Delayed Diagnosis of TSH-Secreting Adenoma Attributed to Worsening Post-Traumatic Stress Disorder Symptoms in a Military Veteran Because of Provider Anchoring Bias.

INTRODUCTION: Anchoring bias occurs when clinicians hold on to previously known information about a patient, with failure to consider the full realm of possibilities to explain new findings. We present a case of delayed diagnosis of thyroid-stimulating-hormone-secreting pituitary adenoma (TSHoma), a rare disorder, in a military veteran whose symptoms were misconstrued as being caused from worsening of his prior diagnosis of post-traumatic stress disorder (PTSD). Anchoring bias in this case led to 2-year delay in the correct diagnosis. METHODS: The clinical, laboratory, radiologic, and pathologic results are presented. RESULTS: We report a case of a 44-year-old retired male Army soldier with a prior diagnosis of PTSD who was evaluated for new symptoms including headaches, blurry vision, palpitations, and anxiety. These symptoms were considered by multiple services as worsening of his PTSD, with acknowledgment of normal thyroid hormone levels from 2 years prior, but with no levels at the time of the new presentation. Attempts to treat with standard PTSD therapies were unsuccessful. When thyroid hormone levels were eventually rechecked 2 years later, he was found to have an inappropriately normal level of thyroid-stimulating hormone (1.9 mcIU/mL) in the setting of elevated free thyroxine (2.30 pg/mL) and free triiodothyronine (5.8 ng/dL). With magnetic resonance imaging revealing a 1.4-cm pituitary macroadenoma, he was diagnosed with a TSHoma. A trial of octreotide, a somatostatin analog, was attempted to shrink the tumor size. However, because of the patient's intolerance of this medication, he underwent endoscopic transsphenoidal surgery as definitive treatment. Pathologic analysis of his tumor was consistent with TSHoma. On various follow-up intervals, he had normalization of thyroid function tests, no evidence of residual tumor on 6-month postoperative imaging, and reported improvement in his symptoms. CONCLUSION: This case highlights the details of a rare diagnosis of TSHoma, which has an estimated 1 to 2 cases per million in the general population and an unknown prevalence in the military population, in a veteran who had symptoms that were presumed to be worsening PTSD. While understandable to attribute new symptoms to pre-existing diagnoses such as PTSD, clinicians should consider the possibility of alternative diagnoses and perform the routine workup when indicated.

Novel Brentuximab Vedotin Combination Therapies Show Promising Activity in Highly Refractory CD30+ Non-Hodgkin Lymphoma: A Case Series and Review of the Literature.

Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of hematologic malignancies which typically respond to standard first-line chemoimmunotherapy regimens. Unfortunately, patients with refractory NHL face a poor prognosis and represent an unmet need for improved therapeutics. We present two cases of refractory CD30+ NHL who responded to novel brentuximab vedotin- (BV-) based regimens. The first is a patient with stage IV anaplastic large cell lymphoma (ALCL) with cranial nerve involvement who failed front-line treatment with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (CHOEP) and second line cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate (MTX), and cytarabine (hyperCVAD) with intrathecal- (IT-) MTX and IT-cytarabine, but responded when BV was substituted for vincristine (hyperCBAD). The second patient was a man with stage IV diffuse large B-cell lymphoma (DLBCL) with leptomeningeal involvement whose disease progressed during first-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and progressed despite salvage therapy with rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP) in whom addition of BV to topotecan resulted in a significant response. This report describes the first successful salvage treatments of highly aggressive, double refractory CD30+ NHL using two unreported BV-based chemoimmunotherapy regimens. Both regimens appear effective and have manageable toxicities. Further clinical trials assessing novel BV combinations are warranted.

Adeno-associated virus site-specific integration is mediated by proteins of the nonhomologous end-joining pathway.

Adeno-associated virus type 2 (AAV 2) is the only eukaryotic virus capable of site-specific integration; the target site is at chromosome 19q13.4, a site termed AAVS1. The biology of AAV latency has been extensively studied in cell culture, yet the precise mechanism and the required cellular factors are not known. In this study, we assessed the relative frequencies of stable site-specific integration by characterization of cell clones containing integrated AAV vectors. By this assay, two proteins involved in nonhomologous end joining (NHEJ), DNAPKcs and ligase IV, exhibit differential effects on AAV site-specific integration. DNAPKcs is not required; its presence increases the frequency of junction formation indicative of site-specific integration, but seems to reduce the ratio of site-specific integration to random integration (i.e., the latter is even more enhanced). In contrast, site-specific integration is significantly reduced relative to random integration in cells deficient in ligase IV expression. Furthermore, we show that single-stranded AAV vectors are better substrates for site-specific integration than are self-complementary AAV vectors; the absence of DNAPKcs did not affect the targeted integration of these double-stranded AAV vectors. Together, these data suggest that NHEJ proteins participate in site-specific integration, and indicate a role for the single-stranded form of AAV DNA in targeted integration.

Gene therapy using adeno-associated virus vectors.

SUMMARY: The unique life cycle of adeno-associated virus (AAV) and its ability to infect both nondividing and dividing cells with persistent expression have made it an attractive vector. An additional attractive feature of the wild-type virus is the lack of apparent pathogenicity. Gene transfer studies using AAV have shown significant progress at the level of animal models; clinical trials have been noteworthy with respect to the safety of AAV vectors. No proven efficacy has been observed, although in some instances, there have been promising observations. In this review, topics in AAV biology are supplemented with a section on AAV clinical trials with emphasis on the need for a deeper understanding of AAV biology and the development of efficient AAV vectors. In addition, several novel approaches and recent findings that promise to expand AAV's utility are discussed, especially in the context of combining gene therapy ex vivo with new advances in stem or progenitor cell biology.