Nationwide trends in the current management of desmoid (aggressive) fibromatosis.

AIMS: The optimal management of desmoid fibromatosis remains unclear, leading to significant variability in patient management. To assess this problem, the current approach of clinicians managing this complex condition in the UK was investigated. MATERIALS AND METHODS: A hypothetical case of intramuscular limb girdle desmoid fibromatosis in a fit 65-year-old patient was devised. Surgical and non-surgical oncology members of the British Sarcoma Group were questioned on how they would manage this case in three scenarios: primary disease with function-sparing surgery possible, primary disease with neurovascular involvement and disease recurrence after a previous R0 resection. Initial management, management of symptomatic disease progression, follow-up preferences and any differences in respondents' management choices in a younger case were investigated. RESULTS: The responses from 14 sarcoma surgeons and 23 oncologists (14 clinical, nine medical) were analysed. Desmoid fibromatosis management is generally shared by surgeons and oncologists within sarcoma multidisciplinary teams in the UK. Variation exists in the chosen initial management of primary desmoid fibromatosis in the UK, with function-sparing surgery possible (observation 51%, resection 51%), primary desmoid fibromatosis with neurovascular involvement (hormone therapy with non-steroidal anti-inflammatory drugs 51%, radiotherapy 27%, observation 22%) and for cases of desmoid fibromatosis recurrence (radiotherapy 41%, hormone therapy and non-steroidal anti-inflammatory drugs 27%, observation 24%). There was a clear preference of surgical resection of symptomatic disease progression in cases of primary desmoid fibromatosis without neurovascular involvement (60%). By contrast, radiotherapy was the preferred treatment for progression in cases with neurovascular involvement (47%) or cases of recurrence after a previous R0 resection (34%). Clinical follow-up was selected 3 months after intervention in 68% of scenarios. Follow-up imaging was selected 3 or 6 months after intervention in 57% and 21% of cases, respectively. Most respondents would not change their chosen management in younger patients. DISCUSSION: Several groups have issued formal guidelines for clinicians managing desmoid fibromatosis, including the British Sarcoma Group, the National Comprehensive Cancer Network and the European Society for Medical Oncology. However, these are in some ways contradictory and may not reflect recent publications, potentially explaining the significant variation in the management of desmoid fibromatosis in the UK shown by this survey. We propose a review of current evidence; a national consensus or a desmoid fibromatosis registry may help to standardise desmoid fibromatosis care.

Adenovirus-mediated hypoxia-targeted gene therapy using HSV thymidine kinase and bacterial nitroreductase prodrug-activating genes in vitro and in vivo.

Hypoxia is an important factor in tumor growth. It is associated with resistance to conventional anticancer treatments. Gene therapy targeting hypoxic tumor cells therefore has the potential to enhance the efficacy of treatment of solid tumors. Transfection of a panel of tumor cell lines with plasmid constructs containing hypoxia-responsive promoter elements from the genes, vascular endothelial growth factor (VEGF) and erythropoietin, linked to the minimal cytomegalovirus (mCMV) or minimal interleukin-2 (mIL-2) promoters showed optimum hypoxia-inducible luciferase reporter gene expression with five repeats of VEGF hypoxic-response element linked to the mCMV promoter. Adenoviral vectors using this hypoxia-inducible promoter to drive therapeutic transgenes produced hypoxia-specific cell kill of HT1080 and HCT116 cells in the presence of prodrug with both herpes simplex virus thymidine kinase/ganciclovir and nitroreductase (NTR)/CB1954 prodrug-activating systems. Significant cytotoxic effects were also observed in patient-derived human ovarian cancer cells. The NTR/CB1954 system provided more readily controllable transgene expression and so was used for in vivo experiments of human HCT116 xenografts in nude mice. Subjects treated intratumorally with Ad-VEGFmCMV-NTR and intraperitoneal injection of CB1954 demonstrated a statistically significant reduction in tumor growth. Immunohistochemistry of treated xenografts showed a good correlation between transgene expression and hypoxic areas. Further investigation of these hypoxia-inducible adenoviral vectors, alone or in combination with existing modalities of cancer therapy, may aid in the future development of successful Gene-Directed Enzyme Prodrug Therapy systems, which are much needed for targeting solid tumors.

Substance-P receptors in human primary neoplasms: tumoral and vascular localization.

Primary human neoplasms were examined for the presence of substance-P receptors by receptor autoradiography with 125I-labelled Bolton-Hunter substance P. Substance-P receptors were localized and characterized in the neoplastic cells of 9/12 astrocytomas, 10/10 glioblastomas, 10/12 medullary thyroid carcinomas, 8/16 breast carcinomas and 4/5 ganglioneuroblastomas. Conversely, substance-P receptors were not or only rarely identified on non-small-cell carcinomas of the lung (1/16), neuroblastomas (0/8), adenocarcinomas of the colon (1/21) or the pancreas (1/9), or on malignant lymphomas (3/18). However, in the great majority of the investigated tumours, substance-P receptors were found on intra- and peritumoral blood vessels. All substance-P receptors detected had the pharmacological characteristics of the neurokinin-I receptor sub-type. In addition, the expression of somatostatin receptors was examined in all the neoplastic tissues mentioned above. Both substance-P and somatostatin receptors were present in astrocytomas and in ganglioneuroblastomas, whereas little or no receptor was found in pancreatic and non-small-cell lung carcinomas. The extent of somatostatin-receptor expression was inversely correlated to that of the substance-P receptors in glioblastomas, neuroblastomas and non-Hodgkin's lymphomas. The tumoral and vascular localization of substance-P receptors in tumours may have clinical implications. The use of radiolabelled substance P for in vivo scintigraphy may supplement the current set of diagnostic tools. Substance-P antagonists might be used in the treatment of tumours, as their binding to vascular receptors may decrease tumoral blood supply and drainage.