Cm In Subjects Research Articles

Suppression of KRAS and CBL Mutations and Hematological Improvement By Lenzilumab and Azacitidine Treatment in Proliferative Chronic Myelomonocytic Leukemia

Introduction: Mutations in RAS-pathway genes ( NRAS, KRAS, CBL) are amongst the most common somatic mutations in cancer and historically resistant to most therapies. Targeted therapies that impact the RAS-pathway constitute a major unmet need in oncology. The proliferative form of chronic myelomonocytic leukemia (CMML) is commonly associated with RAS-pathway mutations and has a high propensity to develop into acute myeloid leukemia. In pre-clinical models, Lenzilumab (LENZ; Humanigen, Inc., Short Hills, NJ), a proprietary Humaneered ® first-in-class monoclonal antibody with best-in-class off-rate and affinity that neutralizes GM-CSF, resulted in a reduction of colony numbers and viability of CMML cells, with the greatest sensitivity in cells possessing RAS-pathway ( NRAS/ KRAS/ CBL) mutations, suggesting benefit in the targeted treatment of CMML. The PREcision Approach to CHronic Myelomonocytic Leukemia (PREACH-M) trial assesses the efficacy of LENZ, in addition to azacytidine (AZA), in CMML subjects with RAS-pathway mutations and high dose sodium ascorbate (ASC) and AZA in CMML subjects without RAS-pathway mutations. Interim data from 11 subjects with RAS-pathway ( NRAS/ KRAS/ CBL) mutations in PREACH-M receiving LENZ/AZA demonstrate reductions in circulating GM-CSF and CRP with 8 subjects achieving complete response or optimal marrow response. This report describes improvements in variant allele frequencies (VAF) for RAS-pathway mutations and hematologic improvements associated with LENZ/AZA treatment in CMML. Methods: PREACH-M is a Phase 2/3 non-randomized, open-label trial in 72 subjects, aged at least 18 years, with newly diagnosed CMML based on the WHO 2016 criteria; and RAS-pathway mutations at a variant allele frequency ≥3%. Subjects received 24 cycles (every 28 days) of AZA (SC; 75 mg/m 2 for 7 days) and LENZ (IV; 552 mg; d1 & d15 of cycle 1 and d1 only for all subsequent cycles). Subjects without RAS-pathway mutations received the same AZA regimen and sodium ascorbate (IV; 30g for 7 days (15g for 1st dose only; 30g thereafter if no evidence of tumor lysis syndrome); PO; 1.1g on all other days). VAF was determined from bone marrow mononuclear cells using a 41-myeloid panel using Illumina Hi-Seq with a depth of 1000x performed on bone marrow aspirates obtained at baseline and Day 1 of treatment cycles 4, 7, and 12. Results: As of July 2023, 11 subjects completed at least 3 months of LENZ/AZA treatments and follow-up sequencing data were available for 10 subjects. Five of 10 subjects showed >10% decrease in VAF for at least one mutation detected at baseline, including 5 decreased alleles in the RAS-pathway ( KRAS, CBL) out of 22 total VAF mutation responses. CBL mutations showed the largest change with a decrease in >50% VAF in three subjects. Decreases in RAS-pathway clones by LENZ/AZA were durable at 6 months. No decreases in VAF for any mutations were observed in 2 evaluable subjects following ASC/AZA treatment. Following 3 months LENZ/AZA treatment, blood monocyte count improved from a baseline of 11.0 ± 6.0 x 10 9/L to 2.0 ± 1.0 x 10 9/L (p=0.030). Blast differential improved from 10.5 ± 5.0% to 4.0 ± 3.5% (p=0.038). Platelet count increased from 90.0 ± 50.0 x 10 9/L to 150.0 ± 60.0 x 10 9/L (p=0.010). Statistical improvements remained durable for at least 6 (n=6) and 12 (n=3) months. Hemoglobin concentration increased 100.0 ± 22.0 g/L to 115.0 ± 10.0 g/L at 3 months (p=NS, n=11) and progressively increased to 122.0 ± 10.0 g/L at 12 months (p=0.024, n=3). Spleen length decreased from 15.0 ± 4.0 cm to 13.0 ± 4.0 cm (p=0.03) and decreased further to 11.0 ± 2.0 cm in subjects who received 12 months of treatment (n=3). No evidence of disease progression or relapse was observed in any subject. Conclusion: In 11 evaluable subjects with proliferative CMML and RAS-pathway mutations, GM-CSF neutralization with LENZ in addition to AZA standard of care, resulted in significant decreases in the proportion of KRAS and CBL mutant leukemic cells, accompanied by clinically significant hematologic improvements and a reduction in splenomegaly. Lenzilumab may have efficacy in preventing outgrowth of RAS-pathway mutations, specifically KRAS and CBL, in the context of CMML and other myeloid malignancies.

Cadaveric and Ultrasound Validation of Percutaneous Electrolysis Approach at the Distal Biceps Tendon: A Potential Treatment for Biceps Tendinopathy.

Distal biceps brachii tendinopathy is a musculoskeletal pain condition-comprising chronic intrasubstance degeneration with alterations of the tendon structure-that is difficult to treat. Preliminary evidence suggests a positive effect for pain and related disability of percutaneous electrolysis treatment in patients with tendinopathy. Ultrasound is an excellent diagnostic tool to identify tendon injuries, such as tendinopathy, and to guide treatment approaches. Different approaches using ultrasound evaluation of the biceps tendon have been described. Our aim was to determine the validity and safety of a percutaneous electrolysis approach, targeting insertion of the distal tendon of biceps brachii, in both human (ultrasound-guided) and Thiel-embalmed cadaver (not ultrasound-guided) models. There were two approaches evaluated: an anterior approach with the elbow in extension and the forearm in supination and a posterior approach with the elbow in flexion and the forearm in pronation. A needle was inserted following the tendon up to its insertion into the radial tuberosity. The anterior approach, both in cadaveric study and US-guided intervention, revealed a close relationship between the distal biceps tendon and the brachial artery. The mean distance of the depth of the biceps tendon distal to the brachial artery was 0.21 ± 0.021 cm in the cadavers and 0.51 ± 0.024 cm in subjects. It was also found that the anterior approach has a potential technical difficulty due to the anatomical location of the brachial artery. With the posterior approach, it was possible to safely identify the tendon insertion and the needle approach, since no important vascular and nervous structures were visualized in the window of insertion of the needle. The clinician rated the posterior approach as low difficulty in all subjects. Current results would support a posterior approach with US guidance as a safe approach for applying the percutaneous electrolysis technique for insertional tendinopathies of the distal biceps brachii tendon. The current study did not assess the effectiveness of the proposed intervention; accordingly, future studies investigating the clinical effectiveness of the proposed intervention are needed.

Measuring the Quality of Cardiopulmonary Resuscitation in the Emergency Department at a Quaternary Children's Hospital.

The aim of this study was to evaluate the quality of cardiopulmonary resuscitation (CPR) as it relates to American Heart Association (AHA) guidelines during cardiac arrests in a pediatric emergency department at a quaternary children's hospital. High-quality CPR increases the likelihood of survival from pediatric out-of-hospital cardiac arrest. However, optimal performance of high-quality CPR during transition of care between prehospital and pediatric emergency department providers is challenging, and survival without comorbidities remains extremely low for out-of-hospital cardiac arrest. This was a retrospective study of data collected from a free-standing children's hospital emergency department and level 1 trauma center. There were 23 pediatric CPR events for subjects younger than 18 years in the emergency department during the time of the study. Median chest compression (CC) fraction was 85% overall with the AHA goal of 80%. Compliance with this recommendation was achieved in all age groups. The CC rate averaged 112 for the entire sample. Median depth was 2.06 cm in subjects younger than 1 year, 3.95 cm in subjects 1 year old to younger than 8 years, and 5.33 cm in subjects 8 years old to younger than 18 years. These compression depth rates fell below the AHA recommendations, with the exception of those 8 years and older. In our study, CC fraction and CC rate were found to meet AHA targets for all age groups, whereas CC depth only met AHA targets for the 8- to 18-year-old group. The most difficult parameter was CC depth for the group of subjects younger than 1 year.

Relationship between thyroid disorders and uterine fibroids among reproductive-age women.

Uterine fibroids and thyroid nodules, both of which are crucially affected by estrogen, are common diseases among reproductive-age women. However, little attention has been paid to the association between the two diseases. This retrospective case-control study aimed to assess the relationships among thyroid nodules, thyroid function and uterine fibroids in China. We reviewed the electronic records of 853 reproductive-age women who attended health check-ups at the Second Affiliated Hospital of Wenzhou Medical University from July 1st, 2017, to June 30th, 2018. All subjects received transvaginal pelvic ultrasound, thyroid ultrasound, thyroid function, and other laboratory tests. We found that the prevalence of thyroid nodules in subjects with uterine fibroids was remarkably higher than that in subjects without fibroids. The proportion of thyroid nodules ≥1 cm in subjects with uterine fibroids was significantly higher than that in subjects without fibroids. Women with thyroid nodules had a higher proportion of multiple uterine fibroids than women without thyroid nodules. Among the parameters of thyroid function, the only statistically significant parameter was total triiodothyronine, i.e., women with uterine fibroids had lower total triiodothyronine levels than unaffected controls; however, the total triiodothyronine levels were within the normal ranges. Moreover, no significant difference was noted in thyroid hormone status between subjects with and without uterine fibroids. Our findings suggest that thyroid nodules are positively correlated with uterine fibroids among reproductive-age women in China. Further studies are needed to confirm this association and fully understand the common pathogenetic mechanism underlying the association between uterine fibroids and thyroid nodules.

Revisiting 35 and 94 GHZ Millimeter Wave Exposure to the Non-Human Primate Eye.

A previous study reported thermal effects resulting from millimeter wave exposures at 35 and 94 GHz on non-human primates, specifically rhesus monkeys' (Macaca mulatta) corneas, but the data exhibited large variations in the observed temperatures and uncertainties in the millimeter wave dosimetry. By incorporating improvements in models and dosimetry, a non-human primate experiment was conducted involving corneal exposures that agreed well with a three-layer, one-dimensional, thermodynamic model to predict the expected surface temperature rise. The new data indicated that the originally reported safety margins for eye exposures were underestimated by 41 ± 20% over the power densities explored. As a result, the expected minimal visible lesion thresholds should be raised to 10.6 ± 1.5 and 7.1 ± 1.0 J cm at 35 and 94 GHz, respectively, provided that the power density is less than 6 W cm for subjects that are unable to blink. If the blink reflex was active, a power density threshold of 20 W cm could be used to protect the eye, although the eyelid could be burned if the exposure was long enough.

Growth perturbations from stimulant medications and inhaled corticosteroids.

Stimulant medications for the treatment of attention deficit hyperactivity disorder (ADHD) and inhaled corticosteroids (ICS) for the treatment of asthma are two classes of medications that are commonly prescribed in pediatrics. Among other adverse effects of these medications, growth attenuation has long been a focus of investigation. With stimulants, growth deficits of 1-1.4 cm/year have been observed in the short term, mainly in the first 2 years of treatment, in a dose-dependent manner. Long-term studies on stimulants have reported divergent effects on growth, with many studies showing no clinically significant height deficits by adulthood. The study that followed the largest cohort of children on stimulants, however, reported an overall adult height deficit of 1.29 cm in subjects who had received stimulant medications, with mean adult height deficit of 4.7 cm among those taking the medication consistently. With ICS use, mild growth suppression is seen in the short term (particularly in the first year of therapy) with growth rates reduced by 0.4-1.5 cm/year. Available current evidence indicates that the impact of ICS use on adult height is not clinically significant, with effects limited to 1.2 cm or less. There is significant individual variability in growth suppression with ICS use, with the specific pharmacologic agent, formulation, dose exposure, age, puberty, medication adherence, and timing of administration being important modifying factors. Based on currently available evidence, the therapeutic benefits of ICS for management of asthma and stimulant medications for management of ADHD outweigh the potential risk for growth suppression. Strategies to minimize growth attenuation and other potential adverse effects of these medications include using the lowest efficacious dose, frequent assessments and dose titration. Particular vigilance is essential with concomitant use of multiple medications that can attenuate growth and to evaluate for potential adrenal insufficiency from ICS use.

Malabsorption and Malnutrition in the Elderly - An Evolution?

Purpose: 80% of the elderly population presenting for hospital admission are either malnourished or potentially malnourished. In a similar cohort, potential malabsorption was identified using a Lactulose/Rhamnose study of small intestinal permeability. Increased permeability was present in 21%. When potential malabsorption begins has not been identified and we proposed to study (over 2 years) a group independently living to determine at what age this process begins. Methods: 154 active, independent living elderly were nutritionally assessed at 3 monthly intervals using the Nestle Mini Nutritional Assessment (MNA) and anthropometrics (hand grip, mid-arm muscle circumference (MAMC), tricep skin-fold thickness, body mass index (BMI), calf circumference). Carbohydrate absorption was measured at 6 monthly intervals with a Rice Breath Hydrogen Test (RBHT) to identify small intestinal bacterial overgrowth (SIBO) and carbohydrate (CHO) malabsorption. The test utilized 100 g of rice, hydrogen levels were measured at 20min intervals for 1 hour, then at 30min intervals for a further hour. A lactulose/rhamnose study of small intestine permeability was completed. Baseline blood tests identify any nutritional deficiencies or coeliac disease. Results: Average age was 80.8 years (60-90 years), ratio 3:1 females to males. At baseline 34.2% had abnormal RBHT's, 22.2% showing evidence of CHO Malabsorption (a RBHT with an increase more than 20 ppm). 12% showed evidence of SIBO (a RBHT with a basal level above 20 ppm). Nutritional assessment revealed 25.1% were malnourished or at risk at baseline which increased to 33.3% at 6 months. Calculated from 12 months data, mean MAMC for subjects with a normal RBHT was 25.7 cm, and 25.4 cm for subjects with an abnormal RBHT. At baseline the mean BMI for the normal RBHT group was 26.9, compared to 26.2 in the abnormal RBHT group. At 6 months the mean BMI for the normal RBHT group was 26.9, whereas the abnormal RBHT group mean BMI was 26.8. At 12 months the mean BMI had declined in both groups, normal RBHT group BMI was 26.3, and abnormal RBHT group BMI was 26.2. Blood tests and urine permeability tests have shown no abnormal results. Conclusion: Evaluations are not sufficient to identify onset of malnutrition. The data suggests that CHO malabsorption and SIBO is present in our independent living elderly with changes in nutritional status shown by MNA, BMI and MAMC. The sequence of events suggests SIBO is perhaps the first marker of potential malabsorption followed by rice CHO malabsorption. There has been no significant disturbance of mucosal permeability. We need to identify individual aspects in the genesis of this process - poor small intestinal motility followed by SIBO.

Timing of onset of contraceptive effectiveness in norplant implant users. Part I. Changes in cervical mucus

Objective: To provide scientific data regarding the changes in cervical mucus within the first hours to days after Norplant implant insertion and to estimate when the cervical mucus is hostile enough to suggest a contraceptive effect. Design: Multicenter, clinical descriptive study. Setting: Family planning clinics. Patient(s): Forty-two women who were between days 8 and 13 of their menstrual cycle and who had requested Norplant implants were admitted to the study. Intervention(s): Cervical mucus and blood samples were obtained. Main Outcome Measure(s): Cervical mucus scores, sperm penetration distances, and serum levels of progesterone, estradiol, and levonorgestrel. Result(s): The median cervical mucus score observed at baseline was 6 (“fair”), indicating that the mucus was already somewhat hostile before insertion of the Norplant implants. The median scores declined to 5 at 12 and 24 hours and continued to decrease through day 7 to 2 (“poor”), a score that is judged as hostile to sperm penetration. Overall, 73% of all subjects had a poor cervical mucus score by 3 days after insertion; at 7 days after insertion, 90% exhibited poor mucus and none had a good score. There was a substantial drop in the overall median distance traveled by the vanguard sperm after 12 hours for each cervical mucus score grouping. The distance traveled decreased rapidly between 12 and 24 hours to <0.5 cm in subjects with fair and poor mucus, and by day 3, 91% of the subjects exhibited poor sperm penetration. Conclusion(s): On the basis of our findings, deterioration of the quality of the cervical mucus and sperm penetration is evident by 24 hours after insertion, although not to a level that would suggest adequate protection until 72 hours after insertion. Therefore, we are confident in recommending that backup methods of contraception (e.g., condoms) need not be used for more than 3 days after insertion, even when the implants are inserted close to ovulation. These findings provide policy makers, clinic managers, and clinicians with important information about how they can improve client access to Norplant implants.

Growth hormone measurements versus auxology in treatment decisions: The Australian experience

Growth hormone (GH) therapy is regulated in Australia by an expert national government committee. A national database (OZGROW) enables regular audits and rational guideline revisions. In 1988 the guidelines were revised to allow eligibility on auxologic criteria alone because of difficulties in diagnosing GH deficiency (GHD) and GH responses in non–GH-deficient children. Initial entry criteria were height less than the 3rd percentile and growth velocity less than the 25th percentile for bone age. Growth hormone testing was continued in most children. More than 3100 children have been treated since 1988 (35% with GHD, 12.5% with Turner syndrome, and 52% with other non-GHDs). Five-year responses (change in height SD scores) were best in the group with complete GHD (+2) (which received the lowest dose of GH) and similar in other groups, including those with partial GHD (+1.5). The increase in final height is 4 to 6 cm in subjects with Turner syndrome. This data is not yet available for subjects with other non-GHDs. In 1994 the guidelines were revised to restrict use of GH therapy to subjects with height less than the 1st percentile, and cessation of GH therapy was brought forward to bone age 13.5 years for girls and 15 years for boys. Subjects with maturational delay were excluded because of the finding that in the presence of significant bone age delay height prognosis was good. New patient accruals have decreased since 1992, from 100/yr to less than 50/yr. Expenditures have also fallen, from $31 to $16 in 1994-95, because of reduced patient numbers and GH pricing. Australian use of GH is 68.7% that of the United States and 42.4% that of Sweden and is in the mid-range internationally. In conclusion, an auxology-based GH program coupled with a comprehensive national database enables rational and economic use of GH in short children. (J P EDIATR 1996;128:S47-51)

GROWTH HORMONE TREATMENT OF TURNER SYNDROME: EFFECT ON FINAL HEIGHT.▴ 568

The effect of growth hormone (GH) therapy, alone, with oxandrolone (OX), or with estrogen (E) was studied in two randomized investigations. GH was administered daily at 0.375 mg/kg/wk and OX at 0.0625 mg/kg/d. In a separate study of GH, subjects were begun on conjugated E (0.3 mg/d for 6 months, then 0.625 mg/d. Final and near-final heights were compared to the projected adult heights (ProjAH) of Turner girls based on Lyon et al. and to the final heights of 25 American untreated historical control subjects. In the first study, subjects treated with GH alone reached a final height of 150.4 ± 5.5 cm, 8.4 ± 4.5 cm taller than their mean ProjAH; subjects treated with GH + OX attained a height of 152.1 ± 5.9 cm, 10.3 ± 4.7 cm taller than their mean ProjAH. Historical controls had a mean adult height of 144.2 ± 6.0 cm, matching their ProjAH of 144.2 ± 6.1 cm. In the second study, near-final height was determined at a mean age of 16.1 years. Subjects on GH + late E (age >14 years) had a mean height of 150.4 cm, compared to 147.0 cm for subjects on GH + early E (age <14 years). We conclude that GH, with and without OX, increases final height, and that early initiation of E compromises adult height. (Funded by Genentech, Inc.)