Musculoskeletal Events Research Articles

Levofloxacin to Prevent Bacterial Infection in Patients with Acute Myeloid Leukemia Treated By Azacitidine and Venetoclax: A Study from the Dataml Registry

Introduction: Antibioprophylaxis in patients with cancer and neutropenia is controversial and is not a broadly recommended intervention in management of patients with hematological malignancies. Previous study showed that prophylactic treatment with levofloxacin (LEVO) is an effective and well-tolerated strategy to prevent febrile episodes and other relevant infection-related outcomes in patients with cancer and neutropenia, including acute leukemia ( Bucaneve et al., NEJM 2005). However, impact on microbial resistance discouraged the widespread use of this strategy., Venetoclax (VEN) and azacitidine (AZA) combination was recently approved in newly diagnosed patients with AML who are ineligible for intensive chemotherapy. VEN-AZA allowed higher rates of complete remission and longer overall survival but twice the incidence of febrile neutropenia compared to AZA alone making primary antibioprophylaxis a relevant question, especially in patients who are treated as outpatients or discharged after the seven days of AZA treatment. Methods: We retrospectively selected AML patients who received VEN-AZA treatment from the Toulouse-Bordeaux DATAML registry. The two centers have similar management protocols, but patients in Toulouse (but not in Bordeaux) receive antibacterial prophylaxis with LEVO 500 mg/day from day 11 during the neutropenia period following the 1 st course of VEN-AZA, until neutrophil recovery (>0.5 G/l). We included ≥ 18-year-old non-APL de novo or secondary AML receiving VEN-AZA treatment between June 2015 and May 2023, excluding patients that deceased before day 11 VEN-AZA or who were receiving antibiotherapy before start of VEN-AZA. The primary endpoint was the incidence of febrile neutropenia during the first course of VEN-AZA. Secondary endpoints included clinically documented infections, microbiologically documented infections, and safety data. Results: The population included 264 patients, 71 received LEVO as primary antibioprophylaxis during 1 st course of VEN-AZA and 193 received no prophylaxis [antibiotherapy in case of febrile neutropenia, i.e. standard of care (SOC)]. The median age was 69 (range 20-87) years, 55.3% of patients were male, 48.5% of patients received VEN-AZA as front-line treatment and others 51.5% ≥ 2 nd line of treatment. Febrile neutropenia occurred in 32.4% of patients who received LEVO prophylaxis leading to a hospitalization of 100% of patient with antibiotherapy for a median of 10 days (range 2-45), as compared with 38.9% of those in SOC group leading to hospitalization of 73.3% of patient with antibiotherapy for a median of 10 days (range 1-31), (23 of 71 vs. 75 of 193; relative risk, 0.90; IC95% 0.74-1.10; P=0.33). Delay from day 1 VEN-AZA to febrile neutropenia was 23 (range 10-38) and 18 (range 7-44) days in LEVO and SOC groups (p=0.008), respectively. The LEVO group had a significantly lower rate of clinically documented infections (26.1% vs 52.0%, relative risk, 0.65; IC95% 0.46-0.91; P=0.03) (Figure 1A), but similar microbiologically documented infections (30.4% vs 32.0%) (Figure 1B). It is noteworthy that among patients receiving LEVO prophylaxis, no urinary tract infections were reported. The rate of lung infections was considerably reduced (5% vs 25%) as well as gram-negative bacterial infections (50% vs 74%), consistent with LEVO's broad spectrum, including non-fermenting micro-organisms. Anaerobia infections could be due to the lack of activity of LEVO on this bacterial spectrum. There was no difference in frequency of intensive care unit (ICU) hospitalization (1.4% vs 5.2%, P=0.29). No selection of extended spectrum beta-lactamase bacteria nor burden of fluoroquinolone resistance has been detected. Clostridium difficile colitis has been detected in 2 patients, both in SOC group. No adverse musculoskeletal events have been observed. Conclusion: A short course of levofloxacin as primary prophylaxis in AML patients treated with VEN-AZA was well tolerated, seemed to have no impact on microbial resistance and was associated with a lower rate of clinically documented infection but not febrile neutropenia.

How We Manage Patients with Indolent B-Cell Malignancies on Bruton’s Tyrosine Kinase Inhibitors: Practical Considerations for Nurses and Pharmacists

The most common forms of B-cell malignancy, non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), have seen a drastic shift in the treatment landscape over the last two decades with the introduction of targeted agents. Among them are Bruton's tyrosine kinase (BTK) inhibitors, which have demonstrated excellent efficacy in indolent B-cell NHLs and CLL. Although BTK inhibitors are generally thought to be more tolerable than chemoimmunotherapy, they are associated with a unique safety profile including varying rates of rash, diarrhea, musculoskeletal events, cardiovascular events, and bleeding. Ibrutinib was the first BTK inhibitor to gain a Health Canada indication, followed by second-generation BTK inhibitors acalabrutinib and zanubrutinib, which have better safety profiles compared to ibrutinib, likely due to their improved selectivity for BTK. As BTK inhibitors are oral agents given continuously until disease progression, long-term adverse event (AE) monitoring and management as well as polypharmacy considerations are important for maintaining patient quality of life. This paper intends to serve as a reference for Canadian nurses and pharmacists on dosing, co-administration, and AE management strategies when caring for patients with indolent B-cell NHL or CLL being treated with BTK inhibitors.

Safety and quality of life analyses of apalutamide plus active surveillance vs active surveillance alone for low, intermediate risk prostate cancer.

352 Background: Active surveillance (AS) is a standard of care for low-risk prostate cancer (PC). However, 20 to 50% of patients (pts) will ultimately require a local treatment following AS. The aim of this study is to assess whether apalutamide could decrease the proportion of pts requiring local treatment within 3 years. We report the 1-year safety and quality of life analyses. Methods: multicentric phase II study conducted in patients with low to intermediate risk PC randomized between apalutamide 6 months (240 mg/d) with AS vs AS alone. Toxicity was evaluated each month during treatment and every 3 months thereafter for both arms. Quality of life (SF12) was assessed at baseline, 6 and 12 months post enrollment. Results: Patients were randomized: 51 in apalutamide and 40 in AS arm. Only 50 pts received apalutamide (one refusal). Median age was 64 yrs (47-76), median PSA 5.9 (1.5-21.5), only 2 pts had Gleason ISUP 2, 14% had >T2, the median cancer positive cores was 14.3%. The median testosterone level was 4.7 mg/l. Only 88 were available for safety analyses (48 in apalutamide arm). Maximal grades of reported adverse events during the first year were for the experimental arm: 25%, 56%, 19% and control arm: 20%, 15% 12.5% for G1, G2, G3 respectively. In the experimental arm, grade 1/2 related adverse events (AE) were cutaneous (25%) and HTA (15%), nausea 15%, diarrhea 10%, arthralgia or musculoskeletal event 17% and anemia 6%. Attention disorders were observed in 6% and hypothyroidism in 8%. The most frequent sexual dysfunctions were erectile dysfunction observed in 29% (7.5% in AS arm), gynecomastia in 60%, loss of libido in 21%, and nipple pain in 33%. One-year post enrollment, the testosterone level was 4.86 mg/l (1.5-9.8) vs 4.6 (2-7.7) in apalutamide and AS arm, respectively. Digestive symptoms were Grade 3. Related AEs were an HTA for 2 pts, rash for 1 pt, asthenia for 1 pt, erectile dysfunction for 1 pt, and decreased libido for 1 pt. One serious related AE was reported: grade 2 cerebral ischemic attack. A reduced dose was required for 16.67% of pts and 33.3% had transient discontinuation. The treatment was stopped for toxicity in 3 pts; 94% completed the 6 months of treatment. No differences were observed in physical component summary (PCS) and mental component summary (MCS) of SF12 for treatment vs AS at 6 mo (PCS: 55.1 vs 56.4; MCS 43.4 vs 41.4) and 12 mo (PCS: 53.6 vs 54.1; MCS 44.1 vs 42.9). Conclusions: This is a large randomized study evaluating apalutamide with active surveillance vs active surveillance. No new safety issues were observed and the safety profile was consistent relative to those previously described with apalutamide and castration, no falls or fracture were observed. No detrimental effect of apalutamide on QOL was observed during and after treatment. AEs are important for pts candidates for active surveillance. Clinical trial information: NCT03088124 .

Assessing the Burden of Adverse Events in a Head-to-Head Trial of Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia (CLL)

Background: In a previously reported phase 3 head-to-head trial of the Bruton tyrosine kinase (BTK) inhibitors acalabrutinib (Acala) and ibrutinib (Ibr) (NCT02477696), Acala demonstrated noninferiority to Ibr and an improved safety profile with statistically fewer atrial fibrillation/flutter (afib/flutter) events (9% vs 16%) and numerically fewer discontinuations due to adverse events (AEs; 15% vs 21%) vs Ibr in patients (pts) with previously treated CLL (Byrd et al. J Clin Oncol 2021;39:3441-52). To further characterize differences in the safety profile between Acala and Ibr, we conducted a post hoc analysis of AEs using a recently developed, novel statistical method (Ruppert et al. Leukemia 2021;35:2854-61), which considers measures not captured by incidence alone, such as event duration, recurrence, and grade weighting. Methods: Pts with previously treated CLL and del(17p) or del(11q) received oral Acala 100 mg twice daily or Ibr 420 mg daily until disease progression or unacceptable toxicity. Any-grade AE incidence was reported overall and for AEs commonly associated with BTK inhibitors. An AE burden score was adapted from Ruppert et al and calculated as the sum of the products of the AE duration and AE severity grade (weight) recorded for each all-cause AE, divided by duration of the evaluable treatment-emergent period for each pt. Grade 1-4 AEs were weighted according to their CTCAE severity grades; grade 5 AEs were weighted as 10 to reflect the fatal outcome. Pts with no AE had a score of 0. Separate scores were calculated for grade 1-4 AEs and grade 1-5 AEs. Results: In total, 529 pts (Acala, n=266; Ibr, n=263) received study treatment; median number of prior therapies was 2 in both arms. Median total treatment exposures were 38.3 and 35.5 mo, respectively, at the September 15, 2020 data cutoff. While the frequency of experiencing any AE was similar between Acala (98%) and Ibr (97%), the overall AE burden score considering all AEs was higher for Ibr vs Acala, with (P=0.0006) or without (P=0.0016) grade 5 events included (Figure). The overall AE burden score was higher with Ibr vs Acala in certain pt subgroups, including age <65 y, age ≥65 y, and 1-3 prior therapies; there was no statistical difference among pts with ≥4 prior therapies (Figure). AE incidences and AE burden scores for events of clinical interest (ECIs) and selected AEs are shown in the Table. Among ECIs, the afib/flutter AE burden score P=0.0201and event incidence (P) were higher with Ibr than Acala. The AE burden score for cardiac events overall was numerically higher for Ibr vs Acala, even when including grade 5 events; the incidence rate was also numerically higher for Ibr. For hypertension and hemorrhage, AE burden scores (P<0.0001 and P=0.0007, respectively) and event incidences (P<0.0001 and P=0.0020, respectively) were higher with Ibr; no difference was observed for major hemorrhage. Neither the incidence nor AE burden score for infections was different between treatment arms. Among notable symptomatic AEs, the incidence and AE burden score of fatigue was similar between Acala and Ibr. Diarrhea was more frequent among Ibr-treated pts (P=0.0075); however, the AE burden score was higher with Acala (P=0.0114). Headache was more frequent with Acala (P=0.0002), with a higher AE burden score vs Ibr (P=0.0002). The AE burden score for musculoskeletal events was higher with Ibr (P=0.0229). Conclusions: The results of this novel analysis using methodology that incorporates event duration and severity weighting further support the superior tolerability of Acala compared with Ibr and confirm the safety differences that have been reported previously between the two drugs. The AE burden score was lower with Acala vs Ibr overall as well as for afib/flutter, hypertension, hemorrhage, and musculoskeletal events, while it was greater with Acala for diarrhea and headache. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immune checkpoint inhibitor-induced arthralgia is tightly associated with improved overall survival in cancer patients.

With the increased use of immune checkpoint inhibitors (ICIs) in cancer patients, arthralgia has been the most commonly reported musculoskeletal immune-related adverse event (irAE). We aimed to characterize arthralgia and its association with overall survival (OS). Randomized controlled trials (RCTs) reporting on data for ICI-induced arthralgia from four online databases were comprehensively investigated. Odds ratios (ORs) with 95% CIs were calculated for arthralgia using a random-effects model meta-analysis. Individual patient data were reconstructed from RCTs assessing OS in patients with or without ICI-induced arthralgia. We also retrospectively collected data on the clinical features and outcomes of ICI-induced arthralgia in the Yokohama City University (YCU) registry. We analysed 14 377 patients from 24 RCTs. The OR of ICI-induced arthralgia was 1.37 (95% CI 1.20, 1.56). Of the 369 patients in the YCU registry, 50 (13.6%) developed ICI-induced arthralgia. Among them, 30 had other grade ≥2 irAEs, which was noticeably more frequent than in those without arthralgia (OR 1.92, 95% CI 1.04, 3.52). By irAE types, a significant difference was found for relative adrenal insufficiency (OR 3.88, 95% CI 1.80, 8.39). In the YCU registry, patients with (vs without) ICI-induced arthralgia had better OS (log-rank, P < 0.001). OS results were validated from RCT patients with matched cancer types, drugs, and time to arthralgia onset (hazard ratio 0.34, 95% CI 0.17, 0.65, P < 0.001). If arthralgia develops after ICIs, another irAE, such as relative adrenal insufficiency, may have developed. The incidence of arthralgia was associated with better OS, and the condition of patients with irAEs must be carefully evaluated to determine optimal management.

Safety of routine childhood vaccine coadministration versus separate vaccination

IntroductionAs new vaccines are developed more vaccine coadministrations vaccines are being offered to make delivery more practical for health systems and patients. We compared the safety of coadministered vaccines with...

Running shoes for preventing lower limb running injuries in adults.

Running shoes for preventing lower limb running injuries in adults.

DI-5-Cuffs: Bone Remodelling and Associated Metabolism Markers in Humans After Five Days of Dry Immersion to Simulate Microgravity

Background: The dry immersion (DI) model closely reproduces factors of spaceflight environment such as supportlessness, mechanical and axial unloading, physical inactivity, and induces early increased bone resorption activity and metabolic responses as well as fluid centralization. The main goal of this experiment was to assess the efficacity of venoconstrictive thigh cuffs, as countermeasure to limit cephalad fluidshift, on DI-induced deconditioning, in particular for body fluids and related ophthalmological disorders. Our specific goal was to deepen our knowledge on the DI effects on the musculoskeletal events and to test whether intermittent counteracting fluid transfer would affect DI-induced bone modifications. Methods: Eighteen males divided into Control (DI) or Cuffs (DI-TC) group underwent an unloading condition for 5 days. DI-TC group wore thigh cuffs 8–10 h/day during DI period. Key markers of bone turnover, phospho-calcic metabolism and associated metabolic factors were measured. Results: In the DI group, bone resorption increased as shown by higher level in Tartrate-resistant acid phosphatase isoform 5b at DI24h. C-terminal telopeptide levels were unchanged. Bone formation and mineralization were also affected at DI24h with a decreased in collagen type I synthesis and an increased bone-specific alkaline phosphatase. In addition, osteocalcin and periostin levels decreased at DI120h. Calcemia increased up to a peak at DI48h, inducing a trend to decrease in parathyroid hormone levels at DI120h. Phosphatemia remained unchanged. Insulin-like growth factor 1 and visfatin were very sensitive to DI conditions as evidenced by higher levels by 120% vs. baseline for visfatin at DI48h. Lipocalin-2, a potential regulator of bone homeostasis, and irisin were unchanged. The changes in bone turnover markers were similar in the two groups. Only periostin and visfatin changes were, at least partially, prevented by thigh cuffs. Conclusion: This study confirmed the rapid dissociation between bone formation and resorption under DI conditions. It revealed an adaptation peak at DI48h, then the maintenance of this new metabolic state during all DI. Notably, collagen synthesis and mineralisation markers evolved asynchronously. Thigh cuffs did not prevent significantly the DI-induced deleterious effects on bone cellular activities and/or energy metabolism.

Exposure-adjusted safety analyses of the VISION phase 3 trial of 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer.

85 Background: In the VISION trial, targeted radioligand therapy with 177Lu-PSMA-617 significantly prolonged radiographic progression free survival (rPFS) and overall survival when added to standard of care (SoC) in patients with advanced prostate-specific membrane antigen (PSMA)-PET-positive metastatic castration-resistant prostate cancer. There was a higher incidence of treatment-emergent adverse events (TEAEs) with 177Lu-PSMA-617 + SoC vs SoC. However, treatment exposure was more than three times longer in the 177Lu-PSMA-617 + SoC arm and thus relative toxicity may have been overestimated. A post hoc analysis of the relationship between exposure and frequency of TEAEs was performed to facilitate comparison of rates between arms. Methods: In this international, open-label study, adult patients previously treated with ≥ 1 androgen receptor pathway inhibitors and 1–2 taxane regimens were randomized 2:1 to 177Lu-PSMA-617 (7.4 GBq Q6W, ≤ 6 cycles) + SoC or SoC. Safety was a secondary endpoint. TEAEs (regardless of causality) were reported from start of randomized treatment for up to 30 days after last treatment administration (including SoC) or 1 day before subsequent anticancer treatment, whichever occurred first. Overall TEAE incidence was adjusted for treatment exposure by calculating incidence per 100 patient treatment-years (PTY). The analysis was performed for the first occurrence of TEAEs. Results: Exposure-adjusted incidence of any grade, grade ≥ 3 and selected TEAEs are listed in the table. There was similar exposure-adjusted incidence of gastrointestinal events and fatigue and higher exposure-adjusted incidence of musculoskeletal and renal events with SoC compared with 177Lu-PSMA-617 + SoC suggesting an association with treatment exposure rather than 177Lu-PSMA-617. Dry mouth, dry eye and acute myelosuppression maintained a higher incidence, confirming relationship with 177Lu-PSMA-617 treatment. Conclusions: The adjusted safety analysis, accounting for a longer safety observation due to longer rPFS in patients receiving 177Lu-PSMA-617, reveals a comparable incidence of TEAEs between arms. This confirms a favorable risk/benefit profile of 177Lu-PSMA-617 added to SoC in this patient population. Clinical trial information: NCT03511664. [Table: see text]

The Effect of Awkward Postures and Musculoskeletal Disorder Incidents: A Case Study of Bakery Workers

Musculoskeletal complaints or MSDs are common in the bakery industry. Observations and analyses of work posture among bakers are crucial to determine the most practical solution to MSD subjective complaints. This study aims to analyze the impact of work posture on musculoskeletal events in bakery industry workers. This research is quantitative research with a cross-sectional approach. This study recruited 52 bakers. Work posture data was obtained by utilizing the Rapid Entire Body Assessment (REBA) instrument. The subjective musculoskeletal complaint data were collected using the Nordic Body Map (NBM) instrument. The results indicated that most workers (90.4%) were in the young category, 67.3% were male, and 51.9% had a long permanent contract. Most respondents are in the high ergonomic risk category (75%). The lower back (63.5%), neck (25%), and ankle (25%) were subjectively reported by the respondents using the NBM instrument. There was no significant relationship between ergonomic risk and MSD complaints (p-value = 0.721 at α = 0.05). The bakers were exposed to ergonomic limitations and experienced some subjective MSD complaints. However, no significant association was found between ergonomic work posture limitations and MSD complaints. The non-significant finding might be related to the small sample study size or the measurement bias.

Safety and use of tetanus-diphtheria-acellular pertussis-5 (Tdap5) vaccine during pregnancy: findings from 11 years of reporting to a pregnancy registry

ABSTRACT The “Adacel (Tdap5) Pregnancy Registry” was used to identify 1182 women who received the tetanus, diphtheria, acellular pertussis [5 components] (Tdap5) vaccine during pregnancy from 2005 to 2016. To evaluate the safety and use of prenatal Tdap5, we calculated the rate of maternal, obstetrical, pregnancy and neonatal outcomes following Tdap5 pregnancy exposure and assessed vaccine uptake by year and trimester of exposure. The most commonly reported maternal adverse events included injection site reactions (2.6%; 95% Confidence Interval 1.8%, 3.7%), nervous system events (1.3%; 0.8%, 2.1%) and musculoskeletal events (1.1%; 0.6%, 1.9%). The most commonly reported complications of pregnancy were hypertension/preeclampsia (5.5%; 3.3%, 8.9%) and gestational diabetes (2.5%; 1.1%, 5.3%), while those for labor and delivery were premature labor (2.9%; 1.4%, 5.7%) and premature membrane rupture (1.5%; 0.4%, 3.8%). These rates were similar to, or lower than those reported for the general population of pregnant women. Among pregnancies with known birth outcomes (N = 275), 90.4% (86.2%, 93.4%) resulted in a live birth, 5.9% (3.6%, 9.5%) in spontaneous abortion, 3.0% (1.4%, 5.8%) in stillbirth, and 0.7% (0.0%, 2.8%) in ectopic pregnancies. Most newborns had normal APGAR scores and birth weights (98.1% and 93.0%, respectively), and only two reported a congenital anomaly (0.7%; 0.0%, 2.8%). An influx of reports in 2012 with third trimester Tdap5 exposure coincided with the 2012 updated Advisory Committee on Immunization Practices recommendations. This analysis did not identify any safety concerns across the continuum of maternal, obstetrical, pregnancy, and neonatal outcomes in women who received Tdap5 vaccination during pregnancy.

A Multicenter, Prospective Study for Pediatric Chronic Myeloid Leukemia in Chronic Phase: The JPLSG CML-08 Study

Background: Tyrosine kinase inhibitor (TKI) has been used in pediatric chronic myeloid leukemia (CML) for more than 10 years, but only a few prospective clinical studies have been conducted in pediatric patients with CML due to their rarity. We conducted the JPLSG CML-08 study to determine the efficacy and tolerability of TKIs in children and adolescents with newly diagnosed CML in chronic phase (CML-CP).Methods: The JPLSG CML-08 study was a prospective multicenter observational study (UMIN000002581). Patients under 18 years of age with untreated BCR-ABL1-positive CML-CP were eligible and treated according to the modified ELN-2009 recommendation, and the efficacy and safety of TKIs were evaluated.Results: From October 2009 until September 2014, 79 patients were enrolled in 46 hospitals in Japan. A total of 78 patients (49 males and 29 females) were eligible for inclusion. Median age at diagnosis was 11 years (range, 1-17). Median observational period for survivors was 82 months (range, 48-118). Median WBC, Hb and platelet counts were 275x10 9/L (range, 8-765), 9.6g/dL (range, 5.8-14.6) and 560x10 9/L (range, 110-2875), respectively. Splenomegaly was found in 76%. High risk of Sokal, Hasford, EUTOS, and ELTS scores were observed in 21, 13, 27, and 9%, respectively. Clonal chromosome abnormalities in Ph-positive cells occurred in 1 patient at diagnosis. Imatinib, dasatinib, and, nilotinib were used as a first-line treatment in 69 (88%), 7 (9%), and 2 (3%) patients, respectively. The median initial dose of imatinib, dasatinib, and nilotinib was 276, 63, and 262mg/m2, respectively. 5y-PFS and OS was 96.2% (95%CI, 88.6 to 98.7%) and 97.4% (95%CI, 90.1 to 99.4%), respectively. Deaths were observed in 2 patients due to transplant complications. Hematopoietic cell transplantation was conducted in 14 patients (18%). Nine patients (12%) discontinued TKI with the aim of treatment-free remission (TFR), and five of them achieved TFR. In 69 patients with first-line imatinib, complete hematologic response was achieved in 95.7% at 3 months, complete cytogenetic response in 75.4% at 12 months, major molecular response (MMR) in 40.1% at 18 months, and MR4.0 in 52.8% at 60 months; If a transplant was performed, the follow-up period was censored at the date of transplant. Of the 69 patients, 52% changed treatment from imatinib to another TKI or transplant due to poor response, and 20% did due to intolerance. The most common cause of intolerance to imatinib was musculoskeletal events. BCR-ABL1 (IS) <10% at 3 months strongly correlated with higher achievement of MMR, MR4.0, and MR4.5. The EUTOS score was significantly associated with achievement of IS <10% at 3 months. Patients with a first-line second-generation TKI had a higher cumulative incidence of MR4.5 (P = 0.0191) than patients with a first-line imatinib. Second-generation TKI was used as first-line therapy only in patients older than 9 years, but other clinical characteristics, including risk scores, did not differ significantly between the two groups. The incidence of grade 3/4 adverse events (≥ 10%) included neutropenia (47%), anemia (39%), leukopenia (13%), arthralgia (13%), and myalgia (11%) for imatinib, neutropenia (21%), anemia (13%), and thrombocytopenia (11%) for dasatinib, and neutropenia (14%), elevated ALT (14%), hyperbilirubinemia (14%), skin rash (14%), and high CPK (14%) for nilotinib. Gastrointestinal bleeding was an adverse event specific to dasatinib (11% in all grades).Conclusion: This clinical study extends and confirms previous data showing that first-line treatment with imatinib is effective in children and adolescents, with response rates similar to those seen in adults. Although longer follow-up is needed to fully assess the long-term toxic effects, adverse events with imatinib, dasatinib, and nilotinib have been acceptable. As reported in adults, there was an advantage in selecting second-generation TKI over imatinib as first-line therapy to achieve deep molecular remission (DMR). Since discontinuation of TKI after achieving DMR is the preferred strategy, second-generation TKI is expected to become the standard therapy for children and adolescents. DisclosuresNo relevant conflicts of interest to declare.

Safety of High-Intensity, Low-Volume Interval Training or Continuous Aerobic Training in Adults With Metabolic Syndrome.

The aim of the study was to evaluate the safety of high-intensity, low-volume interval training (HIIT-low volume) compared with moderate-intensity continuous aerobic training (MICT) in adults with metabolic syndrome. This is a controlled, randomized, clinical trial in patients without history of ischemic heart disease or diabetes, who underwent a supervised, 3 sessions/week, 12-week treadmill exercise program. The HIIT-low volume (n = 29) sessions consisted of 6 intervals with 1-minute, high-intensity phases at 90% of peak oxygen consumption (VO2peak). The MICT (n = 31) trained at 60% of VO2peak for 30 minutes. A new approach to record and classify all clinical events according to possible causality based on Naranjo's algorithm was developed. Patients were 50.8 ± 6.0 years old, 70% women, with body mass index of 30.6 ± 4.0 kg/m2 and VO2peak of 29.0 ± 6.3 mL·kg-1·min-1. In total, 60 clinical events were recorded in the HIIT-low volume group and 48 in the MICT group, with 59.3% classified as general disease. Only 21 events were classified as adverse reactions possibly related to exercise, without any serious adverse reactions. Both interventions had a similar incidence of musculoskeletal events (incidence rate ratio, 1.1; 95% confidence interval, 0.6-1.8), but HIIT-low volume had a higher incidence of cardiovascular events (incidence rate ratio, 2.9; 95% CI, 0.4-22.8) after adjusting for age, sex, and body mass index (HIIT-low volume: chest pain [n = 1] and symptoms of venous insufficiency of lower limbs [n = 2]; MICT: chest pain [n = 1]). The HIIT-low volume and MICT are safe in patients with metabolic syndrome. We recommend a muscle-conditioning program prior to both and to avoid HIIT-low volume in treadmill in patients with venous insufficiency of the lower limbs.Trial registration number NCT03087721.

Rehabilitation Principles in Bone Metastasis

Metastatic bone disease is often associated with a decline in function and overall quality of life. Pain and musculoskeletal events are contributors to decrease mobility and independence.4, 5, 6, 7 In cases where there is neurological involvement, such as in patients with cord compression syndrome, it can be associated with neurogenic bowel and bladder. The role of cancer rehabilitation providers is to improve the overall health-related quality of life and their function and independence. Rehabilitation interventions, including aerobic and resistant exercise prescription, are associated with positive physical and self-reported outcomes with a low rate of adverse events.4 Low impact aerobic activity has been wildly studied in patients with bone metastasis and has been found to be safe.4,9 Rehabilitation physicians focus on designing a rehabilitation and exercise plan that improves the patient's physical function while keeping in mind the necessary precautions to prevent musculoskeletal events. Activity modification and physical activity that prevents the axial loading of the spine can improve the core musculature of patients with spine involvement while decreasing the risk of compression fractures of the vertebral bodies.21 Furthermore, patients who have undergone surgical interventions as part of the treatment of metastatic bone disease frequently present an acute functional decline. Rehabilitation providers are vital in evaluating these functional impairments and developing a comprehensive rehabilitation plan in the appropriate setting (inpatient vs home vs outpatient).26 Overall, patients with metastatic bone disease present with functional impairments that put them at risk for immobility-related complications. Rehabilitation interventions, such as exercise, are safe and effective in improving immobility complications, decreasing caregiver burden, and improving overall quality of life.4,7,9,26

Pembrolizumab with or without enzalutamide in selected populations of men with previously untreated metastatic castration-resistant prostate cancer harbouring programmed cell death ligand-1 staining: a retrospective study

BackgroundThe purpose of this retrospective study was to evaluate the survival outcomes of pembrolizumab (PEM) plus enzalutamide (ENZ) versus PEM alone in selected populations of men with previously untreated metastatic castration-resistant prostate cancer (mCRPC) harbouring programmed cell death ligand-1 (PD-L1) staining.MethodsConsecutive men with previously untreated mCRPC harbouring PD-L1 staining who underwent treatment with PEM plus ENZ (PE) or PEM alone (PA) at our medical centre from January 1, 2017, to January 31, 2021, were retrospectively identified. Follow-up was conducted monthly during the first year and then every 1 month thereafter. The primary outcomes of the study were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were the frequency of key adverse events (AEs).ResultsIn total, 302 men were retrospectively reviewed, 96 of whom were deemed to be ineligible per the exclusion criteria, leaving 206 men (PE: n = 100, median age 64 years [range, 43–85] and PA: n = 106, 65 years [range, 45–82]) who were eligible for the study. The median follow-up for both groups was 34 months (range, 2–42). At the final follow-up, the median OS was 25.1 months (95% confidence interval [CI], 22.3–27.6) in the PE group versus 18.3 months (95% CI, 16.5–20.9) in the PA group (hazard ratio [HR] 0.56; 95% CI, 0.39–0.80; p = 0.001). A marked distinction was also observed in the median PFS (6.1 months [95% CI, 4.7–7.8] for PE vs. 4.9 months for PA (95% CI, 3.2–6.4) for PA; HR 0.55, 95% CI, 0.41–0.75; p = 0.001). There were noteworthy differences in the rate of the key AEs between the two groups (72.0% for PE vs. 45.3% for PA, p < 0.001). Noteworthy differences were also detected for fatigue events (7.0% in the PE group vs. 0.9% in the PA group, p = 0.025) and musculoskeletal events (9.0% for PE vs. 0.9% for PA, p = 0.007), but these events tended to be manageable.ConclusionsAmong selected populations of men with previously untreated mCRPC harbouring PD-L1 staining, PEM added to ENZ treatment may significantly increase the survival benefits compared with PEM treatment alone regardless of tumor mutation status. The safety profile for PE plus ENZ tends to be manageable.

Efficacy of chemotherapy versus chemoradiotherapy for locally advanced endometrial cancer: a systematic review and meta‐analysis

AbstractObjectiveThis meta‐analysis evaluates the efficacy of chemoradiotherapy versus chemotherapy in patients with locally advanced endometrial cancer (EC).MethodsA systematic search in PubMed, Embase, and the Cochrane Library was performed, according to the PRISMA statement, for the past 10 years to May 28 2020 to identify studies on chemoradiotherapy versus chemotherapy in patients with locally advanced EC. Two independent observers evaluated the identified studies. The obtained data were analyzed using the RevMan 5.3 software.ResultsFive studies involving 1346 patients with locally advanced EC were identified and included in this meta‐analysis according to the inclusion criteria. All studies reported the recurrence‐free survival, and found that patients who received chemoradiotherapy had a better recurrence‐free survival than those who received chemotherapy only (hazard ratio 1.53, 95% confidence interval 1.01–2.05, P &lt; 0. Data on overall survival were provided in three studies; the meta‐analysis showed that patients who received chemoradiotherapy had a better overall survival than those who received chemotherapy only (hazard ratio 1.80, 95% confidence interval 1.07–2.53; P &lt; 0.001), and their difference was significant. Toxicity details were reported in the Gynecologic Oncology Group‐258 trial. In summary, constitutional symptoms, fatigue, gastrointestinal events, renal or genitourinary events, and musculoskeletal events were more frequent in patients who received chemoradiotherapy, whereas hematological adverse events were more frequent and more severe in those who received chemotherapy only.ConclusionsThe meta‐analysis showed that patients receiving chemoradiotherapy had a better overall survival and recurrence‐free survival than those who received chemotherapy only. Large‐scale randomized controlled trials are necessary for the future.

Assessment of the risk of musculoskeletal adverse events associated with fluoroquinolone use in children: A meta-analysis.

The use of fluoroquinolone antibiotics has been restricted in children because of their potential to cause adverse musculoskeletal events. This study was performed to systematically evaluate whether there is a difference between fluoroquinolone and non-fluoroquinolone antibiotics in terms of their associated risk of adverse musculoskeletal events in children. Cochrane Library, Embase, and PubMed databases were used to retrieve studies related to fluoroquinolone and non-fluoroquinolone-induced musculoskeletal adverse events in children. A meta-analysis was performed using Stata 11. A total of 10 studies were included in the analysis. The combined results showed that there was no statistical difference between fluoroquinolone and non-fluoroquinolone groups in terms of musculoskeletal adverse events in children (risk ratio = 1.145, 95% confidence interval = 0.974 - 1.345, P = .101). Subgroup analysis was performed using a random-effects model. Here, the effects on the trovafloxacin and levofloxacin groups were significantly different from that of the control group. However, musculoskeletal adverse events due to either drug was not reported after long-term follow-up. The results showed that fluoroquinolone and non-fluoroquinolone antibiotics were not different in terms of their ability to cause musculoskeletal adverse events in children. For this reason, fluoroquinolone antibiotics can be used in children as appropriate. CRD42019133900.

Feasibility And Preliminary Efficacy Of High-intensity Interval Training During Neaodjuvant Chemoradiotherapy For Rectal Cancer

PURPOSE: To assess the feasibility, safety, and preliminary efficacy of a supervised high-intensity interval training (HIIT) program in rectal cancer patients undergoing 5-6 weeks of neoadjuvant chemoradiotherapy (NACRT). METHODS: Thirty-six rectal cancer patients scheduled to receive NACRT followed by surgery were randomized to either exercise training (n=18) or usual care (n=18) in the Exercise During and After Rectal Cancer Treatment (EXERT) Trial in Edmonton, Alberta. Patients in the exercise group were asked to complete 3 supervised HIIT sessions/week for the duration of NACRT. Feasibility was determined by eligibility rate, recruitment rate, follow-up rate and exercise adherence. Safety was assessed by tracking serious adverse events related to exercise. The primary efficacy outcome was cardiorespiratory fitness (VO2 peak) assessed immediately post-NACRT by a graded exercise test. Secondary efficacy outcomes included functional fitness assessed by the Senior’s Fitness Test. RESULTS: From June 2017 to August 2019, 205 rectal cancer patients were screened, 131 (64%) were eligible, and 36 (27%) were recruited. Follow-up fitness testing post-NACRT was completed in 75% (exercise n=14; control n=13). Reasons for missed fitness testing were medical issues. Median attendance for the supervised HIIT sessions during NACRT was 82%. No serious adverse events were observed, however, 2 patients in the exercise group experienced musculoskeletal events which resulted in 4 missed exercise sessions. Analyses of covariance showed no statistically significant or clinically meaningful difference between groups for the primary outcome of VO2 peak (adjusted between-group mean difference, 0.9 ml/kg/min; 95% CI, -1.6, 3.3; p = 0.47). The 8-foot up-and-go was significantly better in the exercise group post-NACRT (adjusted between group mean difference, -0.4 seconds; 95% CI, -0.7, 0.0, p = 0.031). No other significant group differences in functional fitness were observed. CONCLUSIONS: Supervised HIIT during NACRT for rectal cancer was feasible and safe. Further research is needed, however, to better understand the feasibility of completing fitness testing immediately following NACRT and whether HIIT can produce meaningful improvements in fitness in this challenging clinical setting.

Falls: descriptive rates and circumstances in age-unspecified patients with locally advanced esophageal cancer.

Falls can occur in older cancer patients, but few studies have examined falls in an age-unspecified group of patients with locally advanced esophageal cancer. Because these patients are often administered neuropathy-inducing agents, are weak, and can develop orthostatic symptoms, examining falls appears relevant. Electronic medical records were used to examine falls and their circumstances in locally advanced esophageal cancer patients treated with chemotherapy and radiation and often surgery. Among 300 patients, 62 (21%) suffered a fall, yielding 6 falls per 100 patient years. The median age at first fall was 64years (range 31 to 83). The median time from cancer diagnosis to first fall was 11months (range 0 to 107). Forty-two patients (68%) who fell had active cancer; 20 (32%) were cancer-free. Fall-related injuries occurred in 42 patients and included fractures, hematomas, and other musculoskeletal events. Eighteen patients (29%) fell repeatedly. Neuropathy, general weakness, and orthostatic symptoms were associated with falls ("He does state his neuropathy is more bothersome…. He did have a fall last week…." "He has been increasingly weak to the point where he fell down last week…." "Upon rising… [he] felt like somebody had put a sheet over his eyes, felt very lightheaded, and fell to the floor…."). At times, falls occurred under commonplace circumstances, such as slipping on ice or tripping on an underfoot pet. Regardless of patient age, clinicians should remain vigilant for fall risk in adult patients with locally advanced esophageal cancer.

Quinolones-Induced Musculoskeletal, Neurological, and Psychiatric ADRs: A Pharmacovigilance Study Based on Data From the Italian Spontaneous Reporting System.

BackgroundThe use of quinolones has been associated with the development of serious and persistent adverse drug reaction (ADR) mainly affecting muscles, joints and the nervous system. This risk has led the European Medicines Agency (EMA) to endorse some restrictions on the use of this class of antibiotic. Therefore, we performed a study to primary estimate the reporting probability of musculoskeletal, neurological, and psychiatric ADRs among quinolone generations using national data.MethodsWe retrieved Individual Case Safety Reports (ICSRs) with a quinolone as suspected drug among those reported through the Campania spontaneous reporting system from January 1st, 2001 to April 30th 2019. Moreover, we retrieved national aggregated safety data from the online public report system (RAM system) for the period from January 1st, 2002 to March 31st, 2019. Risk factors were classified as “age greater than 60 years,” “therapeutic indication,” “renal failure,” “organ transplantation,” “use of corticosteroid,” and “history of side effects”. Reporting odds ratio (ROR) was computed to evaluate the reporting probability of musculoskeletal, neurological, or psychiatric events among quinolones generations.ResultsA total of 87 ICSRs with a quinolone as suspected drug that reported at least one musculoskeletal, neurological, and psychiatric adverse event were identified in the Campania spontaneous reporting system. Forty-nine (56.3%) ICSRs reported risk factors (total risk factors 59). The most reported risk factor was “age greater than 60 years” (69.5%), followed by “therapeutic indication” (16.9%), “renal failure” (5.1%), “organ transplantation” (3.4%), “use of corticosteroid” (3.4%), and “history of side effects” (1.7%). Second-generation quinolones were associated with a lower reporting probability of musculoskeletal (ROR 0.70; 95% CI 0.63–0.79), neurological (ROR 0.81; 95% CI 0.73–0.90), and psychiatric (ROR 0.55; 95% CI 0.44–0.63) ADRs compared to the third generation of quinolones.ConclusionsOur findings showed that third-generation quinolones were always associated with a higher reporting probability of musculoskeletal, neurological, and psychiatric ADRs compared to the second generation ones. Moreover, we described risk factors in more than half of our cases suggesting that the inappropriate use of quinolones is a phenomenon that may frequently predispose patients to the occurrence of these ADRs.