Transoral laser resection versus lip-split mandibulotomy in the management of oropharyngeal squamous cell carcinoma (OPSCC): a case match study.

The objective of this study was to compare transoral laser microsurgery (TLM) with lip-split mandibulotomy (LSM) and radial forearm free-flap reconstruction, for the resection of squamous cell carcinoma of the oropharynx (SCCOP). This study is designed as a case-control study matching 24 patients treated with TLM for SCCOP with those treated with LSM. Patients were matched by age (in 5-year epochs), sex, TNM stage, tumour sub site and type of neck dissection. Each group comprised 20 males and 4 females (mean age 56 years). Seven patients treated with TLM had an elective tracheostomy compared with all patients undergoing LSM. Moreover, the time for decanulation was reduced in patients undergoing tracheostomy for TLM. Although similar rates of patients were able to swallow to some degree on discharge, 29% of patients having LSM were discharged requiring enterostomy feeding compared with 4% of patients treated using TLM. Of those able to swallow on discharge, patients who had TLM resumed swallowing in half the time taken for those having LSM. Moreover, those treated with TLM remained in hospital for half the length of time than those treated with LSM. Due to these factors, overall cost for TLM is reduced in comparison with LSM. In comparison with LSM, TLM for the treatment of SCCOP results in fewer tracheostomies and shorter time to decanulation; a quicker recovery of swallowing function and a reduced length of hospital stay. As a result of this, treatment with TLM is on average cheaper. These factors should be considered when deciding on the surgical treatment of a patient with SCCOP.

Expression of cell cycle associated proteins influences radiocurability of T2N0 squamous cell carcinoma of the larynx.

Cell cycle modulators are important in carcinogenesis and may be of prognostic and therapeutic relevance. This study has examined the influence of the proliferation index (Ki-67) and immunocytochemical expression of epidermal growth factor receptor (EGFR), cyclin D1, and retinoblastoma protein on recurrence rates at the primary site in 50 patients with T2N0 laryngeal carcinomas treated with radical irradiation. Pre-treatment biopsies were retrieved and sections scored for the four immunocytochemical markers. Statistical analysis for association, interaction and survival was performed. Five cases showed loss of expression of Rb protein. The median Ki-67 index was 50%, the median cyclin D1 index 21% and the median EGFR index 47% of cells. EGFR and cyclin D1 expression were positively correlated and, whilst local recurrence tended to occur with a Ki-67 labelling index of <50%, this was not statistically significant. When interactions were examined using Multiple Logistic Regression it was found that there was a direct relationship between EGFR and cyclin D1 expression. If the EGFR index was >20% and the cyclin D1 index >10%, then the odds ratio in favour of a primary site recurrence was very high (5.32 +/-0.41). This study demonstrates that the relationship between EGFR index and cyclin D1 index has a very strong association with primary site recurrence for T2 N0 laryngeal carcinomas treated by irradiation.

MRI in the diagnosis and treatment of suspected malignant spinal cord compression.

It remains unclear whether MRI is essential in all patients with suspected malignant spinal cord compression (MSCC), or whether some patients can be treated on the basis of plain radiographic findings and neurological examination. A prospective study was carried out of 280 consecutive patients with suspected MSCC, and the results of neurological examination plus plain radiographs were compared with MRI. 201 patients had MSCC (186 extradural, 5 intradural extramedullary and 10 intramedullary) and 11 patients had thecal sac compression without evidence of spinal cord compression. 25% of patients with MSCC had two or more levels of compression, 69% of these involving more than one region of the spine. A paraspinal mass was noted at the site of extradural spinal cord compression in 28%, and only one-third of these were detected on plain radiography. Focal radiographic changes and consistent neurology were present in 91 (33%) patients who had not had previous radiotherapy. MRI confirmed the presence of MSCC in 89/91 patients (specificity and positive predictive value of radiographic/clinical findings 98%) and the level of disease in all. MRI led to a change in the radiotherapy plan in 53% of patients (21% major change). The sensory level when present was four or more segments below the MRI level in 25/121 (21%) patients, and two or more levels above in 8/121 (7%) patients. Although focal radiographic abnormalities with consistent neurological findings, when present, accurately predicted the presence and level of MSCC, whole spine MRI is indicated in most patients with suspected MSCC because the additional information may alter the management plan. Treatment may be appropriately initiated on the basis of focal radiographic changes and consistent neurology if MRI is contraindicated or delayed, and in patients with a poor prognosis. In patients in whom there are no focal radiographic abnormalities and consistent neurological findings, urgent MRI is mandatory before radiotherapy is commenced.

A report of 50 patients with carcinoma of the hypopharynx treated by total pharyngolaryngo-oesophagectomy repaired by gastric transposition.

Extensive carcinoma of the hypopharynx requires aggressive surgery, which can lead to loss of function and a high morbidity and mortality. This paper reports 50 patients with carcinoma of the hypopharynx treated with total pharyngolaryngo-oesophagectomy and gastric transposition. Thirty-two patients had primary surgery and 18 had salvage surgery for recurrence following radiotherapy. Two technical modifications to the standard procedure that have evolved during this period are the use of a diverticuloscope for dissection of the middle third of the oesophagus and the routine insertion of chest drains peroperatively. Complications were relatively unusual in the primary surgery group, but were a problem in those patients undergoing salvage surgery. Stenosis did not tend to occur with gastric transposition repair, but three patients had delayed gastric emptying with prolonged hospital stays. The tumour-specific actuarial survival at 4 years was 39% and the observed survival was 25%. Pharyngolaryngo-oesophagectomy and gastric transposition is becoming safer owing to increased multidisciplinary experience in this form of surgery. Survival is improved with the use of postoperative radiotherapy in patients undergoing primary surgery.

Performance data and survival in head and neck cancer.

A retrospective longitudinal investigation of 2701 patients extending from 1963 was conducted to study the effect of performance status on survival, locoregional recurrence and associations with host and tumour factors. It was found that those patients who are physically fit tended to have smaller tumours, less risk of neck node metastases and more chance of laryngeal cancer. In patients with advanced disease, locoregional recurrence did not appear to be more common in those with poor general condition but the death rate from the tumour appeared to increase as the general physical condition decreased. It is assumed this is due to the development of distant metastases. There is evidence that immunity is less well developed in those with poor general condition and this in turn, may be due to alcohol abuse and poor general nutrition.

Improved survival in patients with head and neck cancer in the 1990s.

It is generally felt amongst the medical profession and the lay public that cancer is being treated more successfully than in the past. This is certainly true for childhood malignancies and leukaemia but evidence that significantly improved survival is occurring in the common solid tumours is lacking. Since 1963 the University of Liverpool Department of Otolaryngology/Head and Neck Surgery has collected data on all patients with head and neck tumours presenting to the department. The present study investigates patients with histologically proven squamous cell carcinoma of the four main sites: larynx, hypopharynx, oral cavity and oropharynx. From 1963 until the end of 1989, 2738 patients were seen by the department and from 1990 a further 717 patients have been seen. Since 1990 patients have tended to be in better general physical condition but, on the other hand, have tended to have more advanced disease at the primary site. The department has latterly tended to see fewer laryngeal cancers and more cancers of the oropharynx. Significantly fewer patients have presented with neck node metastases. Multiple logistic regression suggests that the most significant difference between the two groups is the great reduction in neck node recurrence rates in the group of patients seen since 1990 (P = 0.0001). The recurrence of tumours at the primary site since 1990 has been 35% compared with 41% before 1990, and recurrence in the neck nodes since 1990 has been 12%, compared with 15% before 1990. These differences are significant (P = 0.0141 and P = 0.0494, respectively). When studying survival in the 1960s, 1970s and 1980s, the 5-year cure rate was 50%, whereas since 1990 the figure has risen to 60% tumour-specific 5-year survival--a significant difference. A similar effect was noted in observed survival. This improvement in cure rate occurred for all four main sites. The results were confirmed by Cox's proportional hazards model where year of treatment was highly significantly associated with improved survival (P = 0.0001). It has been demonstrated that locoregional recurrence has improved since 1990 and this is reflected in improved survival figures. Although there are differences in the parameters of tumours referred before 1990 and since 1990, multivariate analysis suggests that the improvement in neck node recurrence rates may be responsible for this improved survival rate. Multivariate analysis for survival also suggests that the improvement in cure rates is independent of compounding variables and dependent on the year of presentation of the tumour. This improved survival may be related to factors, such as the administration of radical postoperative radiotherapy.

Malignant spinal cord compression: prospective study of delays in referral and treatment.

OBJECTIVES: To examine the delay in presentation, diagnosis, and treatment of malignant spinal cord compression and to define the effect of this delay on motor and bladder function at the time of treatment. DESIGN: Prospective study of all new patients presenting to a regional cancer centre with this condition. SETTING: Regional cancer centre. SUBJECTS: 301 consecutive patients. MAIN OUTCOME MEASURES: Interval from onset of symptoms to presentation and treatment, delay at each stage of referral, and functional deterioration. RESULTS: The median (range) delay from onset of symptoms of spinal cord compression to treatment was 14 (0-840) days. Of the total delay, 3 (0-300) days were accounted for by patients, 3 (0-330) days by general practitioners, 4 (0-794) days by the district general hospital, and 0 (0-114) days by the treatment unit. Initial presentation to the regional cancer centre with symptoms of malignant spinal cord compression led to a significant reduction in delay to treatment and improved functional status at the time of treatment. Deterioration of motor or bladder function >=1 grade occurred at the general practice stage in 28% (57) and 18% (36) of patients, the general hospital stage in 36% (83) and 29% (66), and the treatment unit stage in 6% (19) and 5% (15), respectively. CONCLUSIONS: Unacceptable delay in diagnosis, investigation, and referral occurs in most patients with malignant spinal cord compression and results in preventable loss of function before treatment. Improvement in the outcome of such patients requires earlier diagnosis and treatment.

Tumours of the minor salivary glands.

One hundred and forty-five patients were identified with minor salivary gland tumours. General information and tumour-specific information on stage, grade of tumour, resection margins, recurrence and survival were collected. Data was analysed by both univariate and multivariate methods. Indices predicting tumour recurrence and survival were analysed. Forty-two benign lesions, mostly pleomorphic adenomas were identified, one recurred, all survived. One hundred and three malignant lesions were identified, mostly adenoid cystic carcinomas (70%) or mucoepidermoid carcinomas (19%). Late stage disease and the presence of neck node metastases predicted both early recurrence and high eventual mortality. Survival was favoured by the histological type (mucoepidermoid > adenoid cystic), site of primary (oral cavity and oropharynx > nose, sinuses and larynx) and good general condition. Many tumours recurred after 5 years of disease-free survival and late mortality was a feature (80% survival at 5 years, 20% at 20 years). Many patients survive some time with either local recurrence or distant metastases. Long-term follow-up is advocated as local or distant recurrence may be treatable. The value of super radical treatment of the primary is questionable given the likelihood of recurrence at distant sites.

The effects of age on survival and other parameters in squamous cell carcinoma of the oral cavity, pharynx and larynx.

Many papers have been written on the effect of age on survival from cancer and a number of these papers have concentrated on cancer of the head and neck. The literature is fairly evenly split between those studies that claim that the young patient has a better chance of survival and those that suggest the older patient has a better chance of survival. The present study investigates 2647 patients with histologically proven squamous cell carcinoma of the oral cavity, oropharynx, larynx and hypopharynx. The tumour-specific 5-year survival of patients with head and neck cancer from the third decade through to the seventh decade at presentation was 54%, whereas this figure dropped to 44% for the eighth, ninth and tenth decades. This difference was statistically significant (P = 0.0001). When the patients in the third to seventh decades of presentation were compared with those from the eighth to tenth decades, it was found that older patients tended to have significantly more advanced disease at the primary site and fewer neck node metastases when compared with younger patients at presentation. These differences were confirmed by multiple logistic regression. Multivariate analysis of survival confirmed that advanced age was associated with poor survival (P = 0.0001). Whilst patients with head and neck cancer in their eighth, ninth and tenth decades fared worse than younger patients, their mean tumour specific survival at 5 years was in the region of 44%, which makes treatment worthwhile, certainly in selected cases.

A new short practical quality of life questionnaire for use in head and neck oncology outpatient clinics.

A new short questionnaire to assess the quality of life of head and neck patients has been designed at the University of Liverpool Head and Neck Oncology Department. The questionnaire is short, simple and can be easily completed by a patient whilst in the waiting room before consultation. It is filled in 6 months after completion of treatment and shows very good correlation with the standard long exhaustive questionnaires that are difficult to complete on every patient in a busy National Health Service clinic. The University of Liverpool questionnaire provides a simple score from 0%-100% which should prove valuable in the assessment of quality of care and help with decisions regarding treatment options in head and neck cancer patients.

Retinol binding proteinuria and phosphaturia: markers of paracetamol-induced nephrotoxicity.

The occurrence of hypophosphataemia in paracetamol overdose suggests that nephrotoxicity is common, impaired renal tubular reabsorption of phosphate indicating renal damage. To investigate the potential nephrotoxicity of paracetamol, we studied 148 consecutive patients with paracetamol overdose. Serial clinical and biochemical measurements were made, and a fasting overnight urine collection was obtained for creatinine (Cr), phosphate and retinol-binding protein (RBP) determination. Renal threshold phosphate concentration (TmPO4/GFR) was determined from urinary parameters by an established nomogram. The degree of hypophosphataemia correlated with the severity of overdose, and with TmPO4/GFR. The median RBP/Cr ratio was higher in those patients exhibiting biochemical hepatotoxicity compared with those without hepatotoxicity, in whom median RBP/Cr was not significantly higher than controls. Within the group of patients showing biochemical hepatotoxicity, there was a correlation between log RBP/Cr and TmPO4/GFR. RBP/Cr ratio is a less sensitive marker of renal tubular toxicity than phosphaturia in these patients, and may indicate a different mechanism of toxicity.

Accelerated fast neutron therapy: a pilot study.

The clinical role of fast neutron therapy has been limited by excessive late normal tissue damage. A pilot study of accelerated fractionation of fast neutron therapy was performed, based on the rationale that this should result in an increase in the response in acute reacting tissues (normal and malignant), with no change in late damage and a consequent increase in the therapeutic ratio. Further accelerated fractionation should improve the local control of rapidly proliferating tumour, without the potential problem of inadequate reoxygenation inherent in accelerated photon schedules. 6 or 12 fractions of 62 MeV (p-Be) neutrons were given over 12 days to 27 sites in 23 patients with locally advanced tumours. With a dose reduction of 12% (18 Gy), acceptable skin and oral mucosa early reactions were obtained. A larger dose reduction (15%) was required at pelvic sites. The incidence of late EORTC/RTOG grade 4 toxicity was 46%. The overall response rate was 76% with a complete response rate of 16%. For locally advanced breast cancer, the complete response rate was 9%, which compares unfavourably with previous results with conventional neutron fractionation schedules. The combination of a low overall complete response rate and excessive late normal tissue toxicity suggests that accelerated fractionation of fast neutrons does not lead to an improvement in the therapeutic ratio, and that late normal tissue damage will continue to be dose limiting.

POMB/ACE chemotherapy in non-seminomatous germ cell tumours: outcome and importance of dose intensity.

This study reports the outcome of POMB/ACE (cisplatin, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide, etoposide) chemotherapy in 53 male patients with metastatic non-seminomatous germ cell tumour (NSGCT) treated between 1983 and 1989 in one centre. The overall complete response (CR) rate was 62% [95% confidence interval (CI) 49-75%), and for patients with large or very large volume disease (L/VL, MRC criteria), the CR rate was 56% (95% CI 41-71%). The overall 5 year survival was 61%, and for L/VL volume disease 67%. Comparison with previous studies suggests that POMB/ACE chemotherapy is not superior to BEP, even in patients with adverse prognostic factors. Increased average relative dose intensity and increased relative dose intensity of cisplatin over the first seven courses were not associated with improved survival. However, in patients receiving a relative dose intensity of etoposide greater than or equal to 0.75, survival at 5 years was significantly improved compared with those in whom this parameter was less than 0.75 (79% vs. 44%, P less than 0.05), suggesting that dose intensity of etoposide may be an important determinant of outcome in the chemotherapy of metastatic NSGCT.

Ifosfamide encephalopathy: a reappraisal.

Eighteen consecutive cases of encephalopathy occurring after ifosfamide/mesna chemotherapy were prospectively assessed. No relationship was found with tumour type or chemotherapy response. Onset was from 12 to 146 (mean 46) h after the start of the infusion and median duration was 3 days (range 1-12). In two patients recovery was incomplete. A confusional state and agitation were the major clinical features. Plasma potassium fell from a mean of 4.12 mmol/l before chemotherapy to 2.94 mmol/l at the onset of encephalopathy (P less than 0.001) with plasma potassium less than 3.0 mmol/l in 10 patients. Duration of hypokalaemia was not related to duration of encephalopathy. Median survival following encephalopathy was 25 days. The incidence of encephalopathy in 82 patients treated on two protocols was 11% and the sensitivity of a published nomogram was 18%. It is concluded that ifosfamide/mesna encephalopathy is a serious complication which may be irreversible and remains difficult to predict.

The metabolic response to insulin deprivation in idiopathic brittle diabetes.

To test the hypothesis that frequent episodes of ketoacidosis and severe hyperglycaemia in brittle diabetes result from an exaggerated response to insulin withdrawal, the metabolic response to insulin deprivation in 16 severely brittle female diabetics has been compared with that in 6 C-peptide negative stable female diabetic patients of similar age and body weight. 4 hr after stopping insulin infusion, blood glucose was significantly higher in the brittle diabetics (22.8 vs 17.0 mmol/l, p less than 0.001) but blood 3-hydroxybutyrate was not different (1.8 vs 1.6 mmol/l). Concentrations of free insulin and counter-regulatory hormones were similar, basally and during the deprivation. Insulin antibody levels were significantly elevated in the brittle patients (11.2 vs 5.2 mmol/l, p less than 0.05) and there was no relationship between glucose or ketone body response and antibody level. Blood lactate, pyruvate, alanine and glycerol were significantly elevated basally in the brittle diabetic patients, but did not respond differently to insulin deprivation. Basal lactate and pyruvate concentrations were significantly correlated with overnight insulin requirements (lactate, rs 0.62, p less than 0.05; pyruvate, rs 0.70, p less than 0.05) suggesting that the elevated basal concentrations resulted from the higher peripheral insulin delivery rates required to maintain overnight normoglycaemia in the brittle patients. We conclude that although there are demonstrable abnormalities of intermediary metabolism in brittle diabetics, neither elevated levels of counter-regulatory hormones, nor an exaggerated response to insulin withdrawal explains the frequent episodes of ketoacidosis in these patients.

Metabolic changes in the non-insulin-dependent diabetic undergoing minor surgery: effect of glucose-insulin-potassium infusion.

We have compared the metabolic response to minor surgery in the non-insulin dependent diabetic patient with that in the non-diabetic, using transurethral surgery under general anaesthesia as a model. Preoperative blood glucose and 3-hydroxybutyrate concentrations were higher in the diabetic patients, but the response to surgery did not differ. The postoperative cortisol response was lower in the diabetic patients. Glucose insulin potassium infusion (GIK) resulted in lower plasma nonesterified fatty acid, and blood 3-hydroxybutyrate and glycerol concentrations, with markedly higher serum insulin levels compared to patients managed with a 'no insulin' regimen. Blood glucose however was not significantly different except at 2 h postoperatively. Blood metabolite and serum insulin concentrations in the diabetic patients were closer to those in non-diabetic patients in the group not given insulin, than in those given GIK. Rather than rendering the diabetic patient the same as the non-diabetic, GIK produces a further abnormal state which is probably of little benefit. We conclude that there is no indication for the use of insulin in the well or moderately well-controlled non-insulin dependent diabetic patient undergoing minor surgery, provided that glucose containing fluids are not given.

The management of severe brittle diabetes with "Infusaid" implantable pumps.

Two severely brittle diabetic patients were treated with "Infusaid" implantable insulin infusion pumps. Both were young females with recurrent ketoacidosis, prolonged or repeated hospital admissions, and subcutaneous insulin resistance. They also had psychological problems, and had seriously interfered with their treatment to induce glycaemic instability. Delivery of insulin from the pumps was intravenous (i.v.) in one patient, and intraperitoneal (i.p.) in the other. Following implantation, there was a marked improvement in glycosylated haemoglobin level (HbA1), fasting blood glucose (BG), daily insulin dose and hospitalizations. The beneficial effect has continued to date (9 months, and 12 months follow-up) with no major problems.

Management of diabetes during surgery with glucose-insulin-potassium infusion.

One hundred and twenty-eight surgical operations in diabetic patients have been studied to assess the effectiveness, under routine clinical conditions, of a management regimen based on the use of glucose-insulin-potassium infusion (GIK). Forty-four non-insulin-dependent diabetic (NIDDM) and 41 insulin-dependent diabetic (IDDM) patients received GIK. Mean blood glucose on the day of operation was 9.3 +/- S.D. 2.2 mmol/l in NIDDM and 8.9 +/- 2.3 mmol/l in IDDM patients. Acceptable control on the day of operation (defined as mean blood glucose 5-12 mmol/l without hypoglycaemia) was achieved in 70 (82%) patients. Eleven of 15 failures were attributable to incorrect implementation of the protocol. Though 10 units Soluble insulin/500 ml 10% glucose (0.32 units/g glucose) was needed in 61% of patients, 26% required a higher and 13% a lower dose. Plasma potassium concentration did not change after 24 h of GIK infusion, but sodium concentration fell (136 +/- 5 to 132 +/- 5 mmol/l; p less than 0.01), with 12 of 32 patients having post-operative values less than 130 mmol/l. Forty-three NIDDM patients undergoing minor surgery were managed without insulin, and acceptable control was achieved in 40 (93%). We conclude that the regimen described is a satisfactory routine means of managing diabetes during surgery, but that optimal results depend on careful monitoring with appropriate alteration of therapy.

Methods for the control of diabetes after acute myocardial infarction.

Blood glucose control in patients with diabetes after myocardial infarction is often poor, and this may contribute to increased mortality in the diabetic patient. A retrospective review of the records of 71 diabetic patients admitted with suspected myocardial infarction, and managed using a variety of methods, showed that adequate control (mean blood glucose less than 234 mg/dl; 13 mmol/L) was achieved in only 60%. Continuation of oral hypoglycemic agents and the use of irregular intermittent insulin in response to hyperglycemia were particularly associated with poor control. In a prospective study 68 consecutive patients were managed using regular subcutaneous insulin injections three times daily or a glucose-insulin-potassium intravenous infusion (in those with cardiogenic shock, severe hyperglycemia, or unable to eat). Control was adequate in 87% (P less than 0.001 versus retrospective group) and mean blood glucose concentration on days 1 and 2 were significantly lower than in the retrospective group (167 versus 232; 165 versus 236 mg/dl; both P less than 0.001). Simple protocols using three-times-daily subcutaneous insulin or glucose-insulin-potassium infusion provide a practical method for achieving good glycemic control in the diabetic patient with suspected acute myocardial infarction.