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Biomedical subjects

B M Smithers

Publications and source records attributed to B M Smithers.

At least 37 records · Page 2Linked to original sources
PubMed1997

The effects of perfusion conditions on melphalan distribution in the isolated perfused rat hindlimb bearing a human melanoma xenograft.

An isolated rat hindlimb perfusion model carrying xenografts of the human melanoma cell line MM96 was used to study the effects of perfusion conditions on melphalan distribution. Krebs-Henseleit buffer and Hartmann's solution containing 4.7% bovine serum albumin (BSA) or 2.8% dextran 40 were used as perfusates. Melphalan concentrations in perfusate, tumour nodules and normal tissues were measured using high-performance liquid chromatography (HPLC). Increasing the perfusion flow rates (from 4 to 8 ml min(-1)) resulted in higher tissue blood flow (determined with 51Cr-labelled microspheres) and melphalan uptake by tumour and normal tissues. The distribution of melphalan within tumour nodules and normal tissues was similar for both Krebs-Henseleit buffer and Hartmann's solution; however, tissue concentrations of melphalan were significantly higher for a perfusate containing 2.8% dextran 40 than for one containing 4.7% BSA. The melphalan concentration in the tumour was one-third of that found in the skin if the perfusate contained 4.7% BSA. In conclusion, this study has shown that a high perfusion flow enhances the delivery of melphalan into implanted tumour nodules and normal tissues, and a perfusate with low melphalan binding (no albumin) is preferred for maximum uptake of drug by the tumour.

Animals↗
PubMed1997

Relative dispersion of intravascular transit times during isolated human limb perfusions for recurrent melanoma.

AIMS: We have characterized the relative dispersion of vascular and extravascular markers in the limbs of three patients undergoing isolated limb perfusions with the cytotoxic melphalan for recurrent malignant melanoma both before and after melphalan dosing. METHODS: A bolus of injectate containing [51Cr] labelled red blood cells, [14C]-sucrose and [3H]-water was injected into an iliac or femoral artery and outflow samples collected at 1 s intervals by a fraction collector. The radioactivity due to each isotype was analysed by either gamma [51Cr] or beta [14C and 3H] counting. The moments of the outflow fraction-time profiles were estimated by a nonparametric (numerical integration) method and a parametric model (sum of two inverse Gaussian functions). RESULTS: The availability, mean transit time and normalised variance (CV2) obtained for labelled red blood cells, sucrose and water were similar before and after melphalan dosing and with the two methods of calculation but varied between the patients. CONCLUSIONS: The vascular space is not well-stirred but characterized by a CV2 similar that reported previously for in situ rat hind limb and rat liver perfusions. A flow-limited blood-tissue exchange was observed for the permeating indicators. Administration of melphalan did not influence the distribution characteristics of the indicators.

Aged↗
PubMed1997

Isolated limb perfusion with melphalan for human melanoma xenografts in the hindlimb of nude rats: a surviving animal model.

We have established a surviving model of isolated limb perfusion using xenografts of the human melanoma cell line MM 96L injected subcutaneously into the hindlimb of a nude rat. The femoral artery and vein were cannulated via the left renal artery and vein and the hind limb was isolated using tourniquets. The limb was perfused with Krebs Heinseleit buffer at 37 degrees C containing 4.7% bovine serum albumin at a constant flow rate of 4 ml per min for 30-60 min with 100% survival of the animals. Tumour vascularization and blood flow were demonstrated using vascular casts and [51Cr]-microspheres. Following the addition of melphalan (15 or 100 micrograms/ml), drug concentrations in the perfusate, tissues and systemic circulation were determined using high pressure liquid chromatography (HPLC). Systemic leakage, assessed using [125I]albumin and melphalan and detected by a gamma-counter and HPLC respectively, was < 0.5%. The melphalan concentration and tissue flow rate in the tumour deposits were 40 and 30% respectively, when compared with the surrounding subcutaneous tissue. At a dose of 15 micrograms/ml, melphalan caused a reduction in tumour growth after 60 min perfusion, and a significant reduction in tumour size was seen when the melphalan dose was 100 micrograms/ml. The surviving nude rat model of isolated limb perfusion for recurrent melanoma will allow examination of optimal perfusion conditions, along with the pharmacokinetics, pharmacodynamics and efficacy of melphalan and other drugs.

Animals↗
PubMed1997

Melphalan dosing regimens for management of recurrent melanoma by isolated limb perfusion: application of a physiological pharmacokinetic model based on melphalan distribution in the isolated perfused rat hindlimb.

The optimal dosing schedule for melphalan therapy of recurrent malignant melanoma in isolated limb perfusions has been examined using a physiological pharmacokinetic model with data from isolated rat hindlimb perfusions (IRHP). The study included a comparison of melphalan distribution in IRHP under hyperthermia and normothermia conditions. Rat hindlimbs were perfused with Krebs-Hen-seleit buffer containing 4.7% bovine serum albumin at 37 or 41.5 degrees C at a flow rate of 4 ml/min. Concentrations of melphalan in perfusate and tissues were determined by high performance liquid chromatography with fluorescence detection. The concentration of melphalan in perfusate and tissues was linearly related to the input concentration. The rate and amount of melphalan uptake into the different tissues was higher at 41.5 degrees C than at 37 degrees C. A physiological pharmacokinetic model was validated from the tissue and perfusate time course of melphalan after melphalan perfusion. Application of the model involved the amount of melphalan exposure in the muscle, skin and fat in a recirculation system was related to the method of melphalan administration: single bolus > divided bolus > infusion. The peak concentration of melphalan in the perfusate was also related to the method of administration in the same order. Infusing the total dose of melphalan over 20 min during a 60 min perfusion optimized the exposure of tissues to melphalan whilst minimizing the peak perfusate concentration of melphalan. It is suggested that this method of melphalan administration may be preferable to other methods in terms of optimizing the efficacy of melphalan whilst minimizing the limb toxicity associated with its use in isolated limb perfusion.

Animals↗
PubMed1997

Tissue and perfusate pharmacokinetics of melphalan in isolated perfused rat hindlimb.

Melphalan is commonly used as a cytotoxic agent in isolated limb perfusion for locally recurrent malignant melanoma. The time course of melphalan concentrations in perfusate and tissues during a 60-min melphalan perfusion and 30-min drug-free washout in the single-pass perfused rat hindlimb was examined using a physiologically based pharmacokinetic model. The rat hindlimbs were perfused with Krebs-Heinseleit buffer containing 4.7% bovine serum albumin (BSA) or 2.8% dextran 40 at a constant rate of 3.8 ml/min. The concentration of melphalan in perfusate and tissues was determined by high-performance liquid chromatography. The tissue concentrations of melphalan were significantly higher with the perfusate containing dextran than BSA during the 60-min perfusion. During the washout period, the melphalan concentration in the perfusates decreased rapidly in first few minutes, followed by a slower monoexponential decline. The estimated half life (t1/2) for melphalan removal from skin and fat was 59 +/- 2 min for both BSA and dextran perfusates. However, the estimated t1/2 for melphalan removal from muscle was 79 and 96 min for BSA and dextran washout perfusates, respectively. The predicted concentration-time profiles obtained for melphalan with BSA and dextran perfusates appear to correspond closely to the observed data. This study showed that the uptake of melphalan into perfused tissues is impaired by the use of perfusates in which melphalan is highly bound. Melphalan washout from muscle, but not skin and fat, was facilitated by the use of perfusates in which melphalan is highly protein bound.

Adipose Tissue↗
PubMed1996

Laparoscopic versus open appendectomy: prospective randomized trial.

A prospective randomized trial comparing laparoscopic appendectomy with open appendectomy in patients with a diagnosis of acute appendicitis was conducted between October 1992 and April 1994. Of the 158 patients randomized, 7 patients were excluded because of protocol violations (conversion to laparotomy in 4, appendix not removed in 3). The 151 patients randomized to either a laparoscopic (n = 79) or an open appendectomy (n = 72) showed no difference in sex, age, American Society of Anesthesiology (ASA) rating, or previous abdominal surgery. The histologic classification of normal, catarrhal, inflamed, suppurative, and gangrenous appendicitis was not different between the two groups. Conversion from laparoscopic to open appendectomy was necessary in seven patients (9%) who had advanced forms of appendiceal inflammation. When compared to open appendectomy the laparoscopic group had a longer median operating time (63 minutes versus 40 minutes), fewer wound infections (2% versus 11%), less requirement for narcotic analgesia, and an earlier return to normal activity (median 7 days versus 14 days). There was no difference in morbidity, and both groups had a median time to discharge of 3 days. Laparoscopic appendectomy is as safe as open appendectomy; and despite the longer operating time, the advantages such as fewer wound infections and earlier return to normal activity make it a worthwhile alternative for patients with a clinical diagnosis of acute appendicitis.

Adolescent↗
PubMed1996

Malignant sacrococcygeal germ cell tumour in an adult.

In adults, malignant sacrococcygeal germ cell tumour is a rare cause for a presacral tumour, with only 17 cases having been reported in the literature since 1907. We report the case of a 34 year old male who presented with a 6 month history of symptoms relating to a malignant presacral tumour which required en bloc excision including the lower sacrum and rectum. He died with lung and mediastinal metastasis 7 months following surgical excision and adjuvant chemotherapy using Cisplatin, Bleomycin and Etoposide. Prior to his death, he had a severe polyarthritis of his peripheral joints and evidence of hypertrophic osteo-arthropathy. The literature indicates that adults with these tumours have a poor prognosis, with only one reported long-term survivor. Surgical excision offers the only chance of cure, with the role of adjuvant therapy not having been defined because of the small numbers.

Adult↗
PubMed1996

Laparoscopic Nissen fundoplication--200 consecutive cases.

PATIENTS: Laparoscopic Nissen fundoplication was undertaken in 200 patients between 1991 and 1994. METHODS: Pre-operative assessment included symptom score, endoscopy, manometry, and 24 hour pH monitoring of the oesophagus. Patients were evaluated at three and 12 months after surgery with symptom scoring and 96 patients also underwent 24 hour pH studies at three to six months postoperatively. RESULTS: In the first 100 patients median duration of operation was 155 minutes (range: 70-330), conversion rate to laparotomy was 7%, median hospital stay was three days (range: 2-57), and total morbidity was 16%. This compared with a median operation time of 120 minutes (60-240) (p = 0.0003, 95% CI 10, 40), a conversion rate of 2% (p = 0.2), a hospital stay of three days (1-18) (p = 0.0016, 95% CI 0, 1), and total morbidity of 7% (p = 0.15) in the second 100 patients. Median total symptom scores fell from 5/9 to 0/9 after fundoplication (< 0.0001) while median 24 hour oesophageal acid exposure in 96 patients was reduced from 10% to 1% (p < 0.001). CONCLUSIONS: Laparoscopic Nissen fundoplication is a safe and effective procedure for gastro-oesophageal reflux disease. With experience, the duration of operation falls and the hospital stay is shorter. Shortterm symptomatic and pH results are consistently improved by surgery.

Adolescent↗
PubMed1996

Laparoscopic Nissen fundoplication and postoperative dysphagia-can it be predicted?

Temporary swallowing difficulty has been reported in up to 100% of patients after laparoscopic Nissen fundoplication for gastro-oesophageal reflux, but the long-term prevalence of dysphagia is not known. If reliable predictors of persistent postoperative dysphagia exist, their identification may permit tailoring of the fundoplication for specific cases at risk. Of 475 consecutive cases of laparoscopic fundoplication, 202 have undergone detailed symptom scoring at 1 year postoperatively. In each case, a short, 360 degrees loose wrap was constructed over an intra-oesophageal bougie, and short gastric vessels were divided when insufficient fundal mobility was encountered. At one year postoperatively, 24% complained of grade 1 dysphagia (intermittent sensation of food sticking), 9% of grade 2 (food sticking requiring liquids to clear) and 1 patient had regular dysphagia for solids (grade 3). Gender, preoperative complaint of dysphagia, endoscopic grade of oesophagitis, oesophageal motility, lower oesophageal sphincter pressure, and division of short gastric vessels were reviewed in relation to dysphagia. Dysphagia is common after laparoscopic Nissen fundoplication, but is less prevalent than before operation. It is usually mild, intermittent and improves with time. Those with division of short gastric vessels had a reduced risk of postoperative dysphagia.

Adolescent↗
PubMed1995

High-performance liquid chromatographic assay for the measurement of melphalan and its hydrolysis products in perfusate and plasma and melphalan in tissues from human and rat isolated limb perfusions.

A sensitive, specific and rapid reversed-phase high-performance liquid chromatographic (HPLC) assay was developed for the quantitation of melphalan and its hydrolysis products in samples from the isolated perfusion of human and rat limbs. Samples of perfusate, plasma and tissue were analysed, following methanol precipitation, using a phenyl column and fluorescence detection. Dansyl-arginine (38 micrograms ml-1) was employed as the internal standard. Good resolution was observed allowing quantitation of melphalan, monohydroxymelphalan (MOH) and dihydroxymelphalan (DOH) in perfusate and plasma were all 100 +/- 10%. The recovery of melphalan in tissue was 93.5%. A linear response was demonstrated for melphalan in the concentration range 1.8 - 56.8 micrograms ml-1, for DOH in the concentration range 0.5 - 30.0 micrograms ml-1 and for MOH in the range 1.4-25.1 micrograms ml-1, in perfusate and plasma. The lower limits of quantitation of melphalan, MOH and DOH in perfusate and plasma were 1.4, 2.4 and 1.2 ng on column, respectively, and 7.2 ng of melphalan on column in tissue. Intra-assay coefficients of variation (C.V.) for melphalan, MOH and DOH, at low and high concentrations were all less than 5% and the inter-assay C.V.s were less than 9%. An ultra-filtration study to determine the protein binding of melphalan and the hydrolysis products showed that the unbound fractions (fu) of melphalan in buffer containing dextran and bovine serum albumin were 0.873 and 0.521, respectively. The assay was used to quantitate melphalan and its hydrolysis products in samples from isolated perfusions in the human limb and rat hindlimb.

Adipose Tissue↗
PubMed1994

Laparoscopic approach to the left kidney avoiding colonic mobilization.

A technique for laparoscopic removal of the left kidney is described. Using a transperitoneal approach, a window is created in the mesocolon lateral to the inferior mesenteric vein. Through this window the renal vessels can be secured and the kidney removed without mobilization of the left colon. Preoperative stenting facilitates removal of a hydronephrotic kidney with this technique.

Adolescent↗
PubMed1994

Melphalan uptake, hyperthermic synergism and drug resistance in a human cell culture model for the isolated limb perfusion of melanoma.

Isolated limb perfusion with melphalan is a long-standing treatment for melanoma but the clinical conditions have not been subjected to a systematic evaluation. In order to establish optimal conditions for perfusion, three human melanoma cell lines were cultured with melphalan in vitro under conditions comparable to in vivo therapy. The most important findings were that: (a) 41.5 degrees C was synergistic for melphalan killing of three human melanoma cell lines; (b) prolonging the treatment time beyond 1 h had little additional toxicity; and (c) varying the initial pH of the culture medium had no effect. After 1 h of treatment, cells accumulated more melphalan at 41.5 degrees C than at 37 degrees C, relative to the extracellular concentration. A cell line (MM418) derived from a primary tumour was the most resistant of the three lines; pigmented or non-pigmented sublines were equally resistant. The A2058 line showed the lowest level of synergism with hyperthermia, and displayed a marked plateau at 10% of controls in the dose-response for survival, yet no melphalan-resistant subpopulation could be isolated. The implications of this work are that (a) enhanced cellular uptake of melphalan may account for hyperthermic synergism of melphalan; (b) varying conditions other than treatment time will be necessary to deal with the variation in resistance between tumours; and (c) repeated cycles of treatment may be needed for phenotypes such as A2058 where melphalan resistance appears to be based on an epigenetic mechanism.

Chemotherapy, Cancer, Regional Perfusion↗
PubMed1994

Laparoscopic nephrectomy for benign renal disease.

OBJECTIVE: To perform nephrectomies in patients with benign renal conditions using laparoscopic techniques. PATIENTS AND METHODS: A total of five patients with benign renal conditions were treated. Three of the patients were morbidly obese. The operative technique was similar to a transperitoneal nephrectomy and was performed through four to six abdominal ports. Initial dissection involved mobilization of the overlying right colon to expose the retroperitoneum. Early identification of the inferior vena cava and ureter was critical to subsequent dissection and particularly to the exposure of the renal vessels. These vessels were controlled by either Endo-GIA staples (Autosuture Co., USA) or vicryl ties and haemaclips prior to division. After control of the vascular pedicle the kidney was mobilized within Gerota's fascia and removed. RESULTS: In three patients the procedure was performed entirely laparoscopically with retrieval of the kidneys through dilated abdominal port sites. Small incisions were necessary in the remaining two patients--one with a grossly hydronephrotic kidney and the other, a morbidly obese woman with co-existing cholelithiasis, treated laparoscopically also had an epigastric hernia which was repaired using a 5 cm incision through which her kidney and gall-bladder were removed. Operative times ranged from 2 to 4 1/2 h. Narcotic analgesia was required in two cases and the median post-operative stay was 2 days. A superficial skin infection in one patient was the only post-operative complication. CONCLUSION: Laparoscopy appears to have a definite role in the selective removal of kidneys for benign renal disease. Based on our experience this technique is particularly useful in the obese patient--reducing post-operative pain and allowing early mobilization, discharge from hospital and resumption of normal activities.

Adult↗
PubMed1993

Ultrastructure of human melanosis coli with reference to its pathogenesis.

Colonic mucosal biopsies from patients with melanosis coli were examined by electron microscopy. They showed apoptosis of colonic surface epithelial cells and phagocytosis of resulting apoptotic bodies by intraepithelial macrophages. The latter migrated to the lamina propria where intracellular degradation of the apoptotic bodies resulted in formation of lipofuscin, characteristic of this condition. The results showed the pathogenesis of human melanosis coli was identical to that determined in an animal model of this disease.

Aged↗
PubMed1992

Primary adenocarcinoma in a colonic 'oesophageal' segment.

A case of primary adenocarcinoma of the colon in a segment used to reconstruct after an oesophageal resection is reported. The original lesion was a relatively advanced adenocarcinoma of the gastro-oesophageal junction. An ACPS 'C' colon carcinoma was diagnosed 12 years later. A curative resection was achieved. The literature is reviewed in regard to late complications in colonic interpositions, including primary carcinomas.

Adenocarcinoma↗
PubMed1991

Primary adenocarcinoma in a colonic oesophageal segment.

A case of primary adenocarcinoma of the colon in a segment used to reconstruct after an oesophageal resection is described. The original lesion was a relatively advanced adenocarcinoma of the gastro-oesophageal junction. An ACPS 'C' colon carcinoma was diagnosed 12 years later. A curative resection was achieved. The literature is reviewed with respect to late complications in colonic interpositions, including primary carcinomas.

Adenocarcinoma↗
PubMed1991

Diagnosis of ruptured diaphragm following blunt trauma: results from 85 cases.

Between 1975 and 1990, 85 patients with diaphragmatic rupture following blunt trauma were treated at the Royal Brisbane and Princess Alexandra Hospitals, Brisbane. There were 65 on the left, 17 on the right and three were bilateral. Road trauma was the cause in 88% of cases. In the first 48 h the diagnosis was made by chest X-ray in 51 patients, laparotomy in 22, autopsy in two, emergency room thoracotomy, ultrasound and pneumoperitoneum each in a single patient. Seven patients (8%) had delay in diagnosis greater than 48 h ranging from 6 days to 6 months. Diagnosis was subsequently made by pneumoperitoneum (3), chest X-ray (1) and exploratory thoracotomy (1). Two patients presented with a strangulated diaphragmatic hernia 3 and 6 months following an acute admission with blunt chest trauma and urological trauma respectively. During the study period a further five patients presented with an obstructing diaphragmatic hernia. Sixteen patients died (19%), fifteen from associated injuries and one related to the diaphragmatic repair. Ruptured diaphragm should be suspected in patients with severe chest trauma, particularly those requiring positive pressure ventilation, patients with intra-abdominal injuries and those with pelvic fractures. Early recognition and repair results in low morbidity and mortality. Measures that confirmed the diagnosis in patients with delay included repeated chest X-rays and pneumoperitoneum.

Diaphragm↗