A phase Ib/II translational study of sunitinib with neoadjuvant radiotherapy in soft-tissue sarcoma.

BACKGROUND: Preoperative radiotherapy (RT) is commonly used to treat localised soft-tissue sarcomas (STS). Hypoxia is an important determinant of radioresistance. Whether antiangiogenic therapy can 'normalise' tumour vasculature, thereby improving oxygenation, remains unknown. METHODS: Two cohorts were prospectively enrolled. Cohort A evaluated the implications of hypoxia in STS, using the hypoxic tracer (18)F-azomycin arabinoside (FAZA-PET). In cohort B, sunitinib was added to preoperative RT in a dose-finding phase 1b/2 design. RESULTS: In cohort A, 13 out of 23 tumours were hypoxic (FAZA-PET), correlating with metabolic activity (r(2)=0.85; P<0.001). Two-year progression-free (PFS) and overall (OS) survival were 61% (95% CI: 0.44-0.84) and 87% (95% CI: 0.74-1.00), respectively. Hypoxia was associated with radioresistance (P=0.012), higher local recurrence (Hazard ratio (HR): 10.2; P=0.02), PFS (HR: 8.4; P=0.02), and OS (HR: 41.4; P<0.04). In Cohort B, seven patients received sunitinib at dose level (DL): 0 (50 mg per day for 2 weeks before RT; 25 mg per day during RT) and two patients received DL: -1 (37.5 mg per day for entire period). Dose-limiting toxicities were observed in 4 out of 7 patients at DL 0 and 2 out of 2 patients at DL -1, resulting in premature study closure. Although there was no difference in PFS or OS, patients receiving sunitinib had higher local failure (HR: 8.1; P=0.004). CONCLUSION: In STS, hypoxia is associated with adverse outcomes. The combination of sunitinib with preoperative RT resulted in unacceptable toxicities, and higher local relapse rates.

Radiation therapy in the treatment of desmoid tumours reduces surgical indications.

BACKGROUND: While several modalities have been proposed for the treatment of desmoid tumour/aggressive fibromatosis, high local recurrence rates have been reported. We present a retrospective study of including patients treated with radiation therapy, some of them in combination with surgical resection. PATIENTS AND METHODS: Thirty-four consecutive patients were included (mean age 40+/-16 years, 9 male). Complete follow-up was available in 31 patients (51+/-36 months). Seventeen patients (50%) were treated with radiation therapy alone, 17 patients with radiation therapy and surgery. Radiation therapy (external beam) was applied in most cases to a total dose of 50.4 Gy in 28 fractions. The lesion was located in the upper extremity in 11 patients, in the lower extremity in 14 cases and on the trunk in 9 cases. RESULTS: Overall recurrence/progression free survival was 88.5% at 5 years and 77.5% at 10 years. Recurrence free survival of the subset of patients undergoing combined treatment with radiation therapy and surgical resection was 83.6% at 5 years and 10 years. In patients who did not receive surgery but only radiation therapy, MRI showed a complete response in 20%, a partial response in 20%, and stable disease in 53% of cases. In this subset, two-third of patient had a metabolic response to radiotherapy (i.e. decrease uptake on the thallium-210 scan after radiotherapy compared to pre-therapy levels). CONCLUSION: Low recurrence rates can be achieved with the use of radiation therapy alone in selected cases. Patients with a metabolic response (decrease) to radiotherapy may be treated with a non-surgical approach. Surgery might be considered in patients with a poor metabolic response to radiotherapy.

Salvaging the limb salvage: management of complications following endoprosthetic reconstruction for tumours around the knee.

INTRODUCTION: Limb-salvage surgery, including endoprosthetic reconstruction after tumour resection, has become the standard management for local control of tumours around the knee. As the nature of surgery is technically complex and demanding, there is potential for significant morbidity arising from complications. This study describes our experience with complications following endoprosthetic reconstruction around the knee. METHODS: Retrospective analysis of consecutive resections and endoprosthetic reconstructions for tumours around the knee between 1996 and September 2005 performed at St Vincent's Hospital, Melbourne. RESULTS: Fifty consecutive cases were reviewed, with a median follow-up of 24.5 (range, 2-124) months. Median age was 41 (range, 13-79) years. Tumour types included 38 primary musculoskeletal malignancies, 8 metastatic tumours, 2 bony lymphomas and 2 benign lesions. There were eight deaths, nine cases of subsequent metastatic spread and no local recurrences. There were six cases of deep infection, two each of non-resolving nerve palsy, fracture and mechanical wear, and one each of symptomatic patellofemoral impingement, aseptic loosening and intraoperative popliteal artery trauma. Five patients required endoprosthetic revision, and three subsequent amputations were described. Excellent functional outcome and emotional acceptance was observed amongst patients that underwent revision. CONCLUSION: Resection and endoprosthetic reconstruction of tumours around the knee is both technically challenging and resource-intensive. It is imperative that morbidity from complications is limited through the minimisation of their incidence and the provision of optimal management. This series demonstrates that good patient outcomes can be achieved in specialist centres with experienced surgeons and adoption of a multidisciplinary approach.

Pigmented villonodular synovitis of the hip mimicking soft-tissue sarcoma: a case report.

Pigmented villonodular synovitis is a rare and benign but potentially locally aggressive disease that should be considered in younger patients who present with monoarticular joint symptoms and pathology. We present a 30-year-old Sudanese woman with a huge mass arising from the right hip joint. A multimodality radiological approach to investigation and diagnosis is demonstrated and discussed. Histopathological examination of the resected specimen confirmed the diagnosis of pigmented villonodular synovitis with the mass consisting of a proliferation of fibrohistiocytic cells, abundant haemosiderin, foamy histiocytes, and occasional giant cells. The patient made a good recovery, with mobility aided by arm crutches and a hip abduction brace.

Revision surgery in dermatofibrosarcoma protuberans of the trunk and extremities.

AIMS: Dermatofibrosarcoma protuberans is a rare condition which is frequently misdiagnosed at presentation, resulting in a high incidence of local recurrence due to inadequate resection. The archives of the Department of Orthopaedics at the University of Florida were analysed to investigate the natural history and results of treatment for this tumour. METHODS: Between 1975 and 1996, 35 cases of DFSP were treated at the University of Florida. Of these, one was treated primarily, five were treated for local recurrence, 17 had tumour bed excisions following inadequate primary excisions elsewhere and 12 had tumour bed excisions following inadequate resection of local recurrences elsewhere. The data were analysed to assess the impact of age, gender, duration of symptoms, tumour site and size, surgical margin, number of operations and adjuvant treatments on survival and local recurrence outcomes. RESULTS: Complete follow-up was available for 34 patients. Mean follow-up was 58 months (range 12-144 months). Thirty-three patients remain alive and disease-free. One patient died of unrelated causes. The margins obtained were wide in 28 patients, marginal in six and intralesional in one. Of the seven patients with inadequate surgical margins, four received adjuvant radiation therapy and remain disease-free. No patient with an adequate margin developed a local recurrence, but there were three local recurrences in the patients with an inadequate margin who did not receive adjuvant radiation therapy (local recurrence rate: 8%). No patient developed lymphatic or distant metastasis. Local recurrences were more likely to be classified Stage IB (17/17) than primary tumours (1/18) (P<0.001). Local recurrence was more likely where the surgical margin was less than 2.5 cm from the lesion. CONCLUSIONS: Dermatofibrosarcoma protuberans is a low-grade tumour that has a high potential for local recurrence unless it can be completely excised. The overall rate of local recurrence in referred patients in this series was 20/35 cases (57%). All occurred after inadequate margins at previous surgery in other institutions. Revision surgery in these patients showed a local recurrence rate of 8%. To avoid extensive surgery for recurrences, initial treatment should be by wide excision incorporating the underlying deep fascia and a cuff of 2.5-3 cm of normal skin tissue. Radiation therapy provides a useful adjunct where adequate margins cannot be obtained.

Localization of parathyroid hormone-related protein mRNA expression in breast cancer and metastatic lesions by in situ hybridization.

Parathyroid hormone-related protein (PTHrP) has been identified immunohistochemically in 60% of breast carcinoma and in 92% of breast cancer metastases in bone. To establish whether the localization of the PTHrP antigen reflects protein synthesis and also to investigate the role of PTHrP in metastatic disease, as part of an ongoing study, we used in situ hybridization to study the localization of PTHrP mRNA in a retrospective series of primary breast tumors and their metastatic lesions. Paraffin sections of 17 primary and 26 metastatic lesions, 11 of which were in bone, were available for the study: 10 of the 17 (59%) primary lesions, 8 of 11 (73%) breast cancer metastases to bone, and 3 of 15 (20%) metastases to non-bone sites showed specific localization of PTHrP mRNA. These findings establish that PTHrP is commonly synthesized by primary breast cancers and support previous immunohistochemical studies reporting a higher incidence of PTHrP-positive tumor cells in skeletal metastases than in nonskeletal metastases.

Combat and social support as variables in perceived symptomatology of combat-related posttraumatic stress disorder.

This study used an analog approach to the perceptions of tour of duty, combat and noncombat, and levels of social support, high and low. Their influence was assessed in the symptomatology of Posttraumatic Stress Disorder. 80 subjects were randomly assigned to read one of four vignettes depicting levels of combat and social support as main effects. Results were congruent with recent research indicating significant main effects for combat and social support in the symptomatology of Posttraumatic Stress Disorder.

Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites.

Parathyroid hormone-related protein (PTHrP) has recently been identified in 60% of a series of primary breast cancers. The detection of a bone-resorbing factor in tumors with a propensity to metastasize to bone prompted study of PTHrP in breast cancer metastasis. PTHrP was localized by immunohistology in 12 of 13 (92%) breast cancer metastases in bone and in 3 of 18 (17%) metastases in non-bone sites. The statistical difference was highly significant (P less than 0.0001). Production of PTHrP as a bone-resorbing agent may contribute to the ability of breast cancers to grow as bone metastases.

Mental health professionals' views of Afro-American family life and sexuality.

The Survey of Afro-American Behavior (S.A.A.B.) is a scale devised for specific use with mental health professionals to assess the affective and cognitive components of attitudes toward positive (favorable), negative (unfavorable), factual and stereotypic statements regarding Afro-American behavior in seven areas, two of which are examined in this paper: 1) family life patterns and marital relationships, and 2) sexual values and behavior. Significant differences on the factual and stereotypic items emerged among six groups of therapists divided by age and sex. There were statistically significant differences on family life and marital relationship items between the means of Afro-Americans over 45 years of age, who agreed more with positive statements, and Anglo-Americans under 35 years of age; and on sexual issues each of the three groups of Afro-Americans agreed more with the factual statements than three groups of Anglo-American cohorts. Sexual values and belief statements were the most controversial area of knowledge both within and between the two ethnic groups. The implications of this study are discussed in terms of prevention and early intervention programs for Afro-American communities with particular emphasis on the necessary training of mental health professionals to work effectively with Afro-Americans.

An in-progress research report of perceptual-cognitive development of young black children in three cultures.

This paper examines a study of perceptual-cognitive development among black children from three cultures. The study investigates patterns of perceptual and cognitive functioning as a transaction among developmental, genetic, environmental, cultural, and child-rearing variables. The samples consisted of four and eight year olds from three distinct groups: (1) white and black middle socio-economic status (SES) children from the US; (2) lower and middle SES children from St. Kitts in the Caribbean; and (3) middle SES children from Nigeria. The research paradigm permits a cross-cultural comparison of three samples of middle-class, urban, English-speaking, black children in relation to six areas of perceptual-cognitive development, four anthropometric, and three physiological measures. Because of the inclusion of a white sample, the interactions of SES, race, culture, nutritional status, proximity to the equator, and physical growth and development can be correlated with the performance of black children on perceptual-cognitive tasks. Results of data analyzed thus far are reported and implications are discussed.

Children's color perception in relation to habitat and skin color.

Developmental color perception of negroid and caucasoid children in 3 societies is examined in relation to the theories that proximity to the equator and fundus pigmentation (as measured by skin color) reduce shortwave (blue-green) in comparison with long-wave perception. The 278 4- and 8-year-old native-born, urban, English-speaking children were from latitudes 6 degrees 27' N (Enugu, Nigeria), 17 degrees 18' N (Basseterre, Saint Kitts, East Caribbean), and 34 degrees 3' N (Los Angeles, Calif.). Equal numbers of boys and girls from middle socioeconomic homes were medically examined for normal nutritional status and near vision. Children were individually tested on the Gaines Color Perception Test. The results show that short-wavelength perception is less accurate than long-wave-length perception in all locations, but most of the variance is attributable to conditions of low value or chroma stimuli rather than to proximity to the equator. There were no significant differences between Nigerian, Saint Kittitian and California caucasoid children. In accord with the pigmentation theory, young California negroid children had less accurate short-wavelength color perception than California caucasoid children. However, Nigerian and Saint Kittitian negroid children's perceptual accuracy was at least as accurate as that of caucasoid children. Amount of pigmentation does not appear to be a universal variable in children's color perception. Socioeconomic status, nutritional variables, developmental growth of the eye, or controlled stimulus conditions of the present research could account for the lack of positive relationships between color perception and habitat or skin color.

A survey of ethnic and sociocultural issues in medical school education.

A survey of 113 medical schools was conducted to determine whether sociocultural issues in the treatment of minority group patients were dealt with in their curricula. The inclusion of factors such as different value systems, attitudes, early experiences, and economic and ethnic backgrounds and their influence upon the delivery of health care services to minority groups was found to be minimal. The variables which appeared to facilitate ethnic and sociocultural courses in medical education are contrasted with those which result in exclusion of this information from the curricula. These findings emphasize the need for a greater commitment to offering such courses.