Breakthrough Cancer Pain Clinical Features and Differential Opioids Response: A Machine Learning Approach in Patients With Cancer From the IOPS-MS Study.

PURPOSE: A large proportion of patients with cancer suffer from breakthrough cancer pain (BTcP). Several unmet clinical needs concerning BTcP treatment, such as optimal opioid dosages, are being investigated. In this analysis the hypothesis, we explore with an unsupervised learning algorithm whether distinct subtypes of BTcP exist and whether they can provide new insights into clinical practice. METHODS: Partitioning around a k-medoids algorithm on a large data set of patients with BTcP, previously collected by the Italian Oncologic Pain Survey group, was used to identify possible subgroups of BTcP. Resulting clusters were analyzed in terms of BTcP therapy satisfaction, clinical features, and use of basal pain and rapid-onset opioids. Opioid dosages were converted to a unique scale and the BTcP opioids-to-basal pain opioids ratio was calculated for each patient. We used polynomial logistic regression to catch nonlinear relationships between therapy satisfaction and opioid use. RESULTS: Our algorithm identified 12 distinct BTcP clusters. Optimal BTcP opioids-to-basal pain opioids ratios differed across the clusters, ranging from 15% to 50%. The majority of clusters were linked to a peculiar association of certain drugs with therapy satisfaction or dissatisfaction. A free online tool was created for new patients' cluster computation to validate these clusters in future studies and provide handy indications for personalized BTcP therapy. CONCLUSION: This work proposes a classification for BTcP and identifies subgroups of patients with unique efficacy of different pain medications. This work supports the theory that the optimal dose of BTcP opioids depends on the dose of basal opioids and identifies novel values that are possibly useful for future trials. These results will allow us to target BTcP therapy on the basis of patient characteristics and to define a precision medicine strategy also for supportive care.

Etiopathogenesis of sacroiliitis: implications for assessment and management.

The sacroiliac joints connect the base of the sacrum to the ilium. When inflamed, they are suspected to cause low back pain. Inflammation of the sacroiliac joints is called sacroiliitis. The severity of the pain varies and depends on the degree of inflammation. Sacroiliitis is a hallmark of seronegative spondyloarthropathies. The presence or absence of chronic sacroiliitis is an important clue in the diagnosis of low back pain. This article aims to provide a concise overview of the anatomy, physiology, and molecular biology of sacroiliitis to aid clinicians in the assessment and management of sacroiliitis. For this narrative review, we evaluated articles in English published before August 2019 in PubMed. Then, we selected articles related to the painful manifestations of the sacroiliac joint. From the retrieved articles, we found that chronic sacroiliitis may be caused by various forms of spondyloarthritis, such as ankylosing spondyloarthritis. Sacroiliitis can also be associated with inflammatory bowel disease, Crohn's disease, gout, tuberculosis, brucellosis, and osteoarthritis, indicating common underlying etiological factors. The pathophysiology of sacroiliitis is complex and may involve internal, environmental, immunological, and genetic factors. Finally, genetic factors may also play a central role in progression of the disease. Knowing the genetic pre-disposition for sacroiliitis can be useful for diagnosis and for formulating treatment regimens, and may lead to a substantial reduction in disease severity and duration and to improved patient performance.

Molecular Aspects of Regional Pain Syndrome.

The purpose of this review is to summarize the pathophysiology of complex regional pain syndrome (CRPS), the underlying molecular mechanisms, and potential treatment options for its management. CRPS is a multifactorial pain condition. CRPS is characterized by prolonged or excessive pain and changes in skin color and temperature, and/or swelling in the affected area, and is generally caused by stimuli that lead to tissue damage. An inflammatory response involving various cytokines and autoantibodies is generated in response to acute trauma/stress. Chronic phase pathophysiology is more complex, involving the central and peripheral nervous systems. Various genetic factors involved in the chronicity of pain have been identified in CRPS patients. As with other diseases of complex pathology, CRPS is difficult to treat and no single treatment regimen is the same for two patients. Stimulation of the vagus nerve is a promising technique being tested for different gastrointestinal and inflammatory diseases. CRPS is more frequent in individuals of 61-70 years of age with a female to male ratio of 3 : 1. Menopause, migraine, osteoporosis, and asthma all represent risk factors for CRPS and in smokers the prognosis appears to be more severe. The pathophysiological mechanisms underlying CRPS involve both inflammatory and neurological pathways. Understanding the molecular basis of CRPS is important for its diagnosis, management, and treatment. For instance, vagal nerve stimulation might have the potential for treating CRPS through the cholinergic anti-inflammatory pathway.

Factors Influencing the Clinical Presentation of Breakthrough Pain in Cancer Patients.

Background: The aim of this study was to identify potential variables influencing the clinical presentation of breakthrough cancer pain (BTP). Methods: Cancer patients with a diagnosis of BTP were enrolled. Demographic and clinical characteristics, as well as background pain and BTP characteristics were collected. Multivariate analyses were conducted to assess the correlation between BTP characteristics and the variables examined. Results: Data of 4016 patients were analysed. Average daily number of BTP episodes was 2.4, mean intensity was 7.5, and a mean duration was 43.3 min. A short onset BTP was observed in 68.9% of patients. In 30.5% of patients BTP was predictable. There were 86.0% of participants who reported a marked interference of BTP with their daily activities. Furthermore, 86.8% of patients were receiving opioids for the management of BTP. The average time to meaningful pain relief was 16.5 min and 70.9% of patients were satisfied with their BTP medications. Age, head and neck cancer, Karnofsky, background pain intensity, predictable and fast onset BTP were independently associated with the number of BTP episodes. BTP pain intensity was independently associated with background pain intensity, fast onset BTP, and Karnofsky. Neuropathic pain mechanism was independently associated with unpredictable BTP. Variables independently associated with a longer duration of BTP were age, place of visit, cancer diagnosis, disease-oriented therapy, background pain intensity and mechanism, and unpredictable BTP. Age, Karnofsky, background pain intensity, fast onset, and long duration of BTP were independently associated with interference with daily activity. Conclusions: BTP has a variable presentation depending on interdependent relationships among its different characteristics.

Breakthrough Cancer Pain: Preliminary Data of The Italian Oncologic Pain Multisetting Multicentric Survey (IOPS-MS).

INTRODUCTION: An ongoing national multicenter survey [Italian Oncologic Pain multiSetting Multicentric Survey (IOPS-MS)] is evaluating the characteristics of breakthrough cancer pain (BTP) in different clinical settings. Preliminary data from the first 1500 cancer patients with BTP enrolled in this study are presented here. METHODS: Thirty-two clinical centers are involved in the survey. A diagnosis of BTP was performed by a standard algorithm. Epidemiological data, Karnofsky index, stage of disease, presence and sites of metastases, ongoing oncologic treatment, and characteristics of background pain and BTP and their treatments were recorded. Background pain and BTP intensity were measured. Patients were also questioned about BTP predictability, BTP onset (≤10 or >10 min), BTP duration, background and BTP medications and their doses, time to meaningful pain relief after BTP medication, and satisfaction with BTP medication. The occurrence of adverse reactions was also assessed, as well as mucosal toxicity. RESULTS: Background pain was well controlled with opioid treatment (numerical rating scale 3.0 ± 1.1). Patients reported 2.5 ± 1.6 BTP episodes/day with a mean intensity of 7.5 ± 1.4 and duration of 43 ± 40 min; 977 patients (65.1%) reported non-predictable BTP, and 1076 patients (71.7%) reported a rapid onset of BTP (≤10 min). Higher patient satisfaction was reported by patients treated with fast onset opioids. CONCLUSIONS: These preliminary data underline that the standard algorithm used is a valid tool for a proper diagnosis of BTP in cancer patients. Moreover, rapid relief of pain is crucial for patients' satisfaction. The final IOPS-MS data are necessary to understand relationships between BTP characteristics and other clinical variables in oncologic patients. FUNDING: Molteni Farmaceutici, Italy.

Headache, low back pain, other nociceptive and mixed pain conditions in neurorehabilitation. Evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation.

Pain is a disabling symptom and is often the foremost symptom of conditions for which patients undergo neurorehabilitation. We systematically searched the PubMed and Embase electronic databases for current evidence on the frequency, evolution, predictors, assessment, and pharmacological and non-pharmacological treatment of pain in patients with headache, craniofacial pain, low back pain, failed back surgery syndrome, osteoarticular pain, myofascial pain syndrome, fibromyalgia, and chronic pelvic pain. Despite the heterogeneity of published data, consensus was reached on pain assessment and management of patients with these conditions and on the utility of a multidisciplinary approach to pain therapy that combines the benefits of pharmacological therapy, physiotherapy, neurorehabilitation, and psychotherapy. We of the Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) suggest a need to conduct randomized controlled trials on the efficacy of pain treatments and their risk-benefit profile for the conditions we have reviewed.

Protein Supplementation Does Not Further Increase Latissimus Dorsi Muscle Fiber Hypertrophy after Eight Weeks of Resistance Training in Novice Subjects, but Partially Counteracts the Fast-to-Slow Muscle Fiber Transition.

The response to resistance training and protein supplementation in the latissimus dorsi muscle (LDM) has never been investigated. We investigated the effects of resistance training (RT) and protein supplementation on muscle mass, strength, and fiber characteristics of the LDM. Eighteen healthy young subjects were randomly assigned to a progressive eight-week RT program with a normal protein diet (NP) or high protein diet (HP) (NP 0.85 vs. HP 1.8 g of protein·kg(-1)·day(-1)). One repetition maximum tests, magnetic resonance imaging for cross-sectional muscle area (CSA), body composition, and single muscle fibers mechanical and phenotype characteristics were measured. RT induced a significant gain in strength (+17%, p < 0.0001), whole muscle CSA (p = 0.024), and single muscle fibers CSA (p < 0.05) of LDM in all subjects. Fiber isometric force increased in proportion to CSA (+22%, p < 0.005) and thus no change in specific tension occurred. A significant transition from 2X to 2A myosin expression was induced by training. The protein supplementation showed no significant effects on all measured outcomes except for a smaller reduction of 2X myosin expression. Our results suggest that in LDM protein supplementation does not further enhance RT-induced muscle fiber hypertrophy nor influence mechanic muscle fiber characteristics but partially counteracts the fast-to-slow fiber shift.

Quantitative and qualitative adaptations of muscle fibers to glucocorticoids.

INTRODUCTION: The aim of this study was to understand the effects of short-term glucocorticoid administration in healthy subjects. METHODS: Five healthy men received dexamethasone (8 mg/day) for 7 days. Vastus lateralis muscle biopsy and knee extension torque measurement were performed before and after administration. A large number of individual muscle fibers were dissected from the biopsy samples (pre-administration: n = 165, post-administration: n = 177). RESULTS: Maximal knee extension torque increased after administration (∼ 13%), whereas both type 1 and type 2A fibers had decreased cross-sectional area (type 1: ∼ 11%, type 2A: ∼ 17%), myosin loss (type 1: ∼ 18%, type 2A: ∼ 32%), and loss of specific force (type 1: ∼ 24%, type 2A: ∼ 33%), which were preferential for fast fibers. CONCLUSION: Short-term dexamethasone administration in healthy subjects elicits quantitative and qualitative adaptations of muscle fibers that precede (and may predict) the clinical appearance of myopathy in glucocorticoid-treated subjects.

Myosin isoforms and contractile properties of single fibers of human Latissimus Dorsi muscle.

The aim of our study was to investigate fiber type distribution and contractile characteristics of Latissimus Dorsi muscle (LDM). Samples were collected from 18 young healthy subjects (9 males and 9 females) through percutaneous fine needle muscle biopsy. The results showed a predominance of fast myosin heavy chain isoforms (MyHC) with 42% of MyHC 2A and 25% of MyHC 2X, while MyHC 1 represented only 33%. The unbalance toward fast isoforms was even greater in males (71%) than in females (64%). Fiber type distribution partially reflected MyHC isoform distribution with 28% type 1/slow fibers and 5% hybrid 1/2A fibers, while fast fibers were divided into 30% type 2A, 31% type A/X, 4% type X, and 2% type 1/2X. Type 1/slow fibers were not only less abundant but also smaller in cross-sectional area than fast fibers. During maximal isometric contraction, type 1/slow fibers developed force and tension significantly lower than the two major groups of fast fibers. In conclusion, the predominance of fast fibers and their greater size and strength compared to slow fibers reveal that LDM is a muscle specialized mainly in phasic and powerful activity. Importantly, such specialization is more pronounced in males than in females.

Knowledge and expectations of patients in palliative care: issues regarding communication with people affected by life-threatening diseases.

OBJECTIVE: Different social norms influence the type and amount of information transmitted to palliative care patients. In Italy disclosure rate is low and medical decisions are often mediated by the family since communication of diagnosis and prognosis is viewed as harmful and brutal. Aims of our study were to assess palliative care patients' knowledge about their diagnosis and prognosis and expectations; and to evaluate possible differences between palliative care patients with and without cancer. METHOD: 232 palliative care in-patients participated to the study and were interviewed about their knowledge about his/her diagnosis and prognosis, and about cure and disease expectations, perceived family/social support. RESULTS: Overall, 45.4% of the patients knew their diagnosis and 35.3% had partial knowledge of it; 39.2% knew their prognosis. When the prognosis was fatal, only few patients explicitly referred to it (22.0%). Expectations during admission to the palliative care unit were: return back home after symptom management (61.6%), increase personal autonomy (51.3%), and pain relief (45.2%). Family/social support was frequently perceived as good (84.0%). Patients with cancer less frequently knew their diagnosis (44.7% vs. 52.9%) and prognosis (37.7% vs. 64.7%) compared to patients with a non-cancer diagnosis. CONCLUSIONS: About half of our patients were unaware of their diagnosis, although, in reality, about one-third of the patients had some knowledge, albeit partial, of their diagnostic and therapeutic course. What to tell or not to tell in palliative care is still controversial and stems from a tailored intervention involving the patient, his/her family and professionals and silence may be more effective than intrusive communication in helping a patient to approach death with tolerable knowledge and dignity.

Neuromuscular electrical stimulation training induces atypical adaptations of the human skeletal muscle phenotype: a functional and proteomic analysis.

The aim of the present study was to define the chronic effects of neuromuscular electrical stimulation (NMES) on the neuromuscular properties of human skeletal muscle. Eight young healthy male subjects were subjected to 25 sessions of isometric NMES of the quadriceps muscle over an 8-wk period. Needle biopsies were taken from the vastus lateralis muscle before and after training. The training status, myosin heavy chain (MHC) isoform distribution, and global protein pattern, as assessed by proteomic analysis, widely varied among subjects at baseline and prompted the identification of two subgroups: an "active" (ACT) group, which performed regular exercise and had a slower MHC profile, and a sedentary (SED) group, which did not perform any exercise and had a faster MHC profile. Maximum voluntary force and neural activation significantly increased after NMES in both groups (+∼30% and +∼10%, respectively). Both type 1 and 2 fibers showed significant muscle hypertrophy. After NMES, both groups showed a significant shift from MHC-2X toward MHC-2A and MHC-1, i.e., a fast-to-slow transition. Proteomic maps showing ∼500 spots were obtained before and after training in both groups. Differentially expressed proteins were identified and grouped into functional categories. The most relevant changes regarded 1) myofibrillar proteins, whose changes were consistent with a fast-to-slow phenotype shift and with a strengthening of the cytoskeleton; 2) energy production systems, whose changes indicated a glycolytic-to-oxidative shift in the metabolic profile; and 3) antioxidant defense systems, whose changes indicated an enhancement of intracellular defenses against reactive oxygen species. The adaptations in the protein pattern of the ACT and SED groups were different but were, in both groups, typical of both resistance (i.e., strength gains and hypertrophy) and endurance (i.e., a fast-to-slow shift in MHC and metabolic profile) training. These training-induced adaptations can be ascribed to the peculiar motor unit recruitment pattern associated with NMES.

Latissimus dorsi fine needle muscle biopsy: a novel and efficient approach to study proximal muscles of upper limbs.

BACKGROUND: The muscle biopsy based on the Bergström needle has been widely used for more than 40 y for diagnosis and experimental studies on muscle. More recently, thinner needles and tru-cut needles have also been introduced. Such techniques have been largely tested on various muscles, including the quadriceps, with few studies on upper limb muscles like deltoid, and no studies on latissimus dorsi muscle (LDM). In this study, we implemented and validated a protocol to collect samples of LDM for experimental purposes, causing minimal discomfort to volunteers. Two main problems were considered: the anatomical localization of the biopsy site and the selection of an appropriate needle. MATERIAL AND METHODS: A strict protocol of palpatory anatomy was adopted and validated with ultrasonography to localize the biopsy site in LDM in subjects with various degrees of muscle development. A 14 gauge tru-cut needle was selected as the smallest and still effective device for sampling. Biopsy sampling was performed in 18 subjects without any complications, or complains of pain or functional limitations. RESULTS: Approximately 4 mg of tissue were recovered from each introduction of the inner notched cannula of the needle. With three consecutive samplings, an amount of tissue sufficient to prepare proteins for gel electrophoresis and Western blot and to dissect single fiber segment for functional experiments, was obtained. CONCLUSIONS: Taken together, the results suggest that this biopsy technique opens to experimental studies muscles until now never considered accessible.

Resistance training of long duration modulates force and unloaded shortening velocity of single muscle fibres of young women.

The aim of the present study was to clarify the impact of long term (1 year) resistance training (RT) on structure and function of single muscle fibres of vastus lateralis in young female subjects. Five young women (age: 25.4+/-6.2 year) performed exercise sessions at 60% of single subject own repetition maximum (1 RM) 1h twice a week. Maximum voluntary force was determined pre- and post-RT and was found to significantly increase post-RT ensuring a successful impact of RT on muscle performance in vivo. Needle muscle biopsy samples were obtained both pre- and post-RT and the following determinations were performed: myosin heavy chain isoform (MHC) distribution of the whole muscle samples by SDS-PAGE; cross sectional area (CSA), specific force (Po/CSA) and maximum shortening velocity (Vo) of a large population (n=358) of single skinned muscle fibres classified on the basis of MHC isoform composition by SDS-PAGE. The results suggest that the long duration of RT can determine a significant increase in specific force (Po/CSA) and unloaded shortening velocity (Vo) of single muscle fibres in female subjects, whereas no muscle fibre hypertrophy and no shift in MHC isoform content was observed.

Long-term resistance training improves force and unloaded shortening velocity of single muscle fibres of elderly women.

Four elderly women (78 +/- 4.3 years) were resistance trained (RT) for one year and needle biopsies of the vastus lateralis muscle were taken pre- and post-RT. A training intensity of 60% one-repetition maximum (1RM) was adopted for the entire duration of the study. Following RT, significant gain in isometric force of the quadriceps muscles was observed and MHC isoform distribution of vastus lateralis muscle showed a very significant shift from MHC-1 and MHC-2X towards MHC-2A, i.e. a bi-directional shift. A large population (n = 310) of individual skinned muscle fibres were dissected from biopsy samples and used for determination of cross-sectional area (CSA), specific force (Po/CSA) and unloaded shortening velocity (Vo) at 12 degrees C and maximum activation. Fibres were classified on the basis of their MHC isoform content determined by SDS-PAGE in three pure fibre types (1, 2A and 2X) and two hybrid fibre types (1-2A and 2AX). Whereas the CSA of individual muscle fibres did not change, Po/CSA was significantly higher in both type 1 and type 2A fibres post training. Vo of type 1 fibres was significantly higher post-training, whereas no change in Vo was observed in type 2A fibres. The number of pure type 2X fibres was very low especially post-training and did not enable a statistically significant comparison. The data suggest that in elderly women moderate and prolonged RT: (1) can determine similar adaptations in MHC distribution of skeletal muscle to those expected in young subjects; (2) can improve function of muscle fibres.

Neuromuscular adaptations to electrostimulation resistance training.

A combination of in vivo and in vitro analyses was performed to investigate muscular and neural adaptations of the weaker (nondominant) quadriceps femoris muscle of one healthy individual to short-term electrostimulation resistance training. The increase in maximal voluntary strength (+12%) was accompanied by neural (cross-education effect and increased muscle activation) and muscle adaptations (impairment of whole-muscle contractile properties). Significant changes in myosin heavy chain (MHC) isoforms relative content (+22% for MHC-2A and -28% for MHC-2X), single-fiber cross-sectional area (+27% for type 1 and +6% for type 2A muscle fibers), and specific tension of type 1 (+67%) but not type 2A fibers were also observed after training. Plastic changes in neural control confirm the possible involvement of both spinal and supraspinal structures to electrically evoked contractions. Changes at the single muscle fiber level induced by electrostimulation resistance training were significant and preferentially affected slow, type 1 fibers.

Skeletal muscle hypertrophy and structure and function of skeletal muscle fibres in male body builders.

Needle biopsy samples were taken from vastus lateralis muscle (VL) of five male body builders (BB, age 27.4+/-0.93 years; mean+/-s.e.m.), who had being performing hypertrophic heavy resistance exercise (HHRE) for at least 2 years, and from five male active, but untrained control subjects (CTRL, age 29.9+/-2.01 years). The following determinations were performed: anatomical cross-sectional area and volume of the quadriceps and VL muscles in vivo by magnetic resonance imaging (MRI); myosin heavy chain isoform (MHC) distribution of the whole biopsy samples by SDS-PAGE; cross-sectional area (CSA), force (Po), specific force (Po/CSA) and maximum shortening velocity (Vo) of a large population (n=524) of single skinned muscle fibres classified on the basis of MHC isoform composition by SDS-PAGE; actin sliding velocity (Vf) on pure myosin isoforms by in vitro motility assays. In BB a preferential hypertrophy of fast and especially type 2X fibres was observed. The very large hypertrophy of VL in vivo could not be fully accounted for by single muscle fibre hypertrophy. CSA of VL in vivo was, in fact, 54% larger in BB than in CTRL, whereas mean fibre area was only 14% larger in BB than in CTRL. MHC isoform distribution was shifted towards 2X fibres in BB. Po/CSA was significantly lower in type 1 fibres from BB than in type 1 fibres from CTRL whereas both type 2A and type 2X fibres were significantly stronger in BB than in CTRL. Vo of type 1 fibres and Vf of myosin 1 were significantly lower in BB than in CTRL, whereas no difference was observed among fast fibres and myosin 2A. The findings indicate that skeletal muscle of BB was markedly adapted to HHRE through extreme hypertrophy, a shift towards the stronger and more powerful fibre types and an increase in specific force of muscle fibres. Such adaptations could not be fully accounted for by well known mechanisms of muscle plasticity, i.e. by the hypertrophy of single muscle fibre (quantitative mechanism) and by a regulation of contractile properties of muscle fibres based on MHC isoform content (qualitative mechanism). Two BB subjects took anabolic steroids and three BB subjects did not. The former BB differed from the latter BB mostly for the size of their muscles and muscle fibres.