[Diagnosis and therapy of tumors with NTRK gene fusion]. / Diagnostik und Therapie von Tumoren mit NTRK-Genfusionen.

NTRK gene fusions are sporadic genetic alterations that can occur across tumor entities. Whereas they are quite rare in most solid tumors they are present at much higher frequencies in certain rare tumors such as infantile fibrosarcoma, congenital mesoblastic nephroma, secretory breast, or salivary gland carcinoma. NTRK gene fusions or TRK fusion proteins are considered strong oncogenic drivers. If NTRK gene fusions are detected, TRK inhibitors such as entrectinib and larotrectinib can be used regardless of the tumor entity. So far only larotrectinib is approved in the European Union. Both drugs have been shown to be effective and well tolerated in phase I and phase II studies. The low prevalence of TRK fusion-positive cancers poses challenges for diagnostic and clinical work-flows. On one hand, patients with NTRK gene fusions should be identified; on the other hand, epidemiological, histological, and resource-related aspects have to be taken into account. Based on these premises, we suggest a diagnostic algorithm for TRK fusion cancers and present current data on TRK inhibitors.

A randomized controlled trial on the efficacy of intermittent cervical traction for patients with chronic neck pain.

OBJECTIVE: To investigate the efficacy of intermittent cervical traction in the treatment of chronic neck pain over a 12-week follow-up. DESIGN: A randomized controlled trial. SETTING: Hospital-based outpatient practice. SUBJECTS: Seventy-nine patients with chronic neck pain. INTERVENTIONS: Subjects were randomly assigned to either experimental group (n = 39, mean age = 50.5 ± 9.8) or control group (n = 40, mean age = 48.8 ± 9.1). Experimental group received intermittent cervical traction and control group received infrared irradiation alone; twice a week over a period of six weeks. OUTCOME MEASUREMENTS: The values of Chinese version of the Northwick Park Neck Pain Questionnaire (NPQ), verbal numerical pain scale (VNPS), and cervical active range of motion (AROM) were measured at baseline, six-week and 12-week follow-up. RESULTS: No significant differences were found between the two groups in the NPQ (P > 0.05), VNPS (P > 0.05) and AROM (P > 0.05).

Neck pain in Hong Kong: a telephone survey on consequences and health service utilization.

STUDY DESIGN: A regionally representative telephone survey using a 2-stage randomization process. OBJECTIVE: (1) To investigate the prevalence and consequence of neck pain in terms of disability and rate of absenteeism from work. (2) To describe the health services utilization pattern of neck pain subjects and to analyse the factors associated with neck pain and health services utilization pattern. SUMMARY OF BACKGROUND DATA: There has been a lack of reliable information on the health service utilization pattern of neck pain subjects, the consequences and the patient perceived effectiveness of neck pain management in Hong Kong and Asian countries. METHODS: Subjects were interviewed on the sociodemographic characteristics, occurrence and consequences of neck pain, and the health utilization pattern. A random sample of the respondents was re-interviewed 7 to 10 days after the initial interview, by an independent interviewer for the reliability check. RESULTS: A total of 4640 subjects were interviewed. The 12-month prevalence was 64.6% (95% CI: 63.2%-66.0%). About 38.0% of these patients suffered from moderate to severe pain. Moreover, 17.7% of these subjects had to limit their social activities and 19% had to limit their work. About 25% of those subjects had consulted medical or health practitioners. Medical consultation is the majority and physiotherapy came second. Self-massage was the most preferred (83.3%) mode of self-care. Physiotherapy was regarded as the most effective health service, with 60% of the respondents' neck pain completely removed. Although most people chose self-massage to be the most effective self-care treatment, only one-third (30.2%) of them had their neck pain improved by less than a half. CONCLUSION: Neck pain is highly prevalent with an increasing impact in Hong Kong. More than one-third of neck pain patients suffered from moderate to severe pain and around 20% of them had to limit their work. About 25% of neck pain patient have consulted medical or health professionals. Physiotherapy and private medical clinic were the 2 service providers with high percentage of perceived complete improvement. There was a general trend that more neck pain patients used complementary therapies.

The correlation between craniovertebral angle, backpack weights, and disability due to neck pain in adolescents.

PURPOSES: To investigate the responses of the craniovertebral (CV) angle to backpack loadings in adolescents with and without neck pain and to explore the relationships between CV angle, relative backpack weight, neck pain and disability. METHODS: A cross-sectional single-blinded study was conducted on 60 adolescents (30 neck pain and 30 non-neck pain) aged from 13 to 18 years old. The verbal analog scale (VAS) and Chinese version of Northwick Park Neck Pain Questionnaire (NPQ) were used to assess neck pain severity and disability respectively. CV angle was measured in neutral and with backpack loadings of 5% to 30% of subject's body weight by using the Head Posture Spinal Curvature Instrument (HPSCI). RESULTS: In both groups, CV angles gradually decreased with increment of backpack loadings and the amount of decreases became significant from 10% body weight onwards (P < 0.05). Although the changes of CV angles did not show any significant differences at any point of comparison between the groups, the neck pain group showed a clinically significant decrease of CV angle (∼ 5°) at 10% relative loading whereas non-neck pain group did it at 15% relative loading. Change of CV angles did not show significant correlations with relative backpack weight, cervical pain and disability (P > 0.05). CONCLUSIONS: Our findings suggested a safety limit of 10% relative backpack load for adolescents. The results showed the tendency that the ability of maintaining good head posture in response to backpack loadings by non-neck pain subjects might be better than those with neck pain.

The correlation between craniovertebral angle, backpack weights, and disability due to neck pain in adolescents.

PURPOSES: To investigate the responses of the craniovertebral (CV) angle to backpack loadings in adolescents with and without neck pain and to explore the relationships between CV angle, relative backpack weight, neck pain and disability. METHODS: A cross-sectional single-blinded study was conducted on 60 adolescents (30 neck pain and 30 non-neck pain) aged from 13 to 18 years old. The verbal analog scale (VAS) and Chinese version of Northwick Park Neck Pain Questionnaire (NPQ) were used to assess neck pain severity and disability respectively. CV angle was measured in neutral and with backpack loadings of 5% to 30% of subject's body weight by using the Head Posture Spinal Curvature Instrument (HPSCI). RESULTS: In both groups, CV angles gradually decreased with increment of backpack loadings and the amount of decreases became significant from 10% body weight onwards (P < 0.05). Although the changes of CV angles did not show any significant differences at any point of comparison between the groups, the neck pain group showed a clinically significant decrease of CV angle ( approximately 5 degrees ) at 10% relative loading whereas non-neck pain group did it at 15% relative loading. Change of CV angles did not show significant correlations with relative backpack weight, cervical pain and disability (P > 0.05). CONCLUSIONS: Our findings suggested a safety limit of 10% relative backpack load for adolescents. The results showed the tendency that the ability of maintaining good head posture in response to backpack loadings by non-neck pain subjects might be better than those with neck pain.

The role of fear-avoidance beliefs in patients with neck pain: relationships with current and future disability and work capacity.

OBJECTIVES: To investigate the relationship between fear-avoidance beliefs and future disability and work capacity in patients with neck pain. DESIGN: A prospective observational study. SETTING: Physiotherapy outpatient departments. PATIENTS: One hundred and twenty patients with neck pain intensity sufficient to affect their work capacity. INTERVENTIONS: Patients participated in either six-week conventional physiotherapy or an exercise training programme to test whether the type of treatment received by the patients together with other outcome measures affected the predictive power of fear-avoidance beliefs. MAIN OUTCOME MEASURES: Patients underwent examination of the active neck range of movements and neck muscle strength and completed the Fear-Avoidance Beliefs Questionnaire, the Northwick Park Neck Pain Questionnaire, the Medical Outcomes 36-Item Short-Form Health Survey and the 11-point pain numerical rating scale. These were assessed at the beginning and at week 6 of the rehabilitation programme. Patients' work capacity was assessed at week 6 and three months after the six-week rehabilitation programme. RESULTS: Spearman's correlation coefficients between fear-avoidance beliefs and initial and week 6 disability levels were 0.47 and 0.48, respectively. Regression analysis showed that the fear-avoidance beliefs significantly improved the goodness of fit of the model for predicting week 6 disability levels and return to complete work capacity at week 6 and three months after the rehabilitation programme, even after controlling for the physical impairments, the health status, the pain intensity and the type of treatment received. CONCLUSIONS: The fear-avoidance beliefs factor is an important biopsychosocial variable in predicting future disability level and return to complete work capacity in patients with neck pain.

The prevalence of and risk factors for neck pain and upper limb pain among secondary school teachers in Hong Kong.

OBJECTIVE: To investigate the prevalence and occupational risk factors of neck and upper limb disorders among secondary school teachers. METHODS: One hundred secondary schools in Hong Kong were randomly chosen. Every full-time teacher received a questionnaire and a letter describing the purpose of the study. Questionnaires were collected 1 to 3 weeks later. RESULTS: Among 3,100 secondary school teachers, the lifelong prevalence of neck pain and upper limb pain was 69.3% (2091/3018) and 35.8% (1088/3042) respectively. The lifelong cumulative incidence of both neck and upper limb pain was 31.6% (938/2966). Multiple logistic regression analysis showed that gender, age and working in head down posture were identified as risk factors for neck and upper limb pain. High workload, low colleague support and high anxiety were found to be significant on affecting the neck pain and upper limb pain developed after becoming teachers. CONCLUSIONS: Neck pain and upper limb pain were highly prevalent in secondary school teachers in Hong Kong. Gender, age, head down posture and some psychological factors were found to be significant risk factors.

Psychometric properties of the Fear-Avoidance Beliefs Questionnaire in patients with neck pain.

OBJECTIVES: To translate the Fear-Avoidance Beliefs Questionnaire and investigate the validity and reliability of the Chinese version of the questionnaire in patients with neck pain. DESIGN: Observational cross-sectional and prospective study. SETTING: Physiotherapy outpatient departments. SUBJECTS: Four samples with 476 consecutive adult patients with neck pain from four physiotherapy centres. METHODS: The original questionnaire was translated into Chinese by forward and backward translation and reviewed by a panel of experts. The subjects completed the Chinese version of the fear-avoidance questionnaire, Northwick Park Neck Pain Questionnaire, Medical Outcomes 36-Item Short-Form Health Survey and their pain intensity was measured using an 11-point pain numerical rating scale. They were observed and measured at the beginning of physiotherapy, at week 3 and at week 6 after treatment began. RESULTS: The questionnaire had very good content validity and test-retest reliability with an intraclass correlation coefficient of 0.81 and Cronbach's alpha coefficient of 0.90. Spearman's correlation coefficients between fear-avoidance and the neck pain questionnaire, the health survey (physical), health survey (mental) and pain scale were 0.56, 0.45, 0.36 and 0.34, respectively. The standard response mean and effect size at week 6 were 0.38 and 0.32, respectively. Factor analysis yielded three factors which accounted for 61.6% of the total variance of the questionnaire. CONCLUSION: The Fear-Avoidance Beliefs Questionnaire is a valid and reliable tool for patients with neck pain. It has been shown to demonstrate very good content validity, a high degree of test-retest reliability and internal consistency, good construct validity and medium responsiveness.

Correlation between generic health status and region-specific functional measures on patients with neck pain.

This is a cross-sectional and prospective study to examine the correlation between the Northwick Park Neck Pain Questionnaire and the Medical Outcomes 36-Item Short-Form Health Survey on patients with neck pain in the course of physiotherapy. A total of 359 consecutive adult patients with neck pain, from three physiotherapy outpatient departments, who completed the Northwick Park Neck Pain Questionnaire and Medical Outcomes 36-Item Short-Form Health Survey, were observed and measured at different intervals - at the beginning of physiotherapy, at week 3, week 6 and upon discharge from physiotherapy. The results showed that both the Northwick Park Neck Pain Questionnaire and the Medical Outcomes 36-Item Short-Form Health Survey were able to differentiate patients with neck pain in health and diseased states. The Spearman's correlation coefficients between the Northwick Park Neck Pain Questionnaire and the 36-Item Short-Form Health Survey physical and mental component summary scores at entry of physiotherapy were -0.64 with the physical component summary score and -0.44 with the mental component summary score, and, at discharge from physiotherapy, were -0.75 with the physical component summary score and -0.46 with the mental component summary score. The Northwick Park Neck Pain Questionnaire has psychometric properties with both physical and mental dimensions of measurement of pain in patients with neck pain.

Neck pain in Hong Kong: a telephone survey on prevalence, consequences, and risk groups.

STUDY DESIGN: A cross-sectional telephone survey was conducted using a two-stage randomization process. OBJECTIVES: The objectives of this paper were to investigate the prevalence of neck pain and their consequences and risk groups in the Hong Kong population. SUMMARY OF BACKGROUND DATA: There has been a lack of recent information on the prevalence and consequences of neck pain in the population of Hong Kong. METHODS: A total of 664 subjects were interviewed on the socio-demographic characteristics, occurrence, and consequences of neck pain. A random sample of the respondents was reinterviewed after 7 to 10 days later, by another interviewer for the reliability check. RESULTS: The lifetime prevalence of neck pain was 65.4% (95% confidence interval, 61.8%-69.0%). The 12-month prevalence was 53.6% (41.0% in male, 59.0% in female) (95% confidence interval, 49.8%-57.4%). About 15.0% of these patients had moderate to severe pain. Moreover, 4.5% of these subjects had to limit their social activities and 3.1% had to limit their work. Multiple logistic regression analysis showed that females, managers, administrators, and professionals have a high risk of neck pain in the population of Hong Kong. CONCLUSION: Neck pain is highly prevalent in Hong Kong, particularly among females, managers, administrators, and professionals.

A randomized clinical trial of TENS and exercise for patients with chronic neck pain.

OBJECTIVE: To investigate the effect of transcutaneous electrical nerve stimulation (TENS) on acupuncture points and neck exercise in chronic neck pain patients. DESIGN: A randomized clinical trial. SETTING: Hospital-based practice. SUBJECTS: Two hundred and eighteen patients with chronic neck pain. INTERVENTIONS: Subjects were randomized into three groups, receiving either (1) TENS over the acupuncture points plus infrared irradiation (TENS group); (2) exercise training plus infrared irradiation (exercise group); or (3) infrared irradiation alone (control); twice a week for six weeks. OUTCOME MEASURES: The values of verbal numeric pain scale, Northwick Park Neck Pain Questionnaire, and isometric neck muscle strength were assessed before, at the end of the six-week treatment, and at the six-month follow-up. RESULTS: Results demonstrated that after the six-week treatment, significant improvement in the verbal numerical pain scale was found only in the TENS group (0.60+/-2.54, p = 0.027) and the exercise group (1.57+/-2.67, p < 0.001). Though significant reduction in Northwick Park Neck Pain Questionnaire score was found in all three groups, post-hoc tests showed that both the TENS and the exercise group produced better improvement (0.38+/-0.60% and 0.39+/-0.62% respectively) than the control group (0.23+/-0.63%). Significant improvement (p = < 0.001 to 0.03) in neck muscle strength was observed in all three groups, however, the improvement in the control group was not clinically significant and it could not be maintained at the six-month follow-up. CONCLUSIONS: After the six-week treatment, patients in the TENS and exercise group had a better and clinically relevant improvement in disability, isometric neck muscle strength, and pain. All the improvements in the intervention groups were maintained at the six-month follow-up.

Psychometric properties of a generic health measure in patients with neck pain.

OBJECTIVE: To examine the reliability, validity and responsiveness of the generic Current Perceived Health 42 (CPH42) Profile in Chinese patients with neck pain in Hong Kong. DESIGN: A prospective observational study. SETTING: Physiotherapy outpatient departments. SUBJECTS: Two samples with 472 consecutive adult patients with neck pain from seven physiotherapy outpatient departments in Hong Kong. METHODS: Subjects were requested to complete the CPH42 Profile, and their pain intensity was measured using the 11-point numerical rating scale (NRS). They were observed and measured at the beginning of physiotherapy, at seven days, at week 3 and at week 6 after treatment began. RESULTS: The CPH42 Profile had very good test-retest reliability and internal consistency (intraclass correlation coefficient 0.91, Cronbach's alpha 0.90). Validity was confirmed by a moderate correlation with the NRS at the beginning of treatment and week 6 (rank correlation 0.41-0.53). Moreover, a significant difference in scores was found between those who had sought medical consultation and/or had taken medication because of neck pain than those who did not. The responsiveness measured from the beginning of treatment to week 3 and week 6 (standard response means of 0.33 and 0.36) was comparable to the respective changes in pain intensity. CONCLUSION: The CPH42 Profile has been shown to demonstrate good reliability and validity, and it is sensitive to changes in severity over time. It is suitable for use as an outcome measure for evaluation of patients with neck pain.

A randomized controlled trial on the efficacy of exercise for patients with chronic neck pain.

STUDY DESIGN: A randomized controlled trial with single-blind outcome assessments. OBJECTIVE: To evaluate the efficacy of a neck exercise program in patients with chronic neck pain. SUMMARY OF BACKGROUND DATA: The effect of exercise for patients with chronic neck pain has been investigated in a number of studies. The efficacy is, however, questionable. METHODS: A total of 145 patients were randomly allocated into an exercise (n = 67) and a nonexercise (control) group (n = 78). Patients in the control group were given infrared irradiation and neck care advice. In addition to infrared irradiation and advice, patients in the exercise group had undergone an exercise program with activation of the deep neck muscles and dynamic strengthening of the neck muscles for 6 weeks. Subjective pain and disability and isometric neck muscle strength were measured at baseline, 6 weeks, and 6 months. Analysis was by intention-to-treat. RESULTS: At week 6, the exercise group had a significantly better improvement in disability score (P = 0.03), subjective report of pain (P = 0.01), and in isometric neck muscle strength (P = 0.57-0.00) in most of the directions than the control group. However, significant differences between the two groups were found only in the subjective report of pain and patient satisfaction at the 6-month follow-up. CONCLUSIONS: At week 6, patients with chronic neck pain can benefit from the neck exercise program with significant improvement in disability, pain, and isometric neck muscle strength in different directions. However, the effect of exercise was less favorable at 6 months.

Use of modified Northwick Park Neck Pain Questionnaire in patients with postirradiation neck disability: validation study.

BACKGROUND: No available measure exists for postirradiation neck disability. Adoption of the Chinese Northwick Park Neck Pain Questionnaire (NPQ) for patients with postirradiation neck disability was examined in this study. METHODS: Eight physiotherapists and five patients were invited to test the validity of the content. Forty-three patients with neck disability were recruited to evaluate test-retest reliability and internal consistency. The level of neck discomfort, range of neck motion and maximal isometric neck muscle strength, and SF-36 health score were measured for construct validity testing. RESULTS: The questionnaire had good content validity, a high degree of test-retest reliability, internal consistency (intraclass correlation coefficient [ICC], 0.94; Cronbach's alpha, 0.88), and good construct validity. NPQ correlated significantly with most of the subscores of SF-36 (r(s), -0.43 to - 0.71) and numeric rating scale (r(s) = 0.69). CONCLUSION: The modified Chinese NPQ was found to be reliable and valid for the evaluation of postirradiation neck disability.

Maximal isometric muscle strength of the cervical spine in healthy volunteers.

OBJECTIVE: To describe the maximal isometric neck muscle strength in healthy Chinese volunteers, in six different directions, as measured by a Multi Cervical Rehabilitation Unit. DESIGN: A standardized cross-sectional observational study. SETTING: A university rehabilitation unit. SUBJECTS: Ninety-one healthy volunteers aged 20-84. METHODS: During the measurement the subject was instructed to do three consecutive steady contractions as hard as possible, with a 10-second rest in between each contraction and a 2-minute rest between different directions. The peak isometric strength for each of the six directions (flexion, extension, lateral flexions, protraction and retraction) was calculated. RESULTS: No significant difference was found in muscle strength between different age groups. Isometric muscle strength in the direction of right lateral flexion was significantly greater than that to the left in men (p = 0.030), but no difference was found in women (p = 0.297). Isometric strength in all directions in men was 1.2-1.7 times that in women (all p < 0.028). Correlations between physical measurements (height and weight) and strength values were all insignificant in both genders. CONCLUSION: Men have approximately 20-70% greater isometric neck muscle strength than women. Both men and women can maintain high levels of cervical muscle strength in six different directions up to their seventh decade. There is no significant correlation between physical measurements and isometric neck muscle strength.

Spreading and motility of human glioblastoma cells on sheets of silicone rubber depend on substratum compliance.

Although there is a substantial quantity of experimental data examining the effects of adhesion on the morphology and migration of tissue cells, little attention has been focused on how changes in substratum mechanical properties affect these cellular behaviours. To determine whether the ability of a substratum mechanically to support traction influences cell morphology and motility, measurements are taken of the spreading, the fraction of a population with pseudopodia, the number of pseudopodia and the translocation of human SNB-19 glioblastoma cells cultured on films of poly(methylphenyl)siloxane possessing a range of mechanical compliances. Cells cultured on these films generate deformations (i.e. 'wrinkles') that are used as a basis to estimate effective substratum compliances. The average projected cell area decreases by over 60%, with a two-orders-of-magnitude increase in compliance. Time-lapse videomicroscopy reveals that cell migration also decreases with increasing compliance: the average cell speed decreases from approximately 8 microns h-1 on the most rigid substrata to 1.2 microns h-1 on the most compliant substrata examined. Changes in compliance do not alter mean directional persistence time. These results are interpreted in terms of the predictions of mathematical models for the effects of substratum compliance on motility.

Mechanisms of calcium release and sequestration in eggs of Chaetopterus pergamentaceus.

Increases in the intracellular free calcium concentration are of great importance to the initiation of development in deuterostomes. Their involvement has not yet been clearly defined in protostomes. We used endogenous ligands (IP3, cADPR, ryanodine and NAADP) and pharmacological agents (thapsigargin [Tg], thimerosal, caffeine and heparin) to study smooth endoplasmic reticulum Ca2+ pump and release mechanisms in eggs of an annelid, Chaetopterus. Oocyte homogenates effectively sequestered Ca2+ and released it in response to IP3 in a concentration-dependent manner. Repeated additions of IP3 were unable to cause further release. Heparin inhibited Ca2+ release in response to IP3. The homogenates also released Ca2+ in response to thimerosal, and this release was sensitive to heparin. Two antibodies to IP3 receptors recognized an appropriate band in Chaetopterus egg lysates. These results indicate that the oocytes possess type-1 IP3-gated Ca2+ channels. Neither calcium itself, nor strontium, cADPR, ryanodine, caffeine nor NAADP released appreciable Ca2+. At low concentrations, Tg caused a slow release of Ca2+; at higher concentrations, it elicited a rapid release. Release of Ca2+ by Tg activated development. Since one theory of fertilization invokes the introduction of a Ca2+ releasing soluble protein into the egg upon sperm-egg fusion, we also tested whether soluble extracts of Chaetopterus sperm could stimulate Ca2+ release in Chaetopterus egg homogenates. There was no Ca2+ release when the sperm extract was added to the homogenate; however, homogenates exposed to sperm extract became refractory to IP3. Thus, Ca2+ release at fertilization in these oocytes occurs through IP3-gated channels.

False susceptibility of enterococci to aminoglycosides with blood-enriched Mueller-Hinton agar for disk susceptibility testing.

Disk diffusion susceptibility tests for enterococci are frequently modified by adding 5% sheep blood (SB) to Mueller-Hinton agar; the performance standards from the National Committee for Clinical Laboratory Standards sanction this addition. Susceptibility testing of aminoglycoside antibiotics is not recommended for enterococci; in actual practice, however, some laboratories do include aminoglycoside antibiotics routinely, and others may test upon request or in selected situations. In examining 50 clinical isolates of enterococci, SB-enriched Mueller-Hinton agar frequently gave enlarged zone sizes that falsely indicated susceptibility (72% for gentamicin and tobramycin), with the average increase in zone size being 6.3 and 7.6 mm, respectively. Comparison agar dilution MICs demonstrated uniform resistance, with or without added SB. The effect was shown to be caused by heme in concentrations as low as 0.03 micrograms/ml, which, when combined with aminoglycoside antibiotics, caused a synergistic growth inhibition of the enterococci, resulting in larger aminoglycoside antibiotic zones. We postulate that the heme effect is related to a catalytic cleavage of intracellular H2O2 and resultant lipid peroxidation. No other organism or antimicrobial agent tested demonstrated a similar effect, although other investigators have shown a similar phenomenon with the broad-spectrum cephalosporins. Because enterococci grow well and give accurate susceptibility results on Mueller-Hinton agar without SB supplementation and because of the spectrum of definable problems with a number of antimicrobial agents, we recommend that enterococci routinely be tested without SB.