Computer-assisted femoral head reduction osteotomies: an approach for anatomic reconstruction of severely deformed Legg-Calvé-Perthes hips. A pilot study of six patients.

BACKGROUND: Legg-Calvé-Perthes (LCP) is a common orthopedic childhood disease that causes a deformity of the femoral head and to an adaptive deformity of the acetabulum. The altered joint biomechanics can result in early joint degeneration that requires total hip arthroplasty. In 2002, Ganz et al. introduced the femoral head reduction osteotomy (FHRO) as a direct joint-preserving treatment. The procedure remains one of the most challenging in hip surgery. Computer-based 3D preoperative planning and patient-specific navigation instruments have been successfully used to reduce technical complexity in other anatomies. The purpose of this study was to report the first results in the treatment of 6 patients to investigate whether our approach is feasible and safe. METHODS: In this retrospective pilot study, 6 LCP patients were treated with FHRO in multiple centers between May 2017 and June 2019. Based on patient-specific 3D-models of the hips, the surgeries were simulated in a step-wise fashion. Patient-specific instruments tailored for FHRO were designed, 3D-printed and used in the surgeries for navigating the osteotomies. The results were assessed radiographically [diameter index, sphericity index, Stulberg classification, extrusion index, LCE-, Tönnis-, CCD-angle and Shenton line] and the time and costs were recorded. Radiologic values were tested for normal distribution using the Shapiro-Wilk test and for significance using Wilcoxon signed-rank test. RESULTS: The sphericity index improved postoperatively by 20% (p = 0.028). The postoperative diameter of the femoral head differed by only 1.8% (p = 0.043) from the contralateral side and Stulberg grading improved from poor coxarthrosis outcome to good outcome (p = 0.026). All patients underwent acetabular reorientation by periacetabular osteotomy. The average time (in minutes) for preliminary analysis, computer simulation and patient-specific instrument design was 63 (±48), 156 (±64) and 105 (±68.5), respectively. CONCLUSION: The clinical feasibility of our approach to FHRO has been demonstrated. The results showed significant improvement compared to the preoperative situation. All operations were performed by experienced surgeons; nevertheless, three complications occurred, showing that FHRO remains one of the most complex hip surgeries even with computer assistance. However, none of the complications were directly related to the simulation or the navigation technique.

Stability and spectral properties of the dication Ne.

The dication Ne and its stability properties are studied by ab initio methods. Assuming the Born-Oppenheimer approximation and employing multireference configuration interaction techniques, potential energy curves of its low-lying electronic spectrum have been computed and analyzed. In addition to identifying metastable electronic and vibrational states, possible electronic transitions and decay mechanisms are examined. Our results also shed new light on the role of the dication as an excimer system and the interpretation of experimentally observed continua in Ne2 ultraviolet emission spectra.

The first robotic-assisted hysterectomy below the bikini line with the Dexter robotic system™.

Background: Robotic-assisted hysterectomy (RAH) is a widely accepted minimally invasive approach for uterus removal. However, as RAH is typically performed in the umbilical region, it usually results in scars in cosmetically suboptimal locations. This is the first case of RAH with cervicosacropexy performed below the bikini line, using the new Dexter robotic system™. Objectives: The aim of this article is to show the surgical steps of the first RAH with cervicosacropexy performed below the bikini line with the new Dexter robotic system™ (Distalmotion), and furthermore assess the feasibility of this approach using this robotic platform. Materials and Methods: A 43-year-old woman with uterine adenomyosis and recurrent uterine prolapse underwent a robotic-assisted subtotal hysterectomy with cervicosacropexy, performed below the bikini line, using the Dexter robotic system™, at the Clinic of Gynecology and Obstetrics at Universitätsklinikum Schleswig-Holstein (UKHS) in Kiel, Germany. Main outcome measures: Perioperative data, surgical approach specifics, objective, and subjective outcomes of this new approach. Results: The procedure was performed without intra-operative complications; estimated blood loss was 10 ml. Operative time was 150 minutes, console time 120 minutes, total docking time 6 minutes. Dexter performed as expected; no device-related issues or robotic arm collisions occurred. The patient did not require pain medication and was released on the second postoperative day. Conclusion: RAH performed below the bikini line using the Dexter robotic system™ is a feasible, safe, and adequate procedure. These initial results should be confirmed and further extensively refurbished with larger patient cohorts, and functional and psychological outcomes need further investigation.

Computed Tomography Radiomics to Differentiate Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma.

AIMS: Intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) differ in prognosis and treatment. We aimed to non-invasively differentiate iCCA and HCC by means of radiomics extracted from contrast-enhanced standard-of-care computed tomography (CT). MATERIALS AND METHODS: In total, 94 patients (male, n = 68, mean age 63.3 ± 12.4 years) with histologically confirmed iCCA (n = 47) or HCC (n = 47) who underwent contrast-enhanced abdominal CT between August 2014 and November 2021 were retrospectively included. The enhancing tumour border was manually segmented in a clinically feasible way by defining three three-dimensional volumes of interest per tumour. Radiomics features were extracted. Intraclass correlation analysis and Pearson metrics were used to stratify robust and non-redundant features with further feature reduction by LASSO (least absolute shrinkage and selection operator). Independent training and testing datasets were used to build four different machine learning models. Performance metrics and feature importance values were computed to increase the models' interpretability. RESULTS: The patient population was split into 65 patients for training (iCCA, n = 32) and 29 patients for testing (iCCA, n = 15). A final combined feature set of three radiomics features and the clinical features age and sex revealed a top test model performance of receiver operating characteristic (ROC) area under the curve (AUC) = 0.82 (95% confidence interval =0.66-0.98; train ROC AUC = 0.82) using a logistic regression classifier. The model was well calibrated, and the Youden J Index suggested an optimal cut-off of 0.501 to discriminate between iCCA and HCC with a sensitivity of 0.733 and a specificity of 0.857. CONCLUSIONS: Radiomics-based imaging biomarkers can potentially help to non-invasively discriminate between iCCA and HCC.

Reduction techniques for network validation in systems biology.

The rapidly increasing amount of experimental biological data enables the development of large and complex, often genome-scale models of molecular systems. The simulation and analysis of these computer models of metabolism, signal transduction, and gene regulation are standard applications in systems biology, but size and complexity of the networks limit the feasibility of many methods. Reduction of networks provides a hierarchical view of complex networks and gives insight knowledge into their coarse-grained structural properties. Although network reduction has been extensively studied in computer science, adaptation and exploration of these concepts are still lacking for the analysis of biochemical reaction systems. Using the Petri net formalism, we describe two local network structures, common transition pairs and minimal transition invariants. We apply these two structural elements for network reduction. The reduction preserves the CTI-property (covered by transition invariants), which is an important feature for completeness of biological models. We demonstrate this concept for a selection of metabolic networks including a benchmark network of Saccharomyces cerevisiae whose straightforward treatment is not yet feasible even on modern supercomputers.

Comparison of electrical and optical transduction modes of DNA-wrapped SWCNT nanosensors for the reversible detection of neurotransmitters.

In this study, we compare the electrical and optical signal transduction of nanoscale biosensors based on single-walled carbon nanotubes (SWCNTs). Solution processable single-stranded (ss) DNA-wrapped SWCNTs were used for the fabrication of the distinct sensors. For electrical measurements, SWCNTs were assembled from solution onto pre-patterned electrodes by electric-field-assisted assembly in field-effect transistor (FET) configuration. A combination of micro- and nano-fabrication and microfluidics enabled the integration into a sensing platform that allowed real-time and reversible detection. For optical measurements, the near-infrared (NIR) fluorescence of the SWCNTs was acquired directly from solution. The detection of important biomolecules was investigated in high-ionic strength solution (0.5xPBS). Increase in fluorescence intensities correlated with a decrease in the SWCNTs electrical current and enabled detection of the important biomolecules dopamine, epinephrine, and ascorbic acid. For riboflavin, however, a decrease in the fluorescence intensity could not be associated with changes in the SWCNTs electrical current, which indicates a different sensing mechanism. The combination of SWCNT-based electrical and optical transduction holds great potential for selective detection of biomarkers in next generation portable diagnostic assays.

Cytogenetic patterns in multiple myeloma after a phase of preceding MGUS.

BACKGROUND: Presenting the same histological diagnosis, multiple myeloma (MM) shows a large genomic variety, resulting in variable times of overall survival. MATERIALS AND METHODS: To investigate major cytogenetic categories (any 14q-translocation, t(11;14), t(4;14), 13q-deletions, 17p-deletions) and their clinical consequences in MM after a pre-existing monoclonal gammopathy (MM post-MGUS), we performed a comparative analysis of 41 patients with MM post-MGUS and 287 patients with unknown prior history MM (U-MM). RESULTS: In MM post-MGUS, a t(11;14) was found to be more frequent than in U-MM (24% vs. 14%) and it was associated with significantly shortened survival (24 months vs. 70 months in U-MM; P = 0.01). MM post-MGUS was further characterized by a higher frequency of 13q-deletions only (absence of all other specific abnormalities; 28% vs. 12% in U-MM; P = 0.02). A 13q-deletion only was an indicator of long survival in MM post-MGUS (median not yet reached) as opposed to U-MM (median survival, 29 months; P = 0.001). 17p-deletions were infrequent in MM post-MGUS (3% vs. 16% in U-MM; P = 0.04). Survival times for patients with t(4;14) and/or 17p-deletions and other abnormalities were similar in both MM patient cohorts. CONCLUSIONS: Our data suggest that t(11;14) and 13q-deletions have distinct prognostic implications in the context of MM post-MGUS.

Bortezomib in relapsed multiple myeloma: response rates and duration of response are independent of a chromosome 13q-deletion.

Studies of bortezomib in patients with relapsed multiple myeloma (MM) suggested that bortezomib may be active even in the presence of adverse prognostic factors. We therefore evaluated 62 patients with relapsed/refractory MM who were treated with single-agent bortezomib, and addressed the question whether or not the negative prognostic impact of unfavorable cytogenetic abnormalities may be overcome by bortezomib. By interphase fluorescence in situ hybridization (FISH), a deletion of chromosome 13q14 [del(13q14)] was present in 33 patients (53%). Overall response rates to bortezomib were similar in patients with and without del(13q14) (45 versus 55%; P=0.66), and rates of complete remission (CR) near CR were also not different between the two patient populations (18 versus 14%). Three patients had a t(4;14)(p16;q32) in addition to del(13q14), and all of them had a >50% paraprotein reduction. Median duration of response was 12.3 months in patients with del(13q14) compared with 9.3 months in patients with normal 13q-status (P=0.25), and survival was also not different between the two patient populations. Patients not benefiting from single-agent bortezomib were characterized by the combined presence of a del(13q14) and low serum albumin (median survival 4.6 months). Our results provide evidence for remarkable activity of bortezomib in MM with del(13q14). Patients who do not respond to bortezomib and consecutively have short time to treatment failure and overall survival can be identified by low serum albumin in addition to del(13q14) and should be considered for bortezomib combinations.

{Tc(NO)(Cp)(PPh3)}(+) - a novel technetium(i) core.

Reactions between [Tc(I)(NO)X2(PPh3)2(CH3CN)] complexes (X = Cl, Br) and KCp form the pseudotetrahedral organotechnetium compounds [Tc(I)(NO)(Cp)(PPh3)X]. The halide ligands can readily be replaced by other halides or organometallic ligands giving access to a novel family of technetium(i) compounds with the robust {Tc(NO)(Cp)(PPh3)}(+) core.

Predictive role of interphase cytogenetics for survival of patients with multiple myeloma.

PURPOSE: Recent metaphase cytogenetic studies suggested that specific chromosomal abnormalities are of prognostic significance in patients with multiple myeloma (MM). Because the true incidence of chromosomal abnormalities in MM is much higher than that detected by metaphase analysis, we used interphase fluorescence in situ hybridization (FISH) to determine the prognostic value of specific chromosomal aberrations. PATIENTS AND METHODS: Bone marrow plasma cells from 89 previously untreated patients with MM were studied consecutively by FISH to detect the deletions of 13q14, 17p13, and 11q and the presence of t(11;14)(q13;q32). FISH results were analyzed in the context of clinical parameters (response to treatment and survival after conventional-dose chemotherapy), and a multivariate analysis of prognostic factors was performed. RESULTS: By FISH, the deletion of 13q14 occurred in 40 patients (44.9%), deletion of 17p13 in 22 (24.7%), and 11q abnormalities in 14 (15.7%; seven with t(11;14)). Deletions of 13q14 and 17p13 were associated with poor response to induction treatment (46.9% v 77.3% in those without deletions, P =.006 and 40.0% v 73.2%, P =.008, respectively) and short median overall survival (OS) time (24.2 v 88.1 months, P =. 008 and 16.2 v 51.3 months, P =.008, respectively). Short median OS time was also observed for patients with 11q abnormalities (13.1 v 41.6 months, P =.02). According to the number of unfavorable cytogenetic features (deletion of 13q14, deletion of 17p13, and aberrations of 11q) that were present in each patient (0 v 1 v 2 or 3), patients with significantly different OS times could be discriminated from one another (102.4 v 29.6 v 13.9 months, P <.001, respectively). CONCLUSION: For patients with MM who were treated with conventional-dose chemotherapy, interphase FISH for 13q14, 17p13, and 11q provides prognostically relevant information in addition to that provided by standard prognostic factors. This observation may be considered for risk-adapted stratifications of MM patients in future clinical trials.

Both IGH translocations and chromosome 13q deletions are early events in monoclonal gammopathy of undetermined significance and do not evolve during transition to multiple myeloma.

Molecular and genetic events associated with the transition from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are still poorly characterized. We investigated serial bone marrow specimens from 11 patients with MGUS who eventually progressed to MM (MM post-MGUS) by interphase fluorescence in situ hybridization for immunoglobulin heavy-chain gene (IgH) translocations and chromosome 13q deletions (del(13q)). In nine patients, IgH translocations were present both in MGUS and MM post-MGUS plasma cells, including three t(11;14)(q13;q32) and one t(4;14)(p16;q32), which was observed already 92 months prior to MM. Similarly, all five MM patients with del(13q) had this aberration already at the MGUS stage. Two patients without IgH translocation and del(13q) had chromosomal gains suggesting hyperdiploidy, but IgH translocations and/or del(13q) did not emerge at MM post-MGUS. IgH translocations and del(13q) are early genetic events in monoclonal gammopathies, suggesting that additional events are required for the transition from stable MGUS to progressive MM.

Deletions of chromosome 13q in monoclonal gammopathy of undetermined significance.

Since deletion of chromosome 13q is a clinically relevant feature in multiple myeloma (MM), we analyzed bone marrow plasma cells from 29 patients with monoclonal gammopathy of undetermined significance (MGUS) to investigate the chromosome 13 status in MGUS. Studies were performed by interphase fluorescence in situ hybridization (FISH) with a panel of 13q14-specific probes (RB1, D13S319, D13S25, D13S31). Plasma cells with a deletion of at least one of the 13q14 loci were detected in 13 patients (44.8%) with MGUS. In five patients (17.2%), deletions of all four 13q14-specific probes were observed, and the additional deletion of a 13q telomeric region (D13S327) suggested loss of the entire 13q arm or monosomy 13. Loss of 13q14 was observed to be monoallelic and to occur in 11.0 to 35.0% of plasma cells (cut-off levels for a deletion <10% with all probes). Nine of 17 patients (52.9%) with MM progressing from a pre-existing MGUS had evidence for a deletion of 13q14 as determined by FISH with the RB1 probe. These results suggest that deletion of 13q14 is an early event in the development of monoclonal gammopathies, but its role for the eventual progression to MM remains to be determined prospectively.

Diffuse large B-cell lymphomas with plasmablastic/plasmacytoid features are associated with TP53 deletions and poor clinical outcome.

To define reproducible criteria for subgroups of diffuse large B-cell lymphomas (DLBCL), including lymphomas with plasmablastic/plasmacytoid features (PB/PC-Fs), we investigated 66 DLBCL; the samples were categorized as either centroblastic (CB), immunoblastic (IB) or PB/PC-F applying standardized morphologic criteria. Blinded specimens were reviewed by three independent pathologists. The final consensus classification included 44 CB (67%), seven IB (10%) and 15 PB/PC-F (23%). The interobserver agreement between two centers (Vienna, Würzburg) was 93.5%. Most PB/PC-F were CD20+, cIgM+, MUM-1+, CD138+/-, bcl-6-, corresponding to an activated B-cell phenotype. Immunoglobulin-V(H) gene mutation analysis was consistent with a germinal or postgerminal center-cell origin. By fluorescence in situ hybridization analysis, 11/13 (85%) PB/PC-F had a monoallelic TP53 deletion. The pretreatment characteristics of patients with PB/PC-F included a tendency for more B symptoms, extranodal disease and a higher IPI. Importantly, PB/PC-F were resistant to standard chemotherapy (complete remission rate 47%, relapse rate 71%) and even autologous stem-cell transplantation. The median overall survival (OS) (14 months, P<0.002) and disease-free survival (6 months, P=0.02) were significantly shorter compared to patients with CB and IB. The OS difference was pronounced within the low and low-intermediate IPI risk group (P<0.001). Our data indicate a strong association of plasmablastic/plasmacytoid morphology with TP53 deletions, poor response to chemotherapy and short survival.

Expression of the lung resistance protein predicts poor outcome in patients with multiple myeloma.

Expression of the lung resistance protein (LRP) is associated with resistance to various anticancer drugs including melphalan and, therefore, may affect the clinical outcome in multiple myeloma (MM). To determine the clinical significance of LRP, we have compared LRP expression in bone marrow plasma cells with clinical parameters including response to chemotherapy and survival of previously untreated patients with MM (n = 72). LRP expression immunocytochemically assessed by means of the LRP-56 monoclonal antibody was positive (> or =10% staining plasma cells) in 44 (61%) samples. There was no correlation between LRP expression and age, sex, type of the paraprotein, serum creatinine, stage, beta2-microglobulin, serum lactate dehydrogenase, or C-reactive protein. However, LRP expression was more frequently observed in patients with a p53 deletion than in those without such a deletion (P = 0.01). The overall response rate for all of the patients evaluable for response to induction chemotherapy (n = 58) was 67%. The response rate was 87% for patients without LRP expression but only 54% for patients with LRP expression (P = 0.01). Kaplan-Meier analysis revealed that patients with LRP expression had a shorter overall survival (median, 33 months) than those without LRP expression (median not reached; P = 0.04). These data show that LRP expression is an important marker for clinical drug resistance and predicts a poor outcome in MM.

Design and synthesis of potent and highly selective thrombin inhibitors.

Thrombin, a serine protease, plays a central role in the initiation and propagation of thrombotic events. An extensive search for new thrombin inhibitors was performed, using an unconventional approach. Screening of small basic molecules for binding in the recognition pocket of thrombin led to the discovery of (aminoiminomethyl)piperidine (amidinopiperidine) as a weak, but intrinsically selective, thrombin inhibitor. Elaboration of this molecule provided compounds which inhibit thrombin with Ki's in the range of 20-50 nM and with selectivities of 1000-4000 against trypsin. These inhibitor compounds show a new and unexpected binding mode to thrombin. Modification of the central building block and then of one of the hydrophobic substituents led to the discovery of a new family of thrombin inhibitors which has reverted to the former binding mode to thrombin. This last class of compounds shows inhibitory activities in the picomolar range, low toxicity, and a short plasma half life which favors its use for an intravenous application. From this series of thrombin inhibitors, 19f(Ro 46-6240) was selected for clinical development as an antithrombotic agent for intravenous administration.

Hyperacute and acute kidney graft rejection due to antibodies against B cells.

Because of the perception of its uncertain clinical significance, the B cell crossmatch is not universally performed before renal transplantation. Even though sporadic cases of hyperacute rejection associated with B cell antibodies have been reported, doubts remain in light of other studies suggesting no effect on graft survival. This report describes 4 cases of graft rejection (3 hyperacute and 1 acute) that occurred in patients with anti-B-cell antibodies specific against donor HLA-DR or DQ antigens. Absence of anti-donor class I antibodies was confirmed in all cases by 2-color flow cytometry. Strong evidence for an antibody-mediated mechanism was found in one patient with anti-class I and anti-class II antibodies in serum transplanted with a class II mismatched kidney. In this case, only anti-class II antibodies were recovered in the eluate of the nephrectomy specimen. These four cases were compiled from three different institutions over a four-year period, which confirms the infrequent occurrence of these events. While anti-class II antibodies may not always be detrimental for graft survival, these results also confirm that they have the potential to cause hyperacute or acute graft loss. We conclude that the information provided by the B cell crossmatch should be available at the time that a decision to proceed with a renal transplant is made.

Detection of chromosomal aneuploidy by interphase fluorescence in situ hybridization in bronchoscopically gained cells from lung cancer patients.

BACKGROUND: Development and progression of human malignancies involve multiple genetic changes. New techniques to distinguish neoplastic from benign diseases unequivocally with small amounts of cells as gained by bronchoscopy are needed to come closer to the goal of an early diagnosis in lung cancer. STUDY OBJECTIVE: The aim of this study was to determine whether interphase fluorescence in situ hybridization (FISH) can be used to visualize chromosomal aberrations in bronchoscopically gained cells from lung cancer patients and could eventually become a complementary technique to conventional cytology. METHODS: We examined 20 cancerous specimens (10 primary tumors, 10 malignant effusions) of 18 lung cancer patients by FISH with DNA probes specific for chromosomes 3, 8, 11, 12, 17, and 18. From five additional patients, endobronchial brushings and/or forceps biopsy specimens were subjected to interphase FISH analysis. RESULTS: In all primary tumors and malignant effusions, highly aneuploid cells were detectable by FISH. Chromosomal aberrations always consisted of gains of chromosomal signal numbers, and all chromosomes were found to be aneuploid to a similar extent. Using chromosomal aneuploidy as a marker of malignancy, material obtained by bronchoscopy was then examined for the presence of malignant cells. In all specimens, evidence for malignancy was obtained by FISH, including three specimens in which cells appeared to be normal or reactively changed by cytologic criteria. CONCLUSION: We conclude that interphase FISH is useful in detecting aneuploidy associated with malignancy in bronchoscopically gained cells that do not clearly meet the criteria of malignancy by conventional cytologic study.

Aneuploidy of chromosome 7 can be detected in invasive lung cancer and associated premalignant lesions of the lung by fluorescence in situ hybridisation.

In the present study the chromosomal status of seven invasive non small cell lung cancer specimens and associated premalignant lesions was investigated. By fluorescence in situ hybridisation (FISH) with centromere specific probes, an increase in the percentage of aneuploid cells from pre-invasive to invasive lesions could be demonstrated (mean 8.5 and 59%, respectively, for chromosome 7). Furthermore, mean chromosome copy numbers were higher in invasive carcinomas as compared to premalignant lesions, indicating polyploidization during tumor development. Increasing evidence suggests that aberrations of chromosome 7 occur early in the development of lung cancer. Whether these aberrations can be used as a biomarker for future neoplastic progression remains to be determined.

The biology of multiple myeloma.

Multiple myeloma (MM) is a B-cell malignancy originating from pre-switched, follicle center B-lymphocytes which differentiate to plasma cells accumulating in the bone marrow. MM cells are characterized by a profound genetic instability resulting in a complex set of numerical and structural chromosomal abnormalities. Among these abnormalities, translocations involving 14q32, the immunoglobulin heavy-chain locus, are the most frequent aberrations, but translocation partners are remarkably heterogeneous. Chromosome 13q14 may harbor a critical tumor suppressor gene since MM patients with deletion of 13q14 experience short overall survival after conventional-dose and high-dose chemotherapy. Bone marrow stroma cells support growth and survival of MM cells, which in turn influence the bone marrow microenvironment. This is particularly evident by the markedly increased bone marrow vascularization observed in most patients with active MM.