HER2 and tau expression as potential markers for response and survival to first line taxane plus cisplatin therapy in non-small cell lung cancer

Aim:   The aim of this study was to assess the role of various HER2 , tau and bcl2 as prognostic markers of responsiveness to taxane and cisplatin therapy in patients with advanced NSCLC.
Methods:   Amplification of HER2 gene determined by chromogenic in situ hybridization (CISH) and HER2 , tau and bcl2 protein expression determined by immunohistochemistry were assessed in 49 patients with NSCLC enrolled in our four clinical trials of taxane plus cisplatin chemotherapy.
Results:   The patients were classified as responders or non-responders, a negative tau expression was associated with a significantly higher rate of response compared to a positive tau expression ( OR 3.33, 95% CI 1.01–10.97, P  = 0.043). Patients with more than stable disease compared to those with progressive disease showed that negative amplification of the HER2 gene was associated with a significantly higher rate of disease control compared to positive amplification ( OR 7.35, 95% CI 0.83–65.21, P  = 0.048). Furthermore, HER2 gene amplification was strongly associated with the overall survival: 20 months (95% CI 9.007–30.993) in patients with negative amplification of the HER2 gene versus 12 months (95% CI 6.584–17.416) in patients with positive amplification of the HER2 gene ( P  = 0.040). A multivariate analysis with the Cox proportional hazards model confirmed that HER2 gene amplification was a significant independent prognostic factor with a hazard ratio of 2.334 (95% CI 1.060–5.142, P  = 0.035).
Conclusion:   Tau protein expression and HER2 gene amplification are the prognostic factors in NSCLC patients treated with a taxane and cisplatin combination.     

Immunohistochemical analysis of Fas and FLIP in prostate cancers

Fas‐mediated apoptosis is considered a principal pathway for apoptosis induction in normal and cancer cells. Expression of Fas has been reported in prostate tissues several times, but the data were not consistent. Expression of FLICE‐like inhibitory protein (FLIP), an inhibitor of Fas‐mediated apoptosis, has not been studied by immunohistochemistry in prostate tissues. The aim of this study is to explore whether alterations of Fas and FLIP expression occur in prostate cancer tissues. We analyzed the expression of Fas and FLIP in 107 prostate adenocarcinoma tissues by immunohistochemistry using a tissue microarray approach. Normal glandular cells of the prostates strongly expressed both Fas and FLIP proteins. Prostate intraepithelial neoplasm also showed a strong Fas immunoreacitity. Fas expression was strongly positive in 60 cancers (56.1%), but the remaining 47 cancers showed no (6.5%) or markedly decreased (37.4%) Fas immunostaining compared with the normal glandular cells of the same patients. By contrast, FLIP expression was strong in most (103/107; 96.3%) of the cancers, and only four cancers (3.7%) showed decreased immunoreactivities compared with the normal cells. The decreased expression of Fas was not associated with pathologic characteristics, including FLIP expression, size of the cancers, age, Gleason score and stage. The decreased expression of Fas in a large fraction of prostate cancers compared with their normal cells suggested that loss of Fas expression might play a role in tumorigenesis in some prostate cancers possibly by inhibiting apoptosis mediated by Fas.     

The outcome of cementless total hip arthroplasty in haemophilic hip arthropathy

Summary.  Total hip arthroplasty (THA) in haemophilic arthropathy is reported to be less successful than in non-haemophilic indications. Although preliminary results are encouraging, the survival and functional outcome of cementless THA in haemophilia are not known. The aim of this study was to analyse mid-term results of cementless THA in haemophilia. Twenty-seven consecutive cementless THAs with 23 patients performed between June 1995 and June 2003 were reviewed. Mean age at time of operation was 36 years and mean follow-up period was 92 months (range, 60–156). Radiographic assessment was done for fixation of components, loosening, osteolysis, wear and bone responses around the implants. The factor requirements, amount of transfusion and complications associated with bleeding were studied. The mean preoperative Harris hip score changed from 57 to 95.9 at the latest follow-up. The survival at mean follow-up was 95.2%. One patient with osteolysis around acetabular cup was re-operated with bone-grafting and change of polyethylene liner. One loose cup was revised with a cemented cup. All other components were deemed stable at the latest follow-up. A standardized management protocol and dedicated team approach comprising of haematologist, physicians, physical therapist, nurses and coordinators is needed for excellent results. The present retrospective study shows that the functional results of cementless THA in haemophilia are satisfactory as it happens in osteoarthritic patients according to the current literature, mainly the younger. Thus, taking into account that the majority of haemophilia patients requiring a THA are relatively young, cementless THA is currently recommended.     

Penile erectile responses to electric stimulation are enhanced by a new phosphodiesterase type-5 inhibitor

AIM: This study was conducted to investigate the effect of DA-8159, a new phosphodiesterase type-5 (PDE5) inhibitor, on electrostimulation-induced penile erection in rats. METHODS: Intracavernous pressure (ICP) and arterial blood pressure (BP) were simultaneously recorded through electric pelvic-ganglion stimulation (2-10 Hz) after the oral administration of DA-8159 (3 or 10 mg/kg) in normal and streptozotocin-induced diabetic rats. Statistical analysis was performed on the maximal intracavernous pressure (ICP), detumescence time, maximal intracavernous pressure/blood pressure (ICP/BP) ratio, and the area under the curve (AUC) of the ICP/BP ratio. RESULTS: In normal and diabetic rats, electrical stimulation of the pelvic ganglion induced a frequency- and dose-dependent increase in the intracavernous pressure. The ICP/BP ratio and the corresponding AUC values were also significantly and dose-dependently increased after DA-8159 administration. In addition, the detumescence time significantly increased after DA-8159 administration compared to that of the controls. CONCLUSIONS: These results show that the DA-8159 significantly increased the intracavernous pressure response and prolonged the decay period induced by electrical stimulation of the pelvic ganglion, and suggest that DA-8159 might be a potential therapeutic agent for the treatment of erectile dysfunction.     

Pigmented nail with atypical melanocytic hyperplasia

We report two cases showing black discoloration of the thumb nail which were histologically found to be acral lentiginous melanoma (ALM) in situ. A pigmented subungual lesion is more frequently malignant than benign and it is generally believed that diagnosis of subungual melanoma during the radial-growth phase is very difficult. Our cases are particularly interesting because atypical melanocytic hyperplasia was confined to the epidermis despite the lesion being present for a long time.     

Anaesthetic requirement and stress hormone responses in patients undergoing lumbar spine surgery: anterior vs. posterior approach

Background: The intensity of nociceptive stimuli reflects the severity of tissue injury. The anaesthetic requirement and stress hormonal responses were determined to learn whether they differ according to different surgical approaches (anterior vs. posterior) during the spinal surgery.
Methods: Patients undergoing lumbar spine surgery without neurological deficits were divided into two groups: one having posterior ( n =13) and the other having anterior fusion ( n =13). The end-tidal sevoflurane concentrations (ET_SEVO) required to maintain the bispectral index score at 40–50 were determined. Mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), serum osmolality and plasma concentrations of catecholamines, cortisol and vasopressin (AVP) were measured.
Results: There were no differences in MAP, HR, CVP and serum osmolality between the groups. ET_SEVO was higher in the anterior than in the posterior group ( P <0.05). The plasma concentrations of norepinephrine and cortisol increased in both groups during the surgery, whereas those of epinephrine remained unchanged. AVP concentrations increased during the surgery in the anterior group, and remained unaltered in the posterior group. The anterior group needed more analgesics ( P <0.01) during the first 1 h after the operation.
Conclusions: The anterior approach required a deeper level of anaesthesia while undergoing spinal surgery and more use of post-operative analgesics than the posterior approach. It was also associated with a more pronounced AVP release during the surgery.     

Mutational analysis of hypoxia‐related genes HIF1α and CUL2 in common human cancers

Park SW, Chung NG, Hur SY, Kim HS, Yoo NJ, Lee SH. Mutational analysis of hypoxia‐related genes HIF1α and CUL2 in common human cancers. APMIS 2009; 117: 880–5. Hypoxia is a general feature of solid cancer tissues. Hypoxia upregulates hypoxia‐inducible factor 1α (HIF1α) that transactivates downstream genes and contributes to cancer pathogenesis. HIF1α is upregulated not only by hypoxia but also by genetic alterations in HIF1α‐related genes, including VHL. Cullin 2 (CUL2) interacts with the trimeric VHL‐elongin B‐elongin C complex and plays an essential role in the ubiquitinated degradation of HIF1α. The aim of this study was to explore whether HIF1α and CUL2 genes are somatically mutated, and contribute to HIF1α activation in common human cancers. For this, we have analyzed the coding region of oxygen‐dependent degradation domain of HIF1α in 47 colon, 47 gastric, 47 breast, 47 lung, and 47 hepatocellular carcinomas, and 47 acute leukemias by a single‐strand conformation polymorphism assay. In addition, we analyzed mononucleotide repeat sequences (A8) in CUL2 in 55 colorectal and 45 gastric carcinomas with microsatellite instability (MSI). We found one HIF1α mutation (p.Ala593Pro) in the hepatocellular carcinomas (1/47; 2.1%), but none in other cancers. We found two CUL2 frameshift mutations in colon cancers (p.Asn292MetfsX20), which were exclusively detected in high MSI cancers (4.9%; 2/41). Our data indicate that somatic mutation of HIF1α is rare in common cancers, and somatic mutation of CUL2 occurs in a fraction of colorectal cancers (colorectal cancers with high MSI). The data suggest that neither HIF1α nor CUL2 mutation may play a central role in HIF1α activation in gastric, colorectal, breast, lung and hepatocellular carcinomas, and acute leukemias.     

A randomized,double‐blind,placebo‐controlled,phase III study of the human anti‐tumor necrosis factor antibody adalimumab administered as subcutaneous injections in Korean rheumatoid arthritis patients treated with methotrexate

Objective: Adalimumab is a fully human, monoclonal, antitumour necrosis factor antibody approved for the treatment of rheumatoid arthritis (RA) in more than 60 countries. We investigated the efficacy and safety of 40 mg every‐other‐week (eow) subcutaneous injections of adalimumab with methotrexate (MTX) versus placebo with MTX in Korean patients with RA with insufficient responses to MTX. Methods: This was a 24‐week, randomized, double‐blind, placebo‐controlled, phase III study conducted at six sites in Korea. The primary efficacy endpoint was a 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24. Secondary endpoints included ACR50, ACR70, and individual ACR components. Beginning at week 18, non‐responders (< 20% reduction in swollen and tender joint counts) could switch to rescue therapy with open‐label adalimumab 40 mg eow. Results: Of the 128 patients enrolled, 65 received adalimumab and 63 received placebo. An ACR20 response at week 24 was achieved by 61.5% of patients receiving adalimumab versus 36.5% receiving placebo (P < 0.01). ACR50 and ACR70 responses were achieved by 43.1% and 21.5% of adalimumab patients versus 14.3% and 7.9% of placebo patients (P < 0.001 and P < 0.05, respectively). Adalimumab significantly improved all seven ACR core components. Statistically significant improvements in ACR20 were observed with adalimumab as early as week 2. Adalimumab was generally well tolerated; there were no significant differences in incidences of adverse events between groups. Conclusions: In Korean patients with RA with insufficient responses to MTX, combination therapy with adalimumab and MTX was more efficacious than placebo and MTX in reducing RA signs and symptoms.     

Kinetic Interaction between Fluoxetine and Imipramine as a Function of Elevated Serum Alpha-1-acid Glycoprotein Levels

The effect of elevated serum alpha-1-acid glycoprotein (AAG) levels on the pharmacokinetic interaction between imipramine and fluoxetine has been examined by utilizing a novel strain of transgenic mice which express serum AAG levels several times greater than normal. Before fluoxetine treatment, serum imipramine levels were approximately three times greater in transgenic mice than in control mice. Despite higher serum imipramine levels in transgenic mice, brain drug levels were lower than those found in control mice. Fluoxetine pre-treatment (20mg kg^?1 for 5 days) resulted in an increase in serum imipramine levels in both groups of mice and the extent of the increase was greater in transgenic mice than in control mice (4.5-fold increase compared with 3.1-fold). Similarly, fluoxetine pre-treatment resulted in an increase in brain levels of imipramine in both groups of mice and the extent of the increase was greater in transgenic mice than in control mice (3.0-fold increase compared with 2.0-fold). Similar trends were observed for levels of desipramine in the serum and brain. Serum imipramine and desipramine levels did not correlate with their respective brain levels in the presence of elevated serum AAG levels before and after pre-treatment. These findings indicate that the extent of increases in imipramine and desipramine serum and brain levels are greater during elevated serum AAG states than during normal AAG states when imipramine is co-administered with fluoxetine.