Optical genome mapping reveals additional prognostic information compared to conventional cytogenetics in AML/MDS patients.

Cytogenetic diagnostics play a crucial role in risk stratification and classification of myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), thus influencing treatment decisions. Optical genome mapping (OGM) is a novel whole genome method for the detection of cytogenetic abnormalities. Our study assessed the applicability and practicality of OGM as diagnostic tool in AML and MDS patients. In total, 27 patients with AML or MDS underwent routine diagnostics including classical karyotyping and fluorescence in situ hybridization (FISH) or real-time PCR analysis wherever indicated as well as OGM following a recently established workflow. Methods were compared regarding concordance and content of information. In 93%, OGM was concordant to classical karyotyping and a total of 61 additional variants in a predefined myeloid gene-set could be detected. In 67% of samples the karyotype could be redefined by OGM. OGM offers a whole genome approach to cytogenetic diagnostics in AML and MDS with a high concordance to classical cytogenetics. The method has the potential to enter routine diagnostics as a gold standard for cytogenetic diagnostics widely superseding FISH. Furthermore, OGM can serve as a tool to identify genetic regions of interest and future research regarding tumor biology.

Prevalence and potential relevance of hyperuricemia in pediatric kidney transplant recipients-a CERTAIN registry analysis.

BACKGROUND: Asymptomatic hyperuricemia is frequently observed in pediatric kidney transplant recipients; symptomatic hyperuricemia, however, is a rare complication. Only few data are available in this patient population. We, therefore, investigated the prevalence of hyperuricemia and its association with kidney transplant function and blood pressure in a multicenter cohort of pediatric kidney transplant recipients. METHODS: This is a retrospective, observational multicenter registry study. All pediatric kidney transplant recipients in the CERTAIN database with at least one documented serum uric acid level and a follow-up of 5 years posttransplant were eligible. We identified 151 patients with 395 measurements of serum uric acid. We calculated the prevalence of hyperuricemia, analyzed potential risk factors and clinical consequences such as elevated blood pressure and reduced estimated glomerular filtration rate (eGFR). Statistical analysis was performed using IBM SPSS Statistics 26. RESULTS: One hundred and ten of 395 (27.8%) serum uric acid levels were above 416 µmol/L (7.0 mg/dL), defined as the upper limit of normal. Univariate analysis showed a significant (p = .026) inverse association of serum uric acid with eGFR overtime. There was no significant association of serum uric acid concentrations with body mass index (z-score), blood pressure (z-score), or sex. No episodes of gout were documented. CONCLUSION: This study shows that hyperuricemia is present in a considerable number of patients sometime after pediatric kidney transplantation and is associated with lower eGFR. Whether hyperuricemia contributes to faster decline of graft function or to the overall cardiovascular risk of these patients remains to be elucidated.

The Effect of Tactical Tasks and Gear on Muscle Activation of SWAT Officers.

ABSTRACT: Keeler, JM, Pohl, MB, Bergstrom, HC, Thomas, JM, and Abel, MG. The effect of tactical tasks and gear on muscle activation of SWAT officers. J Strength Cond Res 36(1): 238-244, 2022-Special Weapons and Tactics (SWAT) officers perform a variety of tactical operations while wearing tactical gear. Load carriage has been shown to alter muscle activation in the torso and is also associated with lower back pain, which is a prevalent musculoskeletal injury suffered by SWAT Officers. The purpose of this study was to quantify the effect of tactical gear on muscle activation of torso musculature while performing occupational tasks. Twenty male SWAT Officers (age: 34.7 ± 4.5 years; height: 1.79 ± 0.1 m; body mass: 91.5 ± 17.3 kg) performed 4 tasks (standing, rifle walk, sitting, and shield walk) with and without gear (mass of gear: 13.8 ± 1.9 kg). Mean electromyographic amplitude was evaluated bilaterally for the erector spinae, rectus abdominis, and external oblique muscles during the trials and expressed relative to maximal voluntary isometric contraction (MVIC). Addition of gear significantly increased erector spinae mean muscle activation during the rifle walk task (mean delta: +0.16%). However, no differences in muscle activation were identified for any other muscles between gear conditions (effect size ≤ 0.15). The shield walk produced the highest mean activation for each muscle during different tasks. The dynamic tasks yielded (0.24-4.18% MVIC) greater muscle activation levels than sitting and standing tasks. Despite minimal increases in muscle activation levels with the addition of gear, load carriage is known to increase the risk of acute and chronic injury. Collectively, these findings indicate that SWAT Officers should perform most skills without gear during tactical training to simulate task-specific movement patterns but reduce the risk of musculoskeletal injury.

Trastuzumab in combination with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel as perioperative treatment for patients with human epidermal growth factor receptor 2-positive locally advanced esophagogastric adenocarcinoma: A phase II trial of the Arbeitsgemeinschaft Internistische Onkologie Gastric Cancer Study Group.

Perioperative chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) is a mainstay in the treatment of esophagogastric adenocarcinomas (EGA). Trastuzumab improved survival when added to chemotherapy in patients with HER-2-positive metastatic EGA. We investigated the combination of trastuzumab and FLOT as perioperative treatment in patients with locally advanced EGA. A multicenter phase II study evaluated the efficacy and toxicity of perioperative FLOT (24-hours 5-FU 2600 mg/m2 , leucovorin 200 mg/m2 , oxaliplatin 85 mg/mg2 , docetaxel 50 mg/m2 , trastuzumab 6 mg/kg then 4 mg/kg d1, repeated d15 for four cycles preoperatively and postoperatively followed by 9 cycles of trastuzumab monotherapy) in patients with HER-2 positive EGA. Patients had ≥cT2, any N, M0 EGA. The primary endpoint was the rate of centrally assessed pathological complete response (pCR). Secondary endpoints comprised disease-free (DFS) and overall survival (OS), R0 resection rate, toxicity and surgical morbidity. Fifty-six evaluable patients (median age 62 years) were included; n = 40 had tumors originating from the esophagogastric junction; T stage was (cT2/3/4/unknown): 4/42/8/2; n = 50 patients had cN+ disease. Main adverse events grades 3-4: leukopenia (17.9%), neutropenia (46.6%) and diarrhea (17.0%). All patients underwent tumor resections. R0 resection rate was 92.9%. Eight patients had anastomotic leakage. One postoperative death occurred. pCR was found in 12 patients (21.4%) and a further n = 14 patients (25.0%) had near complete response. Median DFS was 42.5 months and the 3-year OS rate was 82.1%. The primary endpoint of achieving a pCR >20% was reached. No unexpected safety issues were observed. Survival data are promising.

Precise variant interpretation, phenotype ascertainment, and genotype-phenotype correlation of children in the EARLY PRO-TECT Alport trial.

Early initiation of therapy in patients with Alport syndrome (AS) slows down renal failure by many years. Genotype-phenotype correlations propose that the location and character of the individual's variant correlate with the renal outcome and any extra renal manifestations. In-depth clinical and genetic data of 60/62 children who participated in the EARLY PRO-TECT Alport trial were analyzed. Genetic variants were interpreted according to current guidelines and criteria. Genetically solved patients with X-linked inheritance were then classified according to the severity of their COL4A5 variant into less-severe, intermediate, and severe groups and disease progress was compared. Almost 90% of patients were found to carry (likely) pathogenic variants and classified as genetically solved cases. Patients in the less-severe group demonstrated a borderline significant difference in disease progress compared to those in the severe group (p = 0.05). While having only limited power according to its sample size, an obvious strength is the precise clinical and genetic data of this well ascertained cohort. As in published data differences in clinical progress were shown between patients with COL4A5 less-severe and severe variants. Therefore, clinical and segregational data are important for variant (re)classification. Genetic testing should be mandatory allowing early diagnosis and therapy of AS.

Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial.

BACKGROUND: Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resectable tumours. METHODS: In this controlled, open-label, phase 2/3 trial, we randomly assigned 716 patients with histologically-confirmed advanced clinical stage cT2 or higher or nodal positive stage (cN+), or both, resectable tumours, with no evidence of distant metastases, via central interactive web-based-response system, to receive either three pre-operative and three postoperative 3-week cycles of 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 plus either 200 mg/m2 fluorouracil as continuous intravenous infusion or 1250 mg/m2 capecitabine orally on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of 50 mg/m2 docetaxel, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin and 2600 mg/m2 fluorouracil as 24-h infusion on day 1 (FLOT; experimental group). The primary outcome of the trial was overall survival (superiority) analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01216644. FINDINGS: Between Aug 8, 2010, and Feb 10, 2015, 716 patients were randomly assigned to treatment in 38 German hospitals or with practice-based oncologists. 360 patients were assigned to ECF/ECX and 356 patients to FLOT. Overall survival was increased in the FLOT group compared with the ECF/ECX group (hazard ratio [HR] 0·77; 95% confidence interval [CI; 0.63 to 0·94]; median overall survival, 50 months [38·33 to not reached] vs 35 months [27·35 to 46·26]). The number of patients with related serious adverse events (including those occurring during hospital stay for surgery) was similar in the two groups (96 [27%] in the ECF/ECX group vs 97 [27%] in the FLOT group), as was the number of toxic deaths (two [<1%] in both groups). Hospitalisation for toxicity occurred in 94 patients (26%) in the ECF/ECX group and 89 patients (25%) in the FLOT group. INTERPRETATION: In locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT improved overall survival compared with perioperative ECF/ECX. FUNDING: The German Cancer Aid (Deutsche Krebshilfe), Sanofi-Aventis, Chugai, and Stiftung Leben mit Krebs Foundation.

Sex and age as determinants for high blood pressure in pediatric renal transplant recipients: a longitudinal analysis of the CERTAIN Registry.

BACKGROUND: High prevalence of arterial hypertension is known in pediatric renal transplant patients, but how blood pressure (BP) distribution and control differ between age groups and whether sex and age interact and potentially impact BP after transplantation have not been investigated. METHODS: This retrospective analysis included 336 pediatric renal transplant recipients (62% males) from the Cooperative European Pediatric Renal Transplant Initiative Registry (CERTAIN) with complete BP measurement at discharge and 1, 2 and 3 years post-transplant. RESULTS: At discharge and 3 years post-transplant, arterial hypertension was highly prevalent (84% and 77%); antihypertensive drugs were used in 73% and 68% of the patients. 27% suffered from uncontrolled and 9% from untreated hypertension at 3 years post-transplant. Children transplanted at age < 5 years showed sustained high systolic BP z-score and received consistently less antihypertensive treatment over time. Younger age, shorter time since transplantation, male sex, higher body mass index (BMI), high cyclosporine A (CSA) trough levels, and a primary renal disease other than congenital anomalies of the kidney and urinary tract (CAKUT) were significantly associated with higher systolic BP z-score. Sex-stratified analysis revealed a significant association between high CSA and higher systolic BP in older girls that likely had started puberty already. An association between BP and estimated glomerular filtration rate was not detected. CONCLUSIONS: BP control during the first 3 years was poor in this large European cohort. The description of age- and sex-specific risk profiles identified certain recipient groups that may benefit from more frequent BP monitoring (i.e. young children) or different choices of immunosuppression (i.e. older girls).

Effects of a Hip Flexor Stretching Program on Running Kinematics in Individuals With Limited Passive Hip Extension.

Mettler, JH, Shapiro, R, and Pohl, MB. Effects of a hip flexor stretching program on running kinematics in individuals with limited passive hip extension. J Strength Cond Res 33(12): 3338-3344, 2019-Tightness of the hip flexor muscle group may theoretically contribute to altered kinematics of the lumbo-pelvic-hip (LPH) complex during dynamic movements. Therefore, the purpose of this study was to analyze the effects of a 3-week home-based stretching program on passive hip extension and sagittal plane kinematics of the LPH complex when running. Twenty healthy subjects with limited passive hip extension underwent a 3D gait analysis both before (PRE) and after (POST) a hip flexor stretching program. After the stretching program, passive hip extension increased significantly (p < 0.001), whereas no improvements during running were reported for active hip extension, anterior pelvic tilt, or lumbar spine extension (p ≥ 0.05). In addition, no relationship was found between the change in passive hip extension with either the change in active hip extension, anterior pelvic tilt, or lumbar spine extension. A 3-week static stretching program of the hip flexor muscle group resulted in an increase in passive hip extension, but the sagittal plane kinematics of the LPH complex during running remained unchanged. The results suggest that passive hip joint flexibility may be of limited importance in determining the kinematics of the LPH complex during submaximal running. However, it is possible that an increase in the range of motion at the hip may be beneficial when running at or near maximal speeds.

Presentation of pediatric Henoch-Schönlein purpura nephritis changes with age and renal histology depends on biopsy timing.

BACKGROUND: This study correlates the clinical presentation of Henoch-Schönlein purpura nephritis (HSPN) with findings on initial renal biopsy. METHODS: Data from 202 pediatric patients enrolled in the HSPN registry of the German Society of Pediatric Nephrology reported by 26 centers between 2008 and 2014 were analyzed. All biopsy reports were re-evaluated for the presence of cellular crescents or chronic pathological lesions (fibrous crescents, glomerular sclerosis, tubular atrophy >5%, and interstitial fibrosis >5%). RESULTS: Patients with HSPN with cellular glomerular crescents were biopsied earlier after onset of nephritis (median 24 vs 36 days, p = 0.04) than those without, whereas patients with chronic lesions were biopsied later (57 vs 19 days, p < 0.001) and were older (10.3 vs 8.6 years, p = 0.01) than those without. Patients biopsied more than 30 days after the onset of HSPN had significantly more chronic lesions (52 vs 22%, p < 0.001), lower eGFR (88 vs 102 ml/min/1.73m2, p = 0.01), but lower proteinuria (2.3 vs 4.5 g/g, p < 0.0001) than patients biopsied earlier. Children above 10 years of age had lower proteinuria (1.98 vs 4.58 g/g, p < 0.001), lower eGFR (86 vs 101 ml/min/1.73m2, p = 0.002) and were biopsied significantly later after onset of nephritis (44 vs 22 days, p < 0.001) showing more chronic lesions (45 vs 30%, p = 0.03). Proteinuria and renal function at presentation decreased with age. CONCLUSIONS: In summary, we find an age-dependent presentation of HSPN with a more insidious onset of non-nephrotic proteinuria, impaired renal function, longer delay to biopsy, and more chronic histopathological lesions in children above the age of 10 years. Thus, HSPN presents more like Immunoglobulin A (IgA) nephritis in older than in younger children.

Effect of Load Carriage on Tactical Performance in Special Weapons and Tactics Operators.

Thomas, JM, Pohl, MB, Shapiro, R, Keeler, J, and Abel, MG. Effect of load carriage on tactical performance in special weapons and tactics operators. J Strength Cond Res 32(2): 554-564, 2018-Special weapons and tactics (SWAT) operators are specially trained personnel that are required to carry equipment to perform high-risk tasks. Given the need to carry this equipment, it is important to understand the potentially deleterious effect that the additional load may have on tactical performance. Furthermore, it is important to identify physical fitness characteristics that are associated with the potential decrement in performance. Therefore, the purpose of this study was to evaluate the effect of load carriage on tactical physical ability and marksmanship and to identify fitness characteristics associated with any decrement in performance. Twelve male SWAT operators were timed while performing a simulated tactical test (STT) on a live firing range with (loaded condition) and without equipment (unloaded condition). A battery of physical fitness assessments were used to assess anaerobic and aerobic power, muscular endurance, strength, agility, and flexibility. Paired-samples t-tests were used to identify differences between STT conditions, and bivariate correlations were used to determine relationships between STT and fitness outcomes. Time to complete the STT in the loaded condition increased by 7.8% compared with the unloaded condition (p < 0.001). Nine of the 13 STT tasks were performed significantly slower in the loaded condition. Fatigue index (r = 0.64) and V[Combining Dot Above]O2peak (r = -0.62) were associated with the decrement in the overall STT time. Marksmanship was not different between load carriage conditions (p = 0.816). These findings indicate that resistance to anaerobic fatigue and aerobic power are related to the decrement in tactical performance produced by load carriage.

Proteinuria in children with autosomal dominant polycystic kidney disease.

BACKGROUND: Proteinuria is a common complication in adults with autosomal dominant polycystic kidney disease (ADPKD) and serves as a risk factor for progression. However, proteinuria has rarely been examined in children with ADPKD and the type of proteinuria has not yet been investigated. The aim of the study was to assess the prevalence and to analyse the types of proteinuria in children with ADPKD. METHODS: Children with ADPKD followed-up in our tertiary centres during the years 2012-2013 were investigated in a cross-sectional study. Morning urine was tested for total protein (PROT), albumin (ALB) and alpha-1-microglobulin (AMG). Renal function was assessed from serum creatinine as estimated glomerular filtration rate. RESULTS: Thirty-seven children of median age 11.2 (2.0-18.0) years were investigated. Median (range) PROT, ALB and AMG (in mg/mmol creatinine) were 15.1 (6.2-64.8), 2.54 (0.54-37.25) and 3.22 (0.04-10.16), respectively. Pathological total proteinuria (>22) was found in 30% of children, albuminuria (>2.2) in 49% of children and alpha-1-microglobulinuria (>0.55) in 65% of children. No correlation was found between PROT, ALB or AMG and office blood pressure, kidney size or estimated glomerular filtration rate. CONCLUSIONS: Proteinuria in children with ADPKD is a frequent finding, the most common type is tubular proteinuria. It should be measured in all ADPKD children.

The RENAISSANCE (AIO-FLOT5) trial: effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction - a phase III trial of the German AIO/CAO-V/CAOGI.

BACKGROUND: Historical data indicate that surgical resection may benefit select patients with metastatic gastric and gastroesophageal junction cancer. However, randomized clinical trials are lacking. The current RENAISSANCE trial addresses the potential benefits of surgical intervention in gastric and gastroesophageal junction cancer with limited metastases. METHODS: This is a prospective, multicenter, randomized, investigator-initiated phase III trial. Previously untreated patients with limited metastatic stage (retroperitoneal lymph node metastases only or a maximum of one incurable organ site that is potentially resectable or locally controllable with or without retroperitoneal lymph nodes) receive 4 cycles of FLOT chemotherapy alone or with trastuzumab if Her2+. Patients without disease progression after 4 cycles are randomized 1:1 to receive additional chemotherapy cycles or surgical resection of primary and metastases followed by subsequent chemotherapy. 271 patients are to be allocated to the trial, of which at least 176 patients will proceed to randomization. The primary endpoint is overall survival; main secondary endpoints are quality of life assessed by EORTC-QLQ-C30 questionnaire, progression free survival and surgical morbidity and mortality. Recruitment has already started; currently (Feb 2017) 22 patients have been enrolled. DISCUSSION: If the RENAISSANCE concept proves to be effective, this could potentially lead to a new standard of therapy. On the contrary, if the outcome is negative, patients with gastric or GEJ cancer and metastases will no longer be considered candidates for surgical intervention. TRIAL REGISTRATION: The article reports of a health care intervention on human participants and is registered on October 12, 2015 under ClinicalTrials.gov Identifier: NCT02578368 ; EudraCT: 2014-002665-30.

Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial.

BACKGROUND: Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma, but has not yet been evaluated in the context of resectable patients. Here we report findings from the phase 2 part of the phase 2/3 FLOT4 trial, which compared histopathological regression in patients treated with a docetaxel-based triplet chemotherapy versus an anthracycline-based triplet chemotherapy before surgical resection. METHODS: In this randomised, open-label, phase 2/3 study, eligible participants were recruited from 28 German oncology centres. Patients with resectable gastric or gastro-oesophageal junction cancer who had clinical stage cT2 or higher, nodal positive (cN+) disease, or both were randomly assigned (1:1) to either three preoperative and three postoperative 3-week cycles of intravenous epirubicin 50 mg/m2 on day 1, intravenous cisplatin 60 mg/m2 on day 1, and either fluorouracil 200 mg/m2 as continuous intravenous infusion or capecitabine 1250 mg/m2 orally (two doses of 625 mg/m2 per day) on days 1 to 21 (ECF/ECX group) or four preoperative and four postoperative 2-week cycles of docetaxel 50 mg/m2, intravenous oxaliplatin 85 mg/m2, intravenous leucovorin 200 mg/m2, and fluorouracil 2600 mg/m2 as a 24 h infusion, all on day 1 (FLOT group). Randomisation was done centrally with an interactive web-response system based on a sequence generated with blocks (block size 2) stratified by Eastern Cooperative Oncology Group performance status, location of primary tumour, age, and nodal status. No masking was done. Central assessment of pathological regression was done according to the Becker criteria. The primary endpoint was pathological complete regression (tumour regression grade TRG1a) and was analysed in the modified intention-to-treat population, defined as all patients who were randomly assigned to treatment excluding patients who had surgery but did not provide resection specimens for central evaluation. The study (including the phase 3 part) has completed enrolment, but follow-up is ongoing and this is an interim analysis. The trial is registered with ClinicalTrials.gov, number NCT01216644. FINDINGS: Between Aug 18, 2010, and Aug 10, 2012, 300 patients (152 patients in the ECF/ECX group; 148 patients in the FLOT group) were enrolled into the phase 2 part of the study, 265 of whom (137 in the ECF/ECX group; 128 in the FLOT group) were assessable on a modified intention-to-treat basis. 119 (93%) of 128 patients in the FLOT group and 126 (92%) of 137 patients in the ECF/ECX group were given all planned preoperative cycles of treatment. FLOT was associated with significantly higher proportions of patients achieving pathological complete regression than was ECF/ECX (20 [16%; 95% CI 10-23] of 128 patients vs eight [6%; 3-11] of 137 patients; p=0·02). 44 (40%) of 111 patients in the ECF/ECX group and 30 (25%) of 119 patients in the FLOT group had at least one serious adverse event involving a perioperative medical or surgical complication. The most common non-surgical grade 3-4 adverse events were neutropenia (52 [38%] of 137 patients in the ECF/ECX group vs 67 [52%] of 128 patients in the FLOT group), leucopenia (28 [20%] vs 36 [28%]), nausea (23 [17%] vs 12 [9%]), infection (16 [12%] vs 15 [12%]), fatigue (19 [14%] vs 11 [9%]), and vomiting (13 [10%] vs four [3%]). INTERPRETATION: Perioperative FLOT was active and feasible to administer, and might represent an option for patients with locally advanced, resectable gastric or gastro-eosophageal junction adenocarcinoma. FUNDING: None.

Therapeutic Strategies in Diseases of the Digestive Tract - 2015 and Beyond Targeted Therapies in Colon Cancer Today and Tomorrow.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer type in Western countries. Significant progress has been made in the last decade in the therapy of metastatic CRC (mCRC) with a median overall survival (OS) of patients exceeding 30 months. The integration of biologic targeted therapies and anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MABs) in the treatment of patients with genomically selected all-RAS wild-type mCRC leads to a significant progress in advanced incurable disease state. After the introduction of the anti-VEGF MAB bevacizumab, the FDA approved with ramucirumab the second antiangiogenic MAB for the mCRC treatment. Further new drugs are on the horizon and new diagnostic tools will be introduced soon. KEY MESSAGES: Molecular heterogeneity of mCRC has been recognized as pivotal in the evolution of clonal populations during anti-EGFR therapies. Mutations in RAS genes predict a lack of response to anti-EGFR MABs. Mutations in the mitogen-activated protein kinase-phosphoinositide 3-kinase pathways like BRAF or PIK3CA mutations or HER2/ERBB2 or MET amplifications bypass EGFR signaling and also may confer resistance to anti-EGFR MABs. HER2/ERBB2 amplification is a further driver of resistance to anti-EGFR MABs in mCRC. The phase II study of HER2 Amplification for Colo-Rectal Cancer Enhanced Stratification (HERACLES) discovers that a dual HER2-targeted therapy may be an option for HER2-amplified mCRC. The mismatch repair deficiency predicts responsiveness to an immune checkpoint blockade with the anti-PD-1 immune checkpoint inhibitor pembrolizumab. CONCLUSIONS: The understanding of primary (de novo) and secondary (acquired) resistance to anti-EGFR therapies, new targeted therapies, immuno-oncology and about predictive biomarkers in mCRC is guiding the development of rational therapeutic strategies. Combinations of targeted therapies are necessary to effectively treat drug-resistant cancers. Liquid biopsy is an upcoming new tool in the primary diagnosis and follow-up analysis of mutations in circulating tumor DNA.

Diagnosis of Alport syndrome--search for proteomic biomarkers in body fluids.

BACKGROUND: The hereditary kidney disease Alport syndrome (AS) has become a treatable disease: intervention with angiotensin-converting enzyme (ACE)-inhibitors delays end stage renal failure by years. The efficiency of ACE inhibition depends on the onset of therapy-the earlier the better. Therefore, early diagnosis has become increasingly important. To date, robust diagnosis requires renal biopsy and/or expensive genetic analysis, which is mostly performed late after onset of the profound clinical symptoms of this progressive renal disease. Thus, disease biomarkers enabling low-invasive screening are urgently required. METHODS: Fourteen potential proteomic candidate markers (proteins) identified in a previous study in sera from patients exhibiting manifest AS were evaluated in the plasma, serum, and urine collected from a cohort of 132 subjects, including patients with AS and other nephropathies and healthy controls. Quantitation was performed by immunoassays. RESULTS: The serum and plasma levels of none of the 14 proteins evaluated were significantly different among the three groups and therefore could not be used to discriminate between the groups. In contrast, the levels of various biomarker combinations in the urine were significantly different between AS patients and healthy controls. Importantly, some combinations had the potential to discriminate between AS and other nephropathies. CONCLUSIONS: These findings open a window of opportunity for the sensitive and specific early diagnosis of AS. Our results increase the potential for larger scale evaluation of an increased number of patients.

Between-limb kinematic asymmetry during gait in unilateral and bilateral mild to moderate knee osteoarthritis.

OBJECTIVE: To compare lower-limb kinematic asymmetries during gait in individuals with unilateral and bilateral symptomatic osteoarthritis and controls. DESIGN: Cross-sectional. SETTING: Laboratory. PARTICIPANTS: Participants (N=54) had symptomatic unilateral (n=18) or bilateral (n=18) knee osteoarthritis. Healthy controls were sex- and age-matched and similar in height and weight to osteoarthritis groups (n=18). INTERVENTION: Three-dimensional motion analysis was conducted while participants walked on a treadmill at 1.1m/s. MAIN OUTCOME MEASURES: Maximum joint angles and velocities of the knee and hip during stance, knee flexion, knee adduction, and hip adduction at initial contact, pelvic drop, stride length, and average toe out. RESULTS: There was a significant limb effect for knee flexion at initial contact (P=.01). The bilateral osteoarthritis group demonstrated the largest between-limb asymmetry (2.83°; 95% confidence interval, .88-4.78; effect size [ES]=.67). The bilateral osteoarthritis group also displayed tendencies toward between-limb asymmetry in hip adduction at initial contact and peak knee adduction during stance; ESs were small (ES=.33 and .48). Lower-limb kinematics was symmetrical in the control and unilateral knee osteoarthritis groups. CONCLUSIONS: Between-limb asymmetries are present even at mild to moderate stages of knee osteoarthritis. During this stage, between-limb asymmetry appears to be more prevalent in patients with bilateral symptomatic disease, suggesting that patients with unilateral disease maintain kinematic symmetry for longer in the knee osteoarthritis process. Further, early treatment strategies should target the restoration of gait symmetry and involve kinematics changes in both lower limbs. Future research is needed to determine the efficacy of such strategies with respect to kinematic asymmetry, pain, and disease progression.

Steps toward the validation of the Trendelenburg test: the effect of experimentally reduced hip abductor muscle function on frontal plane mechanics.

OBJECTIVE: To investigate the validity of the Trendelenburg test (TT) using an ultrasound-guided nerve block (UNB) of the superior gluteal nerve and determine whether the reduction in hip abductor muscle (HABD) strength would result in the theorized mechanical compensatory strategies measured during the TT. DESIGN: Quasi-experimental. SETTING: Hospital. PARTICIPANTS: Convenience sample of 9 healthy men. Only participants with no current or previous injury to the lumbar spine, pelvis, or lower extremities, and no previous surgeries were included. INTERVENTIONS: Ultrasound-guided nerve block. MAIN OUTCOME MEASURES: Hip abductor muscle strength (percent body weight [%BW]), contralateral pelvic drop (cPD), change in contralateral pelvic drop (ΔcPD), ipsilateral hip adduction, and ipsilateral trunk sway (TRUNK) measured in degrees. RESULTS: The median age and weight of the participants were 31 years (interquartile range [IQR], 22-32 years) and 73 kg (IQR, 67-81 kg), respectively. An average 52% reduction of HABD strength (z = 2.36, P = 0.02) resulted after the UNB. No differences were found in cPD or ΔcPD (z = 0.01, P = 0.99, z = -0.67, P = 0.49, respectively). Individual changes in biomechanics showed no consistency between participants and nonsystematic changes across the group. One participant demonstrated the mechanical compensations described by Trendelenburg. CONCLUSIONS: The TT should not be used as a screening measure for HABD strength in populations demonstrating strength greater than 30%BW but should be reserved for use with populations with marked HABD weakness. CLINICAL RELEVANCE: This study presents data regarding a critical level of HABD strength required to support the pelvis during the TT.

Lower extremity kinematics during running and hip abductor strength in iliotibial band syndrome: A systematic review and meta-analysis.

BACKGROUND: Iliotibial band syndrome is a common overuse injury that is twice as likely to affect female runners compared to male runners. It is unclear if there is a consistent running pattern and strength profile exhibited by female and male runners with iliotibial band syndrome. RESEARCH QUESTION: The purpose of this systematic review and meta-analysis was to determine if any differences existed in lower-extremity kinematics and hip strength between runners who retrospectively, currently, or prospectively had iliotibial band syndrome. METHODS: Papers included must have reported three-dimensional kinematic running data and/or hip strength data that were statistically analyzed between runners that never developed iliotibial band syndrome and runners with iliotibial band syndrome. Meta-analysis was performed for each kinematic or strength variable reported in at least three studies. Female and male runners were analyzed separately and grouped into three cohorts (retrospective, current, prospective). RESULTS: Seventeen articles were included in this systematic review. Data from 10 cross-sectional studies were included for meta-analysis. Female runners with current iliotibial band syndrome exhibited smaller peak hip internal rotation angles and lower isometric hip abductor strength compared to controls. SIGNIFICANCE: Although limited biomechanical evidence exists, risk factors for ITBS are different between female and male runners and may vary according to injury status. Specifically, transverse plane hip motion and hip abductor strength weakness may be biomechanical risk factors in female runners with current iliotibial band syndrome only.

Liquid biopsy based HER2 amplification status in gastric cancer patients indicates clinical response.

Gastric carcinomas are among the most common cancers in Germany, with approximately 18,000 new cases per year. About 10 years ago, based on results of the Trastuzumab for gastric cancer (ToGA) trial, the addition of the monoclonal antibody trastuzumab to a platinum-fluoropyrimidine chemotherapy backbone became the standard-of-care 1st-line therapy for human epidermal growth factor receptor 2 (HER2)-positive gastric cancers. Only patients with primary HER2 gene amplification benefit from this therapy. Thus, accurate HER2 gene amplification detection is predictive and critical for therapy selection. As a gold standard the HER2 status is currently determined in tumor tissue specimens using immune histochemistry and fluorescent in situ hybridisation. However, HER2 amplification is detectable in only about 20 % of gastric carcinomas. The recent approval of an antibody-drug conjugate Trastuzumab deruxtecan (T-DXd) and the establishment of a new subgroup of HER2-low tumors due to the bystander effect associated with T-DXd increases the relevance of precise HER2 diagnostics. Aim of this analysis was to determine the HER2 amplification status from circulating DNA fragments in blood using a HER2 Copy Number Variation assay to establish a minimal invasive approach. For the present study, a digital droplet PCR-based method was validated relative to established tissue-based methods. Furthermore and most importantly, the changes of HER2 status during therapy were investigated in seven patients indicating that the changes of HER2 status and number of HER2 copies detected in blood can reflect on therapy efficiency and uncover treatment resistance.