Efficacy of Lapatinib in Patients with HER2-Negative Metastatic Breast Cancer and HER2-Positive Circulating Tumor Cells-The DETECT III Clinical Trial.

BACKGROUND: The phenotypes of tumor cells change during disease progression, but invasive rebiopsies of metastatic lesions are not always feasible. Here we aimed to determine whether initially HER2-negative metastatic breast cancer (MBC) patients with HER2-positive circulating tumor cells (CTCs) benefit from a HER2-targeted therapy. METHODS: The open-label, interventional randomized phase III clinical trial (EudraCT Number 2010-024238-46, CliniclTrials.gov Identifier: NCT01619111) recruited from March 2012 until September 2019 with a follow-up duration of 19.5 months. It was a multicenter clinical trial with 94 participating German study centers. A total of 2137 patients with HER2-negative MBC were screened for HER2-positive CTCs with a final modified intention-to-treat population of 101 patients. Eligible patients were randomized to standard therapy with or without lapatinib. Primary study endpoints included CTC clearance (no CTCs at the end of treatment) and secondary endpoints were progression-free survival, overall survival (OS), and safety. RESULTS: In both treatment arms CTC clearance at first follow-up visit-although not being significantly different for both arms at any time point-was significantly associated with improved OS (42.4 vs 14.1 months; P = 0.002). Patients treated additionally with lapatinib had a significantly improved OS over patients receiving standard treatment (20.5 vs 9.1 months, P = 0.009). CONCLUSIONS: DETECT III is the first clinical study indicating that phenotyping of CTCs might have clinical utility for stratification of MBC cancer patients to HER2-targeting therapies. The OS benefit could be related to lapatinib, but further studies are required to prove this clinical observation. ClinicalTrials.gov Registration Number: NCT01619111.

Determination of the androgen receptor status of disseminated tumor cells in primary breast cancer patients.

PURPOSE: Androgen receptor (AR) can serve as a new therapeutic target since it was shown to play a proliferative role in several breast cancer (BC) subtypes. Moreover, AR positivity has been suggested to reflect the metastatic potential of tumor cells in some BC subtypes. The aim of this study was to determine the AR expression on disseminated tumor cells (DTCs) as a surrogate marker of minimal residual disease (MRD) and potential precursor of metastasis in early BC. METHODS: Bone marrow (BM) aspirates from 62 DTC-positive early BC patients were included into this study and analyzed by immunofluorescence staining for the presence of AR-positive DTCs. CK-positive, CD45-negative cells containing an intact nucleus (DAPI positive) were identified as DTCs. AR expression of the primary tumor (PT) was assessed by immunohistochemistry on formalin-fixed, paraffin-embedded (FFPE) tumor sections from core biopsies and surgical specimens. RESULTS: AR status of DTCs could be determined in 21 patients. We detected AR-positive DTCs in nine samples (43%). AR expression of DTCs and corresponding PT showed a concordance rate of 33%. The DTC-AR status did not correlate with clinicopathological factors, nor did we observe a significant correlation between the AR status of the PT and other established prognostic factors for BC. CONCLUSION: AR-positive DTCs can be detected in BM of early BC patients with a marked discordance of the AR status between DTCs and corresponding PTs. The clinical significance of these findings needs further investigation.

Whole Exome Analysis to Select Targeted Therapies for Patients with Metastatic Breast Cancer - A Feasibility Study.

Introduction: The purpose of this feasibility study was to select targeted therapies according to "ESMO Scale for Clinical Actionability of molecular Targets (ESCAT)". Data interpretation was further supported by a browser-based Treatment Decision Support platform (MH Guide, Molecular Health, Heidelberg, Germany). Patients: We applied next generation sequencing based whole exome sequencing of tumor tissue and peripheral blood of patients with metastatic breast cancer (n = 44) to detect somatic as well as germline mutations. Results: In 32 metastatic breast cancer patients, data interpretation was feasible. We identified 25 genomic alterations with ESCAT Level of Evidence I or II in 18/32 metastatic breast cancer patients, which were available for evaluation: three copy number gains in HER2 , two g BRCA1 , two g BRCA2 , six PIK3CA, one ESR1 , three PTEN , one AKT1 and two HER2 mutations. In addition, five samples displayed Microsatellite instability high-H. Conclusions: Resulting treatment options were discussed in a tumor board and could be recommended in a small but relevant proportion of patients with metastatic breast cancer (7/18). Thus, this study is a valuable preliminary work for the establishment of a molecular tumor board within the German initiative "Center for Personalized Medicine" which aims to shorten time for analyses and optimize selection of targeted therapies.

Consensus Recommendations of the German Consortium for Hereditary Breast and Ovarian Cancer.

Background: The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) has established a multigene panel (TruRisk®) for the analysis of risk genes for familial breast and ovarian cancer. Summary: An interdisciplinary team of experts from the GC-HBOC has evaluated the available data on risk modification in the presence of pathogenic mutations in these genes based on a structured literature search and through a formal consensus process. Key Messages: The goal of this work is to better assess individual disease risk and, on this basis, to derive clinical recommendations for patient counseling and care at the centers of the GC-HBOC from the initial consultation prior to genetic testing to the use of individual risk-adapted preventive/therapeutic measures.

Invasive Breast Carcinoma with Neuroendocrine Differentiation: A Single-Center Analysis of Clinical Features and Prognosis.

Introduction Invasive breast cancer with neuroendocrine differentiation is a rare subtype of breast malignancy. Due to frequent changes in the definition of these lesions, the correct diagnosis, estimation of exact prevalence, and clinical behaviour of this entity may be challenging. The aim of this study was to evaluate the prevalence, clinical features, and outcomes in a large cohort of patients with breast cancer with neuroendocrine differentiation. Patients Twenty-seven cases of breast cancer with neuroendocrine differentiation have been included in this analysis. Twenty-one cases were identified by systematic immunohistochemical re-evaluation of 465 breast cancer specimens using the neuroendocrine markers chromogranin A and synaptophysin, resulting in a prevalence of 4.5%. A further six cases were identified by a review of clinical records. Results Median age at the time of diagnosis was 61 years. 70% of patients had T2 - 4 tumors and 37% were node-positive. The most common immunohistochemical subtype was HR-positive/HER2-negative (85%). 93% were positive for synaptophysin and 48% for chromogranin A. Somatostatin receptor type 2A status was positive in 12 of 24 analyzed tumors (50%). Neuroendocrine-specific treatment with somatostatin analogues was administered in two patients. The 5-year survival rate was 70%. Conclusions Breast cancer with neuroendocrine differentiation is mostly HR-positive/HER2-negative and the diagnosis is made at a higher TNM stage than in patients with conventional invasive breast carcinoma. Moreover, breast cancer with neuroendocrine differentiation was found to be associated with impaired prognosis in several retrospective trials. Due to somatostatin receptor 2A expression, somatostatin receptor-based imaging can be used and somatostatin receptor-targeted therapy can be offered in selected cases.

Multiparametric Circulating Tumor Cell Analysis to Select Targeted Therapies for Breast Cancer Patients.

BACKGROUND: The analysis of liquid biopsies, e.g., circulating tumor cells (CTCs) is an appealing diagnostic concept for targeted therapy selection. In this proof-of-concept study, we aimed to perform multiparametric analyses of CTCs to select targeted therapies for metastatic breast cancer patients. METHODS: First, CTCs of five metastatic breast cancer patients were analyzed by whole exome sequencing (WES). Based on the results, one patient was selected and monitored by longitudinal and multiparametric liquid biopsy analyses over more than three years, including WES, RNA profiling, and in vitro drug testing of CTCs. RESULTS: Mutations addressable by targeted therapies were detected in all patients, including mutations that were not detected in biopsies of the primary tumor. For the index patient, the clonal evolution of the tumor cells was retraced and resistance mechanisms were identified. The AKT1 E17K mutation was uncovered as the driver of the metastatic process. Drug testing on the patient's CTCs confirmed the efficacy of drugs targeting the AKT1 pathway. During a targeted therapy chosen based on the CTC characterization and including the mTOR inhibitor everolimus, CTC numbers dropped by 97.3% and the disease remained stable as determined by computer tomography/magnetic resonance imaging. CONCLUSION: These results illustrate the strength of a multiparametric CTC analysis to choose and validate targeted therapies to optimize cancer treatment in the future. Furthermore, from a scientific point of view, such studies promote the understanding of the biology of CTCs during different treatment regimens.

Prevalence of Circulating Tumor Cells After Adjuvant Chemotherapy With or Without Anthracyclines in Patients With HER2-negative, Hormone Receptor-positive Early Breast Cancer.

BACKGROUND: Use of anthracycline-based chemotherapy in patients with early breast cancer (EBC) has been well-established but is often associated with cardiotoxicity. Based on data suggesting a limited benefit of anthracyclines in human epidermal growth factor receptor 2 (HER2)-negative patients, the Simultaneous Study of Docetaxel Based Anthracycline Free Adjuvant Treatment Evaluation, as well as Life Style Intervention Strategies (SUCCESS) C study randomized patients to either anthracycline-containing or anthracycline-free chemotherapy. Given the proven prognostic value of circulating tumor cells (CTCs) in EBC, we compared the prevalence of CTCs after chemotherapy between both treatment arms for a preliminary efficacy assessment. METHODS: The SUCCESS C trial (NCT00847444) is an open-label, phase III study randomizing 3547 patients with HER2-negative EBC to either 3 cycles of epirubicin, 5-fluorouracil, and cyclophosphamide followed by 3 cycles of docetaxel (FEC-DOC) or 6 cycles of docetaxel and cyclophosphamide (DOC-C). CTC status was prospectively evaluated in hormone receptor-positive patients at the time of last chemotherapy cycle using the US Food and Drug Administration-approved CellSearch System (Janssen Diagnostics). RESULTS: Data on CTC status were available for 1766 patients. Overall, CTCs were found in 221 (12.5%) patients. Univariate analyses revealed that presence of CTCs at time of last chemotherapy cycle was not significantly associated with tumor or patient characteristics (all P > .1). There was no significant difference with respect to presence of CTCs between patients randomized to FEC-DOC or DOC-C (11.5% vs. 13.6%; P = .18). CONCLUSIONS: The comparable prevalence of CTCs at the time of last chemotherapy cycle may indicate that anthracycline-free chemotherapy is equally effective to anthracycline-containing chemotherapy in HER2-negative, hormone receptor-positive EBC. However, efficacy data from the final survival analysis of SUCCESS C have to be awaited to confirm these preliminary findings.

Aberrant regulation of RANKL/OPG in women at high risk of developing breast cancer.

Breast cancer is the most common female cancer, affecting approximately one in eight women during their lifetime in North America and Europe. Receptor Activator of NF-kB Ligand (RANKL), its receptor RANK and the natural antagonist osteoprotegerin (OPG) are essential regulators of bone resorption. We have initially shown that RANKL/RANK are essential for hormone-driven mammary epithelial proliferation in pregnancy and RANKL/RANK have been implicated in mammary stem cell biology. Using genetic mouse-models, we and others identified the RANKL/RANK system as a key regulator of sex hormone, BRCA1-mutation, and oncogene-driven breast cancer and we proposed that RANKL/RANK might be involved in the initiation of breast tumors. We now report that in postmenopausal women without known genetic predisposition, high RANKL and progesterone serum levels stratify a subpopulation of women at high risk of developing breast cancer 12-24 months before diagnosis (5.33-fold risk, 95%CI 1.5-25.4; P=0.02). In women with established breast cancer, we demonstrate that RANKL/OPG ratios change dependent on the presence of circulating tumor cells (CTCs). Finally, we show in a prospective human breast cancer cohort that alterations in RANKL/OPG ratios are significantly associated with breast cancer manifestation. These data indicate that the RANKL/RANK/OPG system is deregulated in post-menopausal women at high risk for breast cancer and in women with circulating tumor cells. Thus, serum levels of RANKL/OPG are potentially indicative of predisposition and progression of breast cancer in humans. Advancement of our findings towards clinical application awaits prior validation in independent patient cohorts.

Discordance in Human Epidermal Growth Factor Receptor 2 (HER2) Phenotype Between Primary Tumor and Circulating Tumor Cells in Women With HER2-Negative Metastatic Breast Cancer.

PURPOSE: Discordance in human epidermal growth factor receptor 2 (HER2) status between primary tumor and metastases might have important implications for treatment response and therapy decisions. Here, we evaluate both the frequency of circulating tumor cells (CTCs) and the factors predicting HER2 discordance between primary tumor and CTCs as a potential surrogate for tumor biology and tumor heterogeneity in patients with metastatic breast cancer. PATIENTS AND METHODS: The number of CTCs in 7.5 mL of peripheral blood and HER2 status were evaluated in 1,123 women with HER2-negative metastatic breast cancer. HER2 discordance was defined as the presence of at least one CTC with a strong immunocytochemical HER2 staining intensity. Factors predicting discordance in HER2 phenotype were assessed using multivariable logistic regression. RESULTS: Overall, 711 (63.3%) of 1,123 screened patients were positive for CTCs (≥ one CTC). Discordance in HER2 phenotype between primary tumor and CTCs was observed in 134 patients (18.8%) and was significantly associated with histologic type (lobular v ductal; odds ratio [OR], 2.67; 95% CI, 1.63 to 4.39; P < .001), hormone receptor status (positive v negative; OR, 2.84; 95% CI, 1.15 to 7.02; P = .024), and CTC number (≥ five v one to four; OR, 7.64; 95% CI, 3.97 to 14.72; P < .001). CONCLUSION: HER2 discordance between primary tumor and CTCs was observed in 18.8% of patients and was associated with histologic type, hormone receptor status of the primary tumor, and CTC number. The clinical utility of CTCs as liquid biopsy to assess tumor heterogeneity of metastatic disease and guide treatment decisions must be evaluated in prospective randomized trials.

Measuring the course of anxiety in women giving birth by caesarean section: a prospective study.

BACKGROUND: Women undergoing elective caesarean section experience anxiety. However, course, extent and duration of anxiety have not been investigated yet. This study aimed to explore anxiety levels during the course of the day of surgery by employing and comparing subjective as well as objective measures. By examining their correlation it is intended to give methodological support for interventional studies. METHODS: This is a monocentric, prospectively planned study in which 47 women with an indication for primary caesarean section took part. Anxiety levels were evaluated using the State-Trait Anxiety Inventory (STAI-trait and STAI-state), the visual analogue scale for anxiety (VASA) as well as saliva cortisol at three time points on the day of the caesarean section (at admission, at skin closure and 2 h post surgery). RESULTS: Peak anxiety levels for the STAI-state and VASA were highest at admission and showed significant decreases to skin closure (p < .001). The subjective measures correlated significantly at all time points (p-values < .001). For cortisol levels the peak level of anxiety was shown at skin closure with a significant increase from admission to skin closure and a significant decrease from skin closure to 2 h post operation (p-values < .001). Additionally women with STAI-trait scores above the median showed significantly higher levels at the peaks of anxiety. CONCLUSION: The study reveals the course of anxiety on the day of the caesarean section. A strong correlation of STAI-state and VASA was demonstrated. Cortisol showed a different course, which fits into its known biological kinetics. Taking into account all measures, anxiety seems to be most bothersome before surgery until skin closure. In a differentiated approach using STAI-trait scores as a discriminator we showed that the group with STAI-trait levels above the median is particularly prone to develop anxiety in the setting of the caesarean section and might therefore mostly be in need of an intervention against anxiety.

Preventing Chronic Pain: A Human Systems Approach-Results From a Massive Open Online Course.

Chronic pain conditions are the top reason patients seek care, the most common reason for disability and addiction, and the biggest driver of healthcare costs; their treatment costs more than cancer, heart disease, dementia, and diabetes care. The personal impact in terms of suffering, disability, depression, suicide, and other problems is incalculable. There has been much effort to prevent many medical and dental conditions, but little effort has been directed toward preventing chronic pain. To address this deficit, a massive open online course (MOOC) was developed for students and healthcare professionals. "Preventing Chronic Pain: A Human Systems Approach" was offered by the University of Minnesota through the online platform Coursera. The first offering of this free open course was in the spring of 2014 and had 23 650 participants; 53% were patients or consumers interested in pain. This article describes the course concepts in preventing chronic pain, the analytic data from course participants, and postcourse evaluation forms.

Las afecciones de dolor crónico son el principal motivo de búsqueda de asistencia sanitaria, la causa más frecuente de discapacidad y toxicomanía, y el factor generador de costos sanitarios más importante, con un coste mayor al generado por el cáncer, la cardiopatía, la demencia y la diabetes. Las repercusiones en cuanto a sufrimiento, discapacidad, depresión, suicidio y otros problemas son incalculables. Se han consagrado grandes esfuerzos a la prevención de muchas enfermedades médicas y dentales, pero no se han dirigido los suficientes hacia la prevención del dolor crónico. Para hacer frente a este déficit, se ha desarrollado un curso en línea masivo y abierto (massive open online course, MOOC) para estudiantes y profesionales sanitarios. La Universidad de Minnesota ofreció el curso "Prevención del dolor crónico: enfoque de un sistema humanista" a través del sitio www.Coursera.org. La primera oferta de este curso abierto y gratuito se hizo en primavera de 2014 y acogió a 23 650 participantes; de los cuales un 53 % eran pacientes o clientes interesados en el dolor. En este artículo se describen los conceptos del curso en la prevención del dolor crónico, los datos analíticos de los participantes y los formularios de evaluación posteriores al curso.

The influence of obesity on survival in early, high-risk breast cancer: results from the randomized SUCCESS A trial.

INTRODUCTION: Obese breast cancer patients have worse prognosis than normal weight patients, but the level at which obesity is prognostically unfavorable is unclear. METHODS: This retrospective analysis was performed using data from the SUCCESS A trial, in which 3754 patients with high-risk early breast cancer were randomized to anthracycline- and taxane-based chemotherapy with or without gemcitabine. Patients were classified as underweight/normal weight (body mass index (BMI) < 25.0), overweight (BMI 25.0-29.9), slightly obese (BMI 30.0-34.9), moderately obese (BMI 35.0-39.9) and severely obese (BMI ≥ 40.0), and the effect of BMI on disease-free survival (DFS) and overall survival (OS) was evaluated (median follow-up 65 months). In addition, subgroup analyses were conducted to assess the effect of BMI in luminal A-like, luminal B-like, HER2 (human epidermal growth factor 2)-positive and triple-negative tumors. RESULTS: Multivariate analyses revealed an independent prognostic effect of BMI on DFS (p = 0.001) and OS (p = 0.005). Compared with underweight/normal weight patients, severely obese patients had worse DFS (hazard ratio (HR) 2.70, 95 % confidence interval (CI) 1.71-4.28, p < 0.001) and OS (HR 2.79, 95 % CI 1.63-4.77, p < 0.001), while moderately obese, slightly obese and overweight patients did not differ from underweight/normal weight patients with regard to DFS or OS. Subgroup analyses showed a similar significant effect of BMI on DFS and OS in patients with triple-negative breast cancer (TNBC), but not in patients with other tumor subtypes. CONCLUSIONS: Severe obesity (BMI ≥ 40) significantly worsens prognosis in early breast cancer patients, particularly for triple-negative tumors. TRIAL REGISTRATION: Clinicaltrials.gov NCT02181101 . Registered September 2005.

Myofascial trigger point pain.

Myofascial trigger point pain is an extremely prevalent cause of persistent pain disorders in all parts of the body, not just the head, neck, and face. Features include deep aching pain in any structure, referred from focally tender points in taut bands of skeletal muscle (the trigger points). Diagnosis depends on accurate palpation with 2-4 kg/cm2 of pressure for 10 to 20 seconds over the suspected trigger point to allow the referred pain pattern to develop. In the head and neck region, cervical muscle trigger points (key trigger points) often incite and perpetuate trigger points (satellite trigger points) and referred pain from masticatory muscles. Management requires identification and control of as many perpetuating factors as possible (posture, body mechanics, psychological stress or depression, poor sleep or nutrition). Trigger point therapies such as spray and stretch or trigger point injections are best used as adjunctive therapy.

Changes in bone metabolic parameters in children with chronic myeloid leukemia on imatinib treatment.

BACKGROUND: Imatinib is a highly effective drug in up-front treatment of chronic myeloid leukemia (CML). In children impaired longitudinal growth has been reported as side effect exerted by this drug under prolonged therapy. We therefore prospectively evaluated alterations of bone biochemical markers in pediatric patients with CML under ongoing imatinib exposure. MATERIAL/METHODS: Bone metabolic markers (calcium, phosphate, magnesium, parathyroid hormone, vitamin D, procollagen type l N propeptide [PINP], and C-terminal cross-linking telopeptide of collagen [CTX-I], osteocalcin [OC]; pyridinoline [PYD], and desoxypyridinoline [DPD]) were determined in 17 patients with CML aged 4-17 years under imatinib treatment in three-month intervals over a 2.5 year period. RESULTS: Hyperparathyroidism developed in 8/17 patients and low 25-hydroxyvitamin-D3 levels were found in 15/17 patients. Increased OC levels were detected in 58% of all specimen showing a linear significant decline of -0.30 µg OC per l per week (p=0.04). Serum PINP was lowered in 25% and serum CTX-I was above the normal range in 57% of the specimen originating exclusively from prepupertal patients. Urine PYD and Urine DPD levels were above the normal range in 10% and 9%, respectively, of all specimen collected and a statistically significant linear decline of -0.16 nmol DPD/mg creatinine/week was calculated (p=0.01). CONCLUSIONS: Bone remodeling may be dysregulated by imatinib. Data suggest that impaired bone formation exceeds that of decreased bone resorption. Regular evaluation of the skeletal actions during long-term imatinib treatment in childhood CML is warranted.

Position paper: appropriate use of pharmacotherapeutic agents by the orofacial pain dentist.

Orofacial Pain Dentistry is concerned with the prevention, evaluation, diagnosis, treatment, and management of persistent and recurrent orofacial pain disorders. The American Dental Association, through the Commission on Dental Accreditation (CODA), now recognizes Orofacial Pain as an area of advanced education in Dentistry. It is mandated by CODA that postgraduate orofacial pain programs be designed to provide advanced knowledge and skills beyond those of the standard curriculum leading to the DDS or DMD degrees. Postgraduate programs in orofacial pain must include specific curricular content to comply with CODA standards. The intent of CODA standards is to assure that training programs develop specific educational goals and objectives that describe the student/resident's expected knowledge and skills upon successful completion of the program. A standardized core curriculum, required for accreditation of dental orofacial pain training programs, has now been adopted.Among the various topics mandated in the curriculum are pharmacology and, specifically, pharmacotherapeutics. The American Academy of Orofacial Pain (AAOP) recommends, and the American Board of Orofacial Pain (ABOP) requires, that the minimally competent orofacial pain dentist* be knowledgeable in the management of orofacial pain conditions using medications when indicated. Basic knowledge of the appropriate use of pharmacotherapeutics is essential for the orofacial pain dentist and, therefore, constitutes part of the examination specifications of the ABOP. The minimally competent orofacial pain clinician must demonstrate knowledge, diagnostic skills, and treatment expertise in many areas, such as musculoskeletal, neurovascular, and neuropathic pain syndromes; sleep disorders related to orofacial pain; orofacial dystonias; and intraoral, intracranial, extracranial, and systemic disorders that cause orofacial pain or dysfunction. The orofacial pain dentist has the responsibility to diagnose and treat patients in pain that is often chronic, multifactorial, and complex. Failure to understand pain mechanisms can lead to inaccurate diagnoses and ineffective, delayed, or harmful treatment. It is the responsibility of the orofacial pain dentist to accurately diagnose the cause(s) of the pain and decide if treatment should be dentally, medically, or psychologically oriented, or if optimal management requires a combination of all three treatment approaches. Management may consist of a number of interdisciplinary modalities including, eg, physical medicine, behavioral medicine, and pharmacology or, in rare instances, surgical interventions. Among the essential armamentarium is the knowledge and proper use of pharmacologic agents.

Quantification of changes in myofascial trigger point sensitivity with the pressure algometer following passive stretch.

In order to determine the relationship between trigger point sensitivity and the referred symptoms of myofascial pain, VAS ratings of referred pain intensity and pressure algometer measures of myofascial trigger point sensitivity were taken pre and post treatment of the muscle containing the trigger point with passive stretch. The results in 20 subjects, experiencing unilateral or bilateral myofascial head and neck pain, showed that myofascial trigger point sensitivity decreases in response to passive stretch as assessed by the pressure algometer, and that trigger point sensitivity and intensity of referred pain are related.

Reliability of the pressure algometer as a measure of myofascial trigger point sensitivity.

Three studies are presented demonstrating the reliability of the pressure algometer as an index of myofascial trigger point sensitivity. The first study showed high reliability between and within experimenters when measuring marked trigger point locations. In study 2, significant between experimenter reliability in locating and measuring the same unmarked trigger point locations was shown, while study 3 supported the idea that trigger points are discrete points of focal tenderness within the muscle. The ability to quantify and reliably measure trigger point sensitivity opens the door to a range of clinical and research possibilities for myofascial and related musculoskeletal pain problems.