonstrated positive staining for malignant disease with LICR-LON-M8. The bone-marrow specimens of four patients demonstrated positive staining: three specimens were "suspicious" for malignant cells and one contained definite malignant cells on cytologic examination. This gave a 2% rate of detectable micrometastatic disease at the time the primary tumour was excised. Patient follow-up averaged 21.5 +/- 9.1 months. The test results did not correlate with outcome. A negative test result with LICR-LON-M8 did not imply a better prognosis. The authors conclude that examination of bone-marrow specimens stained with LICR-LON-M8 in patients with operable breast cancer is of no clinical value. Furthermore, the low rate of micrometastases detected is at variance with that reported by others. In view of the natural history of breast cancer, the authors believe that their results were not unexpected and they question the importance of other results.
Detecting breast cancer after reduction mammoplasty.
Reductive breast surgery may give rise to parenchymal scarring that makes subsequent clinical and radiologic assessment of tumours difficult. The features that help distinguish benign from malignant lesions are discussed. Biopsy is still necessary. A screening protocol that includes preoperative mammography in patients at increased risk is proposed.
Fine needle aspiration cytology in the evaluation of head and neck masses.
One hundred eighty-two fine needle aspirations (FNAs) of head and neck masses performed between the years 1981 and 1987 were studied retrospectively. Seventeen FNAs were unsatisfactory. Of the remaining 165, 148 (90%) were followed up with either surgery or clinical follow-up of at least 12 months' duration. Seventy-one of these aspirates were malignant. Fifty-six cases of metastatic carcinoma and 13 cases of lymphoma were diagnosed. The positive predictive value for metastatic carcinoma and lymphoma was 100%, and the sensitivities were 92% and 100%, respectively. For benign salivary gland lesions, the positive predictive value was 94%, whereas for malignant lesions it was 100%. One case of carcinoma ex-pleomorphic adenoma was missed by FNA. No complications were associated with FNA. We conclude that FNA is a safe and accurate technique, well suited to the in-office evaluation of neck masses of differing causes.
Preoperative radiotherapy for adenocarcinoma of the rectum.
Curative surgery remains the principal treatment for rectal carcinoma. Unfortunately failure following surgery, particularly through local recurrence, is an all too common event. Among the potential adjuvant therapies, preoperative radiotherapy holds clear promise. A review of the clinical trials evaluating this treatment modality shows that it can decrease the rate of local recurrence and may even improve the overall 5-year survival. Preoperative radiotherapy is consistently well tolerated up to doses as high as 60 Gy; it does not complicate the surgical resection or increase the perioperative morbidity and mortality. Preoperative radiotherapy warrants further investigation to select those patients who are most likely to benefit from it.
Follow-up of patients who have undergone ileogastrostomy.
Patients who have had ileogastrostomy for the treatment of morbid obesity require close, long-term follow-up. From a prospective study of a large number of variables in 12 consecutive patients, and from experience with more than 200 patients who have undergone this procedure since 1982, a protocol has evolved. The authors outline the associated morbid conditions, operative complications and biochemical alterations that are important in the management of these patients.
Important modification of the jejunoileal bypass procedure for morbid obesity.
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Tube leukocyte adherence inhibition (LAI) assay in gastrointestinal (GIT) cancer.
Tumor-specific immunity to carcinoma of the colon, pancreas and stomach was assayed by tube LAI. Cancers of the colon, pancreas and stomach, were shown to possess organ-type specific neoantigens. In 115 patients with colon cancer, 100%, 75%, 61% with Dukes' A, B and C cancer were LAI positive, respectively. Even a microfocus of in situ cancer in a colon adenoma was sufficient to stimulate measurable tumor-specific immunity in the host. In Dukes' D cancer, 25% of patients with widespread metastasis were positive, whereas 100% with solitary lesions were positive. Reactive leukocytes from patients with colon cancer did not react to extracts of normal bowel mucosa or villous adenoma from LAI-negative patients. Leukocytes from 19% (3 of 16) of patients with colon adenomas reacted to the extract of colon cancer but not normal colon mucosa. Moreover, the LAI-positive response of the patients with colon adenomas or colon cancer is directed to a colon cancer TSA which is linked to beta2-microglobulin. These studies suggest that some colon adenomas express TSA before morphological evidence of cancer. It is not known if the acquisition of a cell surface TSA is an irreversible step toward unrestrained growth and metastasis. In pancreatic cancer, 100% of patients with cancers less than 5 cm and without metastasis were LAI positive, whereas 29% were positive when the cancer was greater than 5 cm or had metastasized. In Patients with stomach cancer, 100% with Stage II and 46% with Stage III and IV cancer were LAI-positive. Leukocytes from patients with other GIT cancers and from patients with inflammatory bowel disease or pancreatitis did not react with extracts of colon, stomach or pancreatic cancer. Leukocytes from patients with metastatic cancer, usually did not react in the tube LAI assay because their surfaces were coated in vivo with TSA. LAI reactivity was present when CEA was not detectable and when CEA levels were elevated LAI activity was often absent. The present study suggests that the automated tube LAI shows sufficient promise to warrant studies to determine its efficacy for the diagnosis of GIT cancers.
Abrogation of the phenomenon of leukocyte adherence inhibition by excess circulating tumour antigen.
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Human tumor-specific immunity assayed by a computerized tube leukocyte adherence inhibition.
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Leucocyte adherence inhibition for detecting specific tumour immunity in early pancreatic cancer.
Tumour-specific immunity to pancreatic tumour antigens, assayed by an automated tube leucocyte-adherence inhibition assay (L.A.I.), was detected in 3 of 3 patients with localised pancreatic cancer and 3 of 8 patients with more extensive pancreatic cancer. Leucocytes from pancreatic cancer patients with L.A.I. reactivity did not react to antigens of stomach, colon, or lung tumours; leucocytes from patients with stomach, colon, or lung cancer of inflammatory disease of the pancreas and bowel did not show L.A.I. reactivity to pancreatic tumour antigens.
The natural history of antitumour immunity in human breast cancer assayed by tube leucocyte adherence inhibition.
The specificity of the tube LAI in breast cancer was examined in a study with coded samples of PBL. In addition, 64 patients with breast cancer had their LAI reactivity monitored and correlated with their clinical status for up to 3 years after mastectomy. When patients were assayed by tube LAI, 83, 72, and 29% with Stage I, and II and III breast cancer respectively were positive. In Stage IV brest cancer, 88% of those with local recurrence and 15% of those with disseminated cancer were positive. By contrast, 3% of control subjects were LAI+. A select group of patients admitted to hospital with suspicious breast lumps that histopathologically proved to be benign breast disease (BBD) had a higher incidence of LAI+ (12%), whereas of outpatients with BBD only 2% were LAI+. Most breast cancer patients LAI reactivity became negative 2--4 months after mastectomy, even when some harboured micrometastases. LAI reactivity remained absent in those patients who remained clinically "cancer-free". In the follow-up patients, LAI activity returned about 4 months before local recurrence. LAI reactivity was observed in 7/8 patients in the coded study and 14/15 patients in the follow-up study preceding and/or at the time of local recurrence. A few patients (15%) progressed to widespread cancer without preceding positive LAI activity. The results suggest that tumour-specific immunity rapidly fades after surgery and may play no role in the rejection of micrometastases by 6 months after surgery. In addition, the present study has shown that the human hose manifests tumour-specific immunity when the cancer is small, and suggests that the early detection of human cancer would depend upon reliable methods to measure the tumour-specific immune response.
A study of false positive and negative responses in the tube leucocyte adherence inhibition (tube LAI) assay.
A panel of 5 different breast-cancer and 2 other cancer extracts was used to clarify the false-negative responses in patients with Stage I and II breast cancer and the false-positive responses in control subjects. Most patients with Stage I and II breast cancer who had an initially negative LAI response were positive when tested against the panel. The false negatives occurred because of (1) the experimental errors of the assay; (2) changes in the antigenic strength of the extracts; (3) antigenic heterogeneity of a few tumours and (4) lack of tumour-specific reactivity of the host. 3% of control subjects had a false-positive LAI response. The leucocytes from most of these positive patients did not react to the panel of antigens, and hence the false positives appeared to result from experimental error. In-hospital patients with benign breast disease had a 12% positivity rate when initially assayed, and 63% of these patients reacted to the panel of breast-cancer antigens. Those patients with benign breast disease who reacted to the panel of breast-cancer antigens had cytophilic anti-breast-cancer antibody in their serum; their leucocyte LAI reactivity was blocked in an immunologically specific manner by serum from advanced Stage IV breast-cancer patients; their leucocytes reacted to extracts of breast cancer and not fibrocystic breast tissue; their leucocyte reactivity was blocked by isolated breast-cancer TSA that was linked to beta 2 microglobulin, but not by normal breast-tissue proteins; and the kinetics of the LAI response after excision of the breast mass was identical to that observed with breast-cancer patients after mastectomy. In these patients, the breast tissue within the breast lump expressed breast TSA similar to unequivocal breast cancer.
Early diagnosis of cancers of colon, pancreas, stomach, and lung by automated tube leukocyte adherence inhibition assay.
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An overview: antitumor immunity in breast cancer assayed by tube leukocyte adherence inhibition.
The adherence to glass of human peripheral blood leukocytes (PBL) incubated with tumor antigen in vitro, is specifically inhibited if the PBL are sensitized to the antigen. The presence of leukocyte adherence inhibition (LAI) to tumor extracts indicates the presence of systemic antitumor immunity. By the tube leukocyte adherence inhibition assay (tube LAI), it was shown that 85% (191 of 223) Stage I and II, 45% (15 of 34) Stage III and 29% (30 of 103) Stage IV breast cancer patients had LAI reactivity. LAI responsiveness diminished with an increased tumor burden and most patients with advanced cancer exhibited no LAI reactivity. When LAI reactivity was monitored for 1 to 6 months after surgery, 13 of 25 Stage I and II breast cancer patients were negative on the first repeat assay. In general, 7 months after mastectomy most patients clinically free of cancer showed no LAI reactivity. Of thirty-five patients tested between 7 and 18 months after mastectomy, 6 were positive and 4 of the positives had local recurrence. The phenomenon of tube LAI appears to be mediated by monocytes armed with cytophilic antitumor antibody. The serum of patients whose leukocytes responded in the tube LAI assay had free cytophilic antitumor antibody that "armed" or sensitized normal leukocytes to respond in the LAI assay. Serum arming paralleled leukocyte reactivity before and after surgery. Patients with advanced cancer whose leukocytes failed to react in the LAI assay had serum blocking factors (excess tumor antigen) that abrogated the LAI reactivity of leukocytes from reactive patients.
Cortisol in human breast cancer tissue.
Endogenous cortisol levels were measured by radioimmunoassay in 140 primary and 31 metastatic human breast cancer specimens. The adjacent normal breast was assayed in 15 cases. Mean values for normal breast were 17.3 ng/g tissue. Significantly higher levels were found in cancer tissue. Primary lesions contained 26 ng/g and metastases 32.5 ng/g cortisol. These results lend support to our previous data on increased cortisol binding activity in human breast cancer.