Cyclin D1 is a candidate oncogene in cutaneous melanoma

The retinoblastoma pathway has been implicated in melanoma; however, previous studies of one of the key components of this pathway, cyclin D1 (CD1), failed to find amplification of this gene in a large series of melanomas. We have recently shown that a particular subtype of melanoma, acral melanoma (AM), has frequent amplification of the CD1 locus. This suggested that CD1 might be important in AM and that it may also be important in other melanoma types, even though its copy number may not be altered. We compared CD1 gene copy number and protein expression in 137 invasive primary cutaneous melanomas (71 superficial spreading melanomas, 17 nodular melanomas, 19 lentigo maligna melanomas, 18 AMs, and 12 unclassifiable melanomas) using fluorescence in situ hybridization and immunohistochemistry. We found frequent amplification of CD1 in AM (44.4%) and occasional amplification in lentigo maligna melanoma (10.5%) and superficial spreading melanoma (5.6%). CD1 protein was overexpressed in all cases with amplifications and in an additional 20% of cases without amplification. We tested the importance of CD1 in cell growth in melanoma by using adenovirus-mediated antisense treatment targeted to CD1 in two melanoma cell lines, one with and the other without CD1 amplification and overexpression. Antisense mediated down-regulation of CD1 induced apoptosis in vitro and led to significant tumor shrinkage of melanoma xenografts in severe combined immunodeficient mice. However, it did not alter the growth of normal melanocytes. Together, these results suggest that CD1 may be an oncogene in melanoma and that targeting its expression may be therapeutically beneficial.     

Thalamic stimulation reduces essential tremor but not the delayed antagonist muscle timing

BACKGROUND: Electrical stimulation of the thalamus dramatically reduces essential tremor (ET). It has been hypothesized that the cerebellum and inferior olive are involved in the generation of ET, and thalamic stimulation is presumed to dampen ET through interactions with cerebellar output to the thalamus. Evidence suggests that abnormal timing of agonist and antagonist muscle responses contribute to cerebellar tremor (CbT); however, this relationship has not been investigated for ET. The mechanisms of the tremor and improvement are unknown. OBJECTIVE: To measure the effect of ventral intermediate thalamic stimulation in controlling the ET response to sudden stretch of an agonist muscle and to determine whether, in ET, the timing relationships between the initial agonist and antagonist electromyography (EMG) responses show abnormalities similar to those seen in CbT. METHODS: The authors studied ET subjects (with implanted thalamic stimulators turned off and on) and normal controls as they responded to mechanical torque pulses given at the wrist joint. The wrist joint angle, wrist agonist, and antagonist EMG were recorded. RESULTS: Like CbT, patients with ET showed delayed onsets of antagonist EMG and excessive rebound. Thalamic stimulation reduced the tremor but did not alter the antagonist delay or the rebound. CONCLUSIONS: In ET, antagonist muscle responses to a torque pulse are similar to that in CbT. However, benefit from thalamic stimulation did not alter these EMG responses; therefore, suppression of tremor must be caused by mechanisms other than the re-establishment of normal agonist-antagonist timing.     

Systemic lupus erythematosus in three ethnic groups. XII. Risk factors for lupus nephritis after diagnosis

The purpose of this study was to determine the cumulative incidence of lupus nephritis (LN) and the factors predictive of its occurrence in a multiethnic systemic lupus erythematosus (SLE) cohort. We studied 353 SLE patients as defined by the American College of Rheumatology (ACR) criteria (65 Hispanics, 93 African-Americans and 91 Caucasians). First, we determined the cumulative incidence of LN in all patients. Next, we determined the predictors for LN in those with nephritis occurring after diagnosis. The dependent variable, LN, was defined by: (1) A renal biopsy demonstrating World Health Organization (WHO), class II-V histopathology; and/or (2) proteinuria > or = 0.5 g/24 h or 3+ proteinuria attributable to SLE; and/or (3) one of the following features also attributable to SLE and present on two or more visits, which were performed at least 6 months apart--proteinuria > or = 2+, serum creatinine > or = 1.4 mg/dl, creatinine clearance < or = 79 ml/min, > or = 10 RBCs or WBCs per high power field (hpf), or > or = 3 granular or cellular casts per hpf. Independent variables assessed at diagnosis, and if absent, at baseline, were from four domains: sociodemographic, clinical, immunologic and immunogenetic (including the complete antibody profile and MHC class II alleles), and health habits. Variables with P < 0.05 by chi square analyses were entered into domain-specific stepwise logistic regression analyses controlling for disease duration, with LN as the dependent variable. Significant domain-specific regression variables (P < or = 0.1) were then entered into an overall model. The cumulative incidence of LN was 54.3% in all patients, and 35.3% for those developing LN after diagnosis. LN after diagnosis occurred in 43.1% of 65 Hispanics, 50.5% of 93 African-Americans, and 14.3% of 91 Caucasians, P < 0.0001. The duration of follow-up for those with LN after diagnosis was 5.5+/-2.4 vs 4.0+/-2.9 years for those without LN. Hispanic (odds ratio (OR) = 2.71, 95% confidence limits (CL) = 1.07-6.87, P < 0.04) and African-American ethnicities (OR = 3.13, 95% CL = 1.21-8.09, P < 0.02), not married or living together (OR = 3.45, 95% CL = 1.69-7.69, P < 0.0003), higher SLAM score (OR = 1.11, 95% CL = 1.02-1.19, P < 0.007), anti-dsDNA (OR = 3.14, 95% CL = 1.50-6.57, P < 0.0001) and anti-RNP (OR = 4.24, CL = 1.98-9.07, P < 0.0001) antibodies were shown to be significant predictors of the occurrence of LN. Repeated analyses excluding the patients with missing HLA data showed that absence of HLA-DQB1*0201 was also a significant predictor for the occurrence of LN (OR = 2.34, CL = 1.13-5.26, P < 0.04). In conclusion, LN occurred significantly more often in Hispanics and African-Americans with SLE. Sociodemographic, clinical and immunologic/immunogenetic factors seem to be predictive of LN occurring after the diagnosis of SLE has been made.     

Nomograms provide improved accuracy for predicting survival after radical cystectomy.

AIMS: To develop multivariate nomograms that determine the probabilities of all-cause and bladder cancer-specific survival after radical cystectomy and to compare their predictive accuracy to that of American Joint Committee on Cancer (AJCC) staging. METHODS: We used Cox proportional hazards regression analyses to model variables of 731 consecutive patients treated with radical cystectomy and bilateral pelvic lymphadenectomy for bladder transitional cell carcinoma. Variables included age of patient, gender, pathologic stage (pT), pathologic grade, carcinoma in situ, lymphovascular invasion (LVI), lymph node status (pN), neoadjuvant chemotherapy (NACH), adjuvant chemotherapy (ACH), and adjuvant external beam radiotherapy (AXRT). Two hundred bootstrap resamples were used to reduce overfit bias and for internal validation. RESULTS: During a mean follow-up of 36.4 months, 290 of 731 (39.7%) patients died; 196 of 290 patients (67.6%) died of bladder cancer. Actuarial all-cause survival estimates were 56.3% [95% confidence interval (95% CI), 51.8-60.6%] and 42.9% (95% CI, 37.3-48.4%) at 5 and 8 years after cystectomy, respectively. Actuarial cancer-specific survival estimates were 67.3% (62.9-71.3%) and 58.7% (52.7-64.2%) at 5 and 8 years, respectively. The accuracy of a nomogram for prediction of all-cause survival (0.732) that included patient age, pT, pN, LVI, NACH, ACH, and AXRT was significantly superior (P=0.001) to that of AJCC staging-based risk grouping (0.615). Similarly, the accuracy of a nomogram for prediction of cancer-specific survival that included pT, pN, LVI, NACH, and AXRT (0.791) was significantly superior (P=0.001) to that of AJCC staging-based risk grouping (0.663). CONCLUSIONS: Multivariate nomograms provide a more accurate and relevant individualized prediction of survival after cystectomy compared with conventional prediction models, thereby allowing for improved patient counseling and treatment selection.     

Intensified local treatment and systemic therapy significantly increase survival in patients with brain metastases from advanced breast cancer – A retrospective analysis

BACKGROUND: Brain metastases have evolved from a rare to a frequently encountered event in advanced breast cancer due to advances in palliative systemic treatment. PATIENTS AND METHODS: All Patients treated at our centre from 1994 to 2004 with WBRT for brain metastases from breast cancer were included. We performed a multivariate analysis (Cox regression) to explore which factors are able to influence significantly cerebral time to progression (TTP) and overall survival (metastatic sites [visceral versus non-visceral], Karnofsky performance score [KPS], age, intensified local treatment [boost irradiation, neuro-surgical resection] further systemic treatment). RESULTS: Overall 174 patients, median age 51 years, range 27-76 years, were included. Median TTP was 3 months (m), range 1-33+ m. Median overall survival was 7 m, range 1-44 m. Factors significantly influencing TTP were KPS (p = 0.002), intensified local treatment (p < 0.001), and palliative systemic treatment (p = 0.001). Factors significantly influencing survival were intensified local treatment (p = 0.004), metastatic sites (p = 0.008), KPS (p = 0.006), and palliative systemic treatment (p < 0.001). CONCLUSION: As shown by the significant influence of metastatic sites, some patients die from their advanced systemic tumour situation before they would die from cerebral progression. In other individuals however, intensified local treatment and systemic treatment appear to influence cerebral time to progression and overall survival.     

Role of sensation in swallowing function

OBJECTIVES: Sensation in the oral cavity and laryngopharynx has long been believed to be crucial for normal swallowing. One illustration of this belief has been intense interest in reconstruction after cancer resection using sensate tissue transfer as a means of improving swallowing function. A contrarian view is that mucosal sensation, by itself, is, in fact, relatively unimportant to swallowing function. STUDY DESIGN: A prospective study was designed to test the hypothesis that normal swallow function can occur with anesthesia of the upper aerodigestive tract mucosa. METHODS: Baseline (sensate) swallowing function of 13 healthy adults was assessed via video endoscopic swallow studies (VESS). Each subject was then topically anesthetized with lidocaine applied to the oral cavity, oropharynx, hypopharynx, and larynx. Swallowing was then reassessed via VESS and compared to the baseline examination to look for differences in function. RESULTS: There was little difference in swallowing ability between sensate and anesthetized states, even though all the subjects felt that their swallowing had been profoundly disrupted after lidocaine was applied. The main difference was a small increase in the time from food administration to swallowing. A few experienced trace aspiration, which was instantly eliminated on subsequent swallows with simple coaching. CONCLUSION: Normal swallowing can occur spontaneously or with simple coaching even with complete anesthesia of the upper aerodigestive tract mucosa. Current beliefs about the value of sensate free flaps and the importance of sensation in swallowing in general may need refinement.     

Automated peritoneal dialysis with 'on-line'-prepared bicarbonate-buffered dialysate: technique and first clinical experiences

Background. Automated peritoneal dialysis (APD) has the possibility of increasing the dialysis efficacy by using higher fill volumes, frequent dialysate exchanges, and tidal techniques. It is then possible to treat patients adequately without residual renal function. The drawbacks of the required high amounts of dialysis solution of up to 30 litres per session are the high costs of lactate-based dialysate bags and difficulties for the patients in handling these bags. So far, bicarbonate-based peritoneal dialysate, which may be more biocompatible, is only available for CAPD in double-chamber bags. In APD this could be overcome by 'on-line' preparation of bicarbonate-buffered dialysate using advanced technologies originally designed for on-line preparation of substitution fluid for haemofiltration. Methods. Four patients without residual renal function were treated with APD five times weekly in a crossover study design. Patients received standard lactate-based (35 mmol/l) treatment (25 litres per session each) in weeks 1 and 3. In week 2 on-line-produced bicarbonate-buffered (37 mmol/l) dialysate was used. This dialysate was prepared by an AK 100 Ultra haemodialysis machine. The machine was modified for adding glucose from a 50% concentrate to the desired concentration of 1.7%. Electrolytes, pH, pCO2, and dialysis efficacy parameters were measured. Micro-biological testing was carefully performed. Results. Creatinine clearances, Kt/V, and pCO2 did not vary between the different treatment phases, whereas the pH showed a distinct increase during the bicarbonate phase. Repeated determinations of endotoxins and culturing showed no contamination of the dialysate. The composition of the produced dialysate was reproducible with respect to pH, pCO2, sodium, calcium and bicarbonate, whereas the glucose concentration varied by ±20%. Conclusions. On-line preparation of PD fluid with the AK 100 Ultra is easy and safe to handle. APD with dialysate containing 37 mmol/l bicarbonate provides improved acid-base balance and possibly improved biocompatibility, and may lead to a significant cost reduction. Further development in order to provide smaller machines and more precise ways of achieving a desired dialysate glucose concentration is necessary.