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Biomedical subjects

B M Smithers

Publications and source records attributed to B M Smithers.

At least 19 recordsLinked to original sources
PubMed2006

Radiotherapy for metastatic melanoma presenting in pregnancy.

We describe the study of a patient with metastatic melanoma to axillary nodes presenting during pregnancy. The factors considered in her management are discussed, including issues related to staging, the decision not to terminate the pregnancy and the relative efficacy and fetal toxicity of the available treatment options. An overview of the known effects of radiotherapy on the fetus is presented and the technical alterations that were used to decrease the toxicity of radiotherapy are discussed.

Adult↗
PubMed2005

Minimally invasive esophagectomy: short- and long-term outcomes.

BACKGROUND: We aimed to assess the outcomes including the effect on quality of life (QoL) of a group of patients having a minimally invasive esophagectomy (MIE). METHODS: Patients with esophageal cancer were offered MIE over a 22-month period. Data on outcomes were collected prospectively, including formal quality-of-assessments. RESULTS: There were 25 patients offered MIE. Two patients were converted to a laparotomy to improve the lymphadenectomy. There were no deaths. Respiratory problems (pneumonia, 28%) were the most common in the 64% of patients who had a complication. The median blood loss was 300 ml, time of surgery 330 min, and time to discharge 11 days. There was a decrease in the measured QoL both in general and specifically for the esophageal patients, taking 18-24 months to return to baseline. CONCLUSIONS: MIE was performed with morbidity similar to other approaches. There were no clear benefits shown in this group of patients with respect to postoperative recovery or short- to medium-term QoL.

Adenocarcinoma↗
PubMed2005

Symptomatic and functional outcome after laparoscopic reoperation for failed antireflux surgery.

BACKGROUND: The aim was to determine symptomatic and functional outcome after reoperative antireflux surgery for recurrent reflux, persistent dysphagia and severe gas bloat, using a primarily laparoscopic surgical approach. METHODS: This was a retrospective analysis of prospectively collected data from 118 patients, of whom 70 had reoperative surgery for recurrent reflux, 35 for dysphagia and 13 for gas bloat. DeMeester scores before and 1 year after surgery, functional symptoms after surgery and overall patient satisfaction were analysed. RESULTS: Reoperation was completed laparoscopically in 101 patients (85.6 per cent), in 28 after previous open hiatal surgery. The operation was converted from an initial laparoscopic approach to open surgery in 17 patients. One-year follow-up data were available for 104 patients (88.1 per cent). After reoperation for recurrent reflux, 84 per cent had a DeMeester heartburn score of zero or one, and 87 per cent had a regurgitation score of zero or one. After reoperation for dysphagia, 21 of 32 patients had a dysphagia score of zero or one, with improvement observed in 25. All patients undergoing reoperation for severe gas bloat were satisfied with the outcome 1 year after operation. CONCLUSION: Revisional surgery for recurrent reflux using a laparoscopic approach offered high rates of success and patient satisfaction. Swallowing returned to normal in two-thirds of patients after reoperation.

Deglutition Disorders↗
PubMed2004

Use of oesophagogastroscopy to assess the response of oesophageal carcinoma to neoadjuvant therapy.

BACKGROUND: Approximately 25 per cent of patients with oesophageal cancer who undergo neoadjuvant chemoradiotherapy have no evidence of tumour in the resected specimen (complete pathological response). Those who do not respond have a poor 5-year survival compared with complete responders, regardless of whether or not they undergo surgery. Selecting for surgery only those who have a response to neoadjuvant therapy has the potential to improve overall survival as well as to rationalize the management of non-responders. This study assessed the accuracy of oesophagogastroscopy in this setting. METHODS: A prospective database of 804 patients undergoing oesophageal resection for carcinoma was reviewed. Endoscopic assessment of the response to neoadjuvant therapy in 100 consecutive patients was compared with the pathological assessment of response. The survival for each level of response was compared. RESULTS: At endoscopy 30 patients were considered to have had a complete response. This was confirmed pathologically in 15 patients. Survival was improved in those with a pathologically confirmed complete response (3-year survival rate 62.4 (s.e. 12.9) per cent) compared with non-responders (16.3 (s.e. 6.6) per cent). Those with microscopic residual disease also had an improved 3-year survival rate (46.3 (s.e. 12.2) per cent); however, oesophagogastroscopy failed to identify this subset. CONCLUSION: Oesophagogastroscopy may be useful in the assessment of tumour response to neoadjuvant therapy. However, owing to its poor accuracy patients should not be excluded from further therapeutic intervention on the basis of this assessment alone.

Adenocarcinoma↗
PubMed2004

Chemoradiation therapy is effective for the palliative treatment of malignant dysphagia.

Between 1993 and 2001, 106 patients with esophageal cancer were reviewed at a multidisciplinary clinic and treated with palliative intent by chemoradiation therapy. This study assesses the palliative benefit on dysphagia and documents the toxicity of this treatment. The study population comprised 72 men and 34 women with a median age of 69 years. Patients were treated with a median radiation dose of 35 Gy in 15 fractions with a concurrent single course of 5 FU-based chemotherapy. Dysphagia was measured at the beginning and completion of treatment and at monthly intervals until death, using a modified DeMeester (4-point) score. Treatment was well tolerated, with only 5% of patients failing to complete therapy. The treatment-related mortality was 6%. The median survival for the study population was 7 months. The median baseline score at presentation was 2 (difficulty with soft food). Following treatment, 49% of patients were assessed as having a dysphagia score of 0 (no dysphagia). Seventy-eight per cent had an improvement of at least one grade in their dysphagia score after treatment. Only 14% of patients showed no improvement with treatment. Fifty-one per cent maintained improved swallowing until the time of last follow-up or death. This single-institution study shows that chemoradiation therapy administered for the palliation of malignant dysphagia is well tolerated and produces a sustainable normalization in swallowing for almost half of all patients.

Adult↗
PubMed2003

Relapse patterns after chemo-radiation for carcinoma of the oesophagus.

AIM: The detailed review of patterns of failure in this report was undertaken to identify the continuing obstacles to the successful management of oesophageal cancer, and to establish whether there is a case to compare definitive chemo-radiation (Def-CR) and surgery for patients with squamous cancer in a randomized controlled trial. MATERIALS AND METHODS: First and subsequent sites of failure were reviewed in 274 patients treated with Def-CR using two cycles of cisplatin, infusional fluorouracil and 60 Gy; and 92 patients with limited chemo-radiation (CR), using one cycle and 35 Gy, followed by surgery (CR-Surg). All were treated on prospective non-randomized trials run by the Trans-Tasman Radiation Oncology Group between 1985 and 1999. Failure patterns were analysed using competing risks methodology, and pre-treatment variables predicting survival were identified by proportional hazards modelling. RESULTS: Site, stage, performance status and gender were independently predictive of survival following Def-CR. Local failure was evident in 42.3% of patients, but distant failure in isolation occurred in an additional 18.1%. Lowest rates of local and distant failure at 5 years (29.9% and 26%) occurred in patients with squamous cancer (SCC) located in the upper-third, whose 5-year survival was also the most favourable (49.2%). Survival was least favourable in patients with adenocarcinoma (AC) in the lower two-thirds (18.1%) due to higher rates of local (51.5%) and distant (36.1%) failure. Local failure occurred in 31.5% of patients undergoing CR-Surg but distant failure in isolation was observed in a further 34.7%. Outcomes were least favourable in patients with AC of the lower-third in whom 57.7% failed distantly and 5-year survival was 3.8%. Response to pre-operative chemo-radiation was also strongly predictive of outcome. Patients with no residual cancer in the resection specimen had the lowest rates of local (0%) and distant (16.7%) failure and the best survival (64.9%). Survival in patients with residual cancer in nodes, however, was extremely poor (3.5%) with distant failure occurring in 66.7%. CONCLUSION: The concurrent administration of chemotherapy with radiotherapy seems to have improved loco-regional control and has exposed distant failure as an obstacle to further improvements in outcome. Site, histological subtype, gender and response to chemo-radiation may predict biological differences in oesophageal cancer (OC) that influence outcome. A good case for a randomized comparison between Def-CR and CR-Surg in patients with SCC in the lower two-thirds exists.

Adenocarcinoma↗
PubMed2002

Early reoperation for acute dysphagia following laparoscopic fundoplication.

BACKGROUND: A small number of patients develop acute severe dysphagia for which reoperation is necessary within 10 days of laparoscopic fundoplication. The aim of this study was to identify clinical variables that might predict the likelihood of this condition occurring, such that it could be avoided in the future. METHODS: This was a prospective cohort study from three tertiary referral centres, using reoperation for acute dysphagia as the main outcome variable. Gastrointestinal symptom rating scale, and psychological well-being index questionnaires were undertaken before laparoscopic fundoplication, and dysphagia scores were determined before operation and 1 year later. Standard preoperative assessment included gastroscopy, oesophageal manometry and pH studies. RESULTS: Twelve (1.9 per cent) of the 617 patients suffered acute dysphagia, which was predicted by older age and female sex, and resulted in a longer duration of hospital stay. This condition was not predicted by any other demographic, clinical, investigative or operative variables. CONCLUSION: The study did not identify useful criteria by which severe acute dysphagia could be anticipated and thereby avoided following laparoscopic fundoplication.

Acute Disease↗
PubMed2002

Radiation therapy following nodal surgery for melanoma: an analysis of late toxicity.

BACKGROUND: The role of adjuvant radiation therapy following resection of malignant melanoma involving regional lymph nodes remains controversial. There is no published randomized trial comparing surgery alone to surgery with postoperative radiation therapy that shows a benefit in terms of local control. Some retrospective studies, however, suggest that radiation given postoperatively reduces local recurrence. One of the obstacles to patients routinely being offered radiation therapy is the concern over the added late toxicity that may occur. The present article is a report of the first 130 patients of a prospective phase II multicentre study in Australia and New Zealand. METHODS: The study was aimed at patients who had had a resection of melanoma in regional nodes or in a regional node basin. The patients were given adjuvant radiation therapy to a recommended dose of 48 Gy in 20 fractions over 4 weeks using accepted radiation techniques for each of the major node sites. This report describes the late toxicity of the treatment received by these patients. RESULTS: The results of late toxicity experienced in the study were acceptable. CONCLUSION: The regimen of radiation therapy used could form the basis for the treatment arm of a randomized trial.

Adult↗
PubMed2001

Microdialysis and response during regional chemotherapy by isolated limb infusion of melphalan for limb malignancies.

This study sought to use a microdialysis technique to relate clinical and biochemical responses to the time course of melphalan concentrations in the subcutaneous interstitial space and in tumour tissue (melanoma, malignant fibrous histiocytoma, Merkel cell tumour and osteosarcoma) in patients undergoing regional chemotherapy by Isolated Limb Infusion (ILI). 19 patients undergoing ILI for treatment of various limb malignancies were monitored for intra-operative melphalan concentrations in plasma and, using microdialysis, in subcutaneous and tumour tissues. Peak and mean concentrations of melphalan were significantly higher in plasma than in subcutaneous or tumour microdialysate. There was no significant difference between drug peak and mean concentrations in interstitial and tumour tissue, indicating that there was no preferential uptake of melphalan into the tumours. The time course of melphalan in the microdialysate could be described by a pharmacokinetic model which assumed melphalan distributed from the plasma into the interstitial space. The model also accounted for the vascular dispersion of melphalan in the limb. Tumour response in the whole group to treatment was partial response: 53.8% (n = 7); complete response: 33.3% (n = 5); no response: 6.7% (n = 1). There was a significant association between tumour response and melphalan concentrations measured over time in subcutaneous microdialysate (P< 0.01). No significant relationship existed between the severity of toxic reactions in the limb or peak plasma creatine phosphokinase levels and peak melphalan microdialysate or plasma concentrations. It is concluded that microdialysis is a technique well suited for measuring concentrations of cytotoxic drug during ILI. The possibility of predicting actual concentrations of cytotoxic drug in the limb during ILI using our model opens an opportunity for improved drug dose calculation. The combination of predicting tissue concentrations and monitoring in microdialysate of subcutaneous tissue could help optimise ILI with regard to post-operative limb morbidity and tumour response.

Adult↗
PubMed2001

Thoracoscopic mobilization of the esophagus. A 6 year experience.

BACKGROUND: Traditionally, esophageal resection has been performed using a thoracotomy to access the intrathoracic esophagus. With the aim to avoid the potential morbidity of the open thoracic approach, mobilization of the esophagus under direct vision recently has been described. We report our experience at attempting thoracoscopic mobilization of the esophagus in 162 patients during a 6-year period. METHODS: Patients with malignancy or end-stage benign disease of the esophagus considered suitable for a three-stage esophagectomy underwent a thoracoscopy with a view to endoscopic mobilization of the esophagus. Of the 162 patients in whom the procedure was attempted, it was abandoned in 9 patients (6%), and the procedure was converted to open surgery in 11 patients (7%). RESULTS: In the patients whose esophagus was mobilized, the average blood loss was 165 ml, and the average time for the thoracoscopic segment of the surgery was 104 min. In the 133 patients who underwent a resection for invasive malignancy, a limited mediastinal nodal dissection retrieved an average of 11 nodes, and the median survival was 29 months. The 30-day mortality was 3.3% and the in-hospital mortality 5.3%. CONCLUSIONS: Thoracoscopic mobilization can be performed safely with satisfactory outcomes in a center performing a large volume of esophageal surgery and possessing advanced endoscopic surgery skills. Further assessment of this technique and comparisons with traditional open procedures are needed to assess this approach further as an appropriate oncologic procedure.

Adult↗
PubMed2001

Pharmacokinetics and pharmacodynamics of melphalan in isolated limb infusion for recurrent localized limb malignancy.

Isolated limb infusion (ILI) is an attractive, less complex alternative to isolated limb perfusion (ILP). It has a lower morbidity in treating localized recurrences and in transit metastases of the limb for tumours such as melanoma, Merkel cell tumour and Kaposi's sarcoma, allowing administration of high concentrations of cytotoxic agent to the affected limb under hypoxic conditions. Melphalan is the preferred cytotoxic agent for the treatment of melanoma by ILP or ILI. We report pharmacokinetic data from 12 patients treated by ILI for tumours of the limb in Brisbane. The kinetics of drug distribution in the limb was calculated using a two-compartment vascular model, where both tissue and infusate act as well-stirred compartments. Analysis of melphalan concentrations in the perfusate during ILI showed good agreement between the values measured and the concentrations predicted by the model. Recirculation and wash-out flow rates, tissue concentrations and the permeability surface area product (PS) were calculated. Correlations between the PS value and the drug concentrations in the perfusate and tissue were supported by the results. These data contribute to a better understanding of the distribution of melphalan during ILI in the limb, and offer the opportunity to optimize the drug regimen for patients undergoing ILI.

Aged↗
PubMed2001

Saturable dose-response relationships for melphalan in melanoma treatment by isolated limb infusion in the nude rat.

Nude rats bearing melanomas on their hindlimbs were treated by isolated limb infusion (ILI) with increasing doses (7.5-400 microg/ml) of melphalan. The response of tumours to treatment at the end of the observation period was graded, according to diameter, as complete response (CR), partial response (PR), no change (NC) or progressive disease (PD). No linear relationship between the dose of melphalan and the tumour response was observed. All doses above a threshold of 15 microg/ml achieved a PR or CR. The achievement of CR was not related to increased dose. Two major implications arise from this work. Firstly, the typically two- to three-fold increase in cytotoxic drug concentration given in high dose chemotherapy compared with standard drug concentration may not be sufficient to produce the expected increase in tumour response and possibly survival, and the controversial results of high dose chemotherapy in different studies may thus be explained. Secondly, since an increase in melphalan dose above a certain threshold does not greatly increase tumour response, the use of combination therapies would seem to be more likely to be effective than increased chemotherapeutic drug doses in achieving better tumour responses.

Animals↗
PubMed2001

Localization of small esophageal cancers for radiation planning using endoscopic contrast injection: report on a series of eight cases.

Recently, Barrett's esophagus and early adenocarcinomas have been detected increasingly frequently in routine follow-up of patients with gastroesophageal reflux. Although surgery is the treatment of choice, some patients are medically unfit for esophagectomy and, in this case, the only alternative curative therapy is radical chemoradiation therapy. In addition, some patients who present with symptoms have small tumors that cannot be localized accurately using routine imaging techniques. This report describes a series of eight patients with small esophageal cancers in whom the tumors were successfully localized following endoscopic injection of contrast, and treated with chemoradiation therapy. The treatment was successful in seven patients. This method of tumor localization demonstrated that conventional techniques are mostly unreliable when applied to very early cancers.

Adenocarcinoma↗
PubMed2000

Thirty-four patients with carcinoma of the cervical esophagus treated with chemoradiation therapy.

OBJECTIVE: To review the experience of 2 institutions in the management of localized carcinoma of the cervical esophagus with chemoradiation therapy. DESIGN: A series of 34 patients received chemoradiation therapy for a 5-year period. All patients were treated with curative intent. Three different regimens were used, all involving concomitant chemotherapy and high-dose radiation therapy. Data relating to toxic effects, local control of disease, and disease-free and overall survival were prospectively collected. SETTING: Two combined clinics at separate major hospitals where multidisciplinary care is the standard practice for this disease. PATIENTS: Patients with biopsy-proved carcinoma of the cervical esophagus. INTERVENTIONS: Patients received 3 different chemotherapy regimens. Two of the regimens used a combination of cisplatin and fluorouracil. The high-dose cisplatin regimen was a large dose of cisplatin (80 mg/m2) given on days 1 and 22 followed by a 96-hour infusion of fluorouracil (800 mg/m2) from days 2 to 5 and from days 23 to 26. The low-dose cisplatin regimen was cisplatin, 20 mg/m2, from days 1 to 5 and from days 22 to 26 and the same 96-hour infusion of fluorouracil. The third regimen used fluorouracil alone. The mean radiation dose administered was 61.2 Gy in 29.6 fractions during 41.8 days using 4- or 6-mV photons and a shrinking field technique. RESULTS: The results of treatment have shown a high rate of local control, although some patients developed metastases. The local complete response rate following treatment was 91%, and the rate of local control of disease was 88%. The projected actuarial 5-year survival rate was 55%. Death from other causes was common. The acute toxic effects of the treatment were acceptable, with only 5 patients requiring nasogastric feeding or gavage. Two patients died of complications related to strictures. CONCLUSION: Concomitant chemoradiation therapy, should be the treatment of choice for carcinoma of the cervical esophagus.

Adenocarcinoma↗
PubMed2000

Chronic dysphagia following laparoscopic fundoplication.

BACKGROUND: Many surgeons practise tailored laparoscopic antireflux surgery in an attempt to prevent postoperative dysphagia. The aim of this study was to determine the effect of 360 degrees fundoplication (Nissen) or 270 degrees fundoplication (Toupet), and the influence of abnormal oesophageal peristalsis, upon postoperative dysphagia. METHODS: This was a cohort study from three tertiary referral centres, using dysphagia before laparoscopic fundoplication and 1 year after operation as the main outcome variable. Preoperative oesophageal manometry was performed on all patients. RESULTS: Some 761 patients underwent Nissen and 85 underwent Toupet fundoplication. Only 2 per cent reported severe postoperative dysphagia. There was a significant selection bias towards the Toupet operation for patients with abnormal oesophageal motility (P < 0.001). For patients whose oesophageal manometric findings were normal there was a significant improvement in dysphagia after Nissen fundoplication (P = 0.02), and no significant change following Toupet fundoplication. There was no significant change in the rate of dysphagia following either method of fundoplication amongst other subgroups in which oesophageal manometry was stratified as non-specific motor disorder, low-amplitude peristalsis, or aperistalsis. CONCLUSION: A tailored approach to the degree of fundoplication is unnecessary as patients with dysmotility suffer no more dysphagia after full laparoscopic Nissen fundoplication than those who have a partial Toupet wrap.

Chronic Disease↗
PubMed2000

Can tissue drug concentrations be monitored by microdialysis during or after isolated limb perfusion for melanoma treatment?

Isolated limb perfusion (ILP) with melphalan is used to treat recurrent melanoma. This study aimed to develop a microdialysis technique for melphalan tissue concentration measurement during ILP. The effects of melphalan concentration (50-600 microg/ml), microdIalysis flow rate (0.55-17.5 microl/min), probe length (5-50 mm) and temperature (25-41.5 degrees C) on in vitro recovery were studied. In addition, in vivo recovery was measured in rat hindlimbs perfused with melphalan using 50 mm microdialysis probes implanted subcutaneously and into muscle. Both dialysate and tissue sample melphalan concentrations were determined by high performance liquid chromatography. The in vitro recovery of melphalan was not affected by melphalan concentration or temperature, but increased with probe length and decreased with flow rate. The melphalan concentrations in subcutaneous and muscle dialysates were not significantly different. A linear relationship was found between tissue dialysate concentrations and actual tissue concentrations of melphalan (r2 = 0.97). Microdialysis is a potential method for tissue drug monitoring which may assist in the efficacious use of cytotoxics in human ILP.

Animals↗
PubMed1997

A combined modality approach to the management of oesophageal cancer.

This study aims to update the experience of multimodality approaches in the management of oesophageal cancer that have been adopted in several Australian and New Zealand hospitals. Between 1984 and 1985, 92 patients received pre-operative radiotherapy (30-36 Gy over 3 weeks) and one of two chemotherapy regimes (one or two courses of i.v. cisplatin 80 mg/m2 plus a 4-5 day continuous i.v. of fluorouracil 5-800 mg/m2/day) concurrently prior to surgery. Eighty-two patients (89%) underwent resection as planned. Operative specimens were microscopically free of residual tumour in 18 patients. Eight patients (9%) had treatment-related deaths: seven from surgery and one due to pre-operative chemoradiation. The Kaplan-Meier 5-year cause-specific survival estimates were 32.9 +/- 7.8% for the 58 patients with squamous cancer and 0% for the 32 with adenocarcinoma. Complete pathological response to the pre-operative regime was more common in females and was associated with a survival advantage. Five-year cause-specific survival expectation in patients who experienced a complete pathological response was 71.5 +/- 12.4%, whereas it was only 15.9 +/- 5.6% in patients who had residual cancer in their surgical specimens. Although less toxic the pre-operative regime utilizing only one cycle of chemotherapy was no less efficacious either in producing a complete pathological response or in terms of survival expectation. This uncontrolled pilot study has produced encouraging long-term results, especially for patients with squamous carcinoma that experienced a complete response to pre-operative synchronous chemoradiotherapy. A randomized controlled study comparing surgery alone with (one cycle) chemoradiation followed by surgery is now underway.

Adult↗