Revision anterior cruciate ligament reconstruction with quadriceps tendon-patellar bone autograft.

PURPOSE: To evaluate the cause of recurrent pathologic instability after anterior cruciate ligament (ACL) surgery and the effectiveness of revision reconstruction using a quadriceps tendon autograft using a 2-incision technique. TYPE OF STUDY: Retrospective follow-up study. METHODS: Between 1999 and 2001, 31 patients underwent ACL revision reconstruction because of recurrent pathologic instability during sports or daily activities. Twenty-eight patients were reviewed after a mean follow-up of 4.2 years (range, 3.3 to 5.6 years). The mean age at revision surgery was 27 years (range, 18 to 41 years). The average time from primary procedure to revision surgery was 26 months (range, 9 to 45 months). A clinical, functional, and radiographic evaluation was performed. Also magnetic resonance imaging (MRI) or computed tomography (CT) scanning was performed. The International Knee Documentation Committee (IKDC), Lysholm, and Tegner scales were used. A KT-1000 arthrometer measurement (MEDmetric, San Diego, CA) by an experienced physician was made. RESULTS: Of the failures, 79% had radiographic evidence of malposition of their tunnels. In only 6 cases (21%) was the radiologic anatomy of tunnel placement judged to be correct on both the femoral and tibial side. The MRI or CT showed, in 6 cases, a too-centrally placed femoral tunnel. After revision surgery, the position of tunnels was corrected. A significant improvement of Lachman and pivot-shift phenomenon was observed. In particular, 17 patients had a negative Lachman test, and 11 patients had a grade I Lachman with a firm end point. Preoperatively, the pivot-shift test was positive in all cases, and at last follow-up in 7 patients (25%) a grade 1+ was found. Postoperatively, KT-1000 testing showed a mean manual maximum translation of 8.6 mm (SD, 2.34) for the affected knee; 97% of patients had a maximum manual side-to-side translation <5 mm. At the final postoperative evaluation, 26 patients (93%) graded their knees as normal or nearly normal according to the IKDC score. The mean Lysholm score was 93.6 (SD, 8.77) and the mean Tegner activity score was 6.1 (SD, 1.37). No patient required further revision. Five patients (18%) complained of hypersensitive scars from the reconstructive surgery that made kneeling difficult. CONCLUSIONS: There were satisfactory results after ACL revision surgery using quadriceps tendon and a 2-incision technique at a minimum 3 years' follow-up; 93% of patients returned to sports activities. LEVEL OF EVIDENCE: Level IV, case series, no control group.

Topical therapy is underused in patients with ulcerative colitis.

The availability of new topical preparations for the treatment of left sided ulcerative colitis offers a therapy optimization for many patients. Rectal application of steroids and 5-aminosalicylic acid (5-ASA) is associated with fewer side effects and has a higher therapeutic efficacy in left-sided colitis as compared to a systemic therapy. Therefore, we were interested in the use of topical therapy in patients with ulcerative colitis. The key question was whether topical treatment is more frequently used than oral therapy in patients with proctitis and left sided colitis. Data of 800 patients of the Swiss IBD cohort study were analyzed. Sixteen percent of patients of the cohort had proctitis, 21% proctosigmoiditis and 41% pancolitis. Topical therapy with 5-ASA or corticosteroids was given in 26% of patients with proctitis, a combined systemic and topical treatment was given in 13%, whereas systemic treatment with 5-ASA without topical treatment was given in 29%. Proportion of topical drug use decreased with respect to disease extension from 39% for proctitis to 13.1% for pancolitis (P=0.001). Patients with severe colitis received a significantly higher dose of topical 5-ASA than patients in remission. Side effects of topical or systemic 5-ASA or budesonide treatment were less frequently seen compared to other medications. Topical treatment was frequently stopped over time. The quality of life was the same in patients with limited disease compared to patients with pancolitis. Topical treatment in proctitis patients was underused in Switzerland. Since topical treatment is safe and effective it should be used to a larger extend.

Is adjuvant chemotherapy of benefit for postmenopausal women who receive endocrine treatment for highly endocrine-responsive, node-positive breast cancer? International Breast Cancer Study Group Trials VII and 12-93.

To compare the efficacy of chemoendocrine treatment with that of endocrine treatment (ET) alone for postmenopausal women with highly endocrine responsive breast cancer. In the International Breast Cancer Study Group (IBCSG) Trials VII and 12-93, postmenopausal women with node-positive, estrogen receptor (ER)-positive or ER-negative, operable breast cancer were randomized to receive either chemotherapy or endocrine therapy or combined chemoendocrine treatment. Results were analyzed overall in the cohort of 893 patients with endocrine-responsive disease, and according to prospectively defined categories of ER, age and nodal status. STEPP analyses assessed chemotherapy effect. The median follow-up was 13 years. Adding chemotherapy reduced the relative risk of a disease-free survival event by 19% (P = 0.02) compared with ET alone. STEPP analyses showed little effect of chemotherapy for tumors with high levels of ER expression (P = 0.07), or for the cohort with one positive node (P = 0.03). Chemotherapy significantly improves disease-free survival for postmenopausal women with endocrine-responsive breast cancer, but the magnitude of the effect is substantially attenuated if ER levels are high.

Efforts to standardise Ki-67 counting in breast cancer. A pilot study of the Swiss Working Group of Gyneco- and Breast Pathologists

Goals: Adjuvant chemotherapy decisions in breast cancer are increasing based on the pathologist's assessment of the proliferation fraction in the tumor. Yet, how good and how reproducible are we pathologists at providing reliable Ki-67 readings on breast carcinomas. Exactly how to count and in which areas to count within a tumor remains inadequately standardized. The Swiss Working Group of Gyneco- and Breast Pathologists has tried to appreciate this dilemma and to propose ways to obtain more reproducible results.Methods: In a first phase, 5 pathologists evaluated Ki67 counts in 10 breast cancers by exact counting (500 cells) and by eyeballing. Pathologists were free to select the region in which Ki67 was evaluated. In a second phase 16 pathologists evaluated Ki-67 counts in 3 breast cancers also by exact counting and eyeballing, but in predefined fields of interest. In both phases, Ki67 was assessed in centrally immunostained slides (ZH) and on slides immunostained in the 11 participating laboratories. In a third phase, these same 16 pathologists were once again asked to read the 3 cases from phase 2, plus three new cases, and this time exact guidelines were provided as to what exactly is considered a Ki-67 positive nucleus.Results: Discordance of Ki67 assessment was due to each of the following 4 factors: (i) pathologists' divergent definitions of what counts as a positive nucleus (ii) the mode of assessment (counting vs. eyeballing), (iii) immunostaining technique/protocol/antibody, and (iv) the selection of the area in which to count.Conclusion: Providing guidelines as to where to count (representative field in the tumor periphery and omitting hot spots) and what nuclei to count (even faintly immunostained nuclei count as positive) reduces the discordance rates of Ki67 readings between pathologists. Laboratory technique is only of minor importance (even over a large antibody dilution range), and counting nuclei does not improve accuracy, but rather aggravates deviations from the group mean values.Disclosure of Interest: None Declared

Individual patient data systematic review and meta-analysis of optic nerve sheath diameter ultrasonography for detecting raised intracranial pressure: protocol of the ONSD research group.

BACKGROUND: The purpose of the optic nerve sheath diameter (ONSD) research group project is to establish an individual patient-level database from high quality studies of ONSD ultrasonography for the detection of raised intracranial pressure (ICP), and to perform a systematic review and an individual patient data meta-analysis (IPDMA), which will provide a cutoff value to help physicians making decisions and encourage further research. Previous meta-analyses were able to assess the diagnostic accuracy of ONSD ultrasonography in detecting raised ICP but failed to determine a precise cutoff value. Thus, the ONSD research group was founded to synthesize data from several recent studies on the subject and to provide evidence on the diagnostic accuracy of ONSD ultrasonography in detecting raised ICP. METHODS: This IPDMA will be conducted in different phases. First, we will systematically search for eligible studies. To be eligible, studies must have compared ONSD ultrasonography to invasive intracranial devices, the current reference standard for diagnosing raised ICP. Subsequently, we will assess the quality of studies included based on the QUADAS-2 tool, and then collect and validate individual patient data. The objectives of the primary analyses will be to assess the diagnostic accuracy of ONSD ultrasonography and to determine a precise cutoff value for detecting raised ICP. Secondly, we will construct a logistic regression model to assess whether patient and study characteristics influence diagnostic accuracy. DISCUSSION: We believe that this IPD MA will provide the most reliable basis for the assessment of diagnostic accuracy of ONSD ultrasonography for detecting raised ICP and to provide a cutoff value. We also hope that the creation of the ONSD research group will encourage further study. TRIAL REGISTRATION: PROSPERO registration number: CRD42012003072.

Editorial research and the publication process in biomedicine and health: Report from the Esteve Foundation Discussion Group, December 2012.

Despite the fact that there are more than twenty thousand biomedical journals in the world, research into the work of editors and publication process in biomedical and health care journals is rare. In December 2012, the Esteve Foundation, a non-profit scientific institution that fosters progress in pharmacotherapy by means of scientific communication and discussion organized a discussion group of 7 editors and/or experts in peer review biomedical publishing. They presented findings of past editorial research, discussed the lack of competitive funding schemes and specialized journals for dissemination of editorial research, and reported on the great diversity of misconduct and conflict of interest policies, as well as adherence to reporting guidelines. Furthermore, they reported on the reluctance of editors to investigate allegations of misconduct or increase the level of data sharing in health research. In the end, they concluded that if editors are to remain gatekeepers of scientific knowledge they should reaffirm their focus on the integrity of the scientific record and completeness of the data they publish. Additionally, more research should be undertaken to understand why many journals are not adhering to editorial standards, and what obstacles editors face when engaging in editorial research.

Intrathecal analgesia and restrictive perioperative fluid management within enhanced recovery pathway: hemodynamic implications.

BACKGROUND: Intrathecal analgesia and avoidance of perioperative fluid overload are key items within enhanced recovery pathways. Potential side effects include hypotension and renal dysfunction. STUDY DESIGN: From January 2010 until May 2010, all patients undergoing colorectal surgery within enhanced recovery pathways were included in this retrospective cohort study and were analyzed by intrathecal analgesia (IT) vs none (noIT). Primary outcomes measures were systolic and diastolic blood pressure, mean arterial pressure, and heart rate for 48 hours after surgery. Renal function was assessed by urine output and creatinine values. RESULTS: One hundred and sixty-three consecutive colorectal patients (127 IT and 36 noIT) were included in the analysis. Both patient groups showed low blood pressure values within the first 4 to 12 hours and a steady increase thereafter before return to baseline values after about 24 hours. Systolic and diastolic blood pressure and mean arterial pressure were significantly lower until 16 hours after surgery in patients having IT compared with the noIT group. Low urine output (<0.5 mL/kg/h) was reported in 11% vs 29% (IT vs noIT; p = 0.010) intraoperatively, 20% vs 11% (p = 0.387), 33% vs 22% (p = 0.304), and 31% vs 21% (p = 0.478) for postanesthesia care unit and postoperative days 1 and 2, respectively. Only 3 of 127 (2.4%) IT and 1 of 36 (2.8%) noIT patients had a transitory creatinine increase >50%; no patients required dialysis. CONCLUSIONS: Postoperative hypotension affects approximately 10% of patients within an enhanced recovery pathway and is slightly more pronounced in patients with IT. Hemodynamic depression persists for <20 hours after surgery; it has no measurable negative impact and therefore cannot justify detrimental postoperative fluid overload.

Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity.

OBJECTIVE: We investigated whether the oral administration of a low dose (75 micro g) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. METHODS: Plasma concentrations of midazolam, 1'OH-midazolam and 4'OH-midazolam were measured after the oral administration of 7.5 mg and 75 micro g midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2 days with ketoconazole (200 mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4 days with rifampicin (450 mg q.d.), a CYP3A inducer. RESULTS: After oral administration of 75 micro g midazolam, the 30-min total (unconjugated + conjugated) 1'OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean+/-SD): 6.23+/-2.61, 0.79+/-0.39 and 56.1+/-12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1'OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r(2)=0.64, P<0.001) and in the three groups taken together (r(2)=0.91, P<0.0001). Good correlations were also observed between midazolam plasma levels and midazolam clearance, measured between 1.5 h and 4 h. CONCLUSION: A low oral dose of midazolam can be used to phenotype CYP3A, either by the determination of total 1'OH-midazolam/midazolam ratios at 30 min or by the determination of midazolam plasma levels between 1.5 h and 4 h after its administration.

Analysis of TNF-antagonist switch over time and associated risk factors in the Swiss Inflammatory Bowel Disease Cohort

Abstract Background and aims. Limited data from large cohorts are available on tumor necrosis factor (TNF) antagonists (infliximab, adalimumab, certolizumab pegol) switch over time. We aimed to evaluate the prevalence of switching from one TNF antagonist to another and to identify associated risk factors. Methods. Data from the Swiss Inflammatory Bowel Diseases Cohort Study (SIBDCS) were analyzed. Results. Of 1731 patients included into the SIBDCS (956 with Crohn's disease [CD] and 775 with ulcerative colitis [UC]), 347 CD patients (36.3%) and 129 UC patients (16.6%) were treated with at least one TNF antagonist. A total of 53/347 (15.3%) CD patients (median disease duration 9 years) and 20/129 (15.5%) of UC patients (median disease duration 7 years) needed to switch to a second and/or a third TNF antagonist, respectively. Median treatment duration was longest for the first TNF antagonist used (CD 25 months; UC 14 months), followed by the second (CD 13 months; UC 4 months) and third TNF antagonist (CD 11 months; UC 15 months). Primary nonresponse, loss of response and side effects were the major reasons to stop and/or switch TNF antagonist therapy. A low body mass index, a short diagnostic delay and extraintestinal manifestations at inclusion were identified as risk factors for a switch of the first used TNF antagonist within 24 months of its use in CD patients. Conclusion. Switching of the TNF antagonist over time is a common issue. The median treatment duration with a specific TNF antagonist is diminishing with an increasing number of TNF antagonists being used.

Immunochemical characterization of two antigens recognized by new monoclonal antibodies against human colon carcinoma.

Two different monoclonal antibodies (MAb), called L-D1 and L-C5, were produced after immunization with either intact cells or the methanol phase of glycolipid extracts, respectively, from the same human colon carcinoma line, LoVo. As determined by an antibody-binding radioimmunoassay (RIA) on intact cells, MAb L-D1 and MAb L-C5 were highly reactive with all five colon carcinoma lines tested and with only one out of the 21 cell lines of various tissue origin tested. No reactivity of either MAb was observed with peripheral blood lymphocytes, granulocytes, or erythrocytes from healthy donors of various blood groups. Both MAb were tested in competitive binding experiments with an anti-CEA MAb from our laboratory (CEA 35) and with two previously described anti-colon carcinoma MAb from the Wistar Institute called 1083-17-1A (17-1A) and NS-19.9. In competitive binding experiments, MAb L-D1 was inhibited by MAb 17-1A and reciprocally, whereas MAb L-C5 was not inhibited by any of the other MAb tested. MAb L-D1 precipitated a major protein band with an apparent molecular weight (MW) of 41 kilodaltons (kD); interestingly, MAb 17-1A, which was reported to react with an uncharacterized antigen, precipitated the same protein band of 41 kD. This was confirmed with immunodepletion experiments. Furthermore, after treatment of the colon carcinoma cell line with tunicamycin, both MAb L-D1 and 17-1A precipitated a protein band of 35 kD. This shift of 6 kD suggests that the glycoprotein recognized by these 2 MAb contains two to three N-linked carbohydrate side chains. MAb L-C5 precipitated a group of three to four protein bands ranging from 43 to 53 kD that were not modified by tunicamycin treatment. A preliminary study conducted by using immunoperoxidase labeling on frozen sections of primary colon carcinoma showed that the two new MAb react strongly with these tumors, but also weakly with the normal adjacent mucosa, as did the other anti-colon carcinoma MAb tested.

Tension-band wiring of olecranon fractures - Biomechanical analysis of different fixation techniques

Tension-band wiring is a recognised standard treatment for fixation of olecranon fractures. The classical operation technique is well known and widespread among the orthopaedic surgeons. Nevertheless complications like K-wire migration or skin perforation and difficult technical as well as anatomical prerequisites require better-adapted operation fixation methods. In older female patients a cut through of the Kirschner wires with concomitant secondary displacement was observed. We intent to develop a new, better adapted operation technique for olecranon fractures in the old patients, in order to decrease complications and follow-up procedures. In this study we compare two different K-wire positions: 10 models of the classical AO tension-banding to 10 models with adapted K-wire insertion. In this group the K-wire passes from the tip of the olecranon to the posterior cortical of the distal fragment of the ulna. We tested maximal failure load, maximal opening angle as well as maximal work to achieve maximal force. In either technique we were able to determine different variables: a maximal failure load of more than 600N (p = 0.94) for both fixation methods and a maximal opening angle for both techniques of about 10° (p = 0.86). To achieve the maximal force our modified technique required a slightly increased work (p = 0.16). In this study no statistical significant differences between the two fixation techniques was shown. This leads to the conclusion that the modified version is comparable to the classical operation technique considering the stability, but due to the adaption of the angle in the modified procedure, less lesions of neurovascular structures on the volar side can be expected. To support our findings cadaver studies are needed for further investigations.

Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group.

OBJECTIVE: The purpose of this study was to compare the short-term efficacy and safety of risperidone and clozapine in treatment-resistant chronic schizophrenic patients. METHOD: In a controlled double-blind, multicenter study, 86 inpatients with chronic schizophrenia (DSM-III-R), who were resistant to or intolerant of conventional neuroleptics, were randomly assigned to receive risperidone or clozapine for 8 weeks after a 7-day washout period. After a 1-week dose-titration phase, doses were fixed at 6 mg/day of risperidone and 300 mg/day of clozapine for 1 week and then adjusted according to each patient's response. The final mean doses were 6.4 mg/day of risperidone and 291.2 mg/day of clozapine. Treatment efficacy and safety were evaluated with several well-known rating scales. RESULTS: Both risperidone and clozapine significantly reduced the severity of psychotic symptoms (scores on the Positive and Negative Syndrome Scale and the Clinical Global Impression scale) from baseline, with no significant between-group differences. At endpoint, 67% of the risperidone group and 65% of the clozapine group were clinically improved (reduction of 20% or more in total Positive and Negative Syndrome Scale score). Risperidone appeared to have a faster onset of action. In both groups extrapyramidal symptoms and other adverse events were few, and their severity was generally mild. Neither group showed evidence of a relation between drug plasma concentrations and clinical effectiveness. CONCLUSIONS: Risperidone was well tolerated and as effective as medium doses of clozapine in patients with chronic schizophrenia who had been resistant to or intolerant of conventional neuroleptics.

Long-term Outcome and Late Side Effects in Endometrial Cancer Patients Treated with Surgery and Postoperative Radiation Therapy.

BACKGROUND: We retrospectively reviewed the long-term outcome and late side effects of endometrial cancer (EC) patients treated with different techniques of postoperative radiotherapy (PORT). METHODS: Between 1999 and 2012, 237 patients with EC were treated with PORT. Two-dimensional external beam radiotherapy (2D-EBRT) was used in 69 patients (30 %), three-dimensional EBRT (3D-EBRT) in 51 (21 %), and intensity-modulated RT (IMRT) with helical Tomotherapy in 47 (20 %). All patients received a vaginal brachytherapy (VB) boost. Seventy patients (29 %) received VB alone. RESULTS: After a median of 68 months (range, 6-154) of follow-up, overall survival was 75 % [95 % confidence interval (CI), 69-81], disease-free survival was 72 % (95% CI, 66-78), cancer-specific survival was 85 % (95 % CI, 80-89), and locoregional control was 86 % (95 % CI, 81-91). The 5-year estimates of grade 3 or more toxicity and second cancer rates were 0 and 7 % (95 % CI, 1-13) for VB alone, 6 % (95 % CI, 1-11) and 0 % for IMRT + VB, 9 % (95 % CI, 1-17) and 5 % (95 % CI, 1-9) for 3D-EBRT + VB, and 22 % (95 % CI, 12-32) and 12 % (95 % CI, 4-20) for 2D-EBRT + VB (P = 0.002 and P = 0.01), respectively. CONCLUSIONS: Pelvic EBRT should be tailored to patients with high-risk EC because the severe late toxicity observed might outweigh the benefits. When EBRT is prescribed for EC, IMRT should be considered, because it was associated with a significant reduction of severe late side effects.