Despite adjuvant 5-fluorouracil (5-FU) therapy, approximately 30% of patients with International Union against Cancer stage II and III colorectal cancer develop recurrence. In this study, we ...determined the prognostic value of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) expression in colorectal cancer patients treated with adjuvant 5-FU.
A real-time reverse transcription-PCR technique for quantitation of relative gene expression from paraffin-embedded specimen was established first. In a second step, archival paraffin-embedded primary tumor tissue of 309 patients who participated in adjuvant colorectal cancer trials was analyzed for TS and DPD mRNA expression.
TS mRNA expression determined by real-time reverse transcription-PCR correlated with TS protein levels determined by TS immunoblot and immunohistochemistry in cultured colon cancer cell lines and paraffin-embedded primary tumor tissue. TS mRNA levels in fresh-frozen tissues also correlated with TS mRNA levels in corresponding paraffin sections. Among the patients receiving adjuvant 5-FU therapy, those with high TS survived longer than those with low TS, and in each TS subgroup, the ones with low DPD survived longer than the ones with high DPD levels. Multiple Cox regression analysis showed that besides tumor stage (P = 0.010), only the combination of TS and DPD expression turned out to be an independent prognostic factor for survival (P = 0.030).
This suggests that TS and DPD quantitation may be helpful to evaluate prognosis of patients receiving adjuvant 5-FU and that patients with high TS and low DPD may benefit from adjuvant 5-FU chemotherapy.
The study focuses on growth responses of Larix decidua provenances to climatic transfer based on a regional provenance experiment. This comprises a series of 5 trial plots situated in Germany and ...Slovakia, where 12 indigenous Sudetic and West-Carpathian larch provenances are planted. Transfer rates were defined as differences in altitudes or climatic variables between the site of plantation and the site of origin. 1 super(st) and 2 super(nd)-order polynomial regressions were used for the identification of overall trends of growth performance and responses to transfer. Sudetic provenances clearly outperformed the Carpathian ones on all test sites. When all provenances were considered jointly, height and breast-height diameter mostly showed significant monotonous geographical and climatic trends: the performance generally decreased with increasing altitude and precipitations and decreasing temperatures. The relationships between growth response and transfer rates (ecodistances) were mostly linear. However, when Sudetic and Carpathian provenances were considered separately, most significant response curves were unimodal. There is a very good correspondence between the responses in height and diameter growth within geographic groups, but the responses are not consistent between groups. Joint regression analysis showed that most provenances exhibited average stability. Stability indices are quite consistent between the response traits and did not show any association with the geographical position, climate of origin, or growth performance. The results indicate that populations in different climates remain adapted to a common optimum, the extent of local adaptation is quite limited. Possible explanations of this observation are briefly discussed.
Increasing the flexibility of conventional power plants is one key challenge for the massive integration of highly volatile renewable energy resources into the German and European power system. ...Flexible power plants ensure the security of supply by compensating fluctuations in the electrical grid caused by intermittent renewable energy production from wind and sun. In this paper, the future development of the German electricity market is predicted and evaluated in terms of the future flexibility demand of coal-fired power plants based on simulation studies for four distinct years. As the flexibility measures for coal-fired power plants generally use inherent capabilities of the existing power plant systems, they are usually restricted by limiting factors. Here, the limiting factors for reducing the minimum load and increasing load change rates are discussed and potential measures to mitigate their influence are presented. An alternative way to increase the flexibility lies in properly integrating thermal energy storages. This integration is presented and evaluated using a dynamic power plant model in EBSILON®Professional. Simulations show that by integrating this storage concept the electrical minimum load can be reduced while simultaneously increasing the load change rate.
The need for a conversion is a problem inherent in laparoscopic surgery. The present study points up the significance of conversion for the results obtained with laparoscopic colorectal surgery and ...identifies the risk factors that establish the need for conversion.
The study took the form of a multicentric, prospective, observational study within the Laparoscopic Colorectal Surgery Study Group. A total of 33 institutions in Germany, Austria, and Switzerland participated. The study period was 3.5 years. Cases were documented with the aid of a standardized questionnaire.
Within the framework of the Laparoscopic Colorectal Surgery Study Group, a total of 1,658 patients were recruited to a multicenter study over a period of three and one-half years (from August 1, 1995 to February 1, 1999). The observed conversion rate was 5.2 percent (n = 86). The patients requiring a conversion were significantly heavier (body mass index, 26.5 vs. 24.9) than those undergoing pure laparoscopy. Resections of the rectum were associated with a higher risk for conversion (20.9 vs. 13 percent). Intraoperative complications occurred significantly more frequently in the conversion group (27.9 vs. 3.8 percent). The duration of the operation was significantly increased after conversion in a considerable proportion of the procedures performed. Postoperative morbidity (47.7 vs. 26.1 percent), mortality (3.5 vs. 1.5 percent), recovery time, and postoperative hospital stay were all negatively influenced by conversion, in part significantly. Institutions with experience of more than 100 laparoscopic colorectal procedures proved to have a significantly lower conversion rate than those with experience of fewer than 100 such interventions (4.3 vs. 6.9 percent).
Although, of itself, conversion is not considered to be a complication of laparoscopic surgery, it is true that the postoperative course after conversion is associated with appreciably poorer results in terms of morbidity, mortality, convalescence, blood transfusion requirement, and postoperative hospital stay. The importance of experience in laparoscopic surgery can be demonstrated on the basis of the conversion rates. Careful patient selection oriented to the experience of the surgeon is required if we are to keep the conversion, morbidity, and mortality rates of laparoscopic colorectal procedures as low as possible.
Various studies have been performed in general surgery patients comparing low molecular weight heparin (LMWH) with standard heparin (SH) for the prevention of postoperative deep vein thrombosis ...(DVT), revealing contradicting results. Therefore, we have compared the efficacy and safety of a LMWH for the prevention of DVT after major general surgery.
Patients received either 20 mg LMWH (enoxaparm) once daily, or 5,000 IU SH
tid, starting preoperatively in a prospective, randomized, double-blind international multicenter trial. DVT was diagnosed using fibrinogen I 125 leg scanning. Major and minor bleeding were assessed clinically.
A total of 718 patients were randomized to LMWH, and 709 patients to SH. DVT was detected in 58 LMWH-treated patients (8.1%, 95% confidence interval CI 6.2% to 10.3%) and in 45 patients allocated to SH (6.3%, 95% CI 4.7% to 8.4%,
P >0.05). Major bleeding complications occurred in 11 LMWH-treated patients (1.5%, 95% CI 0.8% to 2.7%) and in 18 patients to whom standard heparin was administered (2.5%, 95% CI 1.5% to 3.9%,
P >0.05). Four LMWH-treated patients (0.6%) required reoperation for bleeding as compared to 13 patients in the SH group (1.8%,
P = 0.03).
This LMWH appeared as effective and safe as SH. In view of its more convenient way of administration, this LMWH might be preferred for thromboprophylaxis.
Genetic studies have established anaplastic lymphoma kinase (ALK), a cell surface receptor tyrosine kinase, as a tractable molecular target in neuroblastoma. We describe comprehensive genomic, ...biochemical, and computational analyses of ALK mutations across 1,596 diagnostic neuroblastoma samples. ALK tyrosine kinase domain mutations occurred in 8% of samples—at three hot spots and 13 minor sites—and correlated significantly with poorer survival in high- and intermediate-risk neuroblastoma. Biochemical and computational studies distinguished oncogenic (constitutively activating) from nononcogenic mutations and allowed robust computational prediction of their effects. The mutated variants also showed differential in vitro crizotinib sensitivities. Our studies identify ALK genomic status as a clinically important therapeutic stratification tool in neuroblastoma and will allow tailoring of ALK-targeted therapy to specific mutations.
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•ALK mutations occur in 8% of neuroblastoma patients across all stages of disease•The presence of an ALK tyrosine kinase domain mutation correlates with poor prognoses•A biochemically informed computational approach identifies oncogenic mutations•Oncogenic ALK mutations differ significantly in tumor cell sensitivity to crizotinib
Bresler et al. carry out comprehensive genomic, biochemical, and computational analyses of ALK mutations across a large cohort of diagnostic neuroblastoma samples and develop computational approaches for identifying disease-significant ALK mutations, which will also allow tailoring of ALK-targeted therapies.
Although neoadjuvant chemoradiotherapy achieves low local recurrence rates in clinical stages II to III rectal cancer, it delays administration of optimal chemotherapy. We evaluated preoperative ...infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/bevacizumab with selective rather than consistent use of chemoradiotherapy.
Thirty-two patients with clinical stages II to III rectal cancer participated in this single-center phase II trial. All were candidates for low anterior resection with total mesorectal excision (TME). Patients were to receive six cycles of FOLFOX, with bevacizumab included for cycles 1 to 4. Patients with stable/progressive disease were to have radiation before TME, whereas responders were to have immediate TME. Postoperative radiation was planned if R0 resection was not achieved. Postoperative FOLFOX × 6 was recommended, but adjuvant regimens were left to clinician discretion. The primary outcome was R0 resection rate.
Between April 2007 and December 2008, 32 (100%) of 32 study participants had R0 resections. Two did not complete preoperative chemotherapy secondary to cardiovascular toxicity. Both had preoperative chemoradiotherapy and then R0 resections. Of 30 patients completing preoperative chemotherapy, all had tumor regression and TME without preoperative chemoradiotherapy. The pathologic complete response rate to chemotherapy alone was 8 of 32 (25%; 95% CI, 11% to 43%). The 4-year local recurrence rate was 0% (95% CI, 0% to 11%); the 4-year disease-free survival was 84% (95% CI, 67% to 94%).
For selected patients with clinical stages II to III rectal cancer, neoadjuvant chemotherapy and selective radiation does not seem to compromise outcomes. Preoperative Radiation or Selective Preoperative Radiation and Evaluation Before Chemotherapy and TME (PROSPECT), a randomized phase III trial to validate this experience, is now open in the US cooperative group network.
Food allergy can result in considerable morbidity, impact negatively on quality of life, and prove costly in terms of medical care. These guidelines have been prepared by the European Academy of ...Allergy and Clinical Immunology's (EAACI) Guidelines for Food Allergy and Anaphylaxis Group, building on previous EAACI position papers on adverse reaction to foods and three recent systematic reviews on the epidemiology, diagnosis, and management of food allergy, and provide evidence‐based recommendations for the diagnosis and management of food allergy. While the primary audience is allergists, this document is relevant for all other healthcare professionals, including primary care physicians, and pediatric and adult specialists, dieticians, pharmacists and paramedics. Our current understanding of the manifestations of food allergy, the role of diagnostic tests, and the effective management of patients of all ages with food allergy is presented. The acute management of non‐life‐threatening reactions is covered in these guidelines, but for guidance on the emergency management of anaphylaxis, readers are referred to the related EAACI Anaphylaxis Guidelines.
Background The surgical learning curve persists for years after training, yet existing continuing medical education activities targeting this are limited. We describe a pilot study of a scalable ...video-based intervention, providing individualized feedback on intraoperative performance. Study Design Four complex operations performed by surgeons of varying experience—a chief resident accompanied by the operating senior surgeon, a surgeon with less than 10 years in practice, another with 20 to 30 years in practice, and a surgeon with more than 30 years of experience—were video recorded. Video playback formed the basis of 1-hour coaching sessions with a peer-judged surgical expert. These sessions were audio recorded, transcribed, and thematically coded. Results The sessions focused on operative technique—both technical aspects and decision-making. With increasing seniority, more discussion was devoted to the optimization of teaching and facilitation of the resident's technical performance. Coaching sessions with senior surgeons were peer-to-peer interactions, with each discussing his preferred approach. The coach alternated between directing the session (asking probing questions) and responding to specific questions brought by the surgeons, depending on learning style. At all experience levels, video review proved valuable in identifying episodes of failure to progress and troubleshooting alternative approaches. All agreed this tool is a powerful one. Inclusion of trainees seems most appropriate when coaching senior surgeons; it may restrict the dialogue of more junior attendings. Conclusions Video-based coaching is an educational modality that targets intraoperative judgment, technique, and teaching. Surgeons of all levels found it highly instructive. This may provide a practical, much needed approach for continuous professional development.
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