Analysis of clinical trials in gynecologic cancer—Timing and interpretation

When and how often a clinical trial is analyzed is as important as the use of appropriate methodology. Premature analysis may result in inaccurate estimation of tumor response and adverse effects as well as misrepresentation of survival. Moreover, bias may be introduced or the study may be abandoned entirely. Of parallel importance to the timing is the emphasis given to the analyses. If a randomized comparative trial of two regimens is conducted and a significant therapeutic effect is not discerned, the study is generally classified as a negative study. This view is oversimplified; the negative conclusion drawn must have a much more limited scope than is generally appreciated. Lastly, the pitfalls of interpreting time variable curves such as survival are of special note. Quite often the "tails" of the curves totally belie the true implications of the analysis.     

Usefulness of tumor volumetry by magnetic resonance imaging in assessing response to radiation therapy in carcinoma of the uterine cervix

: Clinical evaluation of tumor size in cervical cancer is often difficult, and clinical signs of radiation therapy failure may not be present until well after completion of treatment. The purpose of this study is to investigate early indicators of treatment response using magnetic resonance (MR) imaging for quantitative assessment of tumor volume and tumor regression rate before, during, and after radiation therapy.

: Thirty-four patients with cervical cancer Stages IB [5], IIB [8], IIIA [1], IIIB [14], IVA [3], IVB [1], and recurrent [2] were studied prospectively with four serial MR examinations obtained at the start of radiation therapy, at 2-2.5 weeks (20–24 Gy), at 4–5 weeks (40–50 Gy), and 1–2 months after treatment completion. Tumor volume was assessed by three-dimensional volumetric measurements using T₂-weighted images of each MR examination. The volume regression rate was generated based on the four sequential MR studies. These findings were correlated with local control, metastasis rate, and disease-free survival. Median follow-up was 18 months (range: 9–43 months).

: The tumor regression rate after a dose of 40–50 Gy correlated significantly with treatment outcome. The actuarial 2-year disease-free survival was 88.4% in patients with tumors regressing to <20% of the initial volume compared with 45.4% in those with ≥20% residual (p = 0.007). The incidence of local recurrence was 9.5% (2 out of 21) and 76.9% (10 out of 13), respectively (p < 0.001). Analysis by initial tumor volume showed that this observation was valid in patients with initial volumes between 40 and 100 cm³. Analysis by FIGO stage confirmed this observation in all patients except those with Stage IB.

: Sequential tumor volumetry using MR imaging appears to be a sensitive measure of the responsiveness of cervical cancer to irradiation. Treatment response can be assessed as early as during the course of radiation therapy by measurement of initial tumor volume and regression rate at 40–50 Gy. In patients with large (>40 cm³) and advanced (Stage ≥ IIIA) tumors, this technique may be helpful in supplementing the clinical examination for response assessment. The identification of patients at high risk for treatment failure may ultimately lead to improved clinical outcome.     

Direct findings of aortic injury on contrast-enhanced CT in surgically proven traumatic aortic injury: a multi-centre review

OBJECTIVE: To review the contrast-enhanced CT findings in surgically proven traumatic aortic injury (TAI). MATERIALS AND METHODS: We searched the trauma registries of three academic medical centres from 1994 to 2000 and found 34 patients with surgically proven TAI that received pre-operative contrast-enhanced chest CT. Two chest radiologists recorded by consensus the size and location of direct (pseudoaneurysm, intimal flap) and indirect (mediastinal haematoma) findings of TAI. The imaging findings were correlated with surgical reports. RESULTS: Direct findings of aortic injury (pseudoaneurysm or intimal flap) were seen on contrast enhanced CT in all patients and confirmed at surgery. Specifically, a pseudoaneurysm was seen in 33 (97%), presenting either as a focal bulge in 22 (65%) or as more diffuse aneurysmal enlargement in 11 (32%). An intimal flap was identified in 31 cases (91%). A periaortic haematoma was seen in 31 cases (91%). In the three patients without periaortic haematoma, the only indications of aortic injury were a focal pseudoaneurysm in two (6%) and an intimal flap in one (3%). CONCLUSION: In this series of surgically proven TAI, direct findings of aortic injury were seen in all cases. Aortic tear occurred without mediastinal haematoma in 9% (3/34) of patients.     

贴报-P2临床毒理学、药理学和疗效研究

5-Flourouracil（5-FU） is one of well known anti-cancer drugs, but its toxicity in normal lymphocytes remains a major problem in chemotherapy. The eastern traditional drug, Bupleuri radix（BR）, has been used for the treatment of liver diseases and contains series of triterpene saponins.     

Establishment and characterization of acquired resistance to the farnesyl protein transferase inhibitor R115777 in a human colon cancer cell line.

R115777 (Zarnestra) is a farnesyl protein transferase inhibitor currently undergoing worldwide clinical trials. As acquired drug resistance may limit the efficacy of the drug, a model of acquired resistance has been established in vitro by continuous drug exposure of the human colon cancer cell line KM12. A stably resistant cell line possessing 13-fold resistance to R115777 was generated. The resistant cells showed cross-resistance to another, structurally different farnesyl transferase inhibitor-277, but not to GGTI-298. A lack of cross-resistance was observed to a variety of other agents, which included clinically used drugs, such as doxorubicin, etoposide, cisplatin, and paclitaxel, as well as signal transduction blockers, such as the mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor UO126, the phosphatidylinositol 3'-kinase inhibitor LY294002, and the epidermal growth factor receptor tyrosine kinase inhibitor PD153035. Resistance did not appear to be related to differences in drug efflux pumps, such as P-glycoprotein or in drug accumulation. Total levels of farnesyl transferase protein subunits were similar in the parent and resistant cells, but, notably, the enzyme activity was markedly reduced in the resistant cell line compared with the parent cells. This was not because of a mutation in the enzyme or a difference in activation of the alpha-subunit of farnesyl transferase by phosphorylation. Hence, resistance to R115777 was generated; the mechanism of resistance in this model may be associated with the enzyme target of the inhibitor. The results suggest that the development of clinical resistance may occur with farnesyl protein transferase inhibitors.     

A Fourier transform infrared spectroscopic and solid-state NMR study of bone mineral in osteogenesis imperfecta

Fourier transform infrared spectroscopy and ³¹P solid-state nuclear magnetic resonance spectroscopy were used to determine if any structural or compositional differences in osteogenesis imperfecta (OI) bone mineral could be detected that might help to explain the bone fragility observed in this disease. A previous study by Cassella et al. used an electron probe X-ray microanalytical technique to compare the calcium to phosphorus (Ca/P) molar ratios in normal bone and bone from patients with OI. It was demonstrated that bone from OI patients had a lower Ca/P molar ratio. This study demonstrated that OI bone mineral had a general hydroxyapatite structure and that isomorphous substitutions in the carbanoapatite lattice could account for the low Ca/P molar ratio. Received: December 28, 1999 / Accepted: March 22, 2000     

Hepatic zonation of the induction of cytochrome P450 IVA, peroxisomal lipid beta-oxidation enzymes and peroxisome proliferation in rats treated with dehydroepiandrosterone (DHEA). Evidence of distinct zonal and sex-specific differences

Dehydroepiandrosterone (DHEA) is an intermediate product in the synthesis of male and female sex hormones in the adrenal cortex of man. In livers of rats and mice DHEA increases the levels of cytochrome P450 IVA and peroxisomal beta-oxidation enzymes associated with peroxisome proliferation. Prolonged treatment of rats with DHEA induces liver tumors that are more frequent in females arising mainly in the periportal regions of the liver lobule (Metzger et al., Toxicol. Pathol. 23, 591-605, 1995). Because of paucity of information on hepatic zonation of peroxisomal response to DHEA and controversial reports on gender-specific differences of its effects the present study was undertaken using qualitative immunohistochemical and quantitative immunoelectron microscopical techniques in addition to Western blotting. Rats were treated for 24 weeks with 0.6% DHEA supplied with diet. Immunoblot analysis revealed marked induction of peroxisomal beta- oxidation enzymes, which by quantitative analysis was equally strong in male and female animals, whilst catalase and urate-oxidase were not increased. Cytochrome P450 IVA, in contrast, was induced significantly stronger in male than in female rats. Immunohistochemistry confirmed the induction of cytochrome P450 IVA showing a marked lobular gradient in female animals with strong induction in pericentral and almost no induction in periportal regions of the liver lobule. In male animals cytochrome P450 IVA was expressed more uniformly across the liver lobule. A similar sex specific zone-dependent response was observed for peroxisomes. DHEA induced in females a significant zonal gradient with marked peroxisome proliferation and a strong induction of peroxisomal hydratase/dehydrogenase in pericentral hepatocytes and a much smaller response in periportal regions. Livers of male animals, in contrast, showed a uniform peroxisomal proliferation to DHEA with only slight zonal differences. The striking homologies of the induction patterns of cytochrome P450 IVA and the peroxisome proliferation in both sexes support the notion of a functional relationship. In view of the almost exclusive periportal localization of DHEA-induced tumors in female rats in contrast to the pericentral localization of the peroxisomal proliferation shown by this study, it seems likely that other factors in addition to peroxisome proliferation may contribute to the hepatocarcinogenic effect of DHEA.      

Azimuthal sensitivity of rat pinna reflex: EMG recordings from cervicoauricular muscles

Electromyographic (EMG) responses of the cervicoauricular muscles (CAM) to free-field sounds were recorded in two groups of rats whose brainstems were dissected transversely either at a pretectal or transtectal level. After the rat recovered from anesthesia, wide-band noise pulses were presented and speaker positions were varied systematically in azimuth. Sound levels were set at 10–15 dB above empirically determined threshold for an EMG response to a sound from azimuth. In both animal groups, transient CAM EMGs with short latency were produced and three main types of azimuthal sensitivity of CAM EMG response were observed. (1) For the majority of the cases, an inverted ‘U’ type of azimuthal sensitivity was identified: the maximum activity occurred around 0° azimuth, but as the speaker was moved toward either the ipsilateral or contralateral fields, the sound-evoked activity declined systematically. This directional tuning is quite different from the passive pinna directionality which is very lateral in the resting positions used in this study. (2) In a small number of cases, the spatial sensitivity curves were not symmetrical about the midline (0° azimuth): the EMG response was vigorous in one hemifield and dropped off systematically as the speaker was moved toward extreme positions of the other hemifield. Regardless of shapes of EMG spatial tuning curves, obstruction of either the ipsilateral or contralateral meatus reduced the sound-elicited response dramatically and eliminated the spatial sensitivity. (3) Some cases exhibited an omnidirectional function: the EMG spike rate had no or minor systematical variation as the speaker position was changed in azimuth. The results of this study indicate that with either pretectal or transtectal decerebrate preparations, the acoustically evoked CAM EMG can exhibit an azimuthal sensitivity which is based on binaural processing.