Musculoskeletal Toxicity Research Articles

Treatment Outcomes Following Proton Therapy for High Grade Spinal Cord Ependymoma in Children

There is limited information published on the outcome of children treated with radiation for high-grade ependymoma of the spinal cord. Thus, little evidence is available to inform decisions of target volume or prescription dose. Moreover, there is virtually no mature outcome data on proton therapy, despite theoretical advantages in normal tissue exposure. We therefore performed a bicentric retrospective study to better inform treatment of this rare tumor in children.Between 2008 and 2019, 14 consecutive pediatric patients with a non-metastatic grade II or III spinal ependymoma were treated with proton therapy at the University of Florida and Massachusetts General Hospital. The median age of the children at the time of radiation was 14 years old (range, 1.5-18 years). Five tumors arose within the cervical cord (C1-5, C1-2, C1-T1, C3-T1, C4-C6), 3 within the thoracic spine (C7-T4, T7-L1, T11-T12), and 6 within the lumbosacral spine (L3-L5, L3-L5, L4-S2, S2-S5, L2-L3, L2-L3). Six tumors were grade II histology and 8 were grade III. Prior to radiotherapy, 3 patients had undergone a subtotal resection while the other 11 had a gross total or near total resection. One patient received chemotherapy according to the International Society of Pediatric Oncology (SIOP) infant regimen and 1 patient received chemotherapy according to Children's Oncology Group (COG) ACNS0831. For radiation, the gross tumor volume (GTV) was defined by the gross disease and/or tumor bed at the time of radiation. The CTV was defined by the GTV + 5-10 mm. The CTV received 50.4 Gy (n = 8), 52.2 (n = 1), or 54 Gy (n = 5), with the latter undergoing boost to just the GTV following the initial 50.4 Gy to respect spinal cord tolerance. For the cohort, the median maximum point dose to the spinal cord was 52.4 Gy (range, 0-53.9 Gy). The median maximum dose to 0.1 cc of spinal cord was 51.3 Gy (range, 0-52.5 Gy). The median volume of cord receiving ≥50.4 Gy was 3.4 cc (range, 0-17.1 cc).With a median follow-up of 6.3 years (range, 1.5 - 14.8 years), no tumors have progressed and all patients are alive. Serious acute toxicity was limited to 1 case of grade 2 nausea. While most patients experienced neurologic sequela following surgery, only 1 patient developed additional neurologic deficits following radiation: An 18-year-old male who received 54 Gy following gross total resection of a lumbosacral tumor developed grade 2 erectile dysfunction. There were 2 cases of chronic musculoskeletal toxicity attributable to surgery and radiation in survivors. No patients have developed cardiac, pulmonary, or other visceral organ complications, nor has any patient developed a second malignancy.These outcomes suggest that radiation to a dose of 50-54 Gy can be safely delivered and plays a beneficial role in the multidisciplinary management of children with grade II/III spinal cord ependymoma. Proton therapy may reduce the late radiation effects and is not associated with unexpected spinal cord toxicity.

Late Effects of Craniospinal Irradiation Using Electron Spinal Fields for Pediatric Patients

<h3>Purpose/Objective(s)</h3> Craniospinal irradiation (CSI) with photons is associated with significant toxicities. The use of electrons for spinal fields is hypothesized to spare anterior structures but its long-term effects remain poorly characterized. We studied late effects of CSI using electrons for spinal radiotherapy (RT). <h3>Materials/Methods</h3> Records of 84 consecutive patients treated with CSI using electrons for the spine at a single institution from 1983-2014 were reviewed. Median age at RT was 5 (range, 1-14) years with 60% male. Most common histologies were medulloblastoma/PNET (59%) and ependymoma (8%). Most commonly used electron energies were 16 (44%) and 20 (25%) MeV (range, 12-21). Median prescribed dose to the entire spine was 30 (range 6-45) Gy. A spinal boost was used in 14%. A subset of 47 (56%) patients was analyzed for late effects with the following inclusion criteria: 1) age between 2 and 14 years at time of CSI, and 2) clinical and radiographic follow-up for ≥ 5 years. Height <b>z</b>-scores adjusted for age before and after CSI were assessed using CDC stature-for-age charts and compared with a <b>t</b>-test. A Cobb angle of > 10° was used to identify scoliosis. <h3>Results</h3> At a median follow-up of 18 (range, 0-37) years, the median survival was 22 (95% confidence interval [CI], 12-28) years with 50 patients (60%) alive at last follow up. On subset analysis for late effects, 18 (38%) patients developed hypothyroidism and 4 (9%) developed secondary malignancies possibly attributable to spine RT (3 papillary thyroid cancer, 1 renal cell carcinoma) at a median 26 (range, 10-33) years after RT. Chronic pulmonary issues were seen in 2 patients (restrictive lung disease, recurrent pneumonia) and 1 patient developed esophageal strictures and periaortic hemorrhage. No patients developed myelopathy or cardiotoxicity. Median height <b>z</b>-score prior to treatment was -0.3 (37^th percentile; interquartile range [IQR], -1.0 to +0.1) and at last follow up after RT was -2.2 (1^st percentile; IQR, -3.1 to -1.5; <b>P</b> < 0.001). Of 42 patients with spinal curvature assessments, 14 (33%) had scoliosis with median Cobb angle 16° (IQR, 14-18°). <h3>Conclusion</h3> Long-term follow-up of children treated with CSI using electron spinal fields showed frequent musculoskeletal toxicity, predominantly decreased height. Scoliosis and hypothyroidism were seen in at least a third of long-term survivors. Esophageal, pulmonary, cardiac and spinal cord toxicities were infrequent.

Bicentric Treatment Outcomes After Proton Therapy for Nonmyxopapillary High-Grade Spinal Cord Ependymoma in Children

Few studies report outcomes in children treated with radiation for nonmyxopapillary ependymoma of the spinal cord, and little evidence exists to inform decisions regarding target volume and prescription dose. Moreover, virtually no mature outcome data exist on proton therapy for this tumor. We describe our combined institutional experience treating pediatric classical/anaplastic ependymoma of the spinal cord with proton therapy. Between 2008 and 2019, 14 pediatric patients with nonmetastatic nonmyxopapillary grade II (n=6) and grade III (n=8) spinal ependymoma received proton therapy. The median age at radiation was 14 years (range, 1.5-18 years). Five tumors arose within the cervical cord, 3 within the thoracic cord, and 6 within the lumbosacral cord. Before radiation therapy, 3 patients underwent subtotal resection, and 11 underwent gross-total or near total resection. Two patients received chemotherapy. For radiation, the clinical target volume received 50.4 Gy (n=8), 52.2 (n=1), or 54 Gy (n=5), with the latter receiving a boost to the gross tumor volume after the initial 50.4 Gy, modified to respect spinal cord tolerance. With a median follow-up of 6.3 years (range, 1.5-14.8 years), no tumors progressed. Although most patients experienced neurologic sequela after surgery, only 1 developed additional neurologic deficits after radiation: An 18-year-old male who received 54 Gy after gross total resection of a lumbosacral tumor developed grade 2 erectile dysfunction. There were 2 cases of musculoskeletal toxicity attributable to surgery and radiation. At analysis, no patient had developed cardiac, pulmonary, or other visceral organ complications or a second malignancy. Radiation to a total dose of 50 to 54 Gy can be safely delivered and plays a beneficial role in the multidisciplinary management of children with nonmyxopapillary spinal cord ependymoma. Proton therapy may reduce late radiation effects and is not associated with unexpected spinal cord toxicity.

Factors affecting creatine phosphokinase elevation during daptomycin therapy using a combination of machine learning and conventional methods

Musculoskeletal toxicity is a typical side effect of daptomycin (DAP). However, the risk factors have not been well established. Here, we aimed to identify independent factors affecting DAP-induced musculoskeletal toxicity using a combination of machine learning and conventional statistical methods. A population-based, retrospective, observational cohort study was conducted using the Japanese electronic medical record database. Patients who received DAP between October 2011 and December 2020 were enrolled. Two definitions of musculoskeletal toxicity were employed: (1) elevation of creatine phosphokinase (CPK) value more than twice from baseline and >200 IU/L, and (2) >1000 IU/L. First, multiple logistic regression analyses (a conventional statistical method) were performed to identify independent factors affecting CPK elevation. Then, decision tree analyses, a machine learning method, were performed to detect combinations of factors that change CPK elevation risk. Of the 2970 patients who received DAP, 706 were included. Elevation of CPK values >200 IU/L and >1000 IU/L occurred in 83 (11.8%) and 17 (2.41%) patients, respectively. In multiple logistic regression analysis, baseline CPK value and concomitant use of hydrophobic statins were commonly extracted as independent factors affecting each CPK elevation, but concomitant use of hydrophilic statins was not. In decision tree analysis, patients who received hydrophobic statins and had high baseline CPK values were classified into the high-risk group. Our novel approach revealed new risk factors for CPK elevation. Our findings suggest that high-risk patients require frequent CPK monitoring.

Comparison of in vitro and in vivo Toxicity of Bupivacaine in Musculoskeletal Applications.

The recent societal debate on opioid use in treating postoperative pain has sparked the development of long-acting, opioid-free analgesic alternatives, often using the amino-amide local anesthetic bupivacaine as active pharmaceutical ingredient. A potential application is musculoskeletal surgeries, as these interventions rank amongst the most painful overall. Current literature showed that bupivacaine induced dose-dependent myo-, chondro-, and neurotoxicity, as well as delayed osteogenesis and disturbed wound healing in vitro. These observations did not translate to animal and clinical research, where toxic phenomena were seldom reported. An exception was bupivacaine-induced chondrotoxicity, which can mainly occur during continuous joint infusion. To decrease opioid consumption and provide sustained pain relief following musculoskeletal surgery, new strategies incorporating high concentrations of bupivacaine in drug delivery carriers are currently being developed. Local toxicity of these high concentrations is an area of further research. This review appraises relevant in vitro, animal and clinical studies on musculoskeletal local toxicity of bupivacaine.

Growth Disturbances in Pediatric Patients Receiving Long-Term Tyrosine Kinase Inhibitor Therapy

Background:Since their approval in 2003, Tyrosine Kinase Inhibitors (TKIs) targeting bcr-abl1 kinase activity have changed the treatment paradigm for children with chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). However, off-target inhibition of kinases, such as src and c-kit, can result in impaired osteoblast function, cause an imbalance in calcium and phosphate metabolism, and result in growth impairment in children. The aim of our study was to examine growth over time in pediatric patients receiving TKIs for CML or Ph+ ALL.Description: This is a single institutional retrospective longitudinal cohort study of patients (≤ 21 years of age) diagnosed with CML or Ph+ ALL between January 2000 and December 2015 who received a TKI and had ≥ 1 year of growth data available as of May 31, 2016. Patient demographics, treatment details including the type and duration of TKI therapy and details of concomitant conventional therapy (chemotherapy and radiation) were abstracted. Growth data was abstracted from the start of TKI at yearly intervals up to a maximum of five years or age 20 and from their last available appointment. Specific variables for growth included height, height percentile, height-SDS (height - standard deviation score or z score) and BMI-SDS (body mass index - standard deviation score). Height-SDS and BMI-SDS were determined using the CDC growth chart by age and gender. Age at diagnosis was used as a surrogate for expected pubertal status: pre-pubertal (3 - 8.9 years), pubertal/peri-pubertal (9 - 15.9 years), post-pubertal (16+ years). Overall change in height-SDS / BMI-SDS from baseline to 1-year and last follow-up were compared by diagnosis, gender, and pubertal age using ANOVA. Statistical analysis was performed using SAS® v9.3 (Cary, NC). For all analyses, a p-value of <0.05 was considered to be statistically significant.Results: Our cohort included 48 patients who received a TKI (n=29 CML, n=19 Ph+ ALL) - 46% were male and 38% were non-Hispanic white. The mean age at diagnosis was 12.1 ± 3.7 years for CML and 9.0 ± 4.6 years for Ph+ ALL patients (p=0.01). As expected, mean duration of TKI treatment was longer in CML (4.3 ± 2.8 years) versus Ph+ ALL (2.7 ± 1.7 years). The average duration of follow-up was similar in both groups (CML 4.6 ± 3.54 years vs Ph+ ALL 4.1 ± 2.9 years, p=0.60). At time of diagnosis, the mean Height-SDS for the entire cohort was 0.13 ± 1.28 with no difference between patients by diagnosis (p=0.92). At one year following treatment with TKI a decrease in mean height-SDS was noted, with a more significant difference in Ph+ ALL patients (-0.54 ± 0.21) compared to CML patients (-0.18 ± 0.39) (p=0.002). This difference remained significant at last follow-up (Ph+ ALL -0.96 ± 0.70, CML -0.52 ± 0.74, p=0.05) (Figure 1). There was no significant difference in mean change in height-SDS at 1 year or last follow-up by gender. Overall, the decrease in height-SDS at 1 year was most significant in the pre-pubertal age group (-0.51 ± 0.27) as compared to pubertal/peri-pubertal and post-pubertal groups (-0.26 ± 0.46 and -0.10 ± 0.24 respectively; p=0.04). BMI-SDS at baseline did not differ by diagnosis but did show a significant decrease at one year in Ph+ ALL versus CML patients (-0.18 ± 0.65 and 0.39 ± 0.54 respectively, p=0.003); this stabilized at the time of last follow up (-0.01 ± 0.75 and 0.38 ± 0.80 respectively, p=0.11).Conclusions: Our data underscores the concern of growth disturbances following prolonged TKI exposure in children, the role of exposure relative to pubertal change in bone growth, and the need for understanding off-target mechanisms in childhood survivors. Stabilization of BMI-SDS at the end of follow up with accompanying drop in mean height-SDS points to a mechanism of growth disturbance beyond nutritional deficiencies. This large pediatric cohort treated with TKIs is the first to include Ph+ ALL patients who were younger at onset of TKI treatment, and more likely to be pre/peripubertal at the start TKI exposure. Future directions will focus on a prospective study of musculoskeletal and other organ toxicities in patients treated with TKIs in childhood. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

C-reactive protein as a biomarker for immune-related adverse events in melanoma patients treated with immune checkpoint inhibitors in the adjuvant setting.

The objective of this study was to evaluate the utility of serum C-reactive protein (CRP) as biomarker for the early diagnosis of immune-related adverse events (irAEs) in melanoma patients treated with immune checkpoint inhibitors (ICIs) in the adjuvant setting, and its potential correlation with relapse-free survival (RFS). Prospectively collected data from 72 melanoma patients treated with adjuvant ICIs were pooled. CRP values at diagnosis of 10 irAEs were descriptively analysed. Correlations between RFS and the occurrence of irAEs, the grade of the irAE, the extent of CRP-elevation and the use of corticosteroids for irAE treatment were investigated. A total of 191 irAEs (grade 1/2, n = 182; grade 3/4, n = 9) occurred in 64 patients [skin toxicity (n = 70), fatigue (n = 50), thyroiditis (n = 12), musculoskeletal toxicity (n = 11), sicca syndrome (n = 10), other (n = 23), pneumonitis (n = 6), colitis (n = 4), hepatitis (n = 3) and hypophysitis (n = 2)]. In pneumonitis and hypophysitis, the median CRP levels at diagnosis exceeded the upper limit of normal (ULN, 5 mg/L). After a median follow-up of 26.5 months, 28 patients (39%) had been diagnosed with a melanoma relapse. Patients who experienced no irAE were at the highest risk for relapse (P = 0.008). A trend was observed for patients diagnosed with an irAE that was associated with an elevated CRP (>2xULN) to be at higher risk for relapse as compared to those diagnosed with an irAE and CRP <ULN (P = 0.054). CRP has potential as biomarker for the early detection of selected irAEs. Dynamic evaluation can guide irAE diagnosis, regression or relapse. The observed correlation between irAEs associated with an elevated CRP and risk for recurrence deserves further investigation.

Polymorphisms of T- cell leukemia 1A gene loci are not related to the development of adjuvant letrozole-induced adverse events in breast cancer

Letrozole, an aromatase inhibitor (AI), is the first-line adjuvant drug for treating hormone receptor-positive (HR+) breast cancer in postmenopausal women. However, harmful adverse events (AEs) and significant differences in drug response among individuals remain a significant problem in clinical application. Current evidence suggests that the observed individual variation in the treatment outcomes of AI is conferred by genetic variants. Hence, in this study, we examined the association of TCL1A gene polymorphisms with letrozole-induced AEs. The study subjects were postmenopausal HR+ breast cancer patients who were receiving adjuvant letrozole. Genomic DNA was isolated by a routine standard phenol-chloroform method. In total, 198 South Indian patients were genotyped for four single nucleotide polymorphisms (SNPs) in the TCL1A gene loci by the TaqMan allelic discrimination assay using the RT-PCR system. We used the odds ratio and 95% confidence interval to assess the genetic association. Musculoskeletal (MS) AEs and vasomotor symptoms (VMSs) are the most common side effects observed in the study cohort. Among 198 patients, 81 experienced musculoskeletal toxicity, reporting MS-AEs, 57 had VMSs, and 33 of them had both. The most frequently identified polymorphic variants in the patient series were rs11849538 (G), with an allele frequency of about 27.3%, followed by rs7158782-G (27.3%), rs7159713-G (25.8%), and rs2369049-G (22.5%). The genetic association analysis indicated no significant difference in the proportion of TCL1A gene variants between patients with and without AEs on either MS-AEs or VMSs. Though we observed high LD in all patient groups, the inferred haplotypes displayed a non-significant association with letrozole-induced specific AEs. However, the SNP functionality analysis by RegulomeDB provided a 2b rank score for rs7158782, suggesting a potential biological function. Our findings suggest that TCL1A gene polymorphisms may not play any role in the prediction of letrozole-induced AEs in South Indian HR+ breast cancer patients.

FDA Approval Summary: Selumetinib for Plexiform Neurofibroma.

On April 10, 2020, the FDA approved selumetinib (KOSELUGO, AstraZeneca) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. Approval was based on demonstration of a durable overall response rate per Response Evaluation in Neurofibromatosis and Schwannomatosis criteria and supported by observed clinical improvements in plexiform neurofibroma-related symptoms and functional impairments in 50 pediatric patients with inoperable plexiform neurofibromas in a single-arm, multicenter trial. The overall reponse rate per NCI investigator assessment was 66% (95% confidence interval, 51-79) with at least 12 months of follow-up. The median duration of response was not reached, and 82% of responding patients experienced duration of response ≥12 months. Clinical outcome assessment endpoints provided supportive efficacy data. Risks of selumetinib are consistent with MAPK (MEK) inhibitor class effects, including ocular, cardiac, musculoskeletal, gastrointestinal, and dermatologic toxicities. Safety was assessed across a pooled database of 74 pediatric patients with plexiform neurofibromas and supported by adult and pediatric selumetinib clinical trial data in cancer indications. The benefit-risk assessment for selumetinib in patients with inoperable plexiform neurofibromas was considered favorable.

Chronic Myeloid Leukemia (CML) in Adolescents & Young Adults (AYA): Single Institution 10 Years Experience with 1st Line Imatinib Mesylate (IM)

Introduction and Aims: CML is the commonest adult leukemia in India and the disease is diagnosed commonly in the 3rd or 4th decade of life - at least 10 years earlier than in the west, making the disease an important issue in AYA cancers. The present study reports our 10 year experience (all patients registered after 2005 with minimum of 3 years follow up) with the use of 1st line IM in patients of CML Chronic Phase (CML-CP) in patients aged 15 to 29 years. Methods: Patients of CML-CP receiving 1st line IM, aged 15 to 29 were included in the study. Standard demographics; hematological response, molecular responses (RQ-PCR on International Scale) q 6 monthly and toxicity of IM were assessed. Results A total of 337 patients of CML-CP were registered, 89 (28.7%) of which were aged between 15 to 29 and were on 1st line IM. These are reported in this study. Age distribution: 15 to 19 years: 17 (19.1%); 20 to 24: 26 (29.2%); 24 to 29: 46 (51.7%). Male female ratio: 53 (59.5%) to 36 (40.5%). Sixty one (68.5%) received innovator IM (Glivec) through the GIPAP (Glivec International Patient Assistance Program), 28 (40.5%) generic IM. At 10 years f/u, 6 (6.7%) patients were lost to f/u, 15 (16.8%) off imatinib (12 sub-optimal molecular response/relapse, and 3 b/o toxicity - 2 hepatitis, 1 renal). Seventy four (74) patients continue on IM, 56 on 400 mg/day and 18 on &amp;gt; 400mg/day. Fifty nine are in deep molecular response, 15 have a bcr/abl between 0.1 to 1.0 but are in complete hematological remission. Musculo-skeletal toxicity, grade I to II: 11/74 (14.8%), skin toxicity grade I: 27/74 (36.5%) and GI grade I to II: 16/74 (21.6%) were seen. Discussion and Conclusion CML is a common cancer in AYA in developing countries. IM, including generic IM, remains the standard 1st line drug for the majority and is effective, well tolerated in most patients. Issues related to treatment-free-remission (TFR), compliance, long-term drug toxicity and fertility need to be studied in this young population. Disclosures No relevant conflicts of interest to declare.

Evaluation of Daptomycin-Induced Cellular Membrane Injury in Skeletal Muscle.

Daptomycin, a cyclic lipopeptide antibiotic, has bactericidal activity against Gram-positive organisms and is especially effective against methicillin-resistant Staphylococcus aureus. Although daptomycin causes unique adverse drug reactions such as elevation of creatine phosphokinase or rhabdomyolysis, the detailed mechanisms underlying these adverse drug reactions in skeletal muscle are unclear. This study aimed to elucidate whether daptomycin causes direct skeletal muscle cell toxicity and investigate the relationship between daptomycin exposure and musculoskeletal toxicity. First, we evaluated the relationship between daptomycin exposure and skeletal muscle toxicity. Of the 38 patients who received daptomycin intravenously, an elevation in creatine phosphokinase levels was observed in five. The median plasma trough concentration of daptomycin in patients with elevated creatine phosphokinase levels was significantly higher than that in patients whose creatine phosphokinase levels were within the normal range, suggesting that increased exposure to daptomycin is related to elevation in creatine phosphokinase levels. In an in vitro study using human rhabdomyosarcoma cells, daptomycin reduced cell viability and increased membrane damage. These effects were more marked under hypoxic conditions. A necroptotic pathway seemed to be involved because phosphorylated mixed lineage kinase domain-like protein expression was enhanced following daptomycin exposure, which was significantly enhanced under hypoxic conditions. These findings indicate that daptomycin elicits cytotoxic effects against skeletal muscle cells via the necroptotic pathway, and the extent of toxicity is enhanced under hypoxic conditions.

Immune checkpoint inhibitor-induced myositis, the earliest and most lethal complication among rheumatic and musculoskeletal toxicities.

In addition to restoring anti-tumor immune responses, immune checkpoint inhibitors (ICI) may also induce immune-related adverse events (irAE) that can affect any organ. We aim to determine the spectrum, timing, clinical features, and fatalities of rheumatic and musculoskeletal immune-related adverse events (RMS-irAE) associated with ICI. We performed an observational, retrospective, pharmacovigilance study using the World Health Organization international pharmacovigilance database, VigiBase, from inception to January 2019. RMS-irAE reporting rate on ICI versus full database was performed using disproportionality analysis with computation of reporting-odds-ratios (ROR) and a Bayesian disproportional estimate (information component, IC). IC025 (lower end of the IC 95% credibility interval) >0 is deemed significant. We identified 1288 RMS-irAE significantly associated with ICI: polymyalgia rheumatica (n=76, ROR=14.6 [11.6-18.4], IC025=3.34), sarcoidosis (n=94; ROR=9.6 [7.9-11.9]; IC025=2.85), Sjogren's syndrome (n=49; ROR=6.9 [5.2-9.2]; IC025=2.24), myositis (n=465; ROR=4.9 [4.5-5.4]; IC025=2.12), arthritis (n=606; ROR=1.4 [1.3-1.5]; IC025=0.34) and scleroderma (n=17; ROR=2.0 [1.2-3.2]; IC025=0.17). Arthritis, myositis, and Sjogren's syndrome were over-reported in patients treated with ICI combination versus those treated with ICI monotherapy (ROR=1.6-2.9, p<.05) and more frequently reported on anti-PD1/PDL1 monotherapy vs. anti-CTLA4 monotherapy (2.1-4.4, p<.05). Median time to onset occurred early for myositis (31days [19.2-57.8]) and was the most delayed for scleroderma (395days [323.8-457.2], p<.0001). The fatality rate for RMS-irAE ranged from 24% for myositis (n=106/441) (up to 56.7% with concurrent myocarditis) to [0-6.7%] for other RMS-irAE (p<.0001). Clinicians should be aware of the spectrum of RMS-irAE. Myositis can be particularly life-threatening, particularly when associated with myocarditis.

Association of CYP19A1 gene variations with adjuvant letrozole-induced adverse events in South Indian postmenopausal breast cancer cohort expressing hormone-receptor positivity.

Musculoskeletal adverse events (MS-AEs) and vasomotor symptoms (VMSs) are the major side-effects of newer generation non-steroidal aromatase inhibitor (AI), letrozole. Single-nucleotide polymorphisms (SNPs) in CYP19A1 gene coding for the enzyme aromatase are related to AI treatment-associated adverse drug reactions. Therefore, we aimed to determine whether SNPs in the CYP19A1 gene are associated with adjuvant letrozole-induced 'specific' AEs in postmenopausal hormone receptor-positive (HR+) breast cancer patients. Genomic DNA was isolated from 198HR+ breast cancer patients by the phenol-chloroform method, and eleven SNPs in the CYP19A1 gene were genotyped by TaqMan genotyping assays on the qRT-PCR system. Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0, and the data were analyzed using SPSS v19.0 and Haploview v4.2 statistical software. Subjects carrying the genetic variants of CYP19A1 gene SNP rs700519 had significantly higher odds (OR 2.33; 95% CI [1.29-4.20], P = 0.0057) of MS-AEs under dominant statistical effect. The frequency of the two distinct haplotypes that include the variant allele 'T' at rs700519 locus, H5-GCTATCTGGCG (P = 0.042) and H11-GCTATTGCACG (P = 0.013) were significantly higher in patients with musculoskeletal toxicity than in those without MS-AEs and thus predisposing to MS-AEs. Similarly, H6-GCCAGCTGGCG (P = 0.037) haplotype exhibited higher frequencies in patients presented with VMSs. However, no such association was observed between CYP19A1 genotypes and VMSs. To the best of our knowledge, this is the first study assessing the impact of CYP19A1 genetic variations with adjuvant letrozole treatment-associated AEs in Indian women. Genetic variations in the CYP19A1 gene is associated with letrozole-induced AEs and warrants further investigation in larger cohorts to validate this finding.

Bench to Bedside: Animal Models of Radiation Induced Musculoskeletal Toxicity.

Ionizing radiation is a critical aspect of current cancer therapy. While classically mature bone was thought to be relatively radio-resistant, more recent data have shown this to not be the case. Radiation therapy (RT)-induced bone loss leading to fracture is a source of substantial morbidity. The mechanisms of RT likely involve multiple pathways, including changes in angiogenesis and bone vasculature, osteoblast damage/suppression, and increased osteoclast activity. The majority of bone loss appears to occur rapidly after exposure to ionizing RT, with significant changes in cortical thickness being detectable on computed tomography (CT) within three to four months. Additionally, there is a dose–response relationship. Cortical thinning is especially notable in areas of bone that receive >40 gray (Gy). Methods to mitigate toxicity due to RT-induced bone loss is an area of active investigation. There is an accruing clinical trial investigating the use of risderonate, a bisphosphonate, to prevent rib bone loss in patients undergoing lung stereotactic body radiation therapy (SBRT). Additionally, several other promising therapeutic/preventative approaches are being explored in preclinical studies, including parathyroid hormone (PTH), amifostine, and mechanical loading of irradiated bones.

Responsiveness to Resistance-Based Multimodal Exercise Among Men With Prostate Cancer Receiving Androgen Deprivation Therapy.

Androgen deprivation therapy (ADT) in the management of prostate cancer (PCa) results in an array of adverse effects, and exercise is one strategy to counter treatment-related musculoskeletal toxicities. This study assessed the prevalence of exercise responsiveness in men with PCa undergoing ADT in terms of body composition, muscle strength, and physical function. Prospective analyses were performed in 152 men (aged 43-90 years) with PCa receiving ADT who were engaged in resistance exercise combined with aerobic or impact training for 3 to 6 months. Whole-body lean mass and fat mass (FM), trunk FM, and appendicular skeletal muscle were assessed with dual x-ray absorptiometry; upper and lower body muscle strength were assessed with the one-repetition maximum; and physical function was assessed with a battery of tests (6-m usual, fast, and backward walk; 400-m walk; repeated chair rise; stair climb). Significant improvements were seen (P<.01) in lean mass (0.4±1.4 kg [range, -2.8 to +4.1 kg]), appendicular skeletal muscle (0.2±0.8 kg [range, -1.9 to +1.9 kg]), and all measures of muscle strength (chest press, 2.9±5.8 kg [range, -12.5 to +37.5 kg]; leg press, 29.2±27.6 kg [range, -50.0 to +140.0 kg]) and physical function (from -0.1±0.5 s [range, +1.3 to -2.1 s] for the 6-m walk; to -8.6±15.2 s [range, +25.2 to -69.7 s] for the 400-m walk). An increase in FM was also noted (0.6±1.8 kg [range, -3.6 to +7.3 kg]; P<.01). A total of 21 men did not exhibit a favorable response in at least one body composition component, 10 did not experience improved muscle strength, and 2 did not have improved physical function. However, all patients responded in at least one of the areas, and 120 (79%) favorably responded in all 3 areas. Despite considerable heterogeneity, most men with PCa receiving ADT responded to resistance-based multimodal exercise, and therefore our findings indicate that this form of exercise can be confidently prescribed to produce beneficial effects during active treatment.

Musculoskeletal toxicities in patients receiving concomitant statin and daptomycin therapy.

This article evaluates the musculoskeletal safety of concomitant therapy with daptomycin and Hydroxymethylglutaryl-coenzyme A (HMG CoA) reductase inhibitors (statins). Often indicated for severe gram-positive infections, daptomycin is commonly administered with statins but there is limited guidance on the appropriate management of concomitant therapy with daptomycin and statins. A narrative review was conducted to review contemporary clinical evidence of the safety of concomitant therapy with daptomycin and statins. A total of 5 studies were identified comparing daptomycin monotherapy versus daptomycin and statin concomitant therapy for the primary outcome of creatine phosphokinase (CPK) elevations in a variety of patient populations with systemic, skin/soft tissue, and bone/joint infections. Of these studies, 4 also compared myalgia or myopathy as a secondary outcome. Case studies, the case-control study and 1 prospective registry comparing statin alone versus daptomycin and statin concomitant therapy were excluded. These studies showed that concomitant therapy with daptomycin and statin was not significantly associated with CPK elevation or higher event rate of myalgia or myopathy, compared to daptomycin monotherapy. Published cohort studies do not demonstrate a statistically significant difference in the rate of CPK elevations or musculoskeletal toxicities between patients receiving daptomycin monotherapy and daptomycin plus a statin. Patients receiving statins who start daptomycin therapy should continue statin but with weekly monitoring of CPK levels. Continuation of statins is especially important in high-risk patients receiving statins for secondary prevention for atherosclerotic cardiovascular diseases. If myalgia develops, it is reasonable to evaluate the degree of CPK elevation and reassess the need for statin use during daptomycin treatment.

Characteristics and Outcomes of Ibrutinib-Associated Musculoskeletal Toxicities in CLL Patients

Characteristics and Outcomes of Ibrutinib-Associated Musculoskeletal Toxicities in CLL Patients

Addition of the SMO Inhibitor Sonidegib to Azacitidine in Patients with Higher Risk Myelodysplastic Syndrome (MDS) Who Failed to Respond or Lost Response to AZA Alone: Results of a Phase 1-2 Add-on Study By the GFM

Background: although azacitidine (AZA) is an established frontline therapy for HR-MDS, approximately 40% of the patients fail to respond and virtually all of the responders will ultimately relapse. We previously reported the poor outcome of patients who failed AZA treatment for whom a median survival of 6 months is expected (Prebet, J Clin Oncol. 2011;29(24):3322). Overexpression of SMO a member of the hedgehog pathways has been observed in HR-MDS. Preclinical data have shown the activity of hedgehog pathway inhibitors and suggested synergism with Hypomethylating agents (HMA) (Zou, PLoSONE 2015; 10(8):e0136843). To harness potential synergism, we designed an add-on trial in which sonidegib (LDE-225), an oral inhibitor, was added to AZA in patients who failed AZA monotherapy.Patients and methods:Eligible patients should have IPSS Int-2 or HR-MDS or AML, (to have 10% to 30% marrow blasts), have received a minimum of 6 cycles of AZA monotherapy and to have failed to achieve a response to AZA (defined as CR, CRi, PR or HI as per IWG criteria) in the absence of marrow progression or have relapsed after achieving a response. Patients were scheduled to receive sonidegib daily from day 1 to 28 of 28-day cycles while continuing on AZA at the maximum previously tolerated dose (ie 50 to 75 mg/m²/d for 5-7 days). Two sonidegib dose levels were evaluated in the phase 1 part of the trial (400 and 800 mg/d) according to a classical 3+3 scheme.Results:23 patients, median age 76, were included in the study. One withdrew consent before starting the study treatment and is not included in the analysis. Characteristics of the remaining 22 patients are summarized in the Table. At the 800 mg/d dose level, 3 pts experienced DLT (grade 4 ASAT elevation (1 pt); grade 4 CPK elevation (2 pts)). The recommended dose for the expansion phase was 400 mg/d and no DLT was observed. 19 patients received 400 mg/d. Pts received a median of 3.5 cycles [IQR 2 ; 5], and 5 pts (23 %) received ≥ 6 cycles. All of them were withdrawn from study: 5 (26%) for disease progression (including 1 pt who progressed before starting cycle 1 and did not received treatment), 5 (26%) for death (all due to infection in the context of active disease) and 9 for miscellaneous reasons. 25 SAEs were reported including 23 infections, 1 intra cranial hemorrhage and 1 urinary retention. The most frequent non-hematologic toxicity was infection that occurred in 16/22 (73%) pts. In addition, 243 non hematologic toxicities of any grade were recorded in 20 pts for a total of 83 cycles, all but 3 of grade 1-2, including GI, cutaneous and musculo-skeletal toxicities and fatigue. Hospitalization was required in 45% of the pts. Only 3 responses were observed (1 CR, 1 marrow CR and 1 PR). Response durations were 1, 9 and 15 months .With a median follow-up of 23 months, 13 pts have died and the median overall survival is 6.8 months.ConclusionSonidegib at the dose of 400 mg/d can be given in combination with azacitidine with an acceptable toxicity. With a response rate of only 13%, our results indicate that the addition of sonidegib failed to reverse resistance to azacitidine in pts with higher risk MDS. This contrasts with the positive effect of the combination of glasdegib, another hedgehog pathway inhibitor with cytarabine in pts with AML and MDS (Cortes, Blood 2016 128:99). Besides potential differences in drug potency, our results may highlight the difficulty to identify active agents in the difficult-to-treat patient population selected after HMA therapy failure. The recommended dose-schedule of AZA-sonidegib established here could be used for further investigation in previously untreated patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Risk of Kyphoscoliosis in Pediatric Patients Receiving Radiation Therapy: Results from the Musculoskeletal Task Force of the Pediatric Normal Tissue Effects in the Clinic (PENTEC) Initiative

Musculoskeletal (MSK) toxicities are common in children treated with radiotherapy (RT), can compromise cosmesis and function. However, RT dose effects on various parts of the MSK system remains largely unclear. The purpose of this analysis is to determine the dose-effect relationship between RT exposure to the axial skeleton and kyphoscoliosis risk. The PENTEC MSK task group conducted a systematic search of PubMed databases of all English language publications from January 1970 through September 2017 for MSK and RT specific search terms and inclusion criteria. Task group screened 2198 abstracts; only eight studies met all inclusion criteria for the analysis. The majority of studies provided 2D dosimetry data for patients treated for Wilms’ tumor and neuroblastoma. Only photon data was included in current analysis due to scarcity of reports on other modalities. The data used in this descriptive analysis was all retrospective with heterogeneous methodology. RT dose exposure ≥20 Gy resulted in more than doubling of kyphoscoliosis incidence (49-100%) compared with children treated to <20 Gy (0-20%). Radiation fields symmetrically encompassing entire vertebral bodies still resulted in scoliosis with incidence and severity correlated with dose received. Younger patients (<6 yo) exposed to RT seemed to be at much higher risk for kyphoscoliosis, with significant pathological changes observed at the dose as low as 15Gy. Kyphoscoliosis development appeared more pronounced during adolescent growth spurt, irrespective of the age at which RT was given. The impact of additional factors, such as age, surgical perturbation, systemic therapy, radiation source, etc., could not be dissected due to lack of data. Of note, there was approximately 9.5% risk of scoliosis in Wilms' and neuroblastoma patients who did not receive radiation. Existing data support strong associations between RT dose and the risk and severity of kyphoscoliosis observed in pediatric population. Until more contemporary data is available for modeling this risk, it is recommended to reduce dose exposure to the axial skeleton to <20 Gy, especially in young children < 6 years of age.

Exercise and nutrition strategies to treat musculoskeletal toxicity in cancer

Exercise and nutrition strategies to treat musculoskeletal toxicity in cancer