Johnny Keller

The effect of ketamine on phantom pain: a central neuropathic disorder maintained by peripheral input.

&NA; Hyperactivity of N‐methyl d‐aspartate (NMDA) receptors may be one of the factors in the maintenance of persistent stump and phantom limb pain. Ketamine (bolus at 0.1 mg/kg/5 min followed by an infusion of 7 &mgr;g/kg/min) was administered intravenously to 11 patients with established stump and phantom limb pain in a double‐blind saline‐controlled study. All 11 patients responded with a decrease in the rating of stump and phantom limb pain assessed by visual analogue scale (VAS) and McGill Pain Questionnaire (MPQ). Ketamine increased pressure‐pain thresholds significantly. Wind‐up‐like pain (pain evoked by repeatedly tapping the dysaesthetic skin area) was reduced significantly by ketamine. In contrast, no effect was seen on pain evoked by repeated thermal stimuli. Side effects were observed in nine patients. The results support the notion that stump and phantom pain are generated by activity in afferent fibres activated by mechanical but not by thermal stimuli and that the NMDA receptor is involved in the maintenance of postamputation pain states. NMDA receptor antagonists may have a potential in the treatment of stump and phantom limb pain.

Hypoxia in human soft tissue sarcomas: Adverse impact on survival and no association with p53 mutations

Clinical and experimental studies have suggested that tumour hypoxia is associated with poor treatment outcome and that loss of apoptotic potential may play a role in malignant progression of neoplastic cells. The tumour suppressor gene p53 induces apoptosis under certain conditions and microenvironmental tumour hypoxia may select for mutant tumour cells with diminished apoptotic potential due to lack of p53 function. The aim of this study was to evaluate the prognostic relevance of oxygenation status for treatment outcome and to compare pre-treatment tumour oxygenation measurements were done in 31 of those by PCR using DNA extracted from paraffin-embaedded sections (n = 2) or frozen biopsies (n = 29). The overall median of the tumour median pO2was 19 mmHg (range 1–58 mmHg). Only 6 tumours had functional p53 mutations and no association was found between mutant p53 and tumour hypoxia. Five out of 6 STS with lower histopathological grade were well-oxygenated whereas high-grade STS were both hypoxic and well-oxygenated. At a median follow-up of 74 months, 16 patients were still alive among 28 available for survival analysis. When stratifying into hypoxic and well-oxygenated tumours patients with the most hypoxic tumours has a statistically poorer disease-specific and overall survival at 5 years. In conclusion hypoxia was an indicator for both a poorer disease specific and overall survival in human STS but hypoxic tumours were not characterized by mutations in the p53 gene.

A Randomized Study of the Effects of Gabapentin on Postamputation Pain

Background:Pain after amputation is common but difficult to treat. Therefore, the authors examined whether postoperative treatment with gabapentin could reduce postamputation stump and phantom pain. Methods:Forty-six patients scheduled to undergo lower limb amputation were randomly assigned to receive oral gabapentin or placebo. Treatment was started on the first postoperative day and continued for 30 days. The daily dose of gabapentin or placebo was gradually increased to 2,400 mg/day. The intensity of stump and phantom pain was recorded every day on a numeric rating scale (0–10) during the 30-day treatment period. Five interviews were performed after 7, 14, and 30 days and after 3 and 6 months. Results:Results from 41 patients were included in the data analysis. The risk of phantom pain (gabapentin vs. placebo) was 55.0% versus 52.6% (risk difference, 2.4%; 95% confidence interval, −28.9 to 33.7%; P = 0.88; 30 days) and 58.8% versus 50.0% (risk difference, 8.8%; 95% confidence interval, −23.3 to 40.9%; P = 0.59; 6 months). The median intensity of phantom pain (gabapentin vs. placebo) was 1.5 (range, 0–9.0) versus 1.2 (range, 0–6.6) (P = 0.60; 30 days) and 1.0 (range, 0–6.0) versus 0.5 (range, 0–5.0) (P = 0.77; 6 months). The median intensity of stump pain was 0.85 (range, 0–8.2) versus 1.0 (range, 0–5.4) (P = 0.68; 30 days) and 0 (range, 0–8.0) versus 0 (range, 0–5.0) (P = 0.58; 6 months). Conclusion:Gabapentin administered in the first 30 postoperative days after amputation does not reduce the incidence or intensity of postamputation pain.

The relationship between tumor oxygenation and cell proliferation in human soft tissue sarcomas

PURPOSE In malignant tumors the oxygenation status and tumor cell proliferation are known to influence local tumor control after radiotherapy. However, the relationship between oxygenation status and tumor cell kinetics in human tumors has not yet been described. Newly developed clinically applicable techniques such as oxygen electrode measurements and assessment of tumor cell proliferation rates have been suggested as promising predictive assays. The purpose of the present study was to characterize tumor oxygenation status in soft tissue sarcomas and to compare this with tumor cell kinetics and clinical parameters. METHODS AND MATERIALS Pretreatment tumor oxygenation status was measured by polarographic oxygen needle electrodes and evaluated as the median pO2 and the percentage of pO2 values < or = 5 mmHg and < or = 2.5 mmHg in 22 patients with primary soft tissue sarcomas. All tumors were characterized by histology, grade of malignancy, the level of microscopic necrosis, the level of effective hemoglobin, and magnetic resonance imaging estimation of tumor volume. The tumor cell potential doubling time and labeling index were measured by flow cytometric and immunohistochemical analysis of tumor biopsy specimens after in vivo incorporation of iododeoxyuridine. RESULTS There was a significant correlation between the median pO2 and the tumor cell potential doubling time (p = 0.041), whereas no correlation was found between the level of hypoxia expressed by the percentage of pO2 values < or = 2.5 and < or = 5 mmHg, respectively, and tumor cell potential doubling time. Furthermore, no correlation was found between either of the three tumor oxygenation parameters and labeling index. The material represented large intertumor heterogeneity in oxygenation status, cell kinetics, and tumor volume, and no correlation was found between oxygenation status and either volume, histopathology, grade of malignancy, or effective hemoglobin. CONCLUSION This report is the first to suggest a correlation between tumor oxygenation and tumor cell doubling time, as the fastest proliferating tumor cells were found in the poorest oxygenated soft tissue sarcomas. More data are needed to clarify if this relation is really a true biological phenomenon. Furthermore, tumor oxygenation status of soft tissue sarcomas was heterogeneous and independent of clinical and histopathological parameters.

Extraskeletal Osteosarcomas: A Clinicopathologic Study of 25 Cases

A follow-up investigation of 25 cases of extraskeletal osteosarcomas diagnosed at the Center for Bone and Soft Tissue Tumors, Aarhus University Hospital, Denmark, in the period from 1970-1995 was undertaken. The immunohistochemical profile of these tumors was evaluated using a panel of 10 antibodies, and the value of alkaline phosphatase staining in differential diagnostic situations also was considered. The study revealed that this tumor is high-grade malignant and affects adults (median age, 67 years; range, 35-82 years) at diagnosis. The thigh (52%) was the most common tumor location. Seven tumors were superficial, whereas the remaining 18 were intramuscular. Two patients with superficial tumors previously received radiation to the area. Local recurrences developed in 9 (36%) patients and distant metastases developed in the lungs in 15 (60%) patients as the most common site. Median survival time was 24 months, and the cause-specific survival rate at 5 years was less than 25%. Thirteen (52%) intramuscularly located extraskeletal osteosarcomas were of the fibroblastic subtype, often with sparse amounts of osteoid. They could be separated from malignant fibrous histiocytoma on the basis of a strongly positive alkaline phosphatase reaction. Immunohistochemistry did not reveal characteristic features because positivity for vimentin, occasional positivity for desmin, actin, S-100, epithelial membrane antigen, cytokeratin, and p-53 may be observed in many other pleomorphic sarcomas. Various histopathologic factors, such as tumor size, tumor depth, histopathologic subtype, malignancy grade (IIIA versus IIIB), MIB-1, and p53 reactivity were analyzed in relation to clinical course. Only MIB proliferation was correlated to prognosis, with significantly longer survival in patients with tumors with MIB-1 values less than 24%. Our study has shown extraskeletal osteosarcoma to behave in a highly aggressive fashion. Alkaline phosphatase staining compared with immunohistochemistry proved to be superior in the differentiation from other pleomorphic sarcomas.

Tumour oxygenation assessed by 18F-fluoromisonidazole PET and polarographic needle electrodes in human soft tissue tumours

BACKGROUND AND PURPOSE The aim of the study was to identify hypoxia in human soft tissue sarcomas (STS) by PET scanning using the hypoxia marker [18F]-fluoromisonidazole ([18F]FMISO) and invasive oxygen sensitive probes (Eppendorf pO2 Histograph, Germany). MATERIALS AND METHODS Thirteen patients with tumours suspected to be STS were examined by [18F]FMISO PET scanning, and eleven of these patients completed a set of Eppendorf pO2 Histograph measurements following the scanning. RESULTS AND DISCUSSION By histopathological diagnosis, seven tumours were shown to be STS and six tumours were benign. Ratios between tumour and muscle radioactivity and time activity curves for tumours and muscle tissue were examined in defined regions of interest. Only two malignant tumours showed [18F]FMISO uptake in higher amounts than muscle tissue over time. Hypoxia was present in both benign and malignant tumours as measured by the oxygen electrode method. CONCLUSIONS [18F]FMISO PET in our setting seemed not to be feasible for the detection of tumour hypoxia in human soft tissue tumours. Neither did it reflect the extent of hypoxia as determined with the oxygen electrode measurements.

Prognostic factors in soft tissue sarcomas : The Aarhus experience

In the present study, the outcome, patterns of local recurrence and survival, as well as prognostic factors, were evaluated in patients surgically treated for soft tissue sarcomas. Between January 1979 and July 1993, 316 consecutive patients were referred to the Sarcoma Centre in Aarhus with localised malignant soft tissue sarcoma of the extremities or trunk. If possible, the patients were treated with a limb-sparing resection, primarily by use of a wide excision. 50 patients received adjuvant radiotherapy. There were 161 men (51%) and 155 women (49%) median age 56 years (range 1-94 years). 94 patients (30%) had tumours in the trunk, including shoulder and buttock lesions, 163 (52%) in the lower extremity and 59 (19%) in the upper extremity. 52 patients (16%) had grade 1 tumour, 60 (19%) grade 2 and 204 (65%) grades 3A-3B. The 5-year local recurrence rate was 18% and the 5-year survival rate was 75%. Multivariate analysis indicated the following variables as independent unfavourable factors for local recurrence: extracompartmental location, histological high grade, local excision, no adjuvant radiotherapy and intralesional/marginal excision. Independent unfavourable factors for survival were advanced age, extracompartmental location, histological high grade, lower extremity location and large tumour size. If the variable local recurrence was included in the analysis, it was found to have a very strong influence on survival. Based on these variables, a prognostic model was developed.

The Scandinavian Sarcoma Group skeletal metastasis register: Survival after surgery for bone metastases in the pelvis and extremities

INTRODUCTION The assessment of the prognosis for the individual patient is important for the choice of surgical treatment of skeletal metastases. In 1999 the Scandinavian Sarcoma Group (SSG) initiated the Skeletal Metastasis Register as a multicentric, prospective study to provide a scientific basis for treatment recommendations. To improve prognostication we analyzed the survival of patients with skeletal metastases surgically treated at 9 SSG centres. PATIENTS AND METHODS 460 patients with an average age of 64 years underwent 501 operations for non-spinal skeletal metastases. 7% were operated for more than one metastasis. Carcinoma of the breast, prostate, kidney and lung were the dominating primary tumors. RESULTS The survival rate was 0.4 at 1 year, 0.3 at 2 years and 0.2 at 3 years. Univariate analysis showed that survival was related to bone localization, skeletal metastatic load, presence of visceral metastases, Karnofsky performance score, primary tumor type, presence of a complete pathological fracture and preoperative hemoglobin content. Multivariate regression analysis showed that pathological fracture, visceral metastases, haemoglobin content < 7 mmol/L and lung cancer were negative prognostic factors for survival. Myeloma was the sole positive prognostic factor for survival.

Treatment of aggressive fibromatosis: A retrospective study of 72 patients followed for 1-27 years

We evaluated prognostic factors for local recurrence-free survival, including expression of estrogen receptors, after surgical treatment of aggressive fibromatosis in 72 patients (53 women) having primary tumors between 1970 and 1998. Their median age at diagnosis was 31 (1 month-77 years) years. 50 patients had extraabdominal and 22 abdominal fibromatosis. Median tumor size was 4 (1-27) cm. 8 patients were treated with an intralesional resection, 32 with marginal, 31 with wide and 1 with radical resection. They were followed for a median of 8 (1-27) years. The overall and local recurrence-free 5-year survival rates were 98% and 73%, respectively. Univariate analysis identified age, compartmentalization and tumor size as prognostic factors for local recurrence-free survival as well as radiotherapy in extraabdominal tumors. In the multivariate analysis, tumor size > 4 cm, extracompartmental location, inadequate margin and age < 32 years were independent negative prognostic factors for local recurrence. None of the tumors expressed estrogen receptors. In conclusion, aggressive fibromatosis has a high local recurrence rate, but a good prognosis, since almost no patients die of their tumor.

Intradermal and subcutaneous leiomyosarcoma: A clinicopathological and immunohistochemical study of 41 cases

Superficial leiomyosarcomas are rare tumours. The lesions confined to the dermis, contrary to those involving the subcutis, have been reported to carry a favourable prognosis.