A venetoclax and azacitidine bridge-to-transplant strategy for NPM1-mutated acute myeloid leukaemia in molecular failure.

NPM1-mutated acute myeloid leukaemia (NPM1mut AML) represents a mostly favourable/intermediate risk disease that benefits from allogeneic haematopoietic stem cell transplantation (HSCT) in case of measurable residual disease (MRD) relapse or persistence after induction chemotherapy. Although the negative prognostic role of pre-HSCT MRD is established, no recommendations are available for the management of peri-transplant molecular failure (MF). Based on the efficacy data of venetoclax (VEN)-based treatment in NPM1mut AML older patients, we retrospectively analysed the off-label combination of VEN plus azacitidine (AZA) as bridge-to-transplant strategy in 11 NPM1mut MRD-positive fit AML patients. Patients were in MRD-positive complete remission (CRMRDpos ) at the time of treatment: nine in molecular relapse and two in molecular persistence. After a median number of two cycles (range 1-4) of VEN-AZA, 9/11 (81.8%) achieved CRMRD -negative (CRMRDneg ). All 11 patients proceeded to HSCT. With a median follow-up from treatment start of 26 months, and a median post-HSCT follow-up of 19 months, 10/11 patients are alive (1 died from non-relapse mortality), and 9/10 patients are in MRDneg status. This patient series highlights the efficacy and safety of VEN-AZA to prevent overt relapse, achieve deep responses and preserve patient fitness before HSCT, in patients with NPM1mut AML in MF.

Successful Pavlik Harness Treatment for Developmental Dysplasia of the Hip and Normal X-Ray at the Age of 2 Years: Is a Longer Follow-up Necessary?

BACKGROUND: Management of developmental dysplasia of the hip (DDH) with a Pavlik harness is a well-known treatment.Follow-up until skeletal maturity is recommended as long-term studies mention late sequelae.The purpose of this study was to determine whether such a follow-up is necessary in patients treated successfully under a strict protocol. METHODS: A retrospective review of a consecutive series of normal infants treated for DDH between January 1995 and July 2004 was undertaken.Only normal infants with frankly pathologic hips treated successfully with a Pavlik harness were included, and with a normal anteroposterior (AP) pelvis x-ray at the age of 2 years.All infants with any type of neurological disease, syndrome, other form of treatment for DDH, and failure of the Pavlik harness were excluded.At the last follow-up, a clinical examination and a standing AP pelvis x-ray were performed. RESULTS: A total of 109 hips in 83 children were available for review. The mean follow-up was of 10 years and 2 months. All 109 hips had a normal clinical examination and a normal AP pelvis x-ray: a mean center-edge angle (CEA) of 29.5 degrees, SD±4.1 degrees, a mean acetabular index (AI) of 1457±3.74 degrees, a mean Sharp's angle of 41.92±3.42 degrees, a Seringe-Severin score of IA, a normal teardrop figure, no signs of avascular necrosis, and Moses circles <2. CONCLUSION: This study strongly suggests that in a selected group of patients treated for DDH with a Pavlik harness, under a strict protocol, and a normal x-ray at 2 years of age, a long-term follow-up is not necessary. LEVEL OF EVIDENCE: Level III-therapeutic.

The role of component separation in the treatment of severe diastasis recti abdominis: a new indication for a known technique.

OBJECTIVE: Diastasis of the rectus abdominis muscle (DRAM) is a widening of linea alba, it also could be accompanied by abdominal bulging. DRAM is often a cause of quality-of-life impairment, especially when it is of large dimensions. Repair with direct rectus plication is the most common treatment for Diastasis Recti Abdominis (DRA), but it can result in high recurrence rates. The authors aimed to show their results in applying the component separation technique in wide DRA cases. PATIENTS AND METHODS: From January 2015 to July 2018, 43 patients with DRA ≥ 10 cm at 3 cm over the umbilicus have been treated with component separation technique associated to panniculectomy. A biologic mesh was positioned onlay in cases of weakness along the semilunaris lines. RESULTS: DRA repair was achieved in all cases. All patients completed the 1-year follow-up and no recurrence nor major complication were registered. Minor complications were observed in 12 (27.9%) cases. CONCLUSIONS: This is the first study describing the component separation technique use in cases of DRA without hernia, associated to abdominoplasty surgery. Preliminary results were encouraging, but larger series are required.

Use of synthetic ligament in reconstruction after massive bone tumour removal.

With advances in medical imaging over the past decades and with a multidisciplinary approach in bone tumour management, limb sparing procedures are more often feasible but come with new challenges. One of these is to deal with the remaining soft tissues, especially muscles, or bony parts and to restore continuity and a correct function. Synthetic ligaments have been used safely for several decades in various ligament reconstruction procedures with good results. We present a technique in which a synthetic ligament is used to augment or replace a joint capsule around a megaprosthesis. The joint is thus stabilized, and the remaining bony parts and muscles are attached to the synthetic material to restore continuity and allow better function of the spared limb.

Assessment of bromhexine as a treatment regimen in Sjögren's syndrome-like disease in the NOD (non-obese diabetic) mouse.

OBJECTIVE: Bromhexine has been reported to alleviate the xerostomia and xerophthalmia associated with secondary Sjögren's syndrome. The aim of this study was to determine if it might prove useful in the treatment of Sjögren's syndrome-like disease of the NOD mouse model for autoimmune sialoadenitis. METHODS: Groups of mice were divided into sets receiving 60 mg/kg bromhexine in drinking water and control pair-fed animals. The efficacy of drug treatment was assessed by weekly measurement of stimulated saliva volumes, protein concentration, and amylase activity. At termination (20 weeks) submandibular and lacrimal glands were removed to assess the levels of lymphocytic infiltration by histological evaluation under light microscopy. RESULTS: Control and bromhexine-treated groups of mice showed no difference in the loss or rate of reduction in stimulated saliva flow over the 12 weeks of treatment. No differences were noted in the protein concentration and amylase loss with increasing age of the animals. Similar temporal changes in total protein profiles and aberrant expression of the 20 kDa parotid secretory protein isoform were observed by SDS-polyacrylamide gel profiles and Western bolt analysis. Histological evaluation of exocrine gland sections failed to detect any reduction in focal lymphocyte infiltration. CONCLUSION: Bromhexine therapy did not alter the development or severity of Sjögren's syndrome-like disease in the NOD mouse model for autoimmune sialoadenitis.

Differential absorption and distribution of epidermal growth factor and insulin-like growth factor in diabetic NOD mice.

Previous studies have shown that absorption of growth factors occurs through the gastrointestinal tract and the oral cavity. The non-obese diabetic (NOD) mouse, a model for spontaneous development of type 1 insulin-dependent diabetes (IDDM), was evaluated for the absorption and systemic distribution of growth factors. Radiolabeled epidermal growth factor (EGF) and insulin-like growth factor, type I (IGF-I), were administered by gavage into the stomach or by lozenge into the sublingual vasculature of either diabetic or nondiabetic mice. After a time-dependent uptake, the levels of absorption and distribution through the tissues were measured. A similar time course of EGF absorption following gavage administration was determined for NOD and C57BL/6 mice, with a maximum tissue distribution by 30-min post infusion. Diabetic NOD mice showed similar levels of IGF uptake and tissue distribution compared with nondiabetic NOD and normal healthy C57BL/6 mice, whether administered by gavage or sublingual lozenge. On the other hand, gavage uptake and tissue distribution of EGF was significantly higher in diabetic mice when compared to sublingual administration in nondiabetic NOD or C57BL/6 healthy control mice. These findings suggest that the overall potential uptake and distribution of saliva-derived growth factors in systemic wound-healing processes is retained with diabetes onset, and may offer a new avenue to treating this complication of diabetes.

Ankle joint range of motion measurements in spastic cerebral palsy children: intraobserver and interobserver reliability and reproducibility of goniometry and visual estimation.

The aim of this study was to assess the intra- and interobserver reliability and reproducibility of goniometry and visual estimation of ankle joint range of motion measurements in children with spastic cerebral palsy. Forty-six ankles of 24 spastic cerebral palsy children were measured under a strict protocol. The global mean measurement error was 5 degrees (SD, 5 degrees) for intra- and interobserver measurements and 3 degrees (SD, 3 degrees) for goniometry versus visual estimation. Statistical analysis showed a high reliability for intra- and interobserver measurements (r>0.75), between visual estimation and goniometry (correlation coefficient, r>0.967; concordance coefficient, r>0.957). Both visual estimation and goniometry ankle range-of-motion measurements are reliable and reproducible in spastic cerebral palsy children if a strict but simple protocol is applied.

PSP expression in murine lacrimal glands and function as a bacteria binding protein in exocrine secretions.

Nonobese diabetic (NOD) mice, an animal model for type I autoimmune diabetes and autoimmune sialoadenitis, abnormally express parotid secretory protein (PSP) in the submandibular glands (Robinson, C. P., H. Yamamoto, A. B. Peck, and M. G. Humphreys-Beher. Clin. Immunol. Immunopathol. 79: 50-59, 1996). To evaluate possible PSP gene dysregulation in the NOD mouse, we have examined a number of organs and tissues for PSP mRNA transcripts and protein expression. Results indicate that PSP is produced in the lacrimal glands of NOD mice as well as most laboratory mouse strains. Although purified salivary PSP from C3H/HeJ or BALB/c mice fails to affect amylase enzyme activity in in vitro assays, PSP bound to whole bacteria in a Zn2+-dependent manner. Additionally, radiolabeled protein bound to specific bacterial membrane proteins using a ligand binding assay. PSP gene transcription, but not protein production, was observed in the heart and pancreas from NOD mice, indicating abnormal transcription of the PSP gene. Sequence analysis of PSP cDNA from NOD mice revealed numerous base differences (compared with the published PSP sequence) capable of leading to significant amino acid substitutions, suggestive of strain-specific differences for the protein in mice. Together these results suggest that there exists in the NOD mouse a dysregulation of PSP transcription in various tissues. However, except for C3H/HeJ mice, PSP appears as a normal product of the lacrimal glands where, as in saliva, it may function as a nonimmune antimicrobial agent in the protection of tissue surfaces exposed to the external environment.

Excessive synthesis of matrix metalloproteinases in exocrine tissues of NOD mouse models for Sjögren's syndrome.

OBJECTIVE: Matrix metalloproteinases (MMP) and their substrates, components of the extracellular matrix, regulate environmental signals for cellular differentiation and tissue function. Changes in the levels of these enzymes may influence cell survival as well as pathology involving ectopic apoptosis. Using the non-obese diabetic (NOD) mouse model for Sjögren's syndrome, we evaluated the synthesis and expression of MMP in the exocrine target tissues of autoimmunity. METHODS: NOD, immunodeficient NOD-scid, and nondiabetic NOD.B10.H2b mice were evaluated for MMP activity in their saliva and exocrine gland lysates by gelatin zymography and reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, changes in protein content of saliva and gland lysates were determined by specific Western blot and by enzymatic activity of amylase and cysteine proteases. Mice continuously treated with the MMP inhibitor GM6001 were evaluated from 7 to 20 weeks of age for the contribution of MMP activity to development of these hallmark biochemical markers of Sjogren's syndrome-like disease of NOD mice. RESULTS: Gelatin zymography of whole saliva and gland lysates indicated the presence of increased proteolytic activity, corresponding to proteins with a molecular mass ranging from 50 to 95 kDa, in the saliva of older (> 20 weeks of age) NOD mice as well as NOD.B10.H2b and NOD-scid mice compared to BALB/c controls. Elevated steady state levels of mRNA transcripts for the gelatinases MMP-2 and MMP-9 were detected in total RNA extracted from parotid and submandibular glands by RT-PCR. Despite prophylactic injection of the broad spectrum MMP inhibitor GM6001 into mice beginning at 7 weeks of age and continuing to 20 weeks, development of the autoimmune exocrinopathy was neither stopped nor retarded. CONCLUSION: These observations suggest that excessive MMP activity is associated with autoimmune Sjögren's syndrome-like disease in NOD mice. However, a possible contribution by increased MMP activity in initiation and progression of this autoimmune disease is yet to be elucidated.