Targeting of small molecule anticancer drugs to the tumour and its vasculature using cationic liposomes: lessons from gene therapy

Cationic (positively charged) liposomes have been tested in various gene therapy clinical trials for neoplastic and other diseases. They have demonstrated selectivity for tumour vascular endothelial cells raising hopes for both antiangiogenic and antivascular therapies. They are also capable of being selectively delivered to the lungs and liver when administered intravenously. These vesicles are being targeted to the tumour in various parts of the body by using advanced liposomal systems such as ligand-receptor and antibody-antigen combinations. At present, the transferrin receptor is commonly used for cancer-targeted drug delivery systems including cationic liposomes. This review looks at the growing utility of these vesicles for delivery of small molecule anticancer drugs

Research: Is resection of tumours involving the pelvic ring justified? : A review of 49 consecutive cases

INTRODUCTION: Pelvic surgery is challenging and impacts significantly on limb and visceral function, thus, raising the question "is heroic surgery justifiable". This study assessed the functional, oncologic and surgical outcomes following pelvis tumour resections. METHODS: Between 1996–2003, 49 patients (mean age 43 years) underwent pelvic tumour resections- 38 primary malignant tumours, 5 secondary tumours and 6 benign tumours. Bone tumours comprised 5 osteosarcomas, 5 Ewings sarcomas, and 12 chondrosarcomas. Of the soft tumours, 9 were of neural origin. Tumours involved the ilium, acetabulum, pubic bones, sacrum or a combination of these. Functional assessment was performed and no patient had metastases at presentation. RESULTS: There were 41 limb sparing resections and 8 hindquarter amputations. Surgical margins were intralesional (1), marginal (13), wide (26), and radical (3). Of limb sparing surgery, prosthetic reconstructions were performed in 10 patients, biologic reconstructions in 6, a combination of these in 3 and no reconstruction in others. There was 1 intraoperative death, 7 local recurrences and 19 metastases. Death from disease occurred at a mean of 14.2 months with a mean followup of 27 (1–96) months. Amputation and periacetabular resections had worse functional outcomes. Emotional acceptance was surprisingly high. CONCLUSION: Pelvic resections are complex. Functional outcome is significantly affected by surgery. Disease control is similar to limb tumours. Emotional acceptance of surgery in survivors was surprisingly high. Major pelvic resection for malignancy appears justified

Post-radiation sarcoma of the neck treated with re-irradiation followed by wide excision

BACKGROUND: Post-radiation sarcoma (PRS) is an uncommon disease manifesting as sarcoma in a previously irradiated field, usually with a latent period of 5 years or more. Literature is limited to small series. Optimal management of this disease is unclear. Positive margins are common following attempted curative surgery and outcomes are poor. Radiotherapy is hardly used and its effect on PRS is not known. We described a case of PRS treated with preoperative radiotherapy followed by margin-negative wide excision. CASE PRESENTATION: The 59-year-old patient presented with a mass in the left supraclavicular fossa and numbness in the arm, six years following radical irradiation of the head and neck for nasopharyngeal carcinoma. Open biopsy showed pleomorphic spindle cell sarcoma. She was treated with pre-operative hyperfractionated radiotherapy followed by margin-negative wide excision and nerve grafting. Cumulative radiation dose to the supraclavicular fossa was 98 Gy. Histological examination of the post-irradiation tumor specimens showed evidence of significant tumor response to re-irradiation. The patient remained free of disease five years after surgery with excellent functional outcome. CONCLUSION: Role of radiotherapy in PRS is uncertain. We described a case that was successfully managed with preoperative radiotherapy and margin-negative wide excision in terms of tumor control and functional outcomes. The impact of radiotherapy was demonstrated in the post-irradiation resected specimen. Further investigation using re-irradiation and surgery in PRS is warranted

Direct anti-metastatic efficacy by the DNA enzyme Dz13 and downregulated MMP-2, MMP-9 and MT1-MMP in tumours

The DNA enzyme Dz13, targeted against the oncogene c-Jun, is capable of inhibiting various model tumours in mice albeit in ectopic models of neoplasia. In previous studies using orthotopic models of disease, the inhibitory effects of Dz13 on secondary growth was a direct result of growth inhibition at the primary lesion site. Thus, the direct and genuine effects on metastasis were not gauged. In this study, Dz13 was able to inhibit both locoregional and distal metastasis of tumour cells in mice, in studies where the primary tumours were unaffected due to the late and clinically-mimicking nature of treatment commencement. In addition, the effect of Dz13 against tumours has now been extended to encompass breast and prostate cancer. Dz13 upregulated the matrix metalloproteinase (MMP)-2 and MMP-9, and decreased expression of MT1-MMP (MMP-14) in cultured tumour cells. However, in sections of ectopic tumours treated with Dz13, both MMP-2 and MMP-9 were downregulated. Thus, not only is Dz13 able to inhibit tumour growth at the primary site, but also able to decrease the ability of neoplastic cells to metastasise. These findings further highlight the growing potential of Dz13 as an antineoplastic agent

Outcome of patients with osteosarcoma over 40 years of age: Is angiogenesis a marker of survival?

BACKGROUND: Osteosarcoma predominantly afflicts young people in their second and third decades of life. When osteosarcoma arises in patients older than 40 years, the prognosis is usually poorer compared to their younger counterparts. Although the clinical, histopathologic features and prognostic indicators are well defined for young patients, much less is known about affected adults. The purpose of this study is to describe our institution's experience with the management of osteosarcoma in patients greater than 40 years and also evaluate, by immunohistochemical analysis, the prognostic significance of microvessel density, as a marker of intratumoural angiogenesis. METHODS: A retrospective clinicopathological analysis was performed on 11 patients over the age of 40 years that were treated at our institution between 1996 and 2004. Archival pre-treatment biopsy tissue was retrieved for immunohistochemical staining against two endothelial cell markers (CD31 and CD34) and also against VEGF. Angiogenesis was assessed by determining the intratumoural microvessel density (MVD) and the degree of VEGF expression in these specimens. This was correlated with patient outcome in terms of local recurrence, metastasis and death. Histological results were also compared to a group of patients less than 40 years of age. RESULTS: Of the 11 patients, 9 were male and 2 were female and the mean age was 58 years (range, 42–85). In 7 patients, osteosarcoma arose secondarily from Paget's disease of the bone. The most common site involved was the humerus (7) followed by the femur (2) then pelvis (1) and ulna (1). At the time of diagnosis, 4 patients had metastatic disease. Preoperative chemotherapy was given to 4 patients, with a good response in 3 patients. Six patients underwent limb-sparing surgery, 4 had amputations and 1 was treated with radiotherapy alone. The mean follow up time was 31.5 months (range, 8–81). At this time, 4 patients (36%) had developed lung metastases and 5 patients (46%) had died. Overall survival was 54.5%. Intratumoural MVD was higher in patients over 40 years, although not statistically significant (p = 0.111, CD31; p = 0.134, CD34). VEGF was uniformly expressed in all sections, however no relationship was found between the degree of expression and patient age. CONCLUSION: The prognosis for older patients with osteosarcoma is generally poor. Initial presentation is commonly associated with metastatic disease and neoadjuvant chemotherapy is often avoided because of its side effects. Increased intratumoural vascularity may contribute to the poorer prognosis in these patients, however further studies are needed

The role of thallium-201 and pentavalent dimercaptosuccinic acid for staging cartilaginous tumours

INTRODUCTION: Heterogeneity of cartilage tumours may confound accurate diagnosis and grading resulting in under and over treatment. Improved preoperative assessment of malignancy and grade would be invaluable for developing a rational plan for treatment. We examined correlations between nuclear tracer avidity and malignancy grade in cartilage tumours. METHODS: Between 1996 and 2000, 92 consecutive patients with cartilaginous tumours (50 benign, 42 non-metastatic malignant) underwent nuclear scanning. Thallium-201 (TL-201) and pentavalent dimercaptosuccinic acid (DMSAV) were used as nuclear isotopes. Scanning with these agents was performed on separate days 48 hours apart. Static and SPECT images were obtained at 30 m and 4 h after injection of nuclear tracer. Pathology review was undertaken blinded to the results of the nuclear scans and correlations between histologic results and trace uptake at 4 hours examined. RESULTS: 25 patients with negative DMSAV had benign tumours. 15/17 tumours with positive TL-201 had malignant tumours. 11/13 patients with both positive DMSAV and TL-201 scans had intermediate or high grade tumours and 4 of these developed metastases. We have developed an algorithm for the management of patients with tumours that aims to avoid over treatment of low grade tumours and under treatment of high grade tumours. CONCLUSION: Functional nuclear scanning with TL-201 and DMSAV complements other imaging modalities in the management of cartilaginous tumours

An interesting diagnosis for a presacral mass: case report

A presacral mass can present a diagnostic dilemma for the surgical oncologist. Differential diagnoses include congenital causes such as teratoma or chordoma, neurological causes such as neurilemoma or neurofibroma or other malignancies such as lymphoma or sarcoma. Diagnosis usually requires imaging such as CT and MRI and tissue biopsy. We present an unusual cause of a presacral mass being extramedullary haematopoiesis, found incidentally in a 71 year old female. Extramedullary haematopoiesis is defined as the production of myeloid and erythroid elements outside of the bone-marrow. This diagnosis is extremely rare in the presacral area especially in a patient with no haematological abnormalities. A review of the literature is presented

New clinically relevant, orthotopic mouse models of human chondrosarcoma with spontaneous metastasis

Chondrosarcoma responds poorly to adjuvant therapy and new, clinically relevant animal models are required to test targeted therapy. Two human chondrosarcoma cell lines, JJ012 and FS090, were evaluated for proliferation, colony formation, invasion, angiogenesis and osteoclastogenesis. Cell lines were also investigated for VEGF, MMP-2, MMP-9, and RECK expression. JJ012 and FS090 were injected separately into the mouse tibia intramedullary canal or tibial periosteum. Animal limbs were measured, and x-rayed for evidence of tumour take and progression. Tibias and lungs were harvested to determine the presence of tumour and lung metastases. JJ012 demonstrated significantly higher proliferative capacity, invasion, and colony formation in collagen I gel. JJ012 conditioned medium stimulated endothelial tube formation and osteoclastogenesis with a greater potency than FS090 conditioned medium, perhaps related to the effects of VEGF and MMP-9. In vivo, tumours formed in intratibial and periosteal groups injected with JJ012, however no mice injected with FS090 developed tumours. JJ012 periosteal tumours grew to 3 times the non-injected limb size by 7 weeks, whereas intratibial injected limbs required 10 weeks to achieve a similar tumour size. Sectioned tumour tissue demonstrated features of grade III chondrosarcoma. All JJ012 periosteal tumours (5/5) resulted in lung micro-metastases, while only 2/4 JJ012 intratibial tumours demonstrated metastases. The established JJ012 models replicate the site, morphology, and many behavioural characteristics of human chondrosarcoma. Local tumour invasion of bone and spontaneous lung metastasis offer valuable assessment tools to test the potential of novel agents for future chondrosarcoma therapy

Measuring mental health of the Dutch population: a comparison of the GHQ-12 and the MHI-5

BACKGROUD: The objective is to compare the performance of the MHI-5 and GHQ-12, both measures of general mental health. Therefore, we studied the relationship of the GHQ-12 and MHI-5 with sociodemographic characteristics, self-reported visits to general practice and mental health care, and with diagnoses made by the general practitioner. METHODS: Data were used from the Second Dutch National Survey of General Practice, which was carried out in 104 practices. This study combines data from a representative sample of the Dutch population with data from general practice. RESULTS: The agreement between the GHQ-12 and MHI-5 is only moderate. Both instruments are however similarly associated with demographic characteristics (except age), self-reported health care use, and psychological and social diagnoses in general practice. CONCLUSIONS: The performance of the MHI-5 and GHQ-12 in terms of predicting mental health problems and related help seeking behaviour is similar. An advantage of the MHI-5 is that it has been widely used, not only in surveys of mental health, but also in surveys of general health and quality of life, and it is shorter. A disadvantage of the MHI-5 is that there is no cut-off point. We recommend a study to establish a valid, internationally comparable cut-off point

Durable remissions are rare following high dose therapy with autologous stem cell transplantation for adults with "paediatric" bone and soft tissue sarcomas

BACKGROUND: The role of high dose therapy (HDT) with autologous stem cell transplantation (AuSCT) for the treatment of bone and soft tissue sarcomas remains investigational. There are few reports examining this strategy focusing on the adult population. METHODS: We retrospectively reviewed our experience of adult patients undergoing HDT and AuSCT for 'paediatric' sarcomas. RESULTS: A total of 17 patients (14 male, 3 female) with median age at transplant of 24 years (range 20 – 41) were identified. The diagnosis was Ewings sarcoma/PNET (10), osteosarcoma (5) and rhabdomyosarcoma (2). Status prior to HDT, following conventional-dose chemotherapy +/- surgery +/- radiotherapy, was complete remission (CR) (6), partial remission (PR) (6), stable disease (1) and progressive disease (4). There was no transplant-related mortality. Two patients remain disease free beyond four years and both received HDT as part of their primary therapy (CR1 and PR1) however, the median progression free survival and overall survival following AuSCT for the entire cohort was only 7 months (range: 2–92 months) and 13 months (range: 2 – 92 months), respectively. CONCLUSION: HDT and AuSCT infrequently achieves prolonged remissions in adult patients and should only be considered in patients who are in a PR or CR following conventional-dose therapy. Further studies are required to define the role of HDT with AuSCT for adult patients with sarcoma