The effect of nicotinamide on spontaneous and induced activity in smooth and skeletal muscle.

BACKGROUND AND PURPOSE: Nicotinamide (NA) is currently undergoing clinical trials as a tumour radiosensitizer. The dose that can be administered is currently 80 mg/kg per day, but this may be restricted to 60 mg/kg per day by the high incidence of nausea and vomiting. To investigate some of NA's underlying mechanisms of action, we have used an ex vivo system to study the direct effect of this drug, over a wide range of concentrations, on isolated spontaneously active rat ileum. Effects on the gut were compared with the action of NA on skeletal and vascular smooth muscle. MATERIALS AND METHODS: Isolated rat ileum rings were perfused with oxygenated Krebs' solution in an organ bath. NA (1 microM to 10 mM) was introduced to the perfusate and the change in amplitude of spontaneous peristaltic activity recorded. Dissected frog sartorius muscle was bathed in modified oxygenated Ringer's solution in an organ bath. The muscle was electrically stimulated to generate isometric contractions. Tension was then measured before and after the addition of a range of NA concentrations (8.2-24.6 mM) to the organ bath. RESULTS: NA inhibited peristalsis in the ileum in a dose-dependent manner. At a drug concentration of 1 mM the amplitude of contractions was reduced to <50% of the initial control value. NA had no effect on the electrically induced contractions in the isolated frog sartorius muscle. CONCLUSIONS: Gut smooth muscle is highly sensitive to the relaxant effect of NA producing 50% relaxation at a concentration approximately 10 fold lower than that required in rat arterial smooth muscle, while having no effect on non-mammalian skeletal smooth muscle. This may provide explanations for the occurrence of emesis in patients undergoing combined nicotinamide therapies and highlight possible alternatives available to counter this unwanted side-effect.

John Kerr and apoptosis.

On 14 March 2000, John Foxton Ross Kerr, Emeritus Professor of Pathology at the University of Queensland, received the Paul Ehrlich and Ludwig Darmstaedter Prize for his description of apoptosis, a form of cell death. The prize, which he shared with Boston biologist Robert Horvitz, is considered to be one of the most prestigious European awards in science, second only to the Nobel Prize.

The anatomy of the extrathoracic intercostobrachial nerve.

BACKGROUND: In the past decade surgeons have become increasingly aware of the morbidity caused by the division of the intercostobrachial nerve (ICBN) during axillary dissection. To prevent this problem and also to explain its variable occurrence, a detailed knowledge of the anatomy of the nerve is required. METHODS: Twenty-eight axillary dissections were performed demonstrating the anatomy of the ICBN. RESULTS: In all dissections the nerve originated from the second intercostal space, with contributions from the first and third intercostal nerve each on one occasion. The posterior axillary branch was constant but may branch early, simulating a second nerve. The ICBN had a variable relationship to the lateral thoracic vein: anterior, posterior or wrapping around it. In 36% there was a connection to the medial cord of the brachial plexus in the axilla. In the upper arm the nerve lies in the subcutaneous fat; in the majority it supplied at least the proximal half of the arm, and in one-third it reached the level of the elbow joint. In 18% there was a connection to the medial cutaneous nerve of the arm. CONCLUSION: The ICBN and its main branch (the posterior axillary nerve) were constant in all dissections. But its origin, size, connection to the brachial plexus and medial cutaneous nerve of the arm were variable, as was its ultimate destination in the arm.

A case report: immune responses and clinical course of the first human use of granulocyte/macrophage-colony-stimulating-factor-transduced autologous melanoma cells for immunotherapy.

The first use of granulocyte/macrophage-colony-stimulating-factor-transduced, lethally irradiated, autologous melanoma cells as a therapeutic vaccine in a patient, with rapidly progressive, widely disseminated malignant melanoma resulted in the generation of a novel antitumour immune response associated with partial, albeit temporary, clinical benefit. An initially negative reaction to non-transduced, autologous melanoma cells was converted to a delayed-type hypersensitivity (DTH) reaction of increasing magnitude following successive vaccinations. While intradermal vaccine sites showed prominent dendritic cell accrual, DTH sites revealed a striking influx of eosinophils in addition to activated/memory T lymphocytes and macrophages, recalling the histology of challenge tumour cell rejection in immune mice. Cytotoxic T lymphocytes (CTL) reactive with autologous melanoma cells were detectable at high frequency after vaccination, not only in limiting-dilution analysis, but also in bulk culture without added cytokines. Clonal analysis of CTL showed a conversion from a purely CD8+ response to a high proportion of CD4+ clones following vaccination. A prominent acute-phase response manifested by a five- to tenfold increase in C-reactive protein was observed, as was a systemic eosinophila. Vaccination resulted in the regression of axillary lymphatic metastases, stabilisation of pulmonary metastases, and a dramatic, reversible increase in cerebral oedema associated with multiple central nervous system metastases: however, lesions in the adrenal glands, pancreas and spleen proved refractory. The antitumour effects and immune response were not detectable 2 months following the last vaccination. Irradiation of the extensive cerebral metastases resulted in rapid deterioration and death of the patient.

Immunotherapy, including gene therapy, for metastatic melanoma.

Current standard therapy for distant metastatic melanoma is ineffective and often compromises the quality of a patient's life. Immunotherapy is briefly reviewed in relation to its many forms: from local non-specific to the more recent specific vaccines, including those using specific melanoma peptides (e.g. from the proteins encoded by melanoma-associated gene (MAGE)) and those involving genetically transduced autologous melanoma cells using retroviral vectors in vitro. The mode of action of genetically transduced melanoma cells incorporating the granulocyte macrophage colony stimulating factor (GM-CSF) gene (GVAX) is presented as a paradigm for cytokine-mediated strategies. Trials of GVAX and other cytokine gene strategies are under way in Brisbane, Boston and Amsterdam, and some interim perspectives on the clinical outcomes and immunological mechanisms involved are sketched. Some of the compounding problems in immunotherapeutic strategies for cancer are identified, and possible adjunct manoeuvres for overcoming them are discussed.

Recommended width of excision for primary malignant melanoma.

Wide local excision for melanoma with margins of 3 to 5 cm have been advocated in the literature for nearly 140 years. These reports have grouped all stages of melanoma rather than addressing primary early stage disease. Breslow first advocated limited excision margins for these tumors. We have been excising all thicknesses of melanoma with a limited margin (1.00-1.50 cm, mostly 1.00 cm) since 1975. We advocate a 1 cm excision margin irrespective of tumor thickness. Clark has shown that melanoma invades in a vertical fashion, and thus one would expect to be more generous in depth than in width on a pathologic basis. Two studies have shown that there is no difference in the increase in locoregional recurrence and no change in death rate from the disease with more conservative treatment margins. Excision of this lesion is not an office procedure. It should be performed meticulously in an operating room, preferably under light general anesthesia.

Angular vein of the axilla and the anatomy of the subscapular vein important in axillary node dissection.

The anatomy of the subscapular vein and its tributaries is described. Importantly, the angular branch of the subscapular vein and its almost constant relationship to the thoracodorsal nerve were demonstrated.

Melanoma recurrence after excision. Is a wide margin justified?

Through retrospective analysis of patient records for 187 patients with melanoma seen between 1975 and 1989, the aim of this study was to determine whether outcome varied according to degrees of surgical intervention in the primary treatment of stage I disease for thin, intermediate, and thick lesions. There were no significant differences in recurrence rate associated with an excision margin of 15 mm or less compared with wider excision margins; with initial excision compared with wider re-excision after excision biopsy; or for primary closure as compared with closure with a graft. There was, however, a significant difference in wound complication rate between wounds closed primarily (6%) and those closed by grafting (31%) (p < 0.01). The authors advocate the more conservative excision margin of 1.00 cm to 1.50 cm in the treatment of stage I melanoma with primary closure of the wound where possible.

The diagnosis of breast cancer: a clinical and mammographic comparison.

The early and accurate diagnosis of breast cancer is of paramount importance in the symptomatic patient. In this study, the sensitivity and false negative rates of clinical assessment and community mammographic imaging are measured and compared. One hundred and sixty-nine histologically proven breast cancers, derived from one surgeon's practice, were clinically assessed. Of these, 108 were additionally assessed by mammography. Eighty-seven per cent of the patients with breast cancer presented with a lump. In 82.8% of cases the patient or her partner found the lump, while 12.3% of lumps were found by the family practitioner. The false negative rate for clinical diagnosis was 19%, and for mammographic diagnosis it was 29%. Premenopausal mammographic diagnosis had a significantly higher false negative rate (54%) than postmenopausal diagnosis (14%). Mammographic examination had a particularly high false negative rate (65%) when cancer was thought clinically to be of "low index of suspicion". The clinical evaluation of and the indications for biopsy of the symptomatic breast remain the essential step in the diagnosis of breast cancer.

Management of Merkel cell tumour.

The records of 13 patients suffering from Merkel cell tumour of the skin have been reviewed and the treatment analysed. Pending further experience of this uncommon tumour, a recommendation is made for wide excision of the primary site with elective postoperative radiation to both the primary site, the in-transit zone where practicable, and regional nodes. If malignant nodes occur, block dissection with postoperative radiotherapy is indicated. If widespread metastases develop, cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy may give a response. The prognosis is poor.

Merkel-cell tumour of the skin.

The case histories of four patients with a Merkel-cell tumour of the skin are presented and the findings are compared with other reports in the literature. An association with other skin tumours is noted and ultraviolet light may be implicated in the causation of Merkel-cell tumours. The Merkel-cell tumours in this series occurred initially on the face. The difficulty of diagnosis is stressed. It is recommended that wide excision of the tumour be followed by radiotherapy to the excision site plus a large margin, in an attempt to prevent local recurrences that are brought about by lymphatic permeation.

Merkel cell tumor with spontaneous regression.

Merkel cell tumor of the skin is now a well-documented tumor. We report on another tumor with local recurrence and skin metastases which spontaneously regressed.

Gallstone pancreatitis.

Gallstone pancreatitis is a disease of high mortality (11%) and significant morbidity (42%). An analysis of 66 patients with this disease revealed the importance of an early aetiological diagnosis; 66% of our patients had evidence of previous biliary disease. Most patients were elderly and the severity of their disease could be predicted using Ranson's predictive indices. Surgery was immediate (within 48 hours) in 11 (17%) patients, early (two-14 days) in 16 (24%) and delayed in 27 (41%) patients. Some patients refused surgery. Our study suggests that very ill patients require immediate surgery--often cholecystostomy alone--and that although in the majority symptoms should settle on conservative treatment, definitive surgery should be carried out at the time of the initial admission. Further delay increases morbidity, mortality and expense.

Carcinoid of the small intestine.

Carcinoid tumour was the most common small bowel tumour found in this series of 179 patients. It occurred in 24% of patients. Forty-six percent of patients were asymptomatic during life, the tumours being found either at autopsy or during other surgical procedures. Of those that were symptomatic, half presented with intestinal obstruction and the rest with long-standing symptoms. An abdominal mass, which occurred in 14% of cases, is an uncommon physical finding since the majority present as small submucosal tumors. Fifty-eight per cent overall and 72% of those having surgery had evidence of regional spread, either by local invasion or in the form of regional nodal involvement. Seven per cent of patients have died of their disease. Excisional surgery should be performed for all cases where feasible, and repeated for recurrent symptoms.

Lymphoma of the small intestine.

In a group of 179 patients with small bowel tumours presenting over a 10 year period, lymphomas (20%) were the second most common group. The tumour was usually a white mass and was usually resectable. Eighty-one per cent of patients had regional invasion or metastasis at the time of surgery. Treatment was by surgery and radiotherapy for regional disease. If patients survived 2 years they were usually cured. The overall survival rate was 57%. Fresh tissue for expert histology is essential. Histological review by an experienced panel revealed many tumours previously classified as undifferentiated and several anaplastic carcinomata to be lymphoma. It has been recommended that the criteria for intestinal lymphoma be revised.

The operating room diagnosis of small bowel tumours.

A scheme is proposed whereby a surgeon in the operating room may identify macroscopically, with accuracy, the nature of a small intestinal tumour. This will help the surgeon to make a correct decision regarding the immediate operative management of the tumour.

Cutaneous malignant melanoma in association with other skin cancers.

A case-control study of 232 cases of cutaneous malignant melanoma and 232 matched controls was performed to assess the association of the disease with nonmelanotic skin tumors--basal cell carcinomas, squamous cell carcinomas, and solar keratoses. There was a fourfold increase in risk of melanoma of all types when actinic tumors were present on the face. The risk was not restricted to the lentigo malignant melanoma class as might be expected but was significantly raised for superficial spreading melanoma and nodular melanoma as well (relative risk, 2.8; 95% confidence interval, 1.1-7.2). This relationship with lesions known to be associated with high-dose solar UV irradiation was supported by quantitative evidence that heavy sun exposure was associated with an increased risk of malignant melanoma.