Adding weekly irinotecan to high-dose 5-fluorouracil and folinic acid (HD-5-FU/FA) after failure for first-line HD-5-FU/FA in advanced colorectal cancer--a phase II study

Irinotecan (CPT-11) has been shown to prolong survival and improve quality of life in comparison to best supportive care in colorectal cancer patients with pretreatment of bolus 5-fluorouracil (5-FU). After first-line 24-h high-dose (HD) 5-FU/folinic acid (FA) an objective response rate of 11% with 3-weekly CPT-11 350 mg/m was reported. In the present study we investigated weekly CPT-11 in combination with 24-h HD-5-FU/FA as second-line treatment after prior exposure to 24-h HD-5-FU. Synergy between 5-FU and CPT-11 is the rationale to combine both substances for second-line therapy in order to overcome resistance to 5-FU. Thirty-five patients were recruited in a single institution to receive 6 x weekly CPT-11 80 mg/m(2), FA 200 mg/m(2) and 24-h HD-5-FU 2000 mg/m(2). Treatment was repeated on day 57. Patient characteristics: M/F=20/15, median WHO performance status 1, range (0-2). Thirty-four patients were evaluable for response: partial response 17% and no change 40%. Median time to progression and overall survival were 3.3 and 8.4 months, respectively. All patients were evaluable for toxicity analysis (National Cancer Institute Common Toxicity Criteria grade 3): leukocytopenia 3%, diarrhea 12% and vomiting/nausea 6%. Of the assigned doses, a median 100% of 5-FU and 92% of CPT-11 were administered during the first cycle of chemotherapy. We conclude that weekly CPT-11 and HD-5-FU/FA is an active and safe combination chemotherapy resulting in response rates in the upper range of other CPT-11-based second-line regimen. The toxicity profile in our series compared to 3-weekly CPT-11 seems favorable.     

Macrophage migration inhibitory factor may contribute to vasculopathy in systemic sclerosis

Increasing evidence supports the concept of macrophage migration inhibitory factor (MIF) as a central proinflammatory cytokine in autoimmune diseases. To further evaluate its role in systemic sclerosis (SSc), serum levels of MIF were determined by enzyme-linked immunoassay, and correlations to clinical manifestations were analyzed in 43 patients. MIF levels were significantly increased in patients (median, 18.8; range, <0.015-189 ng/ml) in comparison to healthy controls (n = 43, 8.0, <0.015-36.5 ng/ml; P < 0.0005). MIF values were higher in diffuse than in limited cutaneous SSc (P < 0.005). Patients with pulmonary hypertension and recurrent digital ulcers showed higher MIF levels than patients without these manifestations (P < 0.005). This association was also observed in limited cutaneous SSc. Sequential studies revealed decreased MIF levels after initiation of immunosuppressive therapy. MIF levels were not significantly different in patients with and without macrovascular disease of the peripheral arteries. The results suggest that MIF might contribute to inflammation and vasculopathy in SSc.     

The transforming growth factor-beta1 gene polymorphism (G915C) is not associated with systemic lupus erythematosus

Lymphocyte production of transforming growth factor (TGF)-beta1 is decreased in systemic lupus erythematosus (SLE). The lack of this immunoregulatory cytokine may contribute to the characteristic T cell disregulation and aberrant B cell stimulation in SLE patients. The less common C allele of the TGFB1 polymorphism (G915C) is associated with a lower TGF-beta1 production capacity. We performed a population-based case-control study to analyse the impact of this polymorphism on disease susceptibility, on clinical SLE manifestations and autoantibody production. A total of 203 German Caucasian SLE patients (fulfilling the 1982 ACR disease duration 11.5 +/- 7.0 years) and 158 ethnically, age- and sex-matched healthy controls were genotyped with a mutagenically separated polymerase chain reaction. There were no significant differences in the genotype distribution and allele frequencies between patients (915 C = 0.08) and healthy controls (915 C = 0.10). Comparing subgroups of patients, we found no association of major disease manifestations or specific autoantibodies with TGFB1 genotypes or alleles. The TGFB1 polymorphism (G915C) neither significantly contributes to the disease susceptibility, nor predisposes to clinical and immunological manifestations typical of SLE. Further studies are needed to corroborate the pathogenic role of TGF-beta1 in SLE patients and to identify the precise genetic elements controlling its production.     

Severe distortion in the representation of foveal visual image locations in short-term memory

The foveal visual image region provides the human visual system with the highest acuity. However, it is unclear whether such a high fidelity representational advantage is maintained when foveal image locations are committed to short-term memory. Here, we describe a paradoxically large distortion in foveal target location recall by humans. We briefly presented small, but high contrast, points of light at eccentricities ranging from 0.1 to 12°, while subjects maintained their line of sight on a stable target. After a brief memory period, the subjects indicated the remembered target locations via computer controlled cursors. The biggest localization errors, in terms of both directional deviations and amplitude percentage overshoots or undershoots, occurred for the most foveal targets, and such distortions were still present, albeit with qualitatively different patterns, when subjects shifted their gaze to indicate the remembered target locations. Foveal visual images are severely distorted in short-term memory.

The representation of visual spatial locations in short-term memory has been one of the most classic means for studying the neural mechanisms of cognitive control in modern-day systems neuroscience (1–6). Experimentally, reporting a remembered target location with a saccadic eye movement has proven extremely useful in demonstrating how different cortical and subcortical brain regions may maintain a memory trace of visual targets (7), and it has also been equally important for oculomotor control studies in dissociating sensory and motor responses (8–11).One mechanism for short-term memory maintenance in multiple brain areas is the persistence of neural activity associated with remembered stimulus locations, even in the absence of sensory drive (7, 12). Such persistence, with temporal drift, can help explain a variety of distortions in memory-based task performance, for example, as a function of how long a location needs to be maintained in short-term memory (12). In addition, such persistence can reveal certain systematic biases with respect to whether stimuli occupy a single visual quadrant or multiple visual quadrants (13), which in turn enables linking visual field asymmetries in perception to representations of remembered target locations. For example, visual performance along the horizontal and vertical retinotopic meridians is different (14–16), and this difference is maintained in tasks involving short-term memory (17). The fact that such visual meridian effects may be related to tissue magnification in visual cortical areas (18–20) might then suggest that other known distortions in short-term memory tasks, such as foveal biases in remembering peripheral target locations (21–23), may also be related to how visual space is represented in topographic maps.If remembering visual target locations depends on both how visual space is topographically represented as well as on how memory information is neurally maintained, then an important remaining open question is whether foveal visual locations are recalled veridically or not, given the normally very high acuity nature of foveal vision in humans. Here, we investigated this question and found that remembering a foveal visual location as near to the line of sight as 0.1° (6 min arc) is subject to severe distortion, even after very short memory delay intervals. This paradoxical foveal distortion in visual short-term memory emerges with or without a constant landmark being available during the response phase of the task, and, perhaps most importantly, it is also qualitatively different depending on whether the remembered location is reported with an eye movement response or with another response modality.     

Cat scratch disease (bartonellosis) mimicking an SLE flare.

Only recently Bartonella species have been recognized as important human pathogens. Cat scratch disease (CSD), caused by infection with Bartonella henselae, shows a steady increase in the number of cases throughout the world. We report a case of an 18-year-old woman with systemic lupus erythematosus (SLE) who presented with ongoing fever, arthralgias and loss of weight which did not respond to increasing doses of corticosteroids. After exclusion of common infections a photograph of her cat in combination with scratch marks on her arms finally led to the suspicion of CSD. This tentative diagnosis was confirmed serologically. Under clarithromycin treatment the patient rapidly responded and her temperature dropped within 2 days.     

Chirurgische Therapieergebnisse beim asymptomatischen primären Hyperparathyreoidismus

Zusammenfassung. Die Behandlung des symptomatischen prim?ren Hyperparathyreoidismus ist die Operation. Ein breiter Einsatz labortechnischer Untersuchungen hat zu einer geh?uften Diagnose eines asymptomatischen prim?ren Hyperparathyreoidismus (pHPT) geführt. Bei diesen Patienten wird die Indikation zum operativen Vorgehen kontrovers diskutiert. Ziel der Studie war eine Morbidit?tsanalyse sowie die potentielle Identifikation prognostischer Parameter in der Gruppe der asymptomatischen Patienten. Im prospektiv erfa?ten HPT-Krankengut unserer Klinik wurden zwischen Januar 1988 und August 1995 243 Patienten an einem pHPT operiert. 76 Patienten erfüllten die Kriterien eines asymptomatischen pHPT. 75 % der Patienten waren weiblich, das Durchschnittsalter lag bei 62 Jahren. Die fakultativ eingesetzte cervicale Sonographie wurde bei 87 % der Patienten zur Lokalisationsdiagnostik durchgeführt. Vor cervicalen Reeingriffen erfolgte eine selektive Halsvenenkatheterisierung zur stufenweisen Parathormonbestimmung. Eine univariate statistische Analyse zur Identifikation von Risikofaktoren für postoperative Komplikationen wurde erstellt. Chirurgisch wurden 68 singul?re Epithelk?rperchenadenome, 3 Doppeladenome und eine prim?re Hyperplasie erfolgreich therapiert (94,7 %). Vier Patienten verblieben hypercalci?misch, die Persistenzrate betrug somit 5,2 %. Eine korrekte Lokalisationsdiagnostik fand sich bei 58 % der cervicalen Sonographien und bei 77 % der selektiven Venenkatheteruntersuchungen. Postoperativ waren eine permanente Recurrensparese und zwei Nachblutungen, welche durch einen Reeingriff kontrolliert werden konnten, zu verzeichnen. 18 Patienten wiesen einen passageren Hypoparathyreoidismus auf, bei einem Patienten erfolgte auch nach zwei Jahren noch eine Medikation zum Ausgleich einer Hypocalci?mie. Eine postoperative Letalit?t trat nicht auf. Die Analyse potentieller Risikofaktoren wies nur für den cervicalen Reeingriff nach vorausgegangener Epithelk?rperchenrevision ein erh?htes operatives Risiko nach (p = 0,02). Die Operation beim asymptomatischen HPT ist von einer geringen Morbidit?t begleitet. Cervicale Reeingriffe bedürfen einer kritischen Indikation bei nachweisbar erh?hter Morbidit?t, abgesehen von dieser kleinen Gruppe aber sollten alle Patienten mit einem asymptomatischen pHPT für eine Operation evaluiert werden.      

P03Type‐I and ‐IV hypersensitivity to platinum salts

A 28‐year‐old female analytical chemist visited our patch test clinic with initially complaints of severe hand dermatitis. Later on she developed rhinitis, bronchial asthma and tightness of the chest. The complaints seemed work related: her condition improved during holidays and on sick leaves. She worked in a laboratory with several platinum salts and used different kinds of gloves (latex, nitril, etc.).
Methods:  Patch tests were performed with the European Standard series and prick tests with common inhalant allergens. Patch‐, prick‐ and open patch tests were carried out with various aqueous dilutions of platinum chloride (PtCl2).
Results:  Patch tests with 0.01–2% PtCl2 were positive on day 2, 3 and 6, and at 0.001% a follicular reaction was found. The prick‐test was already positive at the lowest concentration tested (0.001%). The open patch test, carried out retro‐auricular, showed a positive reaction at 1 and 2% PtCl2 after 20 min. Controls in healthy volunteers (n = 5) were all negative.
Discussion:  It is well known that platinum salts can cause type‐I hypersensitivity reactions like allergic rhinitis, conjunctivitis, bronchial asthma and urticaria, also referred to as platinosis. Contact dermatitis to platinum salts, however, is very rare. In our patch test clinic, 78 patients were tested between 1987 and 2001 with PtCl2 2%. Only 2 women showed a positive patch test for PtCl2. The patient presented here, stopped working with platinum salts and recovered from all complaints. We interpret our case as occupational type‐I and type‐IV hypersensitivity to platinum salts with mucosal and dermal manifestations.     

Double-blind randomized Phase I study comparing rdESAT-6 to tuberculin as skin test reagent in the diagnosis of tuberculosis infection

Limited specificity of the tuberculin skin test incited the development of in vitro assays based on Mycobacterium tuberculosis-specific antigens such as ESAT-6 that are lacking in Bacillus Calmette Guérin (BCG). In animal studies, intradermal ESAT-6 was safe and induced specific skin test responses. The aim of the study was to assess the safety of intradermal recombinant dimer ESAT-6 (rdESAT-6) compared with tuberculin and to determine the human dose. The study design was a double-blind Phase I study with intra-subject randomization to the left and right forearm, comparing 2 Tuberculin Units (TU) intradermal tuberculin (RT23) with 0.01, 0.1, 1 or 10 microg rdESAT-6 in groups of five healthy controls or treated tuberculosis (TB) patients. The risk of sensitization after skin testing was assessed in healthy volunteers. All doses were tolerated well by healthy volunteers and responses to rdESAT-6 were limited to transient redness after 24 h only at the highest dose. No sensitization was observed. Because 1 microg rdESAT-6 induced large responses with local side effects in some TB patients, the 10 microg dose of rdESAT-6 was not tested. Mean responses to 0.01, 0.1 and 1 microg rdESAT-6 measured 14.0, 19.8 and 38.8 mm of redness, respectively, and 7.0, 13.4 and 14.6 mm of induration. The response to tuberculin was similar to the responses to 0.1 microg rdESAT-6. Mild local side effects due to tuberculin and rdESAT-6 were observed in 8/15, respectively, 6/15 patients, more pronounced at the highest rdESAT-6 dose. In conclusion, this pilot Phase I study of safety, feasibility and dose finding of intradermal rdESAT-6 provides proof of principle of a specific skin test for human use. No serious adverse events were observed but the study was not sufficiently powered to demonstrate complete safety. Intradermal rdESAT-6 did not seem to sensitize healthy volunteers. In treated TB patients, responses to rdESAT-6 were optimal at 0.1 microg. Further studies are needed to evaluate sensitization after repeated doses and to study the effect of additional CFP-10 on the sensitivity of a TB-specific skin test.