Incidence and survival trends of lip, intra-oral cavity and tongue base cancers in south-east England.

BACKGROUND: Oral cavity cancers are on the increase in the UK. Understanding site-specific epidemiological trends is important for cancer control measures. This study demonstrates the changing epidemiological trends in lip, intra-oral cavity and tongue base cancers in south-east England from 1987 to 2006. METHODS: This was a retrospective study using anonymised data obtained from the Thames Cancer Registry (TCR) London. Data were analysed using SPSS v.17 and survival analyses with Kaplan-Meier and Cox regression. Age standardisation of the incidence rates was performed. It was conducted in south-east England, which has an average population of 12 million. The study analysed 9,318 cases (ICD-10 code C00-C06, C14). Kent Research Ethics Committee UK granted ethical approval. RESULTS: Oral cancers were more common in men, with male: female ratio of 1.6:1. Tongue cancers had the highest frequency at 3,088 (33.1%). Incidence varied with each cancer type. Mean incidence (per 1,000,000) ranged from 2.3 (lip cancer) to 13.8 (tongue cancer). There has been a statistically significant increase in incidence for cancers of the tongue base, other parts of tongue, gum and palate (p<0.001). Median survival time varied by sub-site, with lip cancer having the best median survival time (11.09 years) compared with tongue base cancer (2.42 years). Survival analyses showed worse prognosis for men, older age at diagnosis, and presence of synchronous tumours (p<0.001). CONCLUSION: There is a rising incidence of tongue and tongue base, gum and palate cancers in south-east England with wide variability in survival. Oral cancer awareness and screening programmes should be encouraged.

A 20-year retrospective study of tonsil cancer incidence and survival trends in South East England: 1987-2006.

BACKGROUND: There has been an increasing incidence of tonsil cancer worldwide. Documenting these changes is crucial to cancer prevention and control measures, resource allocation and understanding disease aetiology. OBJECTIVE: To analyse the changing epidemiology of tonsil cancer in South East England over a 20-year period between 1987 and 2006. DESIGN: A retrospective, quantitative study using secondary anonymised data obtained from the Thames Cancer Registry, London. Data were analysed using spss v.17 and survival analyses with Kaplan-Meier and Cox regression. SETTING: This study was conducted in South East of England comprising London, Kent, Surrey and Sussex counties with an average population of 12 million. This population increased from 10.7 to 11.8 million (a 10% increase) between 1987 and 2006. PARTICIPANTS: All patients with tonsil cancer in South East England registered with the Thames Cancer Registry (ICD-10 code C09) between 1987 and 2006. A total of 1794 patients' data were analysed. Ethical Considerations: Ethical approval was granted by the Kent Research Ethics Committee. MAIN OUTCOME MEASURES: Data were analysed for demographic trends including gender, age at diagnosis, yearly incidence and survival. RESULTS: Tonsil cancer incidence has increased significantly from 0.60 to 1.45 per 100,000 in the 20 years (P < 0.001). This increase is mainly amongst men and age groups 40-59 years with a significant reduction in age at diagnosis by 2 years from 61.6 years in the first decade to 59.6 years in the second decade (P < 0.001). Survival was worse in men, older age groups and in the presence of synchronous tumours (P < 0.001). There has been a statistically significant increase in median survival times from tonsil cancer by about 3 years from 2.7 years in the first decade to 5.7 years in the second decade of this study (P < 0.001). CONCLUSIONS: Tonsil cancer incidence has increased in the 20 years of this study in South East England, especially amongst men and age groups 40-59 years. There has also been significant reduction in the mean age at diagnosis and an increase in median survival times for tonsil cancer. Further studies are needed to explain these trends.

Near-infrared spectroscopy reflects changes in mesenteric and systemic perfusion during abdominal compartment syndrome.

BACKGROUND: Continuous and minimally invasive near-infrared spectroscopy (NIRS)-derived gastric tissue oxygen saturation (GStO(2)) and muscle tissue oxygen saturation (MStO(2)) were evaluated in a clinically relevant porcine model of hemorrhagic shock and abdominal compartment syndrome (ACS). METHODS: Phenobarbital-anesthetized swine underwent pulmonary artery catheter insertion for mixed venous oxygen saturation (SvO(2)) measurement and midline laparotomy to permit placement of a gastric NIRS probe, a jejunal (regional carbon dioxide [PrCO(2)]) tonometer, superior mesenteric artery (SMA) flow probe, and a portal vein oxygen saturation (SpvO(2)) catheter. A muscle NIRS probe was placed on the front limb. After randomization, Group 1 underwent hemorrhage and resuscitation. Group 2 had no hemorrhage or resuscitation. ACS was induced by peritoneal fluid infusion in both groups. A significant decrease in SMA flow, SpvO(2), GStO(2), SvO(2), and MStO(2) was observed after hemorrhage in Group 1 and with abdominal hypertension in both groups. RESULTS: GStO(2) significantly correlated with SMA flow (Group 1: r(2) = 0.90; Group 2: r(2) = 0.83) and mesenteric oxygen delivery (mesenteric oxygen delivery, Group 1: r(2) = 0.73; Group 2: r(2) = 0.89). MStO(2) significantly correlated with SvO(2) (Group 1: r(2) = 0.99; Group 2: r(2) = 0.65) and systemic oxygen delivery (SDO2, Group 1: r(2) = 0.60; Group 2: r(2) = 0.88). Tonometer-derived PrCO(2) values did not change at any time point in either group. CONCLUSIONS: NIRS measurement of GStO(2) and MStO(2) reflected changes in mesenteric and systemic perfusion respectively during hemorrhage and ACS.

Utility of near-infrared spectroscopy in the diagnosis of lower extremity compartment syndrome.

OBJECTIVE: To determine the utility of near-infrared spectroscopy in the diagnosis of lower extremity compartment syndrome (CS). METHODS: Nine patients with CS confirmed by physical examination and elevated compartment pressures (64 +/- 17 mm Hg) were evaluated before and after fasciotomy. Control readings were also performed on 33 surgical patients who had no evidence of CS. The deltoid muscle was used as a reference value. RESULTS: The deltoid muscle oxygen saturation (StO2) readings revealed a mean = 84 +/- 17% prefasciotomy and mean = 83 +/- 12% postfasciotomy in the CS group. The control group had a mean StO2 of 83 +/- 11%. In the CS group, the leg compartment with the highest pressure had a StO2 mean = 56 +/- 27% before fasciotomy. This value was statistically significantly lower (p < 0.05) than either the postfasciotomy mean StO2 in that compartment (82 +/- 16%) or the values found in matched control patients with no evidence of CS (87 +/- 7%). CONCLUSION: Near-infrared spectroscopy-derived StO2 values in the lower extremities of trauma patients with CS were diminished relative to the control patients and usually normalized after fasciotomy. Near-infrared spectroscopy evaluation may offer a rapid, noninvasive method of assessing extremities at risk for CS.

Management of unresectable malignant tumors at the skull base using concomitant chemotherapy and radiotherapy with accelerated fractionation.

Between January 1988 and June 1992, 20 patients with unresectable malignant tumors at the skull base were treated. Eleven had T4 lesions of the paranasal sinus/cavity complex, and 9 had T4 nasopharynx cancer. All patients had stage IV disease by the American Joint Committee on Staging Criteria. The histology was squamous cell cancer in 15 patients and other minor salivary gland histologies in 5. There was brain and/or dural invasion in 11 patients and orbital invasion in 9. All patients received radiation therapy with accelerated fractionation to a total of 70 Gy in 6 weeks. Concomitant cisplatin (100 mg/m(2)) was given on days 1 and 22 of radiation. Seven patients received mitomycin C (7.5 mg/m(2)) on days 1 and 22, plus adjuvant chemotherapy with cisplatin and vinblastine. Median follow-up was 11 (range: 1 to 43) months. At 2 years, local progression-free survival was 94%, distant metastases-free survival was 57%, and overall survival was 80%. Complications occurred in 20% and caused the death of 1 patient. Treatment of this group of patients with aggressive chemotherapy and radiation therapy produced excellent local control in our early experience, but longer follow-up is needed. There is a high rate of distant failure. Future strategies are outlined.

A phase II trial of carboplatin in patients with advanced APUD tumors.

BACKGROUND: Chemotherapy remains inadequate for patients with carcinoid tumors, islet cell tumors, and medullary carcinomas of the thyroid. Carboplatin has shown activity in oat cell carcinoma of the lung, another tumor of neuroectodermal origin. METHODS: Forty-two patients with advanced APUD tumors (20 carcinoid tumors, 9 islet cell carcinomas, 5 medullary carcinomas of the thyroid, and 9 neuroendocrine tumors of unknown primary site) were treated with carboplatin in a Phase II study. RESULTS: Carboplatin was inactive in carcinoid and islet cell tumors, with 0 of 20 and 0 of 9 patients responding, respectively. Of the 41 total patients evaluable for response, only 2 (5%) achieved a partial response. Both of these responding patients had neuroendocrine tumors of unknown primary site. No complete responses were seen. Toxicities were those previously noted with carboplatin, with myelosuppression, particularly thrombocytopenia, being dose limiting. CONCLUSIONS: Carboplatin is inactive in carcinoid tumors and did not show evidence of activity in islet cell tumors. Further investigations are needed to identify active agents in the treatment of neuroendocrine malignancies.

Pre-operative combined 5-FU, low dose leucovorin, and sequential radiation therapy for unresectable rectal cancer.

PURPOSE: We performed a Phase I trial to determine the maximum tolerated dose of combined pre-operative radiation (5040 cGy) and 2 cycles (bolus daily x 5) of 5-FU and low dose LV (20 mg/m2), followed by surgery and 10 cycles of post-operative LV/5-FU in patients with unresectable primary or recurrent rectal cancer. METHODS AND MATERIALS: Twelve patients were entered. The initial dose of 5-FU was 325 mg/m2. 5-FU was to be escalated while the LV remained constant at 20 mg/m2. Chemotherapy began on day 1 and radiation on day 8. The post-operative chemotherapy, was not dose escalated; 5-FU: 425 mg/m2 and LV: 20 mg/m2. The median follow-up was 14 months (7-16 months). RESULTS: Following pre-operative therapy, the resectability rate with negative margins was 91% and the pathologic complete response rate was 9%. For the combined modality segment (preoperative) the incidence of any grade 3+ toxicity was diarrhea: 17%, dysuria: 8%, mucositis: 8%, and erythema: 8%. The median nadir counts were WBC: 3.1, HGB: 8.8, and PLT: 153,000. The maximum tolerated dose of 5-FU for pre-operative combined LV/5-FU/RT was 325 mg/m2 with no escalation possible. Therefore, the recommended dose was less than 325 mg/m2. CONCLUSIONS: Since adequate doses of 5-FU to treat systemic disease could not be delivered until at least 3 months (cycle 3) following the start of therapy, we do not recommend that this 5-FU, low dose LV, and sequential radiation therapy regimen be used as presently designed. However, given the 91% resectability rate we remain encouraged with this approach.

Biochemical modulation of bolus fluorouracil by PALA in patients with advanced colorectal cancer.

PURPOSE: N-(phosphonacetyl)-L-aspartic acid (PALA) is a pyrimidine synthesis inhibitor that modulates fluorouracil (FU) cytotoxicity. Two previous studies of patients with colorectal carcinoma documented complete response (CR) and partial response (PR) rates of 40% and 43% using weekly low-dose PALA followed by a 24-hour FU infusion. We investigated whether comparable results could be obtained with biochemical modulation by low-dose PALA using bolus instead of infusional FU. PATIENTS AND METHODS: Forty-five patients without prior chemotherapy who had advanced colorectal carcinoma were treated with PALA 250 mg/m2 followed 24 hours later by bolus FU at three dose levels, 600, 700, 800 mg/m2, repeated weekly for 6 weeks followed by a 2-week break. RESULTS: The CR and PR rate was 15 of 43 patients or 35% (95% confidence interval [CI], 21% to 49%), with an overall median survival of 18 months. Grade 3 or 4 diarrhea was the major toxicity observed in 24% of patients receiving FU at 700 mg/m2 and in 43% of patients receiving 800 mg/m2. Hematologic toxicity was observed only with an FU dose of 800 mg/m2, and 29% (four of 14) of patients developed grade 4 leukopenia. We also noted the development of ascites in six patients, mild hyperbilirubinemia in 16 patients, and a decreased albumin level in 22 patients; these abnormalities occurred more frequently in responding patients. CONCLUSIONS: The observed response rate, median survival, and toxicity in this study are similar to those obtained with PALA plus infusional FU and with other methods of FU modulation. Larger phase III studies are needed to compare bolus FU/PALA regimens with other PALA and non-PALA-containing combinations. Our future focus will be attenuate this regimen's toxicity while maintaining or improving its response rates and survival.

Inhibition of gluconeogenesis and glycogenolysis by 2,5-anhydro-D-mannitol.

2,5-Anhydro-D-mannitol (100 to 200 mg/kg) decreased blood glucose by 17 to 58% in fasting mice, rats, streptozotocin-diabetic mice, and genetically diabetic db/db mice. Serum lactate in rats was elevated 56% by 2,5-anhydro-D-mannitol, but this could be prevented by dichloroacetate (200 mg/kg) or thiamin (200 mg/kg). In hepatocytes from fasted rats, 1 mM 2,5-anhydro-D-mannitol inhibited gluconeogenesis from a mixture of alanine, lactate, and pyruvate. It also inhibited glucose production and stimulated lactate formation from glycerol or dihydroxyacetone. Glycogenolysis in hepatocytes from fed rats was markedly inhibited by 1 mM 2,5-anhydro-D-mannitol both in the presence or absence of 1 microM glucagon. 2,5-Anhydro-D-mannitol can be phosphorylated by fructokinase or hexokinase to the 1-phosphate and then by phosphofructokinase to the 1,6-bisphosphate. Rat liver glycogen phosphorylase was inhibited by 2,5-anhydro-D-mannitol 1-phosphate (apparent Ki = 0.66 +/- 0.09 mM) but was little affected by 2,5-anhydro-D-mannitol 1,6-bisphosphate. Rat liver phosphoglucomutase was inhibited by 2,5-anhydro-D-mannitol 1-phosphate (apparent Ki = 2.8 +/- 0.2 mM), whereas 2,5-anhydro-D-mannitol 1,6-bisphosphate served as an alternative activator (apparent K alpha = 7.0 +/- 0.5 microM). Rabbit liver pyruvate kinase was activated by 2,5-anhydro-D-mannitol 1,6-bisphosphate (apparent K alpha = 9.5 +/- 0.9 microM), whereas rabbit liver fructose 1,6-bisphosphatase was inhibited by 2,5-anhydro-D-mannitol 1,6-bisphosphate (apparent Ki = 3.6 +/- 0.3 microM). The phosphate esters of 2,5-anhydro-D-mannitol would, therefore, be expected to inhibit glycogenolysis and gluconeogenesis and stimulate glycolysis in liver.