Clitoral Enlargement Secondary to Neurofibromatosis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67126/2/10.1177_000992289303200511.pd

Organic Corn Production in Kentucky

The number of organic dairy cows in Kentucky has been steadily increasing for years, yet there’s not enough organic corn produced in the state to feed the growing herds. In fact, most of the organic corn consumed in Kentucky is produced outside of the state. The growing organic livestock and poultry industries in Kentucky face the same feed constraints. In short, a new market has developed in the state, but few local farmers are taking advantage of it

Ureterocele associated with a single collecting system of the involved kidney

Objective. This is a study concerning ureteroceles associated with a single collecting system of the involved kidney.Methods. Over an eight-year period 9 children (5 boys, 4 girls) had a ureterocele subtending a single collecting system, whereas 63 children had duplex ureteroceles. Malformations of other organ systems were present in only I patient.Results. Three patients have undergone surgical interventions: a transureteral incision of bilateral obstructive ureteroceles in I and nephroureterectomy in 2. In 4 cases cystic/dysplastic kidneys involuted and were reabsorbed with collapse of the ureteroceles. The last 2 patients have received antibiotic treatment for single episodes of a urinary tract infection.Conclusions. Earlier reports of a high incidence of concomitant anomalies and male predominance in patients with single-system ectopic ureteroceles could not be verified by our experience. Our current policy for a patient is careful evaluation, individualized therapy, and long-term surveillance.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31559/1/0000486.pd

Single sysem ectopic ureters and ureteroceles associated with dysplastic kidney

Eight children forming an uncommon subgroup of renal obstructive dysplasia are presented. Each child had a nonfunctioning dysplastic kidney with a single collecting system with ectopic ureteral insertion and/or ureterocele. Five of the children had classic multicystic dysplastic kidneys, one had they hdyronephrotic type of multicystic dysplasia kidney had two had hypoplastic kidneys. Other significant medical problems in 5 of the 8 children (63%Z) included VACTERL association, congenital heart diseaise and other genitourinary malformations. Unlike some children with unilateral multicystic dysplasia kidney, this subgroup of children ahs an increased risk of infection. The must be correctly identified on imaging so that tailored clinical management decisions can be made and associated anomalies detected.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46698/1/247_2005_Article_BF02012501.pd

Urologic manifestations of Goldenhar syndrome

ObjectiveGoldenhar syndrome (oculoauriculovertebral dysplasia) is associated with anomalies in multiple organ systems. Renal abnormalities have also been reported with the complex, but the incidence of associated genitourinary malformations has not been defined.MethodWe have reviewed our experience with 28 children with Goldenhar syndrome evaluated during the past twelve years. Twenty children underwent imaging evaluation of the urinary tract and 14 (70% of those imaged) children had urinary tract anomalies.ResultsThe majority of anomalies presented as an incidental finding on a screening ultrasound (8 patients) or during cardiac catheterization (2 patients). Two children presented with urinary tract infection, 1 child presented with renal failure, and another was diagnosed antenatally. The genitourinary anomalies included the following: ectopic and/or fused kidneys (8 patients), renal agenesis (7), vesicoureteral reflux (5), ureteropelvic junction obstruction (2), ureteral duplication (2), and multicystic kidney (1 patient). Four children have undergone surgical intervention.ConclusionOur experience in children with Goldenhar syndrome suggests that the incidence of genitourinary anomalies is higher than previously reported. A screening ultrasound in the neonatal period allows for early intervention in those children with significant urologic abnormalities.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31881/1/0000833.pd

Antibody-drug conjugates plus Janus kinase inhibitors enable MHC-mismatched allogeneic hematopoietic stem cell transplantation

Despite the curative potential of hematopoietic stem cell transplantation (HSCT), conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADCs) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely focused on syngeneic HSCT. However, to treat acute leukemias or induce tolerance for solid organ transplantation, this approach must be expanded to allogeneic HSCT (allo-HSCT). Using murine allo-HSCT models, we show that pharmacologic Janus kinase 1/2 (JAK1/2) inhibition combined with CD45- or cKit-targeted ADCs enables robust multilineage alloengraftment. Strikingly, myeloid lineage donor chimerism exceeding 99% was achievable in fully MHC-mismatched HSCT using this approach. Mechanistic studies using the JAK1/2 inhibitor baricitinib revealed marked impairment of T and NK cell survival, proliferation, and effector function. NK cells were exquisitely sensitive to JAK1/2 inhibition due to interference with IL-15 signaling. Unlike irradiated mice, ADC-conditioned mice did not develop pathogenic graft-versus-host alloreactivity when challenged with mismatched T cells. Finally, the combination of ADCs and baricitinib balanced graft-versus-host disease and graft-versus-leukemia responses in delayed donor lymphocyte infusion models. Our allo-HSCT conditioning strategy exemplifies the promise of immunotherapy to improve the safety of HSCT for treating hematologic diseases

Is adrenalectomy necessary during unilateral nephrectomy for Wilms Tumor? A report from the Children\u27s Oncology Group.

PURPOSE: To determine whether performing adrenalectomy at the time of nephrectomy for unilateral Wilms tumor impacts clinical outcome. METHODS: We reviewed information on all patients enrolled on National Wilms Tumor Study-4 and -5. Data were abstracted on patient demographics, tumor characteristics, surgical and pathologic status of the adrenal gland, and patient outcomes. The primary endpoints were intraoperative spill and five-year event-free survival (EFS) in patients who did or did not undergo adrenalectomy. RESULTS: Of 3825 patients with complete evaluable data, the adrenal was left in situ in 2264 (57.9%) patients, and was removed completely in 1367 patients (36.7%) or partially in 194 patients (5.2%). Of the adrenal glands removed, 68 (4.4%) contained tumor. Adrenal involvement was more common in patients with stage 3 (9.8%) than stage 2 disease (1.9%; p \u3c 0.0001). After controlling for stage and histopathology, five-year EFS was similar whether or not the adrenal gland was removed (p = 0.48), or involved with tumor (p = 0.81); however, intraoperative spill rates were higher in patients undergoing adrenalectomy (26.1% vs 15.5%, p \u3c 0.0001), likely due to larger tumor size or technical factors. No patient had clinical evidence of adrenal insufficiency or tumor recurrence in the adrenal gland during follow-up (median 9.9 years). CONCLUSIONS: Sparing the adrenal gland during nephrectomy for unilateral Wilms tumor was not associated with a higher incidence of intraoperative spill and was associated with a similar oncologic outcome, on a per-stage basis, with cases where the adrenal was removed. Thus, adrenalectomy should not be considered mandatory during radical nephrectomy for Wilms tumor

Risk Factors for End Stage Renal Disease in Non-WT1-Syndromic Wilms Tumor

PURPOSE: We assessed risk factors for end stage renal disease in patients with Wilms tumor without known WT1 related syndromes. We hypothesized that patients with characteristics suggestive of a WT1 etiology (early onset, stromal predominant histology, intralobar nephrogenic rests) would have a higher risk of end stage renal disease due to chronic renal failure. We predicted a high risk of end stage renal disease due to progressive bilateral Wilms tumor in patients with metachronous bilateral disease. MATERIALS AND METHODS: End stage renal disease was ascertained in 100 of 7,950 nonsyndromic patients enrolled in a National Wilms Tumor Study during 1969 to 2002. Risk factors were evaluated with cumulative incidence curves and proportional hazard regressions. RESULTS: The cumulative incidence of end stage renal disease due to chronic renal failure 20 years after Wilms tumor diagnosis was 0.7%. For end stage renal disease due to progressive bilateral Wilms tumor the incidence was 4.0% at 3 years after diagnosis in patients with synchronous bilateral Wilms tumor and 19.3% in those with metachronous bilateral Wilms tumor. For end stage renal disease due to chronic renal failure stromal predominant histology had a HR of 6.4 relative to mixed (95% CI 3.4, 11.9; p<0.001), intralobar rests had a HR of 5.9 relative to no rests (95% CI 2.0, 17.3; p=0.001), and Wilms tumor diagnosis at less than 24 months had a HR of 1.7 relative to 24 to 48 months and 2.8 relative to greater than 48 months (p=0.003 for trend). CONCLUSIONS: Metachronous bilateral Wilms tumor is associated with high rates of end stage renal disease due to surgery for progressive Wilms tumor. Characteristics associated with a WT1 etiology markedly increased the risk of end stage renal disease due to chronic renal failure despite the low risk in non-WT1 syndromic cases overall

CS1 CAR-T targeting the distal domain of CS1 (SLAMF7) shows efficacy in high tumor burden myeloma model despite fratricide of CD8+CS1 expressing CAR-T cells

Despite improvement in treatment options for myeloma patients, including targeted immunotherapies, multiple myeloma remains a mostly incurable malignancy. High CS1 (SLAMF7) expression on myeloma cells and limited expression on normal cells makes it a promising target for CAR-T therapy. The CS1 protein has two extracellular domains - the distal Variable (V) domain and the proximal Constant 2 (C2) domain. We generated and tested CS1-CAR-T targeting the V domain of CS1 (Luc90-CS1-CAR-T) and demonstrated anti-myeloma killing in vitro and in vivo using two mouse models. Since fratricide of CD8 + cells occurred during production, we generated fratricide resistant CS1 deficient Luc90- CS1- CAR-T (ΔCS1-Luc90- CS1- CAR-T). This led to protection of CD8 + cells in the CAR-T cultures, but had no impact on efficacy. Our data demonstrate targeting the distal V domain of CS1 could be an effective CAR-T treatment for myeloma patients and deletion of CS1 in clinical production did not provide an added benefit using in vivo immunodeficient NSG preclinical models

An off-the-shelf CD2 universal CAR-T therapy for T-cell malignancies

T-cell malignancies are associated with frequent relapse and high morbidity, which is partly due to the lack of effective or targeted treatment options. To broaden the use of CAR-T cells in pan T-cell malignancies, we developed an allogeneic universal CD2-targeting CAR-T cell (UCART2), in which the CD2 antigen is deleted to prevent fratricide, and the T-cell receptor is removed to prevent GvHD. UCART2 demonstrated efficacy against T-ALL and CTCL and prolonged the survival of tumor-engrafted NSG mice in vivo. To evaluate the impact of CD2 on CAR-T function, we generated CD19 CAR-T cells (UCART19) with or without CD2 deletion, single-cell secretome analysis revealed that CD2 deletion in UCART19 reduced frequencies of the effector cytokines (Granzyme-B and IFN-γ). We also observed that UCART19ΔCD2 had reduced anti-tumor efficacy compared to UCART19 in a CD19+NALM6 xenograft model. Of note is that the reduced efficacy resulting from CD2 deletion was reversed when combined with rhIL-7-hyFc, a long-acting recombinant human interleukin-7. Treatment with rhIL-7-hyFc prolonged UCART2 persistence and increased survival in both the tumor re-challenge model and primary patient T-ALL model in vivo. Together, these data suggest that allogeneic fratricide-resistant UCART2, in combination with rhIL-7-hyFc, could be a suitable approach for treating T-cell malignancies