Indications and diagnostic outcome of antineutrophil cytoplasmic antibody testing in hospital medicine: a pattern of over-screening.

INTRODUCTION/OBJECTIVE: Antineutrophil cytoplasmic antibodies (ANCA) serology can aid in the diagnosis and classification of ANCA-associated vasculitides (AAV). However, it is often ordered in patients without clinical manifestations of vasculitis. In this retrospective chart review, we aim to better understand the clinical practices on ANCA testing. METHODS: We retrospectively reviewed patients' charts for the indications and diagnostic outcomes of ANCA tests. All ANCA tests ordered at two Canadian hospitals (a community hospital and an academic tertiary hospital) between January and December 2016 were included in the study. Descriptive statistics are used. RESULTS: A total of 302 ANCA tests were included. The majority (n = 198, 65.6%) were ordered without an indication for testing. For those patients with at least 1 clinical manifestation of AAV (n = 104), 25% were ANCA positive and 18.3% resulted in a diagnosis of AAV. In comparison, among those without a clinical manifestation of AAV (n = 198), only 1.5% were ANCA positive and none was diagnosed with AAV. All patients diagnosed with AAV had at least 1 indication for ANCA testing. The three most common clinical presentations in patients with a final diagnosis of AAV were glomerulonephritis (81.8%), pulmonary hemorrhage (45.5%), and multiple lung nodules (31.8%). CONCLUSION: To our knowledge, this is the first study that evaluates patients with both positive and negative ANCA test results in an inpatient setting. We demonstrated a low rate of ANCA positivity and AAV diagnosis in patients without clinical manifestations of AAV. Overall, there is a high rate of ANCA testing without an indication at our academic institution. This over-testing may be curbed by strategies such as a gating policy, culture changes, and clinician education. Key Points • AAV is a clinical-pathological diagnosis, and despite the usefulness of ANCA testing, it does not confirm nor rule out AAV. • ANCA testing for the diagnosis of AAV is generally only indicated when there is a clear manifestation of AAV. • Although patients with AAV may occasionally present without classic signs and symptoms, the diagnostic utility of ANCA serology in this setting is low, and testing is more likely to result in a false-positive or false-negative test. • If clinical suspicion remains high despite negative ANCA testing, clinicians should seek consultation with a rheumatologist.

Management of newly diagnosed high-risk and intermediate-risk follicular lymphoma with 90 Y ibritumomab tiuxetan in a phase II study.

Five-year overall survival for high-risk Follicular Lymphoma International Prognostic Index follicular lymphoma is only approximately 50% compared with 90% for low risk. To evaluate an approach to improve upon this poor outcome, we completed an exploratory phase II trial of intensified treatment for patients with intermediate and high-risk follicular lymphoma. Front-line treatment with chemo-immunotherapy consisting of rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone was followed by radio- immunotherapy with 90-Yttrium ibritumomab tiuxetan consolidation, and 2 years of rituximab maintenance. The 5-year overall survival for intermediate and high-risk patients was 88% and 83%, respectively. Of 33 enrolled patients, 3 were off study before receiving radio-immunotherapy. Three months post radio-immunotherapy, 28/33 (85%) patients had achieved complete response including 6 patients who had only a partial response to chemo-immunotherapy and converted to complete response after radio-immunotherapy. The 5-year progression-free survival for intermediate and high risk was 79% and 58%, respectively. Nine of 19 patients with molecular markers patients remain in molecular and clinical complete remission with a median follow-up of 48 months (range 3-84 months). Post radio-immunotherapy, hematologic toxicities were mostly grade 1 and 2. However, asymptomatic grade 3 or 4 thrombocytopenia and neutropenia occurred in 11%-36% and 10%-24% of patients, respectively. Myelodysplastic syndrome occurred in 1 patient 4 years post treatment. Whereas many patients had prolonged B-cell reduction and low immunoglobulin levels post treatment, previous immunities to rubella were maintained. More aggressive upfront approaches such as this may benefit higher risk follicular lymphoma, but confirmatory trials are required. http://www.clinicaltrials.gov: NCT01446562.

Hypoxia induces escape from innate immunity in cancer cells via increased expression of ADAM10: role of nitric oxide.

One key to malignant progression is the acquired ability of tumor cells to escape immune-mediated lysis. Whereas tumor hypoxia is known to play a causal role in cancer metastasis and resistance to therapy, the link between hypoxia and immune escape in cancer remains poorly understood. Here, we show that hypoxia induces tumor cell resistance to lysis mediated by immune effectors and that this resistance to lysis occurs via a hypoxia-inducible factor-1 (HIF-1)-dependent pathway linked to increased expression of the metalloproteinase ADAM10. This enzyme is required for the hypoxia-induced shedding of MHC class I chain-related molecule A (MICA), a ligand that triggers the cytolytic action of immune effectors, from the surface of tumor cells. Indeed, our findings show a mechanistic link between hypoxia-induced accumulation of the α-subunit of HIF-1 (HIF-1α), increased expression of ADAM10, and decreased surface MICA levels leading to tumor cell resistance to lysis mediated by innate immune effectors. Nitric oxide mimetic agents interfered with the hypoxia-induced accumulation of HIF-1α and with the hypoxia-induced upregulation of ADAM10 expression required for decreased surface MICA expression and resistance to lysis. Furthermore, treatment of tumor-bearing mice with nitroglycerin, a nitric oxide mimetic, attenuated tumor growth by a mechanism that relied upon innate immune effector cells. Together, these findings reveal a novel mechanism by which the hypoxic tumor microenvironment contributes to immune escape in cancer, lending support to potential immunotherapeutic strategies involving the use of nitric oxide mimetics.