The effectiveness of interventions to treat hypothalamic obesity in survivors of childhood brain tumours: a systematic review.

BACKGROUND: Survivors of childhood brain tumours (SCBT) are at risk of type 2 diabetes and cardiovascular diseases. Obesity is a major driver of cardiometabolic diseases in the general population, and interventions that tackle obesity may lower the risk of these chronic diseases. The goal of this systematic review was to summarize current evidence for the presence of interventions to manage obesity, including hypothalamic obesity, in SCBT. METHODS: The primary outcome of this review was the body mass index z-score change from baseline to the end of the intervention and/or follow-up. Literature searches were conducted in PsycINFO, CINAHL, the Cochrane Library, Medline, SPORTDiscus, EMBASE and PubMed. Two reviewers completed study evaluations independently. RESULTS: Eleven publications were included in this systematic review (lifestyle intervention n = 2, pharmacotherapy n = 6 and bariatric surgery n = 3). While some studies demonstrated effectiveness of interventions to manage obesity in SCBT and alter markers of obesity and cardiometabolic risk, the evidence base was limited and of low quality, and studies focused on hypothalamic obesity. We conclude that there is urgent need to conduct adequately powered trials of sufficient duration, using existing and novel therapies to manage obesity, reduce the burden of cardiometabolic disorders and improve outcomes in SCBT.

Dosimetric advantages and superior treatment delivery efficiency of RapidArc over conventional intensity-modulated radiotherapy in high-risk prostate cancer involving seminal vesicles and pelvic nodes.

AIMS: To compare the dosimetry and treatment delivery efficiency of RapidArc with conventional intensity-modulated radiotherapy (IMRT) in the treatment of high-risk prostate cancer. MATERIALS AND METHODS: Fifteen patients with high-risk localised prostate cancer were studied. Sequential treatment was used. The initial planning target volume (PTV-L) included the prostate, seminal vesicles and pelvic lymphatics, whereas the prostate boost PTV (PTV-P) included the prostate and seminal vesicles only. The total prescription dose was 76 Gy (44 Gy to PTV-L, 32 Gy to PTV-P; 2 Gy/fraction). Two separate planning techniques were generated for each patient: seven static-field IMRT versus two-arc RapidArc. Dose-volume parameters for the organs at risk, conformity index and homogeneity index for the PTVs, the calculated monitor units and treatment delivery time for both techniques were compared. RESULTS: RapidArc gave more conformal plans than IMRT for both PTVs. RapidArc gave a higher homogeneity index to the PTV-P and a similar homogeneity index to the PTV-L. The two techniques gave similar dosimetric results for the rectum, bladder and femoral heads. The mean dose (Dmean) and the maximum dose (Dmax) of the bowel space were reduced by 3.06 and 2.83%, respectively, with RapidArc. The V20 Gy, V30 Gy and V40 Gy for healthy tissues were reduced by 7.77, 14.25 and 17.55%, respectively, with RapidArc. The calculated treatment delivery time and monitor units were reduced by 74.09%/60.93% and 68.32%/48.06% for the PTV-L/PTV-P, respectively, with RapidArc. CONCLUSION: RapidArc is better than conventional IMRT in terms of dosimetry and delivery efficiency for high-risk prostate cancer.

The incidence of physiological radiolucency following Oxford unicompartmental knee replacement and its relationship to outcome.

Narrow, well-defined radiolucent lines commonly observed at the bone-implant interface of unicompartmental knee replacement tibial components have been referred to as physiological radiolucencies. These should be distinguished from pathological radiolucencies, which are poorly defined, wide and progressive, and associated with loosening and infection. We studied the incidence and clinical significance of tibial radiolucent lines in 161 Oxford unicondylar knee replacements five years after surgery. All the radiographs were aligned with fluoroscopic control to obtain views parallel to the tibial tray to reveal the tibial bone-implant interface. We found that 49 knees (30%) had complete, 52 (32%) had partial and 60 (37%) had no radiolucent lines. There was no relationship between the incidence of radiolucent lines and patient factors such as gender, body mass index and activity, or operative factors including the status of the anterior cruciate ligament and residual varus deformity. Nor was any statistical relationship established between the presence of radiolucent lines and clinical outcome, particularly pain, assessed by the Oxford Knee score and the American Knee Society score. We conclude that radiolucent lines are common after Oxford unicompartmental knee replacement but that their aetiology remains unclear. Radiolucent lines were not a source of adverse symptoms or pain. Therefore, when attempting to identify a source of postoperative pain after Oxford unicompartmental knee replacement the presence of a physiological radiolucency should be ignored.

The effect of leg alignment on the outcome of unicompartmental knee replacement.

Varus malalignment after total knee replacement is associated with a poor outcome. Our aim was to determine whether the same was true for medial unicompartmental knee replacement (UKR). The anatomical leg alignment was measured prospectively using a long-arm goniometer in 160 knees with an Oxford UKR. Patients were then grouped according to their mechanical leg alignment as neutral (5 degrees to 10 degrees of valgus), mild varus (0 degrees to 4 degrees of valgus) and marked varus (> 0 degrees of varus). The groups were compared at five years in terms of absolute and change in the Oxford Knee score, American Knee Society score and the incidence of radiolucent lines. Post-operatively, 29 (18%) patients had mild varus and 13 (8%) had marked varus. The mean American Knee Society score worsened significantly (p < 0.001) with increasing varus. This difference disappeared if a three-point deduction for each degree of malalignment was removed. No other score deteriorated with increasing varus, and the frequency of occurrence of radiolucent lines was the same in each group. We therefore conclude that after Oxford UKR, about 25% of patients have varus alignment, but that this does not compromise their clinical or radiological outcome. Following UKR the deductions for malalignment in the American Knee Society score are not justified.

Tibial component overhang following unicompartmental knee replacement--does it matter?

As implants are made in incremental sizes and usually do not fit perfectly, surgeons have to decide if it is preferable to over or undersize the components. This is particularly important for unicompartmental knee replacement (UKR) tibial components, as overhang may cause irritation of soft tissues and pain, whereas underhang may cause loosening. One hundred and sixty Oxford UKRs were categorised according to whether they had minor (<3 mm, 70%) or major (>or=3 mm, 9%) tibial overhang, or tibial underhang (21%). One year post surgery, there was no significant difference in outcome between the groups. Five years after surgery, those with major overhang had significantly worse Oxford Knee Scores (OKS) (p=0.001) and pain scores (p=0.001) than the others. The difference in scores was substantial (OKS=10 points). There was no difference between the 'minor overhang' and the 'underhang' group. We conclude that surgeons must avoid tibial component overhang of 3 mm or more, as this severely compromises the outcome. Although this study showed no difference between minor overhang or underhang, we would advise against significant underhang because of the theoretical risk of component subsidence and loosening.

Influence of component alignment on outcome for unicompartmental knee replacement.

This study's aim was to assess the effect of component mal-alignment on outcome of Oxford Unicompartmental Knee Replacement (UKR). Two hundred and eleven knees implanted with a medial UKR, using a minimally invasive approach, were followed up at a minimum of 4 years. Sagittal and frontal plane femoral and tibial component alignments were determined from antero-posterior and lateral radiographs. The cohort was divided into alignment groups which represented consecutive 2.5 degrees intervals over the range of measured values for femoral varus/valgus, femoral flexion/extension, tibial varus/valgus and tibial tilt. The Oxford Knee Score (OKS) and incidence of radiolucency (RL) were compared between alignment groups for each alignment parameter. In 98% of cases the femoral components were positioned between 10 degrees varus and 10 degrees valgus; all femoral components were within +/-10 degrees flexion. In 92% of cases the tibial components were positioned between +/-5 degrees varus/valgus and superior/inferior tilt (neutral tilt being 7 degrees). Within these ranges there were no significant differences in OKS or RL between the alignment groups; nor were there any differences between those at the extremes of component alignment compared to those in the inner ranges of alignment. We conclude that, because of the spherical femoral component, the Oxford UKR is tolerant to femoral mal-alignment of 10 degrees and tibial mal-alignment of 5 degrees.

A split-organ delineation approach for dose optimisation for intensity-modulated radiotherapy for advanced T-stage nasopharyngeal carcinoma.

AIMS: To assess the dosimetric effect of using a split-organ delineation approach during intensity-modulated radiotherapy (IMRT) treatment planning for advanced T-stage nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Twenty NPC patients with T3-4 tumours were studied. A reference (REF) IMRT plan was generated based on a standard treatment planning protocol, with a set of user-defined dose constraints for optimisation. An investigative (INV) IMRT plan was then generated based on the same protocol, but treating several organs at risk (OARs; parotid glands, temporal lobes, cochlea, auditory nerves and planning organ at risk volume [PRV] of the brainstem) as split organs consisting of target-overlapping and non-target-overlapping sub-segments. These sub-segments were assigned independent dose constraints. The REF and INV plans were compared with respect to target coverage and OAR sparing. Target coverage was evaluated by the Dmin (minimum dose), V66/V60 (percentage volume of gross target volume [GTV]/planning target volume [PTV] receiving 66 Gy/60 Gy), target conformity index (CI), and tumour control probability (TCP). The sparing of OARs was evaluated by the commonly used dose end points for the respective OAR, and normal tissue complication probability (NTCP). RESULTS: For PTV coverage, the INV plan was superior to the REF plan in terms of Dmin (P=0.000), CI (P=0.005) and TCP (P=0.002). This is attributed to an increase in dose to the PTV-OAR overlapping sub-segments. Regarding the sparing of OARs, there was a significant reduction in the mean dose of the parotid glands (P=0.002), and a slight, but non-significant, increase in NTCP of the temporal lobes, cochlea and brainstem. CONCLUSIONS: Using a split-organ delineation approach in IMRT treatment planning for advanced T-stage NPC, a significant improvement in the target coverage and TCP could be achieved, whereas the mean dose of the parotid was reduced significantly. There was insignificant change in the NTCP of the temporal lobe, parotid gland, cochlea and brainstem, but a significant change in the NTCP of the auditory nerve. The approach provides the planner extra room to manipulate the dose constraints during optimisation, and to obtain the desired result in less attempts. This approach also has the potential to be used in a broader context for IMRT planning for other tumour sites.

Emergency intensive care admission following elective thoracic surgery.

AIM: The aim of this study was to analyse the outcomes of patients admitted to the intensive care unit (ICU) following initial recovery after elective thoracic surgery. METHODS: The case notes of all patients who underwent elective thoracic surgery over a one-year period were reviewed. Patients who were admitted to ICU following an initial recovery on the ward were identified and their postoperative course analysed. The clinical and demographic characteristics of these patients were recorded and their outcomes analysed. RESULTS: A total of 20 patients were admitted to ICU of whom 13 (65%) were admitted for respiratory complication, 5 with sepsis and 2 with cardiovascular instability. Sixteen (80%) patients required CPAP or BIPAP, of whom only 7 (35%) required mechanical ventilation. Renal support was required in 7 patients, with 2 (10%) requiring haemofiltration. ICU survival was 15 patients (75%), whilst overall three-month survival post ICU admission was 65%. Requirement for renal support was the only predictor of mortality on univariate and multivariate analysis. CONCLUSIONS: Salvage ICU admission following elective thoracic surgery is associated with significant mortality, however the outcome is far from hopeless. The majority of patients can be managed without recourse to mechanical ventilation or haemofiltration. The need for renal support is, however, a significant adverse prognostic indicator.

NF-kappaB inhibition sensitizes hepatocytes to TNF-induced apoptosis through a sustained activation of JNK and c-Jun.

Hepatocyte resistance to tumor necrosis factor alpha (TNF)-induced apoptosis is dependent on activation of the transcription factor nuclear factor kappaB (NF-kappaB). To determine the mechanism by which NF-kappaB protects against TNF toxicity, the effect of NF-kappaB inactivation on the proapoptotic c-Jun NH(2)-terminal kinase (JNK) signaling pathway was examined in the rat hepatocyte cell line RALA255-10G. Adenovirus-mediated NF-kappaB inactivation led to a prolonged activation of JNK and increased activating protein-1 (AP-1) transcriptional activity in response to TNF treatment. Inhibition of the function of the JNK substrate and AP-1 subunit c-Jun blocked cell death from NF-kappaB inactivation and TNF as determined by measures of cell survival, numbers of apoptotic and necrotic cells, and DNA hypoploidy. Inhibition of c-Jun function blocked mitochondrial cytochrome c release and activation of caspase-3 and -7. NF-kappaB therefore blocks the TNF death pathway through down-regulation of JNK and c-Jun/AP-1. In conclusion, sustained JNK activation that occurs in the absence of NF-kappaB initiates apoptosis through a c-Jun-dependent induction of the mitochondrial death pathway.

Induction of cyclooxygenase-2 by tumor promoters in transformed and cytochrome P450 2E1-expressing hepatocytes.

The induction of cyclooxygenase (COX)-2 expression has been implicated as a mechanism for the formation of non-hepatic tumors. Recent investigations have demonstrated COX-2 expression in human hepatocellular carcinomas, but little is known about the regulation of hepatocyte COX-2 expression. Employing the adult, rat hepatocyte line RALA255-10G, the effects of cellular transformation or expression of the alcohol-inducible cytochrome P450 2E1 (CYP2E1) on COX-2 expression were examined. Transformed and non-transformed hepatocytes did not express COX-2 by western and northern blot analysis. The tumor promoters phorbol 12-myristate 13-acetate (PMA) and chenodeoxycholic acid (CD) induced COX-2 protein expression in transformed, but not non-transformed cells. CYP2E1-expressing cells lacked constitutive COX-2 expression, and PMA but not CD induced COX-2 in these cells. PMA-treated transformed and CYP2E1-expressing cells expressed functional COX-2 as demonstrated by marked inductions in prostaglandin E(2) synthesis. PMA-induced COX-2 expression in both transformed and CYP2E1-expressing cells resulted from an induction in COX-2 mRNA, and was dependent on extracellular signal-regulated kinase, p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase. The differential induction of COX-2 by PMA in transformed and non-transformed cells could not be explained by differences in NF-kappaB or C/EBPalpha activation. PMA did not induce COX-2 transcriptional activity as determined by transient transfections with a luciferase reporter gene driven by the COX-2 promoter. The data demonstrate that cellular transformation and CYP2E1 expression fail to lead to the induction of COX-2 expression in hepatocytes. However, these conditions do render hepatocytes susceptible to COX-2 induction from tumor promoters by post-transcriptional mechanisms.

Three-dimensional dosimetric evaluation of a conventional radiotherapy technique for treatment of nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: The aim of this study is to evaluate and delineate the deficiencies in conventional two-dimensional (2-D) radiotherapy planning of nasopharyngeal carcinoma (NPC) treatment and to explore the means for improvement of the existing treatment technique aiming at enhancing local tumor control and reducing treatment complications. METHODS AND MATERIALS: Ten patients with NPC sparing the skull base and without intracranial extension or cranial nerve(s) palsy were chosen in the present study. Two sets of CT images for Phases I and II of the radiotherapy treatment were taken with patient immobilized in the flexed-head and the extended-head positions, respectively. Based on the CT images and endoscopic findings, the gross tumor volume (GTV) was defined. The clinical target volume (CTV) circumscribing the GTV was defined according to Ho's (Halnan, K.E. (ed.) Treatment of Cancer. London: Chapman and Hall, 1982. pp. 249-268) description of the organs at risk of tumor infiltration. The planning target volume (PTV) was defined by adding a margin to the CTV which catered for geometrical inaccuracies. The field borders and shields were set at standard distances from certain bony landmarks and were drawn on the simulator radiograph. Data on the beams and shield arrangements were then transferred to the planning computer via a digitizer. By applying 3-D volumetric dose calculation using a commercial three-dimensional (3D) treatment planning computer, the dose-volume-histograms (DVHs) of GTV, CTV, PTV and critical normal organs were generated for both phases of Ho's treatment technique. The same patients were re-planned using a modified Ho's technique which used 3-D beams-eye-view (BEV) in placing the shielding blocks and the same set of DVHs were generated and compared with those obtained from Ho's technique. RESULTS: The median volumes of GTV, CTV and PTV covered by the 95% isodose in Ho's phase I treatment were around 60%. The dose coverage was unsatisfactory in the superior and inferior and the posterolateral regions. In phase II treatment, the median volume of GTV, CTV and PTV covered by the 95% isodose were 99, 96 and 72%, respectively. Even though the dose coverage of the PTV in both phases of treatment were unsatisfactory, radiotherapy with the original Ho's technique had consistently produced good local control for NPC. However, there is potential room for enhancing the local control further because after modifying Ho's technique by using 3-D BEV customization of the treatment portals, the median volume of the target covered by the 95% isodose was defined as V(95). The V(95) of the PTV during the Phase II treatment was improved by 13%. The 90% of the volume of temporo-mandibular joints and parotid glands were both irradiated to 53 Gy and 43.6 Gy of the total prescribed dose of 66 Gy, respectively, in phase I and II treatments. With the addition of a hypothalamus-pituitary shield to Ho's technique, 50% of the volume of optic chiasma and temporal lobes received, respectively, 19.3 Gy and 4.5 Gy. However, small volume of the temporal lobes received a maximum dose (D(max)) of 62.8 Gy (95.2% of 66Gy). Most of the brainstem was shielded from the lateral portals but 5% of its volume received a dose ranging from 25.4 to 50.4Gy. The spinal cord (at C1/C2 level) received a D(max) of 40.8 Gy in phase I and of 4.8 Gy in phase II. After modifying Ho's technique by 3-D BEV customization of the treatment portals, the D(max) to the brainstem, the optic chiasma and the temporal lobes could be reduced by 8, 12 and 5%, respectively. CONCLUSIONS: Our study indicated that the dose-coverage of the PTV in Ho's radiotherapy technique for the early T-stage NPC was less than satisfactory in the superior and inferior and the posterolateral regions. However, in view of the excellent historical local tumor control with Ho's technique, we have to postulate that the present definition of CTV (and hence the PTV after adding margins to the CTV) lacks clinical significance and can be improved. It appears that the inclusion of the entire sphenoid sinus floor and both medial and lateral pterygoid muscles in the CTV is not necessary for maximal tumor control in the absence of clinical/radiological evidence of tumor infiltration of these organs. Ho's technique can be improved by using 3-D BEV to customize the treatment portals with multileaf collimators or blocks.

Final report of a randomized trial on altered-fractionated radiotherapy in nasopharyngeal carcinoma prematurely terminated by significant increase in neurologic complications.

PURPOSE: The aim of the present study was to compare the survival, local control and complications of conventional/accelerated-hyperfractionated radiotherapy and conventional radiotherapy in nonmetastatic nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: From February 1993 to October 1995, 159 patients with newly diagnosed nonmetastatic (M0) NPC with N0 or 4 cm or less N1 disease (Ho's N-stage classification, 1978) were randomized to receive either conventional radiotherapy (Arm I, n = 82) or conventional/accelerated-hyperfractionated radiotherapy (Arm II, n = 77). Stratification was according to the T stage. The biologic effective dose (10 Grays) to the primary and the upper cervical lymphatics were 75.0 and 73.1 for Arm I and 84.4 and 77.2 for Arm II, respectively. RESULTS: With comparable distribution among the T stages between the two arms, the free from local failure rate at 5 years after radiotherapy was not significantly different between the two arms (85.3%; 95% confidence interval, 77.2-93.4% for Arm I; and 88.9%; 95% confidence interval, 81.7-96.2% for Arm II). The two arms were also comparable in overall survival, relapse-free survival, and rates of distant metastasis and regional relapse. Conventional/accelerated-hyperfractionated radiotherapy was associated with significantly increased radiation-induced damage to the central nervous system (including temporal lobe, cranial nerves, optic nerve/chiasma, and brainstem/spinal cord) in Arm II. Although insignificant, radiation-induced cranial nerve(s) palsy (typically involving VIII-XII), trismus, neck soft tissue fibrosis, and hypopituiturism and hypothyroidism occurred more often in Arm II. In addition, the complications occurred at significantly shorter intervals after radiotherapy in Arm II. CONCLUSION: Accelerated hyperfractionation when used in conjunction with a two-dimensional radiotherapy planning technique, in this case the Ho's technique, resulted in increased radiation damage to the central nervous system without significant improvement in efficacy.

The roles of multileaf collimators and micro-multileaf collimators in conformal and conventional nasopharyngeal carcinoma radiotherapy treatments.

The purpose of this work is to study the efficacy and limitations of using standard multileaf collimators (MLCs) and micro-multileaf collimators (mMLCs) in the treatment of nasopharyngeal carcinoma (NPC) by conventional and conformal radiotherapy techniques. The penumbra characteristics of MLC, mMLC, and customized block collimated beams are measured with respect to leaf edge angle, beam energy, treatment depth, and field size and compared with those generated by a commercial three-dimensional planning computer system. Upon verification of the planning system, it is used to evaluate the treatment plans generated with these beam shapers for conventional and conformal NPC treatments. The effective penumbra of a MLC beam is strongly influenced by its edge angle, leaf width, and treatment depth. The suitability of standard MLCs in conventional NPC treatments is determined mainly by the edge angle to be used. For conformal NPC treatments involving six or more fields, dose volume histograms comparable to those of customized beam blocks are obtained with a standard MLC. The mMLC does not have the same restrictions as those on standard MLC but is limited to phase II treatment by its small usable field size. Both standard MLCs and mMLCs can be used to replace customized divergent beam blocks in both conventional and conformal NPC treatments. However, a MLC, due to its larger effective penumbra, may be unsuitable for use in cases when the tumor volumes extend very close to the critical normal structures. A mMLC, on the other hand, is limited by its small maximum field size and can only be used for collimating the facial portals in the second phase treatment.

Increased incidence of tongue cancer after primary radiotherapy for nasopharyngeal carcinoma--the possibility of radiation carcinogenesis.

The aim of this study was to define the risk of tongue and other aerodigestive tract cancers developing after primary radiation therapy for nasopharyngeal carcinoma (NPC). A cohort of 903 patients with non-disseminated NPC given radical radiotherapy between 1984 and 1989 was studied for the incidence of tongue cancer and other malignancies during follow-up. A contemporary cohort of 87 patients with tongue cancer, without a history of NPC, was studied for demographic data, cigarette smoking and alcohol consumption habits. These were then compared with all the NPC patients and with the NPC patients who later developed tongue cancers. There was a significantly increased number of tongue cancers following radiotherapy for NPC. The risk of developing tongue cancer after radiotherapy for NPC was 0.13% per patient per year. There was no increase in the number of other malignancies. The association between NPC and tongue cancer was that of a non-random temporal sequence with tongue cancers following NPC but not in the reverse order. The demographic data and smoking and alcohol consumption history of the 7 NPC patients who subsequently developed tongue cancer were significantly different from the de novo tongue cancer patient population. The absence of common aetiological factors between NPC and tongue cancer and the non-random sequence of tongue cancers occurring after NPC suggests that these seven tongue cancers could be radiation induced. The estimated radiation dose received by the part of the tongue developing cancer was substantial and significantly higher than the dose to the cancer-free tongue. An increase of tongue cancers after radiotherapy for NPC is reported and arguments are made in support of the hypothesis that these were radiation-induced malignancies. We suggest a decrease in the volume of tongue included within the planning target volume of NPC in the absence of oropharyngeal and/or parapharyngeal infiltration. Awareness of the association should make early diagnosis of this likely radiation-induced cancer possible.

Functional magnetic resonance (fMR) imaging of a rat brain tumor model: implications for evaluation of tumor microvasculature and therapeutic response.

Functional MR (fMR) imaging techniques based on blood oxygenation level dependent (BOLD) effects were developed and applied to a rat brain tumor model to evaluate the potential utility of the method for characterizing tumor growth and regression following treatment. Rats bearing 9L brain tumors in situ were imaged during inhalation of room air and after administration of 100% oxygen + acetazolamide (ACZ) injected 15 mg/kg intravenously. Pixel-to-pixel fMR maps of normalized signal intensity change from baseline values were calculated from T2 weighted spin echo (SE) images acquired pre- and post- oxygen + ACZ administration. Resultant fMR maps were then compared to gross histological sections obtained from corresponding anatomical regions. Regions containing viable tumor with increased cellular density and localized foci of necrotic tumor cells consistent with hypoxia were visualized in the fMR images as regions with decreased signal intensities, indicating diminished oxyhemoglobin concentration and blood flow as compared to normal brain. Histological regions having peritumor edema, caused by increased permeability of tumor vasculature, were visualized in the fMR images as areas with markedly increased signal intensities. These results suggest that fMR imaging techniques could be further developed for use as a non-invasive tool to assess changes in tumor oxygenation/hemodynamics, and to evaluate the pharmacologic effect of anti-neoplastic drugs.

Liposome-mediated therapy of intracranial brain tumors in a rat model.

PURPOSE: Malignant brain tumors represent a serious therapeutic challenge, and survival often is low. We investigated the delivery of doxorubicin (DXR) to rat brain tumors in situ via liposomes, to test the hypothesis that intact liposomes undergo deposition in intracranial tumor through a compromised blood-tumor vasculature. Both therapeutic effect and intra-tumor drug carrier distribution were evaluated to identify variables in carrier-mediated delivery having impact on therapy. METHODS: The rat 9L gliosarcoma tumor was implanted orthotopically in Fischer 344 rats in the caudate-putamen region. The tumor-bearing rats were treated with DXR, either free or encapsulated in long-circulating, sterically-stabilized liposomes. Anti-tumor efficacy was assessed by survival time. In parallel, liposomes labeled with a fluorescent phospholipid analog were injected into tumor-bearing rats. At predetermined intervals, the brains were perfused with fixative, sectioned, and imaged with laser scanning confocal microscope (LSCM) to investigate the integrity of the tumor vascular bed and the intratumor deposition of liposomes. RESULTS: Free DXR given in 3 weekly iv injections was ineffective in increasing the life span of tumor-bearing rats at cumulative doses < or = 17 mg/kg, and at the highest dose (17 mg/kg) decreased survival slightly, compared to saline-treated controls. In contrast, DXR encapsulated in long-circulating liposomes mediated significant increases in life span at 17 mg/kg. Rats showed a 29% percent increase in median survival, respectively, compared to saline-control animals. The delay of treatment after tumor implantation was a major determinant of therapeutic effect. Fluorescent liposomes were deposited preferentially in tumor rather than normal brain, and were distributed non-uniformly, in close proximity to tumor blood vessels. CONCLUSIONS: Liposomes can be used to enhance delivery of drugs to brain tumors and increase therapeutic effect. The therapeutic effect may arise from release of drug from liposomes extravasated in discrete regions of the tumor vasculature and the extravascular space.

[Cell cycle and apoptosis].

The progression of cell cycle in embryonic cells from oceanic bionts to mammalians is initiated, promoted and terminated under the regulation of cell cycle gene products, named cyclins, and a p34 (cdc 2). Besides, oncogene (proto-oncogene) products such as p53 and pRB also directly regulate the progression of cell cycle. However, the p34 (cdc 2) which promotes the mitotic cell division also initiates the apoptosis of certain cells. Therefore, mutations of genes that regulate the normal progression of cell cycle would cause cells in the cell cycle undergoing either apoptosis or uncontrollable proliferation.

Prevention of spontaneous tumours in female rats by fadrozole hydrochloride, an aromatase inhibitor.

Mammary tumours are oestrogen dependent in female Sprague-Dawley rats and in a significant proportion of women, so pharmacological treatment to inhibit oestrogen production is a valuable therapeutic measure to prevent or slow the progression of disease. Here we show that a non-steroidal aromatase inhibitor, which competitively inhibits the conversion of androstenedione to oestrone, prevents the development of both benign and malignant spontaneous mammary neoplasms in female Sprague-Dawley ats. It also slows the spontaneous development of pituitary pars distalis adenomas in female rats, and reduces the incidence of spontaneous hepatocellular tumours in male and female rats.

[Anti-retinoblastoma reaction developed in vivo through immunization of retinal ganglion neuronotrophic factor].

Isolated retinal ganglion neuronotrophic factor (RGNTF) was used as an antigen to immunize Group A Balb/c mice intraperitoneally prior to the inoculation into the anterior chamber of eye with human retinoblastomal cell line Y-79 (Rb). In Group B mice, Rb cells were inoculated into the eyes before RGNTF immunization. In Group C mice, empty gel without RGNTF was used in immunization 10 days after the Rb inoculation, to serve as a control. The results revealed that the inhibitory rate of Rb tumor development in Group A was 65% (13/20); in Group B only 10% (2/20); and in Group C 0% (0/20). The T-test for difference in the inhibitory rate between Group A and B was statistically significant (T > 2.58; P < 0.01). Sera were collected from these mice and their content of the anti-RGNTF antibody was quantified by ELISA method. The results showed that the anti-RGNTF antibody titer in Group A antisera at 1:600 dilution was measured with an average optical density of 0.156 +/- 0.015; that in Group B 0.103 +/- 0.016; and that in Group C only 0.048 +/- 0.018. Those of controls for normal mouse serum and culture medium were 0.050 +/- 0.008 and 0.043 +/- 0.014, respectively. The t test for difference in the antibody titer measurements between Group A and B was statistically significant (t > t0.05; p < 0.05). Therefore, the above results indicated that active immunization of RGNTF can enhance the specific immunity against the development of retinoblastomal tumor in Balb/c mice, which may have clinical significance in treating human retinoblastoma.

Boronated metalloporphyrins: a novel approach to the diagnosis and treatment of cancer using contrast-enhanced MR imaging and neutron capture therapy.

Porphyrins are a unique class of metal chelating agents that have shown specific affinity for neoplasms. The water-soluble free-base derivative, tetrakiscarborane carboxylate ester of 2,4-(alpha,beta-dihydroxyethyl) deuteroporphyrin IX (BOPP), an agent designed for neutron capture therapy, has previously demonstrated selective localization and retention in a C6 murine glioma. In the present work, the authors demonstrate that the manganese chelate of BOPP also selectively localizes in a rat 9L gliosarcoma and preferentially enhances the tumor-normal brain contrast of T1-weighted images for at least 92 hours. The data indicate a maximal enhancement of contrast between tumor and normal brain at 24 hours after injection, compared with 5 minutes for manganese (III) tetraphenylporphine sulfonate (TPPS4). The results also indicate that Mn-BOPP may have a slower uptake in the 9L glioma than Mn-TPPS4 but a longer retention in the tumor. Mn-BOPP is unique in that it represents, to the authors' knowledge, the first example of a single agent that can enhance contrast between tumor and normal tissue and be potentially effective as an agent for boron neutron capture therapy.