[Large clinical registries for acute aortic dissection: interpretation and comparison of latest results].

Despite the improvements in the diagnosis and management during the past six decades, acute aortic dissection (AAD) remains a life-threatening condition associated with significant morbidity and mortality rates. Due to the relatively rare occurrence of AAD, several clinical registries have been established to gain insights into this lethal disease in a large number of patients, such as the International Registry of Acute Aortic Dissection (IRAD), the German Registry for Acute Aortic Dissection Type A (GERAADA), and the Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database Aortic Section. This review aims to interpret and compare the latest results of the IRAD, STS and GERAADA database. It focuses on several controversial and key issues in the diagnosis and management of acute aortic dissection in hope of providing some insights and references for cardiovascular professionals engaged in the care of this deadly disease.

Application of Specific Fragment Length Polymorphism of Algae rDNA in Identification of Drowning Cases.

OBJECTIVES: To identify the drop-off location of victims in drowning cases, and confirm whether it is a fatal drowning or the victim is thrown into the water after death by detecting part of 5.8S sequence and second internal transcribed spacer （ITS2） （5.8S+ITS2） of diatom rDNA in water and organs. METHODS: Two cases identified by diatom examination, which received by Nanjing Municipal Public Security Bureau Forensic Center, were taken as the research objects. The difference of the population structure of algae in water and human tissue was analysed by length polymorphism of 5.8S+ITS2 marker. RESULTS: In case 1, similar species of diatom were detected from victim's lung and liver tissues and the water sample. Two kinds of DNA fragments with length of 330 bp and 376 bp were detected from victim's lung tissue and the water sample using 5.8S+ITS2 marker, which could confirm the victim was drowning before death. In case 2, there was no diatom found in victim's lung and liver tissues. Only one kind of DNA fragment with length of 331 bp and low relative fluorescence unit （RFU） was obtained from victim's lung tissue using 5.8S+ITS2 marker, thus the victim was thrown into the water after death. CONCLUSIONS: The experimental results of the two cases in present study are consistent with the actual facts and the result of the diatom microscopic examination. The difference of population structure of specific microorganism in water and human tissue can be detected by 5.8S+ITS2 marker, which can help to identify the drop-off location of victims in drowning cases, and confirm whether it is a fatal drowning or the victim is thrown into the water after death.

[Cytotoxic effects of γδT cells on bladder cancer cells and expression of MICA/B in bladder cancer].

OBJECTIVE: To explore the role of γδT cells against bladder cancer and to detect the expression of stress proteins MICA/B recognized by γδT cells in bladder cancer. METHODS: γδT cells from peripheral blood drawn from 6 bladder cancer patients with pamidronate stimulating were expanded. Flow cytometry was used to detect the purity and expansion folds of γδT cells, and the expression of CD107a on γδT cells after PMA/ionomycin stimulated. The cytotoxicity assay was carried out to test the cytotoxicity of γδT cells against human bladder cancer cell lines. The expression of MICA/B on bladder cancer cell lines and in bladder cancer tissues were detected through flow cytometry and immunohistochemistry respectively. RESULTS: γδT cells from peripheral blood drawn from 6 bladder cancer patients were successfully expanded. The purity was 75%-94% and the expansion folds were 109-371 times. After being stimulated by PMA/ionomycin, the proportion of CD107a+ γδT cells increased significantly, reaching 40%-82%. γδT cells from the 6 bladder cancer patients showed obvious cytotoxic effects on 3 human bladder cancer cell lines which was enhanced as the effector: the target ratio increased. MICA/B were detected both in 3 bladder cancer cell lines and in 26 bladder cancer tissues. The staining score of MICA/B in invasive bladder cancer was slightly higher than that in non-invasive bladder cancer, and in advanced bladder cancer was higher than that in low grade bladder cancer, but the statistical analysis showed that the staining score of MICA/B was no significant correlation between the tissue and the tumor stages and grades. CONCLUSION: γδT cells from the peripheral blood of the bladder cancer patients could be successfully expanded in vitro, and showed significant anti-bladder cancer effect. MICA/B were detected both in bladder cancer cell lines and in bladder cancer tissues. The statistical analysis showed that there was no significant correlation between the staining scores of MICA/B in the tissue and the tumor stages and grades.

[Genetic Polymorphisms of 24 Y-STR Loci in Nanjing Han Population].

OBJECTIVES: To investigate the genetic polymorphism of DYS391 and other 23 Y-STR loci and to explore its application value in forensic science. METHODS: Y-STRs loci of 580 unrelated Han males in Nanjing were amplified using AGCU Y-PLUS PCR （24） kit. The genetic parameters of 24 Y-STR loci such as gene frequency were calculated by software, and compared with the data of Hubei, Liao- ning, Guangdong, Beijing and Chengdu Han population. RESULTS: Total 580 haplotypes were detected among 24 Y-STR loci in 580 unrelated Han males in Nanjing. The genetic diversity （GD） of each locus was from 0.294 6 to 0.939 8, and the haplotypes diversity （HD） was 0.983 7. There was a significant difference between the GD of 6 areas. CONCLUSIONS: The 24 Y-STR loci such as DYS391 in Nanjing Han population have an application value in forensic science. They can also be used for cases testing and pedigree investigation.

Combination of 1alpha,25-dihydroxyvitamin D(3) with dexamethasone enhances cell cycle arrest and apoptosis: role of nuclear receptor cross-talk and Erk/Akt signaling.

Previously we have shown that dexamethasone (DEX) enhances the antitumor activity and ligand binding of the active form of vitamin D, 1alpha,25-dihydroxyvitamin D(3) (1,25-D(3)), in the murine squamous cell carcinoma model SCC VII/SF. DEX also reduces the hypercalcemia toxicity of 1,25-D(3) treatment. However, the mechanism of the enhanced antitumor activity has not been defined. Here, we demonstrate that both cell cycle arrest and apoptosis were enhanced by DEX, effects that were inhibited by RU486. We also demonstrate that vitamin D receptor (VDR) protein levels were increased by the combination of 1,25-D(3) and DEX above the level observed with 1,25-D(3) treatment alone, whereas protein levels of the heterodimeric partner of VDR, retinoid X receptor, were lower for the combination than for 1,25-D(3) alone. Glucocorticoid receptor protein levels and ligand binding were increased by 1,25-D(3) but not by the combination. Treatment with the combination of 1,25-D(3) and DEX did not result in greater activation of a vitamin D response element-reporter than 1,25-D(3) alone or of a glucocorticoid response element-reporter than DEX alone. Nevertheless, the levels of phospho-Erk1/2 and phospho-Akt, signaling molecules that are modulated in 1,25-D(3)-treated squamous cell carcinoma cells, were reduced by the combination of 1,25-D(3) and DEX more than by either agent alone. These trends were also observed in vivo. Our results suggest the involvement of the Erk and Akt signaling pathways in the antiproliferative effects of the combination of 1,25-D(3) and DEX and that phospho-Erk1/2 and phospho-Akt may be useful markers of response to this combination.

Calcitriol (1,25-dihydroxycholecalciferol) enhances paclitaxel antitumor activity in vitro and in vivo and accelerates paclitaxel-induced apoptosis.

We demonstrated that calcitriol has antiproliferative activity in squamous cell carcinoma and prostatic adenocarcinoma and enhances the antitumor activity of platinum-based agents. In this study, we examined whether calcitriol also increases paclitaxel cytotoxicity. The effect of treatment on growth of the murine squamous cell carcinoma (SCCVII/SF) and human prostatic adenocarcinoma (PC-3) was determined by clonogenic assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and monitoring tumor growth. Treatment of SCC or PC-3 cells in vitro with calcitriol prior to paclitaxel significantly reduced clonogenic survival compared with either agent alone. Median-dose effect analysis revealed that calcitriol and paclitaxel interact synergistically. Treatment of SCC or PC-3 tumor-bearing mice with calcitriol prior to paclitaxel resulted in substantially greater growth inhibition than was achieved with either agent alone, supporting the combined use of calcitriol and paclitaxel in the treatment of solid tumors. To explore the molecular basis for the enhanced antitumor activity of this combination, the effect of treatment on p21(Waf-1) (p21), Bcl-2, and poly(ADP-ribose) polymerase expression was evaluated in PC-3. A 72-h pretreatment with calcitriol reduced p21 expression and increased paclitaxel cytotoxicity (measured after 24 h) without evidence of apoptosis [poly(ADP-ribose) polymerase cleavage]. After 48 h, paclitaxel induced apoptosis, the extent of which was increased similarly by pretreatment or concurrent treatment with calcitriol. We therefore propose a model for calcitriol enhancement of paclitaxel cytotoxicity in which the "early" (24 h) effects are schedule dependent and not attributed to enhancement of paclitaxel-induced apoptosis. In contrast, the "delayed" (48-h) enhancement of paclitaxel activity by calcitriol is schedule independent and associated with acceleration of apoptosis.

Combined effects of estrogen and progesterone on the anterior cruciate ligament.

Previous studies from the authors' laboratory have established the presence of estrogen and progesterone receptors in the human anterior cruciate ligament. The purpose of the current study was to investigate the combined effects of 1beta-estradiol and progesterone on cell proliferation and procollagen synthesis of the human anterior cruciate ligament fibroblasts. Fibroblast proliferation and procollagen synthesis in response to logarithmic concentrations of 17beta-estradiol (0.0025 ng/mL, 0.025 ng/mL, 0.25 ng/mL) and progesterone (1 ng/mL, 10 ng/mL, 100 ng/mL) were assessed with the measurement of 3H-thymidine incorporation and Types I and III procollagen specific equilibrium radioimmunoassays. On Days 1, 3, and 5 there was a dose dependent decrease in the fibroblast proliferation and procollagen Type I synthesis with increasing estradiol concentrations. The effect was attenuated with increasing progesterone concentrations. Controlling for estrogen levels, a dose dependent increase in fibroblast proliferation and procollagen Type I synthesis was observed with increasing progesterone concentrations. The effect was more pronounced at lower concentrations of estrogen, suggesting estrogen levels were the dominant factor. The effects of estrogen and progesterone became less apparent by Day 7. No significant differences in Type III procollagen synthesis were seen with varying estradiol concentrations at any of the designated times. These early physiologic changes in fibroblast proliferation and Type I procollagen synthesis may provide a biologic explanation for the increased anterior cruciate ligament injury rate observed in female athletes, suggesting the acute cyclical hormonal variations in the female athlete during menstruation predispose her to ligamentous injury.

Metal debris from titanium spinal implants.

STUDY DESIGN: A prospective study of tissue surrounding spinal instrumentation was performed using histologic and chemical analysis. OBJECTIVES: To identify and quantify the amount of metal debris generated by titanium pedicle screw instrumentation and to evaluate the histologic response in the spinal tissues. SUMMARY OF BACKGROUND DATA: Microscopic metal particles from the soft tissue surrounding joint arthroplasties have been shown to activate a macrophage response that leads to bone resorption and increased inflammation. The use of titanium spinal implants for spine surgery projects the possibility of generating wear debris in the spine. METHODS: Nine patients with titanium instrumentation from a prior lumbar decompression and fusion procedure who were undergoing reoperation were entered into this study. Tissue samples were collected from areas near the pedicle screw-rod junction, the scar tissue overlying the dura, and the pedicle screw holes. Metal levels for titanium were determined by electrothermal atomic absorption spectroscopy, and histologic analysis was performed by light and electron microscopy. RESULTS: Tissue concentrations of titanium were highest in patients with a pseudarthrosis (30.36 micrograms/g of dry tissue). Patients with a solid fusion had low concentrations of titanium (0.586 microgram/g of dry tissue). Standard light microscopy identified metal particles in the soft tissues. Transmission electron microscopy demonstrated macrophages with numerous secondary lysosomes containing electron-dense bodies and collagenous stroma with electron-dense rod-like profiles consistent with metal debris. CONCLUSIONS: Wear debris is generated by the use of titanium spinal instrumentation in patients with a pseudarthrosis. These particles activate a macrophage cellular response in the spinal tissues similar to that seen in surrounding joint prostheses. Patients with a solid spinal fusion have negligible levels of particulate matter.

MR imaging of cervical spine motion with HASTE.

The HASTE (half-Fourier acquisition single-shot turbo spin-echo) technique delivers images with T2-weighting in about half a second and could be ideal for fast dynamic studies when T2-weighting is needed. We evaluated cardiac-triggered HASTE to study cervical spine flexion/extension. The cervical spines of ten asymptomatic volunteers were studied during flexion/extension motion on a 1.5 Tesla imager using a cardiac triggered version of the HASTE technique. Midline sagittal images were acquired every 2 to 3 s during neck flexion and extension. Image quality was compared to traditional T2-weighted Turbo spin-echo. The study duration per flexion/ extension was typically less than 20 seconds and well tolerated. The cardiac-gated T2-weighted HASTE images compared favorably to the traditional T2-weighted TSE images in quality and overall anatomic detail. Range of motion averaged: flexion 30 degrees (range 8 degrees -48 degrees) and extension 23 degrees (range 0 degrees -57 degrees ). Greatest motion occurred in the lower cervical spine (C4-C7). At the intervertebral discs the canal diameter, anterior and posterior CSF spaces were widest in neutral position and decreased with flexion and extension. Therefore, Cardiac-gated T2 HASTE sequences provide diagnostic and time-efficient dynamic MR images of cervical spine motion.

Effect of estrogen on cellular metabolism of the human anterior cruciate ligament.

Previous studies from this laboratory have established the presence of estrogen receptors in the human anterior cruciate ligament. The purpose of this study was to investigate the effects of 17 beta-estradiol on cell proliferation and procollagen levels, as an indicator of collagen synthesis, in the human anterior cruciate ligament fibroblasts. Fibroblast proliferation and procollagen synthesis in response to near log concentrations of 17 beta-estradiol (at 0.0029 ng/mL, 0.025 ng/mL, 0.25 ng/mL, 2.5 ng/mL, and 25 ng/mL) were assessed with the measurement of 3H-thymidine incorporation and Types 1 and 3 procollagen specific equilibrium radioimmunoassays. On Days 1 and 3, there was a dose dependent decrease in the proliferation of anterior cruciate ligament fibroblasts with increasing estradiol concentrations. This dose dependent effect of decreased fibroblast proliferation with increasing estradiol concentrations became less apparent at 7, 10, and 14 days. On Days 1 and 3, procollagen synthesis decreased in a dose dependent manner with increasing estradiol concentrations. On Days 7, 10, and 14, this dose dependent effect was attenuated. No significant differences in Type 3 procollagen synthesis by anterior cruciate ligament fibroblasts were observed with varying estradiol concentrations at any of the designated points. These early physiologic changes in fibroblast proliferation and Type I procollagen synthesis may provide a biologic explanation for the increased anterior cruciate ligament injury rate observed in female athletes, suggesting that it is the acute cyclic variations in the female athlete who is menstruating that predisposes her to ligamentous injury.

Cysts and other masses about the knee: identifying and treating common and rare lesions.

Masses about the knee are most commonly benign cysts. The diagnosis can often be made with a history and physical exam, but radiographs and MRI are sometimes required, and histologic evaluation is occasionally necessary. Popliteal (Baker's) cysts are often indicative of arthritis; treatment for the underlying pathology may reduce swelling and permit resorption. Meniscal cysts indicate an underlying tear; treatment is resection and cyst excision. Symptomatic ganglion cysts generally require surgical excision. Treatment for bursitis is conservative. The less-common synovial chondromatosis, pigmented villonodular synovitis, synovial sarcoma, and lesions of the proximal tibiofibular joint generally require referral and surgery.

A comparison of magnetic resonance and computed tomographic image quality after the implantation of tantalum and titanium spinal instrumentation.

STUDY DESIGN: Tantalum- and titanium-based lumbar interbody fusion devices were implanted into two fresh human cadavers, and magnetic resonance and computed tomographic imaging were performed to evaluate adjacent spinal structures and the amount of metallic artifact. OBJECTIVE: The objective of this study was to prospectively compare the preliminary results of magnetic resonance imaging and computed tomography scanning image quality after the implantation of both titanium and tantalum spinal implants. SUMMARY OF BACKGROUND DATA: The availability of tantalum and titanium spinal implants brings theoretical magnetic resonance imaging compatibility along with several other desirable characteristics. The magnetic resonance imaging and computed tomographic imaging of tantalum spinal instrumentation has never been studied previously or compared with titanium instrumentation. METHODS: Titanium and tantalum spinal implants produced for anterior spinal fusion were each placed at two levels in the lumbar spine of two fresh cadaver specimens. Sequential spin echo T1-weighted and T2-weighted magnetic resonance imaging studies and computed tomographic scans were obtained. The resulting images were then graded to describe and compare the behavior of tantalum metal in magnetic resonance imaging and computed tomographic studies. RESULTS: Good T1 and T2 images were obtained that allowed visualization of the neural structures with minimal artifact. The optimal T1 images for tantalum metal were similar in quality to the optimal T1 parameters for titanium metal. T2 images for both tantalum and titanium metal were obtained with similar results for both metals. Gradient echo magnetic resonance imaging scans of both were poorly imaged with a large amount of artifact. Computed tomographic studies of tantalum implants produced a large amount of metal artifact when compared with computed tomographic studies of titanium implants. CONCLUSIONS: High-quality magnetic resonance imaging studies can be obtained after the implantation of both titanium and tantalum spinal instrumentation. Both of the metals produce similar images on magnetic resonance imaging studies with comparable amounts of metallic artifact. High-quality computed tomographic scans of titanium implants can be obtained with minimal distortion secondary to artifact. However, computed tomographic scanning is not the imaging modality of choice for the tantalum spinal implants because of the large amounts of artifact.

Enhancement of 1,25-dihydroxyvitamin D3-mediated antitumor activity with dexamethasone.

BACKGROUND: The active metabolite of vitamin D, i.e., 1,25-dihydroxycholecalciferol (1,25-D3), inhibits the growth of murine SCCVII/SF squamous cell carcinoma cells, both in vitro and in vivo. However, in vivo use of 1,25-D3 is hampered as a result of hypercalcemia (i.e., elevated levels of calcium in the blood). Glucocorticoids, such as dexamethasone, affect calcium absorption and modulate vitamin D receptor binding and have been used to treat hypercalcemia. In this study, we examined the effect of dexamethasone on tumor growth inhibition by 1,25-D3. METHODS: The effects of 1,25-D3 and dexamethasone, alone and in combination, on the growth of SCCVII/SF cells in in vitro culture or in vivo in female C3H/HeJ mice were determined by clonogenic tumor cell assay and/or by actual changes in tumor volume. Vitamin D receptor-ligand-binding activities in whole-cell extracts from cells (in culture), tumors, and normal tissues were assayed by single-point saturation analysis and equilibrium binding. RESULTS: Treatment of cultured SCCVII/SF cells with 500 nM dexamethasone for 24 hours before addition of 1,25-D3 reduced their survival. The growth of SCCVII/SF tumors was inhibited in mice treated simultaneously with dexamethasone and 1,25-D3 (as compared with no treatment or single-agent treatment); hypercalcemia was also reduced. Total vitamin D receptor content in SCCVII/SF cells was increased after treatment with dexamethasone. Treatment of tumor-bearing animals with dexamethasone (9 microg/day) for 7 days led to increased vitamin D receptor-ligand-binding activities in whole-cell extracts from tumor or kidneys and decreased activity in intestinal mucosa. CONCLUSIONS: Dexamethasone may enhance the antitumor effect of 1,25-D3 by increasing vitamin D receptor-ligand-binding activity.

Fractures of the fifth metatarsal: careful identification for optimal treatment.

Fractures of the fifth metatarsal are common in active people. Proximal metaphyseal and distal fractures are usually amenable to conservative treatment, but some proximal fractures, such as Jones, stress, and acute-on-chronic fractures, are often associated with nonunion or delayed union. Such fractures are often best treated by early operative intervention. Correct identification of fifth metatarsal fractures is important because prompt surgical treatment when indicated can shorten recovery and allow a quick return to sports activity. Other causes of lateral foot pain, including accessory ossicles, neuromas, osteoporosis, herniated disks, and osteoid osteoma, should be considered when suspected fractures fail to show up on radiographs.

Potentiation of cisplatin antitumor activity using a vitamin D analogue in a murine squamous cell carcinoma model system.

In a murine squamous cell carcinoma (SCC) model, we have demonstrated that both 1,25-dihydroxycholecalciferol (1,25-D3) and the analogue 1,25-dihydroxy-16-ene-23-yne-cholecalciferol (Ro23-7553) have significant in vitro and in vivo antitumor activity. We have examined here the cell cycle effect of 1,25-D3 and Ro23-7553 on SCCVII/SF tumor cells by quantitating nuclear DNA using a detergent-trypsin method via flow cytometry analysis. Both 1,25-D3 and Ro23-7553 resulted in a significant increase of cells in G0-G1, with an accompanying decrease of cells in S phase. The ability to arrest cells in G0-G1 has been exploited by combining Ro23-7553 with the cytotoxic agent cisplatin (cis-diamminodichloroplatinum; cDDP). Using the in vitro clonogenic assay, pretreatment with Ro23-7553 for 24-48 h significantly enhanced cDDP-mediated tumor cell kill as compared to concurrent treatment with Ro23-7553 and cDDP or cDDP alone. To examine the effect of Ro23-7553 and cDDP in vivo, C3H/HeJ mice with 9-14-day SCC tumors were treated either for 3 days with varying i.p. doses of Ro23-7553 or for 7 days continuously through the use of Alzet pumps, and on the last day of Ro23-7553 treatment, cDDP (1-6 mg/kg) was administered. Using the in vivo excision tumor cell clonogenic assay, in which tumors were removed from animals 24 h after cDDP treatment and plated in a clonogenic assay, pretreatment with Ro23-7553 markedly enhanced cDDP-mediated clonogenic tumor cell kill, even at low doses of cDDP as compared to cDDP treatment alone. Similarly, a significant decrease in fractional tumor volume and increase in tumor regrowth delay was observed when animals were pretreated before cDDP with Ro23-7553 as compared to either agent alone. These results demonstrate a significant enhanced antitumor effect with Ro23-7553 pretreatment before cDDP both in vitro and in vivo and suggest that Ro23-7553 may potentiate cDDP cytotoxicity through effects on cell cycle progression.

Interleukin-1alpha synergistic in vivo enhancement of cyclophosphamide- and carboplatin-mediated antitumor activity.

Interleukin-1alpha (IL-1alpha) has potent acute antitumor activity in vivo and can enhance the efficacy of chemotherapeutic drug-mediated antitumor responses. Studies were undertaken to examine the ability of IL-1alpha to enhance the activity of cyclophosphamide (CTX) administered in combination with carboplatin. To determine the in vivo effect of IL-1alpha, CTX and/or carboplatin, mice bearing 14-day RIF-1 tumors were treated on day 0 with a concurrent i.p. injection of varying doses of CTX (5-150 mg/kg), human IL-1alpha (125 microg/kg), and carboplatin (50 mg/kg) and examined 24 h later for the surviving fraction by the in vivo excision clonogenic-tumor-cell assay. Even at the lowest doses of CTX, IL-1alpha significantly enhanced the clonogenic tumor cell kill when compared to treatment with CTX alone. When carboplatin was added to the treatment schema, significantly greater clonogenic cell killing and tumor regrowth delay were observed as compared to any agent alone or a two-drug combination (CTX/IL-1alpha or CTX/carboplatin). Significant enhancement was observed even at low doses of CTX in combination with carboplatin and IL-1alpha. The interaction between the three-drug combination was found to be synergistic as determined by the median dose effect with significant dose reduction apparent for IL-1alpha and CTX when used in this combination. These results demonstrate that IL-1alpha can synergistically enhance the antitumor efficacy of CTX and the combination of CTX and carboplatin.

MR parameters for imaging titanium spinal instrumentation.

The presence of stainless steel implants along a spinal column causes extreme distortion of data collected by magnetic resonance (MR) imaging. The recent availability of titanium alloy spinal instrumentation systems suggests that MR imaging evaluation of the instrumented spine may now be feasible. The objective of this study was to perform MR imaging examinations on spines implanted with titanium alloy instrumentation and to determine the parameters that yield the highest quality images with the least amount of artifact. A titanium pedicle screw construct was implanted into the lumbar spine of two fresh human cadaveric specimens. Sequential spin echo MR scans were performed using various TE and TR ratios on each intact specimen. The resultant images were quantitatively graded for clarity of adjacent soft tissue and osseous structures. Excellent T1- and T2-weighted images with well-defined neural structures were obtained with minimal artifact. The optimal T1-weighted image was obtained with TE = 16 and TR = 500-600, whereas the optimal T2-weighted image was obtained with TE = 60 and TR = 1,300-1,600. By using appropriate settings, high-quality MR scans in both the T1- and T2-weighted modes can be obtained with minimal metal artifact.

Antitumor activity of interleukin-1 alpha and cisplatin in a murine model system.

BACKGROUND: Interleukin-1 alpha (IL-1 alpha) has potent antitumor activity either alone or combined with alkylating agents such as cisplatin and mitomycin C or porfiromycin. Cisplatin is an effective chemotherapeutic agent in the treatment of advanced squamous cell carcinoma of the head and neck (SCCHN). In the murine SCCVII/SF squamous cell carcinoma tumor model, IL-1 alpha induced acute hemorrhagic necrosis and increased clonogenic cell kill. OBJECTIVE: To determine the efficacy of cisplatin and IL-1 alpha, singly and in combination, in the treatment of SCCHN. METHODS: Syngeneic C3H/HeN mice were treated with single-dose, concurrent, intraperitoneal injections of cisplatin and interleukin-1 alpha 14 days after subcutaneous tumor implantation and were monitored for delayed tumor regrowth. RESULTS: Cisplatin alone, but not IL-1 alpha, induced significant delayed tumor regrowth when compared with control. The combination of IL-1 alpha and cisplatin was even more effective in delaying tumor regrowth than cisplatin alone. Fractional tumor volume was significantly reduced in animals treated with the combination of cisplatin and IL-1 alpha compared with those treated with IL-1 alpha alone. CONCLUSIONS: Results of interleukin-1 alpha and cisplatin dose-response experiments reveal that the combination of low-dose cisplatin and interleukin-1 alpha is more effective than high-dose cisplatin alone. Our data suggest that cisplatin and IL-1 alpha may be efficacious in the treatment of SCCHN.

Potentiation by interleukin 1 alpha of cisplatin and carboplatin antitumor activity: schedule-dependent and pharmacokinetic effects in the RIF-1 tumor model.

We have previously demonstrated that the cytokine interleukin 1 alpha (IL-1 alpha) significantly potentiates the antitumor activity of a variety of chemotherapeutic agents, including cisplatin (cDDP). In studies described here, we examined the potential of combining IL-1 alpha and the platinum analogue carboplatin (CBDCA) and compared the schedule-dependent and pharmacokinetic effects for IL-1 alpha combinations with cDDP and CBDCA. RIF-1 tumor-bearing mice (C3H/HeJ) received i.p. injections of varying doses of CBDCA, alone or concurrently with IL-1 alpha (48 or 480 micrograms/kg). Clonogenic cell kill and tumor regrowth delay were significantly increased when CBDCA was combined with IL-1 alpha, at both doses, compared to either CBDCA or IL-1 alpha alone (P < 0.001 and P < 0.01, respectively). Although pretreatment with IL-1 receptor antagonist blocked the acute tumor hemorrhagic response induced by IL-1 alpha alone, IL-1 receptor antagonist only partially blocked IL-1 alpha enhancement of CBDCA or cDDP-mediated tumor cell kill. The IL-1 alpha enhancement of CBDCA-mediated tumor cell kill was highly schedule dependent, with maximum antitumor activity observed when IL-1 alpha was administered 4-12 h before CBDCA. In contrast, administration of IL-1 alpha from 24 h before or as late as 6 h after cDDP resulted in the same antitumor activity as simultaneous administration of cDDP and IL-1 alpha. Tumor and normal tissue platinum content were significantly increased by IL-1 alpha in animals treated with CBDCA (P < 0.01) but not in those treated with cDDP. The observed differences between cDDP and CBDCA may be explained by their known differential rates of clearance and protein binding affinities and are compatible with an induced alteration in CBDCA pharmacokinetics.