RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non-small-cell lung cancer.

PURPOSE: RRM1 has important functions in the determination of the malignant phenotype. It controls cell proliferation through deoxynucleotide production and metastatic propensity through PTEN induction. It is located in a region of loss of heterozygosity in non-small-cell lung cancer (NSCLC), which is a predictor of poor survival. We hypothesized that RRM1 expression would be a significant predictor of outcome in NSCLC. PATIENTS AND METHODS: A retrospective data set of 49 patients and a prospective data set of 77 patients with resectable NSCLC were studied. RNA was extracted from tumor and normal lung tissue, and expression of the genes RRM1, PTEN, and RRM2 was determined by real-time quantitative polymerase chain reaction. RESULTS: RRM1 expression was significantly correlated with PTEN and RRM2 expression in tumor tissue. RRM1 and PTEN expression in tumor tissue was highly predictive of overall (P =.011 and.018, respectively) and disease-free survival (P =.002 and.026, respectively). Patients with high levels of expression lived longer and had disease recurrence later than patients with low levels of RRM1 and PTEN. In a multivariate analysis, high RRM1 expression was predictive of long survival independent of tumor stage, performance status, and weight loss. CONCLUSION: RRM1 is a biologically and clinically important determinant of malignant behavior in NSCLC. Knowing the level of expression of this gene adds significant information to management decisions independent of the currently used outcome predictors of tumor stage, performance status, and weight loss. Future clinical trials should stratify patients based on expression of this gene to avoid unwanted biases.     

A phase II study of carboplatin and paclitaxel in esophageal cancer.

BACKGROUND: This study was conducted to evaluate the efficacy and toxicity of combination carboplatin and paclitaxel in patients with esophageal cancer. MATERIALS AND METHODS: Thirty-five patients were enrolled. Patients were treated with paclitaxel 200 mg/m(2) intravenously (i.v.) over 3 h and carboplatin i.v. at an AUC of 5 mg/h/ml. Thirty-three patients were assessable for toxicity and objective response. RESULTS: A total of 166 treatment courses were administered with a median of five courses per patient. The objective response rate was 43% [90% confidence interval (CI) 0.3-0.58] by the intention-to-treat analysis. The median response duration was 2.8 months (90% CI 2.1-5.4). The median survival time was 9 months (90% CI 7-13.8) and the 1-year survival rate was 43% (90% CI 0.29-0.57). The major grade 3-4 toxicity observed was neutropenia, occurring in 17 patients (52%). There were no treatment-related deaths. CONCLUSIONS: The combination of carboplatin and paclitaxel is an moderately active and tolerable regimen in advanced esophageal cancer.     

Long-term follow-up after liver transplantation for alcoholic liver disease under tacrolimus

BACKGROUND: Liver transplantation (LTx) for alcohol-related liver disease (ALD) is an accepted modality of treatment and is one of the most common indications for LTx in the United States. The present report examines the long-term patient survival, graft survival, rates of recidivism, and development of de novo cancers in this group, and compares these results with a contemporaneous group of patients who were transplanted for non-ALD indications. METHODS: Between August 1989 and December 1992, 185 adults received LTx for ALD (group I). During the same time interval, 649 adults received LTx for non-ALD (group II). The mean follow-up time was 94+/-10.7 months for group I vs. 92+/-11 months for group II. Kaplan-Meier survival estimates and the incidence of cancers using Surveillance Epidemiologic End Result data were compared in both groups. RESULTS: At 5 years after orthotopic LTx, the overall patient survival and graft survival for group I were 72.0% and 66.5% vs. 66.5% and 60.3% for group II, respectively. After 5 years, the patient survival and graft survival for the alcoholic group were significantly lower (P=0.001) compared to the non-alcoholic group. The rate of de novo oropharyngeal cancer and lung cancer was 25.5 times and 3.7 times higher, respectively, in ALD group compared with the general population matched for age, sex, and length of follow-up (P=0.001), whereas this was not higher in the non-ALD group. Prior pretransplant length of sobriety and alcohol rehabilitation was not associated with the rate of post-LTx rate of recidivism, which was 20%. Out of 79 deaths in group I, only 1 was attributed to recidivism and 3 to noncompliance with recidivism. The other deaths occurred from de novo cancer (n=13), posttransplant lymphoproliferative disorder (n=5), age-related complications (n=23), and other infection or miscellaneous causes (n=34). CONCLUSIONS: Patient and graft survival past 5 years after orthotopic LTx is significantly lower for ALD for a variety of reasons (P=0.001). The rate of upper airway malignances was significantly higher in ALD patients than for non-ALD post-LTx patients and the general public. Graft loss/death related to recidivism or chronic rejection was extremely low. More attention is needed for early diagnosis of de novo cancer and prevention of cardiorespiratory and cerebrovascular complications.     

Nuclear factor-kappaB mediates angiogenesis and metastasis of human bladder cancer through the regulation of interleukin-8.

PURPOSE: Interleukin (IL)-8 is an important mediator of angiogenesis, tumorigenicity, and metastasis in transitional cell carcinoma (TCC) of the bladder. Nuclear factor kappaB (NF-kappaB)/relA regulates IL-8 expression in several neoplasms. The purpose of this study was to determine whether the organ microenvironment (hypoxia, acidosis) regulates the expression of IL-8 in TCC via NF-kappaB, and whether inhibition of NF-kappaB function by mutant IkappaB-alpha prevents induction of IL-8 expression. EXPERIMENTAL DESIGN: IL-8 mRNA expression and protein production by human TCC cell lines (UM-UC-14, HTB-9, RT-4, KU-7 and 253J B-V) were measured by Northern blot analysis and ELISA under acidic (pH 7.35-6.0) and hypoxic (1.0% O(2)) conditions. The involvement of NF-kappaB and activator protein 1 in the regulation of IL-8 production was evaluated by electrophoretic mobility shift assay. Furthermore, the tumorigenicity and metastatic potential of UM-UC-14 cells were determined after transfection with mutant IkappaB-alpha. RESULTS: We found that acidic and hypoxic conditions increased IL-8 mRNA expression and protein production by several, but not all, TCC cell lines evaluated. NF-kappaB, but not activator protein 1, was inducibly activated in UM-UC-14 under both acidic and hypoxic conditions, but not in UM-UC-14 mutant IkappaB-alpha transfectants. Tumor growth and lymph node metastasis were inhibited in UM-UC-14 mutant IkappaB-alpha transfectants compared with UM-UC-14 controls. This effect was associated with the inhibition of IL-8 production, cellular proliferation, and angiogenesis. CONCLUSIONS: These results suggest that TCCs of the bladder have heterogenic responses to physicochemical changes in the microenvironment and identify NF-kappaB as a potential molecular target for therapy.     

Heterogeneity in Klippel-Feil syndrome: a new classification

Background. Klippel-Feil syndrome (KFS) is characterised by congenital vertebral fusion of the cervical spine and a wide spectrum of associated anomalies. KFS has often been considered a sporadic syndrome. However, since the publication of the original KFS classification early this century, a number of KFS families have indicated heterogeneity complicated by a broad range of variable expression. Objective. The two major objectives of this study were (1) to identify differences and similarities in the postnatal appearance, morphology, position and inheritance of vertebral fusions within and between KFS families and (2) to establish a new KFS classification focussed on KFS aetiology. Materials and methods. Vertebral fusions were assessed via spinal radiography. Chromosomal karyotypes were performed using routine cytogenetics. Results. The medical histories of three KFS families are presented. The postnatal time, position and appearance of vertebral fusions, associated anomalies and mode of inheritance were different for the three KFS families. Four classes of KFS are described in a comprehensive classification table that allays much of the uncertainty arising from KFS heterogeneity and variable expression. Conclusion. We have described four different KFS classes (KF1–4) within a comprehensive classification that addresses KFS genetic heterogeneity. The position of vertebral fusions in the cervical spine and their incidence within affected families are delineating features of KFS. Received: 10 October 1997 Accepted: 20 April 1998     

Tumours of the parapharyngeal space

A series of 14 parapharyngeal tumours has been studied with regard to their symptology, pre-operative evaluation and surgical management. High resolution computed tomography is now the best initial diagnostic study because it helps to determine the size and extent of the tumour, differentiate tumours of parotid and extraparotid origin, demonstrate degree of tumour vascularity, separate benign from malignant lesions, plan the surgical approach and predict prognosis.     

Pulse radiolysis of the DNA-binding bisbenzimidazole derivatives Hoechst 33258 and 33342 in aqueous solutions

PURPOSE: The DNA-minor-groove-ligands bisbenzimidazoles Hoechst 33258 and 33342 have been reported to protect against radiation-induced DNA-strand breakage. In order to elucidate the mechanisms of protection by these DNA-binding compounds, pulse radiolysis studies on the reactions of the OH radical, the solvated electron and the H atom with Hoechst as well as OH-radical-induced nucleotide radical quenching by free Hoechst (model level) was investigated. MATERIALS AND METHODS: The pulse radiolysis of Hoechst 33258 and 33342 was studied in N2O and N2O/O2-(4:1)-saturated aqueous solutions in the absence and presence of azide and bromide ions and nucleotides. RESULTS: In a fully scavenged system (3 x 10(-2) mol x dm(-3) t-butanol, N2O/O2-saturated), a transient is formed which in the presence of phosphate buffer is no longer observed. This is assigned metastable quinonoid forms of Hoechst (lambdamax(Hoechst) = 340; lambdamax(transient) = 370 nm) which is generated in protonation/ deprotonation reactions by H+/OH- formed during the pulse. To prevent their formation 10(-3) mol x dm(-3) phosphate buffer was added in all other experiments. The transient spectra formed upon OH-radical attack (k=9 x 10(9) dm3 x mol(-1) x s(-1)) indicate that a major part of the primary OH-adduct radicals undergo rapid transformation (k approximately 5 x 10(5) x s(-1)), attributed to water elimination yielding an N-centered radical. This intermediate, also generated by N3. (k = 4 x 10(9) dm3 mol(-1) x s(-1)), subsequently complexes with a Hoechst molecule [k = 8 x 10(8) dm3 x mol(-1) x s(-1) epsilon(440 nm) = 1.4 x 10(4) dm3 mol(-1) x cm(-1)]. The N-centered radical does not react with O2 (k < 5 x 10(5) dm3 mol(-1) x s(-1)), but reacts readily with the superoxide radical (k= 1.0 x 10(9) dm3 x mol(-1) x s(-1)). Hoechst reacts with the peroxyl radicals derived from uridine (k approximately 5 x 10(6) dm3 x mol(-1) x s(-1)) or 5'-UMP (k approximately 1 x 10(7) dm3 mol(-1) x (s-1)), but not with the less oxidizing (e.g. methylperoxyl radical) yielding intermediates whose spectral properties are similar to those of the N-centered radical. However, they decay at a much lower rate (2k approximately 1 x 10(8) dm3 mol(-1) x s(-1)) than the N-centered radicals generated by N3. (2k= 1.1 x 10(9) dm3 x mol(-1) s(-1)), and it has been suggested that these peroxyl radicals form adducts rather than undergoing electron transfer. The H atom (k= 7 x 10(9) dm3 x mol(-1) x s(-1)) and the solvated electron (k= 2.3 x 10(10) dm3 x mol(-1) x s(-1)) yield, albeit noticeably different, H-adduct radicals which also strongly absorb in the 440 nm region. The reduction potential of Hoechst 33258 has been determined electrochemically at 0.84-0.90 V vs. NHE at pH 6.8. CONCLUSION: Hoechst reacts fast only with strongly oxidizing radicals by electron transfer (e.g. with the adenine-and guanine-derived heteroatom-centered radicals), but also more slowly with nucleo-base-derived peroxyl radicals, here albeit via addition. This may have important implications with regard to its protection owing to DNA-radical quenching under oxic vs. anoxic conditions.     

Management of jugular paragangliomas: the Gruppo Otologico experience.

OBJECTIVE: The objective of this study was to review the outcome of surgical management in patients of jugular paragangliomas. STUDY DESIGN: We conducted a retrospective case review. SETTING: Tertiary care otology and skull base center. MATERIALS AND METHODS: Fifty-five patients with the diagnosis of a jugular paraganglioma (Fisch Class C and D Glomus Jugulare) were managed over a period of 15 years. All patients with adequate follow up and complete records (53 cases) were reviewed with emphasis on the results of surgical management and the factors influencing them. INTERVENTION: All 53 patients were managed with a view to surgically extirpate the tumor. The primary approach was the infratemporal fossa approach-Type A used in the majority of the patients. In eight cases, the procedure was staged owing to the presence of large intracranial extension. Three patients required additional procedures to ameliorate the after-effects of lower cranial nerve resection. RESULTS: Gross total tumor removal was achieved in 49 patients. There were five cases of recurrence. Coupled with the residual tumors in five patients, the surgical control achieved was 83%. There was no perioperative mortality. There were two cases of postoperative cerebrospinal fluid leak, both of which required surgical exploration and closure. The facial nerve was resected in seven patients. The overall preservation rate of clinically uninvolved lower cranial nerves was 75%. CONCLUSIONS: The low level of complications along with a high surgical control achieved makes surgery the primary mode of treatment in the vast majority of these tumors, regardless of the size and location.     

Neurilemmoma of cervical sympathetic chain

Neurilemmoma of the cervical sympathetic chain is a rare nerve tumour. Less than 40 confirmed cases have been reported in the literature.1 2 Sometimes they can he mistaken as carotid body tumour but usual presentation of these lesions is an asymptomatic neck mass. Because of the rarity of the tumour we report another case of neurilemmoma arising from cervical sympathetic chain in a 19 years old male.