Attempted replication of pharmacogenetic association of variants in PPP1R14C and CCDC148 with aromatase inhibitor-induced musculoskeletal symptoms.

Third-generation aromatase inhibitors (AI) are the standard treatment for patients with hormone receptor positive (HR+) breast cancer. While effective, AI can lead to severe adverse events, including AI-induced musculoskeletal syndrome (AIMSS). Genetic predictors of AIMSS have the potential to personalize AI treatment and improve outcomes. We attempted to replicate results from a previous genome-wide association study that found a lower risk of AIMSS in patients carrying PPP1R14C rs912571 and a higher risk in patients carrying CCDC148 rs79048288. AIMSS data were collected prospectively from patients with HR+ breast cancer prior to starting and after 3 and 6 months of adjuvant AI via the Patient-Reported Outcome Measurement Information System and Functional Assessment of Cancer Therapy-Endocrine Symptom. Germline genotypes for PPP1R14C rs912571 and CCDC148 rs79048288 were tested for a similar association with AIMSS as previously reported via $2 tests. Of the 143 patients with AIMSS and genetics data were included in the analysis. There was no association identified between PPP1R14C rs912571 and AIMSS risk ( P  > 0.05). Patients carrying CCDC148 rs79048288 variant alleles had lower AIMSS incidence in a secondary analysis ( P  = 0.04); however, this was in the opposite direction of the previous finding. The study did not replicate previously reported associations with AIMSS risk for genetic variants in PPP1R14C and CCDC148 and AIMSS risk. Further research is needed to discover and validate genetic predictors of AIMSS that can be used to personalize treatment in patients with HR+ breast cancer.

Aromatase Inhibitor-Associated Musculoskeletal Syndrome: Understanding Mechanisms and Management.

Aromatase inhibitors (AIs) are a key component in the chemoprevention and treatment of hormone receptor-positive (HR+) breast cancer. While the addition of AI therapy has improved cancer-related outcomes in the management of HR+ breast cancer, AIs are associated with musculoskeletal adverse effects known as the aromatase inhibitor-associated musculoskeletal syndrome (AIMSS) that limit its tolerability and use. AIMSS is mainly comprised of AI-associated bone loss and arthralgias that affect up to half of women on AI therapy and detrimentally impact patient quality of life and treatment adherence. The pathophysiology of AIMSS is not fully understood though has been proposed to be related to estrogen deprivation within the musculoskeletal and nervous systems. This review aims to characterize the prevalence, risk factors, and clinical features of AIMSS, and explore the syndrome's underlying mechanisms and management strategies.

Evidence-based approaches for the management of side-effects of adjuvant endocrine therapy in patients with breast cancer.

The growing availability of more effective therapies has contributed to an increased survival of patients with breast cancer. In hormone receptor-positive early disease, increased survival is strongly correlated with the use of adjuvant endocrine therapy, but this therapy can cause side-effects that have major consequences in terms of treatment adherence and patients' quality of life. In premenopausal breast cancer survivors, these side-effects might be even more prominent due to the abrupt suppression of oestrogen associated with the most intense endocrine therapies. An important ambition of cancer care in the 21st century is to recover pre-cancer quality of life and emotional and social functions, which is only possible through the mitigation of the side-effects of anticancer treatments. This Review presents a comprehensive summary of the efficacy and safety data of the available interventions (hormonal and non-hormonal pharmacological strategies, non-pharmacological approaches, and complementary and alternative medicine) to control selected side-effects associated with adjuvant endocrine therapy (hot flashes, sexual dysfunction, weight gain, musculoskeletal symptoms, and fatigue), providing updated, evidence-based approaches for their management.

Long-term safety and efficacy of imatinib in pediatric patients with chronic myeloid leukemia: single-center experience from China.

Chronic myeloid leukemia (CML) is a rare disease among children. A retrospective study was conducted from November 2002 to March 2019 at a single institution in China. A total of 36 pediatric CML patients (25 male and 11 female) were enrolled. Median follow-up time was 51 months (range 8-144), and 5-year overall survival and event-free survival were 95.5 ± 4.4% and 88.9 ± 6.0%, respectively. Among the 25 patients whose response to imatinib mesylate (IM) was regularly monitored, 92.0% achieved complete hematologic response at 3 months, 80.0% achieved complete cytogenetic response at 12 months, and 64.0% achieved major molecular response at 18 months after IM therapy. A higher WBC count at diagnosis was associated with failure to achieve early molecular response (EMR). Height standard deviation score after long-term treatment was significantly and positively correlated with age at diagnosis and at the start of IM therapy. Overall, IM therapy was effective in treating pediatric CML, and WBC count at diagnosis might be an ideal predictor of EMR. Moreover, retardation of height and weight growth due to IM tended to affect patients younger than 9 years old at diagnosis, and longitudinal growth might normalize further into treatment.

Aromatase Inhibitor Symptom Management Practices: A Retrospective Study.

PURPOSE: Aromatase inhibitor (AI)-associated symptoms contribute to early therapy discontinuation. Although guidelines exist for management of these symptoms, little is known about the degree to which physicians address symptoms and adhere to the guidelines for treatment. PATIENTS AND METHODS: In this retrospective chart review, women with hormone receptor-positive breast cancer who were prescribed an AI between October 15, 2012, and September 14, 2017, were randomly selected from the institution's cancer registry. Patient medical records were reviewed to identify the prevalence of symptom documentation and management. Documented symptoms were categorized into musculoskeletal, vasomotor, and urogenital. Symptom treatment guidelines were compiled from the National Comprehensive Cancer Network (NCCN) and the American Cancer Society/American Society of Clinical Oncology (ACS/ASCO). Treatments were categorized as either meeting or not meeting the guidelines. Among patients with symptoms recorded, chi-square tests and time-to-event models were used to examine factors associated with treatment and factors associated with guideline-based treatment. RESULTS: Among 179 women prescribed an AI, 82% had at least one symptom and 46% had multiple symptoms. Of the 147 women with any documented symptom, 97 (66%) received some form of symptom-palliating treatment. Seventy-seven patients (52%) received guideline-based treatments or guideline-based treatments in combination with non-guideline-based treatments. There were no differences in receipt of treatment overall (ie, guideline based or non-guideline based) for either vasomotor or musculoskeletal symptoms by age, race, or stage. CONCLUSION: Although 82% of patients had symptoms documented in their medical records, just over half of those patients received guideline-based treatment.

Aromatase Inhibitors-Induced Musculoskeletal Disorders: Current Knowledge on Clinical and Molecular Aspects.

Aromatase inhibitors (AIs) have radically changed the prognosis of hormone receptor positive breast cancer (BC) in post-menopausal women, and are a mainstay of the adjuvant therapy for BC after surgery in place of, or following, Tamoxifen. However, AIs aren't side effect-free; frequent adverse events involve the musculoskeletal system, in the form of bone loss, AI-associated arthralgia (AIA) syndrome and autoimmune rheumatic diseases. In this narrative review, we reported the main clinical features of these three detrimental conditions, their influence on therapy adherence, the possible underlying molecular mechanisms and the available pharmacological and non-pharmacological treatments. The best-known form is the AIs-induced osteoporosis, whose molecular pathway and therapeutic possibilities were extensively investigated in the last decade. AIA syndrome is a high prevalent joint pain disorder which often determines a premature discontinuation of the therapy. Several points still need to be clarified, as a universally accepted diagnostic definition, the pathogenetic mechanisms and satisfactory management strategies. The association of AIs therapy with autoimmune diseases is of the utmost interest. The related literature has been recently expanded, but many issues remain to be explored, the first being the molecular mechanisms.

Health status among greenhouse workers exposed to different levels of pesticides: A genetic matching analysis.

(1) Objective: Greenhouse workers are considered a special occupational group who are exposed to more toxic and harmful substances than ordinary farmers. The health problem of this group is a public health problem that warrants attention. Taking greenhouse workers in Ningxia, China, as the research sample, this study analyzed the health risk to practitioners posed by the greenhouse working environment. (2) Method: To analyze the relationship between pesticide exposure and the health of greenhouse workers, the genetic matching method was used to exclude the influence of covariates on the results. (3) Results: The results showed a statistical significance regarding the prevalence of cardiovascular diseases (CVD), skeletal muscle system diseases (SMSD) and digestive diseases between the different exposure groups. Researching the disease symptoms found that different levels of exposure to pesticides in greenhouses could cause multisystem and multisymptom discomfort. In addition to some irritant symptoms such as eye itching, itching, and sneezing, there were also differences in terms of the frequency of discomfort such as back pain, a decline in sleep quality, memory loss, joint pain, swelling and weakness, upper abdominal pain and flatulence, in the different exposure groups. (4) Conclusion: Different levels of exposure to pesticides in greenhouses may be one of the risk factors for practitioners to suffer from various systemic diseases, affecting their health and work efficiency. This hazard is manifested not only in some acute irritant symptoms but also in chronic diseases due to long-term exposure.

An MRI study of immune checkpoint inhibitor-induced musculoskeletal manifestations myofasciitis is the prominent imaging finding.

OBJECTIVE: To assess: (i) the prevalence, and clinical and imaging characteristics of immune checkpoint inhibitor (ICI)-induced musculoskeletal immune-related adverse events (ir-AEs) in a prospective manner and (ii) whether serum levels of cytokines associated with the Th1/Th2/Th17 response are differentially expressed in patients with and without musculoskeletal Ir-AEs. METHODS: All patients treated with ICI who developed musculoskeletal manifestations were referred to the Rheumatology Department, and an MRI of the involved area(s) was performed. RESULTS: During the study period, a total of 130 patients were treated with ICIs. Of these, 10 (7.7%) developed ICI-induced Ir-AEs. The median time from ICI treatment since development of symptoms was 2.5 months. Three different patterns of musculoskeletal manifestations were found: (i) prominent joint involvement (n = 3); (ii) prominent 'periarticular' involvement (n = 4). These patients had diffuse swelling of the hands, feet or knees. MRI depicted mild synovitis with more prominent myositis and/or fasciitis in the surrounding tissues in all cases; (iii) myofasciitis (n = 3). Clinically, these patients presented with pain in the knee(s)/thigh(s), whereas MRI depicted myofasciitis of the surrounding muscles. Patients with musculoskeletal ir-AEs had significantly higher oncologic response rates compared with patients not exhibiting musculoskeletal ir-AEs (50% vs 12.5%, respectively, P = 0.0016). Cytokine levels associated with a Th1/Th2/Th17 response were similar between patients with and without musculoskeletal ir-AEs. Overall, symptoms were mild/moderate and responded well to treatment, with no need for ICI discontinuation. CONCLUSION: In our cohort, ICI-induced musculoskeletal manifestations developed in 7.7% of patients. Imaging evidence of myofasciitis was found in most patients, indicating that the muscle/fascia is more frequently involved than the synovium.

The effect of exercise on aromatase inhibitor-induced musculoskeletal symptoms in breast cancer survivors :a systematic review and meta-analysis.

BACKGROUND: Evidence is mixed regarding the effect of exercise programs on improving musculoskeletal symptoms and quality of life. Previous meta-analyses have not focused specifically on the musculoskeletal symptoms. Therefore, this meta-analysis aimed to evaluate the effect of exercise on these outcomes in breast cancer survivors taking aromatase inhibitors. METHODS: PubMed, CINAHL, EMBASE, Web of Science, Wan Fang, CNKI, VIP, and CBM were searched for randomized control trials or quasi-experimental studies from the establishment of the database to May 2019. Studies comparing exercise programs with usual care among breast cancer survivors taking aromatase inhibitors were included. The primary outcome was the degree of musculoskeletal symptoms, as assessed by scores of pain, stiffness, and grip strength. The secondary outcome was the total quality of life score. RESULTS: A total of 9 studies involving 743 participants were included. Exercise programs were more effective than usual care in improving musculoskeletal symptoms among breast cancer patients taking AIs. The subgroup scores of pain (SMD = -0.46, 95% CI -0.79 to -0.13, P = 0.006), stiffness (SMD = -0.40, 95% CI -0.71 to -0.08, P = 0.01), and grip strength (SMD = 0.43, 95% CI 0.16 to 0.71, P = 0.002) benefited from exercise interventions. Similar effects were found for the quality of life scores (SMD = 2.24, 95% CI 0.28 to 4.21, P = 0.03). CONCLUSIONS: Results indicate that exercise relieves musculoskeletal symptoms and improves quality of life, which can be used to motivate patients to exercise actively under professional guidance. Due to a small sample size, further research is required to ensure the effectiveness of exercise on musculoskeletal symptoms and quality of life.

Risk factors for immune-related adverse events associated with anti-PD-1 pembrolizumab.

We investigated risk factors for immune-related adverse events (irAEs) in patients treated with anti-programmed cell death protein1 antibody pembrolizumab. A retrospective medical record review was performed to identify all patients who received at least one dose of pembrolizumab at Samsung Medical Center, Seoul, Korea between June 2015 and December 2017. Three hundred and ninety-one patients were included in the study. Data were collected on baseline characteristics, treatment details, and adverse events. Univariate and multivariate logistic regression models were used to identify risk factors for irAEs. Sixty-seven (17.1%) patients experienced clinically significant irAEs; most commonly dermatologic disorders, followed by pneumonitis, musculoskeletal disorders, and endocrine disorders. Fourteen patients (3.6%) experienced serious irAEs (grade ≥ 3). Most common serious irAEs were pneumonitis (2.3%). Four deaths were associated with irAEs, all of which were due to pneumonitis. In multivariate regression analysis, a higher body mass index (BMI) and multiple cycles of pembrolizumab were associated with higher risk of irAEs (BMI: odds ratio [OR] 1.08, 95% confidence interval [CI] 1.01-1.16; pembrolizumab cycle: OR 1.15, 95% CI 1.08-1.22). A derived neutrophil-lymphocyte ratio (dNLR) greater than 3 at baseline was correlated with low risk of irAEs (OR 0.37, 95% CI 0.17-0.81). Our study demonstrated that an elevated BMI and higher number of cycles of pembrolizumab were associated with an increased risk of irAEs in patients treated with pembrolizumab. Additionally, increased dNLR at baseline was negatively correlated with the risk of developing irAEs.

Toxicity of cadmium in musculoskeletal diseases.

Epidemiological studies have reported that exposure to toxic metals like cadmium (Cd) may promote the development of musculoskeletal diseases, such as osteoporosis, rheumatoid arthritis (RA), and osteoarthritis (OA), among others. The objective of this review is to summarize the molecular mechanisms of inflammation and oxidative stress activated by Cd at the bone level, particularly in osteoporosis, RA, and OA. Cadmium can increase bone resorption, affect the activity of osteoclasts and calcium (Ca) absorption, and impair kidney function, which favors the development of osteoporosis. In the case of RA, Cd interferes with the activity of antioxidant proteins, like superoxide dismutase (SOD) and catalase (CAT). It also promotes an inflammatory state, inducing the process of citrullination, which affects the proteins of immune response. On the other hand, accumulation of Cd in the tissues and blood of smokers has been related to the development of some musculoskeletal diseases. Therefore, knowing the negative impact of Cd toxicity at the articular level can help understand the damage mechanisms it produces, leading to the development of such diseases.

Musculoskeletal Effects of Antineoplastic Agents.

Cancer remains a common disease with approximately 40% of Americans diagnosed with cancer in their lifetime. Medical advances in the field of oncology have led to an increased life expectancy and a decreased mortality rate. Antineoplastic agents such as taxanes and targeted therapies are indicated in the treatment of many cancers, and their use can be associated with various musculoskeletal complaints and adverse effects. Orthopaedic Surgeons are trained to identify primary bone tumors and metastasis to bones. It is also important for them to have an understanding of the profile of musculoskeletal adverse effects associated with the treatment of the more common neoplasms. This article reviews the current literature on the commonly used chemotherapeutic agents and their associated musculoskeletal effects.

Association between body mass index and response to duloxetine for aromatase inhibitor-associated musculoskeletal symptoms in SWOG S1202.

BACKGROUND: Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) negatively impact adherence to and persistence with therapy. In SWOG S1202, patients with AIMSS who were treated with duloxetine, a serotonin norepinephrine reuptake inhibitor, reported improvement in pain by 12 weeks compared with placebo. Based on the authors' prior observation that responses to pain interventions differ between obese and nonobese patients, the current study examined whether response to duloxetine therapy differed by obesity status. METHODS: In SWOG S1202, a total of 299 AI-treated postmenopausal women with stage I to III (AJCC 7th Edition) breast cancer who developed new or worsening average pain were enrolled, randomized to duloxetine or placebo, and treated for 12 weeks. Patient-reported outcomes were obtained at baseline and through 12 weeks. Patients were categorized into nonobese (body mass index [BMI] <30 kg/m2 ) or obese (BMI ≥30 kg/m2 ). The authors tested the interaction between intervention and obesity with respect to average pain at 12 weeks in the 289 eligible patients, using a P value of .05 to indicate statistical significance. RESULTS: In approximately 54% of evaluable patients with a BMI ≥30 kg/m2 , the reduction in the mean average pain score between baseline and 12 weeks was statistically significantly greater for patients treated with duloxetine compared with those receiving placebo (-2.73 vs -1.64 points; P = .003). Conversely, in the nonobese patients, the reduction in the mean average pain score was similar in the 2 cohorts (-2.46 vs -2.34 points; P = .75). The P value for interaction was .02, thereby meeting the threshold criteria of the current study. Similar findings were evident for other pain-related patient-reported outcomes. CONCLUSIONS: In this trial, obese patients with AIMSS obtained more analgesic benefit from duloxetine compared with nonobese patients. Additional studies are warranted to determine the biologic basis for these findings.

Tyrosine kinase inhibitor interruptions, discontinuations and switching in patients with chronic-phase chronic myeloid leukemia in routine clinical practice: SIMPLICITY.

SIMPLICITY (NCT01244750) is an observational study exploring tyrosine kinase inhibitor (TKI) use and management patterns in patients with chronic phase-chronic myeloid leukemia in the US and Europe in routine clinical practice. Herein we describe interruptions, discontinuations and switching of TKI therapy during the initial 2 years of treatment among 1121 patients prospectively enrolled between October 1, 2010 and March 7, 2017. Patient characteristics were broadly similar between the imatinib (n = 370), dasatinib (n = 376), and nilotinib (n = 375) cohorts. Treatment interruptions occurred in 16.4% (year 1) and 4.0% (year 2) of patients, mainly attributed to hematologic intolerances. Treatment discontinuations occurred in 21.8% (year 1) and 10.2% (year 2) of patients, with the highest rate within the first 3 months for intolerance. Switching of TKI was seen in 17.8% (year 1) and 9.5% (year 2) of patients. Significant associations were found between TKI switching and female gender (year 1), age ≥65 years at diagnosis (year 2) and treatment with imatinib (year 2). Intolerance was the most common reason given for patients discontinuing and for switching TKI therapy; however resistance was also cited. Lack of response monitoring in routine clinical practice may have resulted in lower identification of resistance in this dataset. Data from SIMPLICITY suggest that, in routine clinical practice, intolerance and resistance to TKIs influence decisions to change treatment. Changes in TKI therapy are frequent, with nearly a third of patients discontinuing their first-line TKI.

[Management of side effects related to adjuvant hormone therapy in young women with breast cancer]. / Gestion des effets secondaires de l'hormonothérapie du cancer du sein chez la femme jeune.

Despite proven survival benefits after breast cancer, long-trem compliance with adjuvant hormone therapy remains a major issue, partly due to the side effects of treatment. In young women treated for breast cancer, these treatments include tamoxifen, anti-aromatase and LH-RH analogues, with even more side effects when these treatments are combined, especially for younger patients with more aggressive disease. The management of the potential side effects requires first of all detailed and precise information at initiation of treatment, and preventive measures including patient education. Once the treatment has been initiated, clinicians should be able to propose to their patients appropriate measures to alleviate the potential of the side effects, which can be of various types: biological (dyslipidemia), physical (weight gain, hot flushes, vaginal dryness, sexual disorders with low libido, musculoskeletal symptoms…) or psychosocial (anxio-depressive disorders, poor body image, difficulties of professional reintegration). Management of these effects can combine various modalities: drugs (switching hormone therapy, anti-depressants, hormonal treatments of vaginal dryness in some cases, gabapentin), physical treatments (CO2 laser for vulvovaginal atrophy) or psycho-physical techniques (physical activity, mindfulness, acupuncture…). Eventually, the lenghth of these adjuvant hormonal treatments requires supportive measures to help young patients engage in new lifestyle measures, in particular in term of physical activity and diet. This will help them mitigate the symptoms related to these side-effects while reducing the long-term risks related to their disease and treatments.

The Role of Diuretics in Treatment of Aromatase Inhibitors Induced Musculoskeletal Symptoms in Women with Non Metastatic Breast Cancer

Background: Around 50% of women receiving Aromatase Inhibitors (AIs) develop musculoskeletal symptoms which may become severe causing interruption of treatment. Patients with AI-induced arthralgia had higher rates of joint effusions and fluid in the tendons, so use of diuretics may be helpful. Methods: This prospective phase II study was conducted in department of clinical oncology and nuclear medicine, Menoufia University Hospital, Egypt, between Jan. to Dec. 2015. Fifty Women with stage I,II and III breast cancer receiving AIs as adjuvant hormonal treatment complaining of AIs related musculoskeletal symptoms received Lasilactone® 50 mg tablet; (an oral combination of Frusemide 20mg/Spironolactone 50 mg), every other day for 4 weeks. Patients were assessed by modified Western Ontario and McMaster Universities osteoarthritis (WOMAC) index for lower limb and the quick Disabilities of the Arm, Shoulder and Hand Score (DASH) scoring system for upper limbs, Arabic versions, at baseline and after 4 weeks of treatment. Results: The mean WOMAC pain score improved significantly (6.0 v 10; P < 0.001), the mean WOMAC stiffness score improved (2.3 v 3.9; P = 0.002), the mean WOMAC functional score improved (8.7 v 15; P < 0.001), the total WOMAC score improved (17 v 29; P < 0.001), also a significant difference was noticed for the quick DASH score; total score (16 v 25; P = 0.02) After use of diuretics for 4 weeks of treatment compared with baseline scores. Conclusions: The use of diuretics effectively reduces AI related musculoskeletal symptoms with good tolerance.

Preservation of muscle mass as a strategy to reduce the toxic effects of cancer chemotherapy on body composition.

PURPOSE OF REVIEW: Cancer patients undergoing chemotherapy often experience very debilitating side effects, including unintentional weight loss, nausea, and vomiting. Changes in body composition, specifically lean body mass (LBM), are known to have important implications for anticancer drug toxicity and cancer prognosis. Currently, chemotherapy dosing is based on calculation of body surface area, although this approximation does not take into consideration the variability in lean and adipose tissue mass. RECENT FINDINGS: Patients with depletion of muscle mass present higher chemotherapy-related toxicity, whereas patients with larger amounts of LBM show fewer toxicities and better outcomes. Commonly used chemotherapy regimens promote changes in body composition, primarily by affecting skeletal muscle, as well as fat and bone mass. Experimental evidence has shown that pro-atrophy mechanisms, abnormal mitochondrial metabolism, and reduced protein anabolism are primarily implicated in muscle depletion. Muscle-targeted pro-anabolic strategies have proven successful in preserving lean tissue in the occurrence of cancer or following chemotherapy. SUMMARY: Muscle wasting often occurs as a consequence of anticancer treatments and is indicative of worse outcomes and poor quality of life in cancer patients. Accurate assessment of body composition and preservation of muscle mass may reduce chemotherapy toxicity and improve the overall survival.