Angiotensin II Type 1 receptor antibodies are associated with inflammatory cytokines and poor clinical outcomes in pediatric kidney transplantation.

Angiotensin II type 1 receptor (AT1R) antibody has been linked to poor allograft outcomes in adult kidney transplantation. However, its clinical consequences in children are unknown. To study this, we examined the relationship of AT1R antibody with clinical outcomes, biopsy findings, inflammatory cytokines, and HLA donor-specific antibodies (DSA) in a cohort of pediatric renal transplant recipients. Sixty-five patients were longitudinally monitored for AT1R antibody, HLA DSA, IL-8, TNF-α, IL-1ß, IFN-γ, IL-17, and IL-6, renal dysfunction, hypertension, rejection, and allograft loss during the first two years post transplantation. AT1R antibody was positive in 38 of the 65 of children but was not associated with HLA DSA. AT1R antibody was associated with renal allograft loss (odds ratio of 13.1 [95% confidence interval 1.48-1728]), the presence of glomerulitis or arteritis, and significantly higher TNF-α, IL-1ß, and IL-8 levels, but not rejection or hypertension. AT1R antibody was associated with significantly greater declines in eGFR in patients both with and without rejection. Furthermore, in patients without rejection, AT1R antibody was a significant risk factor for worsening eGFR over the two-year follow-up period. Thus, AT1R antibody is associated with vascular inflammation in the allograft, progressive decline in eGFR, and allograft loss. AT1R antibody and inflammatory cytokines may identify those at risk for renal vascular inflammation and lead to early biopsy and intervention in pediatric kidney transplantation.

Bortezomib may stabilize pediatric renal transplant recipients with antibody-mediated rejection.

BACKGROUND: Current therapeutic strategies to effectively treat antibody-mediated rejection (AMR) are insufficient. Thus, we aimed to determine the benefit of a therapeutic protocol using bortezomib for refractory C4d + AMR in pediatric kidney transplant patients. METHODS: We examined seven patients with treatment-refractory C4d + AMR. Immunosuppression included antithymocyte globulin or anti-CD25 monoclonal antibody for induction therapy with maintenance corticosteroids, calcineurin inhibitor, and anti-metabolite. Estimated glomerular filtration rate (eGFR) calculated by the Schwartz equation, biopsy findings assessed by 2013 Banff criteria, and human leukocyte antigen (HLA) donor-specific antibodies (DSA) performed using the Luminex single antigen bead assay were monitored pre- and post- bortezomib therapy. RESULTS: Seven patients (86 % male, 86 % with ≥6/8 HLA mismatch, and 14 % with pre-formed DSA) age 5 to 19 (median 15) years developed refractory C4d + AMR between 1 and 145 (median 65) months post-transplantation. All patients tolerated bortezomib. One patient had allograft loss. Of the six patients with surviving grafts (86 %), mean pre-bortezomib eGFR was 42 ml/min/1.73 m(2) and the mean 1 year post-bortezomib eGFR was 53 ml/min/1.73 m(2). Five of seven (71 %) had improvement of histological findings of AMR, C4d staining, and/or acute cellular rejection. Reduction in HLA DSAs was more effective for class I than class II. CONCLUSIONS: Bortezomib appears safe and may correlate with stabilization of eGFR in pediatric kidney transplant patients with refractory C4d + AMR.

Olfactory Neuroblastoma: Re-Evaluating the Paradigm of Intracranial Extension and Cyst Formation.

The purpose of the current study was to assess the prevalence of cyst formation at the brain-tumor interface in olfactory neuroblastoma. We used the UCLA patient-based Pathology and Radiology Head and Neck Database (UPP&R HAND) to identify the largest patient cohort reported to date with imaging and pathology data. Eighteen of thirty-one patients (58.1%) had evidence of intracranial extension on MRI, while four (22.0%) demonstrated cyst formation at the brain-tumor interface. The extent of intracranial extension was by far the strongest predictor for intracranial cyst formation, regardless of Hyams tumor grade, using a binary logistics regression model (p = 0.002) and ROC curve analysis (AUC 94.6%). Cyst formation at the brain-tumor interface was an uncommon imaging finding, and tends to occur with a larger component of intracranial tumor extension.

Scaffold-Assisted Artificial Hair Implantation in a Rat Model.

IMPORTANCE: Current treatments for alopecia with autograft hair transplantation face limitations that may preclude complete hair restoration and leave patients with donor site scars. Scaffold assisted artificial hair implantation as demonstrated in a rat model may provide an adjunct for hair restoration without donor site morbidity. OBJECTIVE: To design and create porous high-density polyethylene (PHDPE) and expanded polytetrafluoroethylene (ePTFE) hair-bearing scaffolds and evaluate their biocompatibility in a rat model. DESIGN, SETTING, AND PARTICIPANTS: For this single-institution randomized prospective animal study, 34 Sprague Dawley rats were randomly selected into 2 groups: 24 rats for direct implantation and 10 rats for delayed implantation. The direct-implantation group was randomly divided into 3 subgroups of 8 rats, which were observed for 2, 12, and 24 week. INTERVENTIONS: Each rat dorsum was implanted with 4 scaffolds-PHDPE and ePTFE with and without hair-in a randomized 4-quadrant manner. The rats in the direct-implantation group were observed to their selected time points of 2, 12, and 24 weeks. The rats in the delayed-implantation group were observed for 4 weeks at which, all well-healed scaffolds without hair were then percutaneously implanted with 2 follicular units of hair. These rats were then observed for another 4 weeks. MAIN OUTCOMES AND MEASURES: During the clinical observation period, scaffolds were observed for signs of infection, extrusion, and persistence of follicular units. Following sacrifice, sagittal sections of scaffold and surrounding skin were fixed in formalin, stained with hematoxylin-eosin, and evaluated for degree of fibrovascular invasion and acute and chronic inflammation. RESULTS: Overall 94.5% (86 of 91) of the scaffolds were well healed at time of evaluation (2 week, 100% [32 of 32]; 12 week, 96.3% [26 of 27]; 24 week, 87.5% [28 of 32]); while 85.6% of artificial hair follicular units were intact at time of evaluation (2 week, 93.8% [30 of 32]; 12 week, 86.7% [26 of 30]; 24 week, 75.0% [21 of 28]). Within the delayed implant group 100% (19 of 19) of the hair-implanted scaffolds were well healed at 8 weeks, with 94.7% (36 of 38) of the follicular units intact; 100% of the delayed-hair implant scaffolds were well healed with 86.1% (36 of 38) of the follicular units intact. Kaplan-Meier log-rank analysis showed no significant difference in survival between ePTFE and PHDPE scaffolds, as well as scaffolds with hair and scaffolds without hair. Upon histological analysis, overall scaffolds with hair were noted to have greater chronic inflammation (95% CI, -0.81 to -1.10; P = .01), and PHDPE was noted to have significantly great fibrovascular integration (95% CI, -11.42 to -1.96; P = .01) compared with ePTFE. CONCLUSIONS AND RELEVANCE: Overall, PHDPE and ePTFE hair bearing scaffolds were well tolerated in a rat model. Progressive loss of artificial hair may be percutaneously implanted without significant increases in infection or extrusion. LEVEL OF EVIDENCE: NA.

Incidental finding of lymphoma after septoplasty.

INTRODUCTION: Septoplasty, or surgical correction of the deviated septum, is an elective, routinely performed rhinologic procedure to address nasal airway obstruction. In many cases, resected septal cartilage and bone fragments are sent for pathologic review, although there is no consensus on this practice. We reported two cases of incidentally diagnosed lymphoma after elective septoplasty and discussed clinical presentation, diagnosis, and management. METHODS: Retrospective chart review of two patients who underwent septoplasty at a tertiary academic medical center and found to have incidental lymphoma based on histopathology. RESULTS: Two patients who underwent septoplasty had an incidental diagnosis of lymphoma on pathologic analysis. One patient was noted to have an S-shaped septal deviation that produced bilateral nasal obstruction. She underwent a difficult septoplasty, in which the mucoperichondrial flap was firmly adherent to the underlying septum and bone. Final pathology demonstrated diffuse large B-cell lymphoma. She was treated with chemoradiation and remained free of disease at 59 months. The other patient had a history of nasal trauma, which produced left septal deviation. He underwent an uncomplicated septoplasty, with pathology that demonstrated low-grade B-cell lymphoma. Because there was no evidence of active disease, the decision was made to not treat and to observe the patient clinically. CONCLUSIONS: This is the first reported series of septal lymphoma incidentally diagnosed on routine septoplasty. Although histopathologic review of specimens from routine nasal and sinus surgery is not routinely performed, this report highlighted the importance of this process, on a case-by-case basis, in detecting unexpected malignancies that otherwise were clinically silent.

Esthesioneuroblastoma: an update on the UCLA experience, 2002-2013.

Objectives To profile the clinical presentation and treatment results of esthesioneuroblastomas at the University of California, Los Angeles (UCLA), from 2002 to 2013. Design Retrospective review. Setting Tertiary academic institution. Participants Forty-one patients with esthesioneuroblastomas treated at UCLA. Main Outcome Measures Overall survival (OS) and recurrence-free survival (RFS). Results Thirty-six patients were included with a mean age of 50.1 years and a median duration of follow-up of 33 months. The 5-year RFS and OS were 54% and 82%, respectively. Modified Kadish stage was the only factor identified to affect OS. Multivariate analysis demonstrated that tumor grade was the only factor that had an independent impact on RFS. There was no statistical difference in survival among the surgical approaches chosen. Conclusions The updated data on the UCLA experience reveals that all three surgical approaches chosen provide comparable survival, although longer follow-up will be needed to ascertain if these findings hold true. The endoscopic approach had a statistically significant decrease in length of hospital stay and a trend toward reduced blood loss, intensive care unit admission, and complications. The modified Kadish staging was the only factor identified to predict OS. Multivariate analysis revealed that tumor grade was an independent predictor of recurrence; therefore, its importance should be emphasized in future staging systems.

Histoplasmosis mimicking malignant adenopathy during diagnostic thyroid lobectomy.

IMPORTANCE: Benign granulomatous disease may mimic malignant disease in the evaluation of mediastinal or pulmonary lesions. However, histoplasmosis as a cause of cervical lymphadenopathy is relatively rare. We report the first case of Histoplasma infection mimicking malignant adenopathy discovered during diagnostic thyroid lobectomy. OBSERVATIONS: A 2.5-cm, calcified, right paratracheal lymph node intimately involving the recurrent laryngeal nerve was discovered during lobectomy for a follicular lesion of undetermined significance with a positive NRAS mutation. Although metastatic thyroid cancer was the most probable diagnosis, results of gross inspection of the bisected thyroid nodule suggested a benign process. Partial removal of the node, sparing the nerve, established the diagnosis of Histoplasma capsulatum infection. CONCLUSIONS AND RELEVANCE: Histoplasmosis is a rare cause of cervical adenopathy that should be considered in cases in which a discordance arises between the malignant gross appearance of the adenopathy and the benign gross appearance of an associated thyroid nodule.

Multifactorial hypercalcemia and literature review on primary hyperparathyroidism associated with lymphoma.

The most common cause of hypercalcemia in hospitalized patients is malignancy. Primary hyperparathyroidism most commonly causes hypercalcemia in the outpatient setting. These two account for over 90% of all cases of hypercalcemia. Hypercalcemia can be divided into PTH-mediated and PTH-independent variants. Primary hyperparathyroidism, familial hypocalciuric hypercalcemia, familial hyperparathyroidism, and secondary hyperparathyroidism are PTH mediated. The most common PTH-independent type of hypercalcemia is malignancy related. Several mechanisms lead to hypercalcemia in malignancy-direct osteolysis by metastatic disease or, more commonly, production of humoral factors by the primary tumor also known as humoral hypercalcemia of malignancy that accounts for about 80% of malignancy-related hypercalcemia. The majority of HHM is caused by tumor-produced parathyroid hormone-related protein and less frequently production of 1,25-dihydroxyvitamin D or parathyroid hormone by the tumor. We report the rare case of a patient with hypercalcemia and diagnosed primary hyperparathyroidism. The patient had persistent hypercalcemia after surgical removal of parathyroid adenoma with recorded significant decrease in PTH level. After continued investigation it was found that the patient also had elevated 1,25-dihydroxyvitamin D and further studies confirmed a large spleen mass that was later confirmed to be a lymphoma. This is a rare example of two concomitant causes of hypercalcemia requiring therapy.

Sinonasal mucosal melanoma: 20-year experience at a tertiary referral center.

BACKGROUND: Sinonasal melanoma (SNM) is a rare cancer with extremely poor prognosis. Detecting melanoma on frozen section has historically been considered to be unreliable. A review of cases of sinonasal melanoma treated at a tertiary referral center was conducted to analyze treatment outcomes and identify prognostic factors for survival. In addition, an investigation was performed correlating sinonasal melanoma on frozen section and permanent analysis. METHODS: An institutional review board-approved search of the pathology database for cases of primary sinonasal melanoma treated between 1991 and 2011 was performed. Fourteen cases were identified and the medical charts were reviewed. RESULTS: Eleven patients had tumors arising from the nasal cavity, 2 arose from the maxillary sinus, and 1 from the ethmoid sinuses. Mean duration of follow-up was 20.7 (range, 1.4 to 84.5) months. Overall, 5-year recurrence-free survival and overall survival was 23% and 35%, respectively. All patients had surgical resection with intent for cure and all but 1 patient had adjuvant therapy. Survival analysis showed that positive margin status (log rank p = 0.031) and the presence of perineural/lymphovascular invasion (log rank p = 0.021) negatively affected recurrence-free survival and overall survival, respectively. Nine cases had evaluation of intraoperative frozen sections with 32 total sections submitted for analysis. When compared with final pathology, there was a 0% false negative rate. CONCLUSION: Based on this series, positive margins and the presence of perineural/lymphovascular invasion are negative predictors of survival. In addition, intraoperative frozen section analysis of sinonasal mucosal melanoma correlates well with final pathology.