Proposal of human spinal cord reirradiation dose based on collection of data from 40 patients

PURPOSE: Driven by numerous reports on recovery of occult radiation injury, reirradiation of the spinal cord today is considered a realistic option. In rodents, long-term recovery was observed to start at approximately 8 weeks. However, prospective clinical studies are lacking. Therefore, a combined analysis of all published clinical data might provide a valuable basis for future trials. METHODS AND MATERIALS: We collected data from 40 individual patients published in eight different reports after a comprehensive MEDLINE search. These represent all patients with data available for dose per fraction and total dose of each of both treatment courses. We recalculated the biologically effective dose (BED) according to the linear-quadratic model using an alpha/beta value of 2 Gy for the cervical and thoracic cord and 4 Gy for the lumbar cord. In this model, a dose of 50 Gy given in single daily fractions of 2 Gy is equivalent to a BED of 100 Gy(2) or 75 Gy(4). For treatment with two daily fractions, a correction term was introduced to take incomplete repair of sublethal damage into account. RESULTS: The cumulative doses ranged from 108 to 205 Gy(2) (median dose, 135 Gy(2)). The median interval between both series was 20 months. Three patients were treated to the lumbar segments only. The median follow-up was 17 months for patients without myelopathy. Eleven patients developed myelopathy after 4-25 months (median, 11 months). Myelopathy was seen only in patients who had received one course to a dose of > or =102 Gy(2) (n = 9) or were retreated after 2 months (n = 2). In the absence of these two risk factors, no myelopathy developed in 19 patients treated with < or =135.5 Gy(2) or 7 patients treated with 136-150 Gy(2). A risk score based on the cumulative BED, the greatest BED for all treatment series in a particular individual, and interval was developed. Low-risk patients remained free of myelopathy and 33% of intermediate-risk patients and 90% of high-risk patients developed myelopathy. CONCLUSION: On the basis of these literature data (and with due caution), the risk of myelopathy appears small after < or =135.5 Gy(2) when the interval is not shorter than 6 months and the dose of each course is < or =98 Gy(2). We would recommend limiting the dose to this level, whenever technically feasible. However, it appears prudent to propose the collection of prospective data from a greater number of patients receiving doses in the range of 136-150 Gy(2) to assess the safety of higher retreatment doses for those patients in whom limited doses might compromise tumor control.     

Comparison of the FreeHand® robotic camera holder with human assistants during endoscopic extraperitoneal radical prostatectomy

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? The use of robotic arms for instrument and camera manipulation has been proposed for more than a decade. The current study provides a direct comparison of robotic camera movement to the conventional human camera holding assistance in real operative room setting.

OBJECTIVE

? To assess, in a prospective randomized study, the efficiency of the FreeHand® (Prosurgics Ltd, Bracknell, UK) compared to manual camera control during the performance of endoscopic extraperitoneal radical prostatectomy (EERPE).

PATIENTS AND METHODS

? Three surgeons performed 50 EERPE for localized prostate cancer. In group A (n= 25), procedures were performed with manual control of the camera by the assistant, whereas group B (n= 25) patients were treated with the assistance of the FreeHand® robotic device. ? The EERPE procedure was divided into several steps. ? Total operation duration, time for each surgical step, number of camera movements, number of movement errors, number of times the lens was cleaned, blood loss and margin status were compared.

RESULTS

? No statistically significant difference was observed in terms of patient age, preoperative prostate‐specific antigen level, Gleason score, positive cores and prostate volume. ? The average operation duration required for the performance of each step did not differ significantly between the two groups. ? Significant differences in favour of the FreeHand® camera holder were observed in case of horizontal and zooming camera movement, camera cleaning and camera errors. ? Vertical camera movements were performed significantly faster by the human assistant compared to the robotic camera holder. ? The average total operation duration was similar for both groups. ? Positive surgical margins were detected in one patient in each group (4% of the patients).

CONCLUSIONS

? A comparison of the FreeHand® robotic camera holder with human camera control during EERPE showed a similar time requirement for the performance of each step of the procedure. ? The robotic system provided accurate and fast movements of the camera without compromising the outcome of the procedure.     

Identification of new target molecules PTK2, TGFBR2 and CD9 overexpressed during advanced bone marrow remodelling in primary myelofibrosis

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by remodelling of the bone marrow, including progressive myelofibrosis and exaggerated angiogenesis. Advanced PMF frequently shows a full-blown fibre meshwork, which avoids aspiration of cells, and the expression profile of genes related to stroma pathology at this stage remains largely undetermined. We investigated bone marrow core biopsies in PMF showing various degrees of myelofibrosis by custom-made low density arrays (LDA) representing target genes with designated roles in synthesis of extracellular matrix, matrix remodelling, cellular adhesion and motility. Among a set of 11 genes up-regulated in advanced stages of PMF ( P  ≤ 0·01) three candidates, PTK2 protein tyrosine kinase 2 ( PTK2 ), transforming growth factor β type II receptor ( TGFBR2 ) and motility-related protein-1 (CD9 molecule, CD9 ), were investigated in more detail. PTK2 , TGFBR2 and CD9 were significantly overexpressed in larger series of advanced PMF stages ( P  ≤ 0·01 respectively). Endothelial cells of the increased microvessel network in PMF could be identified as a predominant source for PTK2 , TGFBR2 and CD9 . CD9 also strongly identified activated fibroblasts in advanced myelofibrosis. We conclude that PTK2 , TGFBR2 and CD9 represent new target molecules involved in bone marrow remodelling of PMF and warrant further investigation for potential targeted therapy.     

The changing scene of allogeneic stem cell transplantation for chronic myeloid leukemia—a report from the German Registry covering the period from 1998 to 2004

Due to the recent changes in the indication to allogeneic stem cell transplantation (SCT) in chronic myeloid leukemia (CML), we retrospectively analyzed 1,716 patients with different CML stages who received an allograft from related (n?=?767) or unrelated donors (n?=?938) within the German Registry of Stem Cell Transplantation (DRST) from 1998 to 2004. Myeloablative conditioning was performed in 724/871 cases (83%), dose-reduced conditioning in 147/871 (17%). Annual transplantations were decreasing from 357 to 98 (28%) in the period of study, but the proportion of advanced cases was increasing from 32% (112/346) to 53% (50/94) of all SCTs. Stage of disease, intervals from diagnosis, and patients’ age were independent prognostic parameters, while peripheral stem cells and unrelated transplantation seemed equal to bone marrow/related transplantation. This study demonstrates that allo-SCT still has an important role in advanced CML, which emphasizes the need for optimized transplantation strategies for these high-risk patients.     

Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans

BACKGROUND: Exogenous use of the intestinal hormone glucagon-like peptide 1 (GLP-1) lowers glycaemia by stimulation of insulin, inhibition of glucagon, and delay of gastric emptying. AIMS: To assess the effects of endogenous GLP-1 on endocrine pancreatic secretion and antro-pyloro-duodenal motility by utilising the GLP-1 receptor antagonist exendin(9-39)amide (ex(9-39)NH2). METHODS: Nine healthy volunteers underwent four experiments each. In two experiments with and without intravenous infusion of ex(9-39)NH2 300 pmol/kg/min, a fasting period was followed by intraduodenal glucose perfusion at 1 and 2.5 kcal/min, with the higher dose stimulating GLP-1 release. Antro-pyloro-duodenal motility was measured by perfusion manometry. To calculate the incretin effect (that is, the proportion of plasma insulin stimulated by intestinal hormones) the glycaemia observed during the luminal glucose experiments was mimicked using intravenous glucose in two further experiments. RESULTS: Ex(9-39)NH2 significantly increased glycaemia during fasting and duodenal glucose. It diminished plasma insulin during duodenal glucose and significantly reduced the incretin effect by approximately 50%. Ex(9-39)NH2 raised plasma glucagon during fasting and abolished the decrease in glucagon at the high duodenal glucose load. Ex(9-39)NH2 markedly stimulated antroduodenal contractility. At low duodenal glucose it reduced the stimulation of tonic and phasic pyloric motility. At the high duodenal glucose load it abolished pyloric stimulation. CONCLUSIONS: Endogenous GLP-1 stimulates postprandial insulin release. The pancreatic alpha cell is under the tonic inhibitory control of GLP-1 thereby suppressing postprandial glucagon. GLP-1 tonically inhibits antroduodenal motility and mediates the postprandial inhibition of antral and stimulation of pyloric motility. We therefore suggest GLP-1 as a true incretin hormone and enterogastrone in humans.     

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