Clinical impact of margin reduction on late toxicity and short-term biochemical control for patients treated with daily on-line image guided IMRT for prostate cancer

To evaluate the impact of PTV reduction when delivering image-guided IMRT (IG-IMRT) for patients with prostate cancer. Between 2001 and 2007, 165 men were treated with daily IG-IMRT using a 3D ultrasound-based system. Median dose prescribed to the prostate was 78 Gy [74 Gy-78 Gy]. Patients were stratified regarding the CTV to the PTV margin: group A (n=87)=5mm or group B (n=78)=10mm. Late toxicity was scored using the CTC v3.0 scale. Biochemical progression-free survival (bPFS) was calculated using the Phoenix definition. Grade 2 genitourinary toxicity was 7.0% for group A and 6.6% for group B (p=1.00). Grade 2 gastrointestinal toxicity was 1.2% and 2.6% (p=0.38). With a median follow-up of 38.3 months [5.25-87.3], bPFS at 3 years was 92.5% [82.4%-96.9%] in group A and 94.3% [85.5%-97.8%] in group B (p=0.84). IG-IMRT yielded very low rates of late toxicity. Margin had impact neither on short-term bPFS nor late toxicity.     

Peroxisome proliferator-activated receptor γ agonists potentiate the cytotoxic effect of valproic acid in multiple myeloma cells

The main challenge in using chemotherapy to treat multiple myeloma (MM) is drug resistance. In order to evaluate the anti-neoplastic properties of a new drug combination in MM, two clinically available drugs, valproic acid (VPA) a histone deacetylase (HDAC) inhibitor and pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, were tested in vitro on MM cell lines and MM patient cells. The sensitivity towards VPA alone was observed on several MM cell lines tested and also on primary myeloma cells and peripheral blood mononuclear cells from healthy donors. Importantly, the addition of a PPARγ agonist to the VPA treatment increased the cytotoxic effect of VPA in a synergistic/additive manner on the different MM cell lines and MM patient cells. This effect was observed at the physiological range of VPA used to treat epileptic patients. The mechanisms underlying this increase induced a cell cycle arrest and caspase-dependent apoptosis. The potentiation of the effect of VPA by pioglitazone was mediated by higher acetylation levels of histones H3 and H4 compared to levels induced by HDAC inhibitors alone. This association reveals a new promising chemotherapeutic combination to be tested in MM.     

Muscle hypertrophy driven by myostatin blockade does not require stem/precursor-cell activity

Myostatin, a member of the TGF-β family, has been identified as a powerful inhibitor of muscle growth. Absence or blockade of myostatin induces massive skeletal muscle hypertrophy that is widely attributed to proliferation of the population of muscle fiber-associated satellite cells that have been identified as the principle source of new muscle tissue during growth and regeneration. Postnatal blockade of myostatin has been proposed as a basis for therapeutic strategies to combat muscle loss in genetic and acquired myopathies. But this approach, according to the accepted mechanism, would raise the threat of premature exhaustion of the pool of satellite cells and eventual failure of muscle regeneration. Here, we show that hypertrophy in the absence of myostatin involves little or no input from satellite cells. Hypertrophic fibers contain no more myonuclei or satellite cells and myostatin had no significant effect on satellite cell proliferation in vitro, while expression of myostatin receptors dropped to the limits of detectability in postnatal satellite cells. Moreover, hypertrophy of dystrophic muscle arising from myostatin blockade was achieved without any apparent enhancement of contribution of myonuclei from satellite cells. These findings contradict the accepted model of myostatin-based control of size of postnatal muscle and reorient fundamental investigations away from the mechanisms that control satellite cell proliferation and toward those that increase myonuclear domain, by modulating synthesis and turnover of structural muscle fiber proteins. It predicts too that any benefits of myostatin blockade in chronic myopathies are unlikely to impose any extra stress on the satellite cells.     

A deficit of brain dystrophin 71 impairs hypothalamic osmostat

Patients with Duchenne muscular dystrophy (DMD) and mdx mice, devoid of dystrophin proteins, show altered ionic homeostasis. To clarify dystrophin's involvement in the central control of osmotic stimuli, we investigated the effect of the disruption of Dp71, the major form of dystrophin in the brain, on the hypothalamoneurohypophysis system (HNHS) osmoregulatory response. Dp71 and Dp140 are the principal DMD gene products in the supraoptic nucleus (SON) and neurohypophysis (NH). They are present in astrocyte and pituicyte end‐feet, suggesting involvement in both intrinsic osmosensitivity of the SON and vasopressin (AVP) release from the NH. In Dp71‐null mice, the cellular distribution of Dp140 was modified, this protein being detected on the membrane of magnocellular soma. The plasma osmolality of Dp71‐null mice was lower than that of wild‐type mice under normal conditions, and this difference was maintained after salt loading, indicating a change in the set point for osmoregulation in the absence of Dp71. The increase in AVP levels detected in the SON and NH of the wild‐type was not observed in Dp71‐null mice following salt loading, and the increase in AVP mRNA levels in the SON was smaller in Dp71‐null than in wild‐type mice. This suggests that Dp71 may be involved in the functional activity of the HNHS. Its astrocyte end‐feet localization emphasizes the importance of neuronal–vascular–glial interactions for the central detection of osmolality. In the SON, Dp71 may be involved in osmosensitivity and definition of the “osmostat,” whereas, in the neurohypopohysis, it may be involved in fine‐tuning AVP release. © 2009 Wiley‐Liss, Inc.     

Ultrasound-guided block of the brachial plexus at the humeral canal

Purpose

Conduction block of the brachial plexus block at the humeral canal, as described by Dupre, has certain clinical indications. The aim of this preliminary study was to assess the feasibility of this technique under ultrasound guidance.

Methods

After ultrasound evaluation of the brachial plexus at the humeral canal in 61 adult volunteers, we performed ultrasound-guided blocks in another 20 adult patients. A linear 38 mm probe, 13–6 MHz, and a 50-mm insulated block needle were used to guide injection of lidocaine 1.5% with epinephrine.

Results

Ulnar and median nerves are superficial and located at similar depths. Ultrasound imaging showed the musculocutaneous nerve to be located dorsally. The radial nerve is dorsal to the plane of the musculocutaneous nerve. Relative to the brachial artery, the median nerve is situated between 12 and 1 o’clock in 66% of the cases. Relative to the basilic vein, the ulnar nerve is situated at 3 o’clock in 46% of the cases. The evaluated block sequence was radial, ulnar, musculocutaneous and median nerve; two points of puncture were mandatory, and 6.85 ± 0.37 min were required to perform the blocks. Sensory onset times were similar for the four nerves. Injectate volume was lower for the musculocutaneous nerve compared to other nerves (P < 0.05). All 20 patients experienced complete sensory and motor blocks.

Conclusion

We describe an approach to, and the feasibility of ultrasound-guided block of the brachial plexus at the humeral canal. Further study will be required to establish the effectiveness and the safety of this technique.     

Outcome of recurrent and metastatic small cell carcinoma of the bladder

Background

Previous studies have shown an association between diabetes mellitus (DM) and urinary incontinence (UI) in women, especially severe UI. The purpose of this study was to investigate whether diabetes related variables could explain this association.

Methods

The study is part of the EPINCONT study, which is based on the large Nord-Trøndelag Health Study 2 (HUNT 2), performed in the county of Nord-Trøndelag, Norway, during the years 1995 - 1997. Questions on diabetes and UI were answered by a total of 21 057 women aged 20 years and older. Of these 685 were identified as having diabetes, and thus comprise the population of our study. A variety of clinical and biochemical variables were recorded from the participants.

Results

Blood-glucose, HbA1c, albumine:creatinine ratio (ACR), duration of diabetes, diabetes treatment, type of diabetes, cholesterol and triglycerides did not significantly differ in women with and without UI in crude analyses. However, the diabetic women with UI had more hospitalizations during the last 12 months, more homecare, and a higher prevalence of angina and use of oestrogene treatment (both local and oral/patch). After adjusting for age, BMI, parity and smoking, there were statistically significant associations between any UI and angina (OR 1.89; 95% CI: 1.22 - 2.93), homecare (OR 1.72; 95% CI: 1.02 - 2.89), and hospitalization during the last 12 months (OR 1.67; 95% CI: 1.18 - 2.38). In adjusted analyses severe UI was also significantly associated with the same variables, and also with diabetes drug treatment (OR 2.10; 95% CI: 1.07 - 4.10) and stroke (OR 2.47; 95% CI: 1.09 - 5.59).

Conclusion

No single diabetes related risk factor seems to explain the increased risk for UI among women with diabetes. However, we found associations between UI and some clinical correlates of diabetes.