Cryobiopsy during outpatient flexible bronchoscopy facilitated confident multidisciplinary consensus diagnosis of DPLD in more than two thirds of cases, and appears sufficient to establish the histopathologic diagnosis of usual interstitial pneumonia, with a complication rate that compares favorably to that reported for SLB.

SummaryRecombinant human factor VIIa (rFVIIa; NovoSeven®) is a two-chain activated clotting factor that is used in the treatment of haemophilia. The distribution of radioactivity in male and pregnant and non-pregnant female rats has been examined by whole-body autoradiography (WBA) after single intravenous doses of 125I-radiolabelled rFVIIa at a dosage level of ca. 0.1 mg/kg.Concentrations of radioactivity were highest in the blood and the highly perfused major thoracic and visceral organs and gonads. This distribution of radioactivity was generally similar in pregnant and non-pregnant females, and although radioactivity was concentrated in the foetal thyroid, it was present in other foetal tissues only at trace levels. Radioactivity in thyroid, urinary bladder and gastrointestinal tract of all rats was apparently associated with detached 125I-iodide. At early sacrifice times (up to 2 h), radioactivity was present in the bone marrow, but at later times (6-24 h) it was apparently associated with the mineralised bone structures.The quantitative distribution of total and trichloroacetic acid precipitable radioactivity in the tissues of rats also was studied after single intravenous doses of 125I-rFVIIa and 125I-rFVII, the non-activated single chain precursor of FVIIa, which is normally present in the circulation. These studies confirmed the WBA findings and showed that the tissue distribution of 125I-rFVII and 125I-rFVIIa was similar, indicating that the distribution of rFVIIa during therapy would be similar to that produced from endogenous FVII as a physiological response to vascular injury.

SummaryRecombinant human factor VII a (rFVIIa) is an activated coagulation factor for intravenous use as a haemostatic agent in haemophiliacs who generate antibodies against factor VIII or IX. Plasma kinetic studies are important for the understanding of the action of rFVIIa which is exerted in the vascular compartment of the body, more specifically on the vessel walls at the site of injury. In the present study, rats were dosed 100 or 500 μg/kg 125I-rFVIIa i. V., without any side effects being observed, and the plasma profile of rFVIIa was studied by 3 different assays that were shown to correlate well at early times post-dose: trichloroacetic acid (TCA)-precipitable drug-related radioactivity, rFVIIa antigen determination by ELISA technique, and the assay of clot activity which is the only clinically applicable assay. The plasma concentration curve could be resolved into 1-3 exponentials, depending on the FVIIa detection principle that was employed. Initially, there was a short (ca. 10 min) phase of increasing concentrations before the attainment of C max. This was followed by a plasma recovery (C max × plasma volume/dose) in the vicinity of one half of the administered dose. The initial volume of distribution (V 1) corresponded to the vascular compartment whereas the volume of distribution at steady state (V ss) was somewhat larger. Whole body clearance (CL-B) of rFVIIa was approx. 1 ml/min per kg, and mean residence time (MRT) and the half-life assumed to be associated with the loss of biological activity was approx. 1 h and 20-45 min, respectively. From these plasma data, rFVIIa appears to be a low clearance compound with limited tissue distribution and a short half-life. Tissue distribution studies showed that high 125I levels, assumed to be rFVIIa-related, included mineralised bone and well-perfused organs such as the liver which suggested that this organ was responsible for a major proportion of CL-B. Finally, mass balance studies showed that almost 90% of the administered radioactivity could be accounted for following an i. v. dose, predominantly as non drug-related radioactivity, even though a small amount of TCA-precipitable radioactivity was excreted via the biliary route. In conclusion, dose- or sex-dependent plasma kinetics and tissue distribution within a dose range of 100 to 500 μg/kg of rFVIIa was not observed. In the early and pharmacologically relevant phase after rFVIIa administration there appears to be good agreement between the various plasma assays employed in the study, indicating that the clot assay yields useful information in studies of rFVIIa plasma pharmacokinetics.

Patients with recurrent/refractory (R/R) classical Hodgkin's Lymphoma (cHL) have poor survival with conventional therapy.In these patients, autologous hematopoietic stem cell transplant (SCT) is the most commonly employed salvage therapy. 1 Immune checkpoint inhibitors also have significant activity in recurrent HL. 2 Program death-1 (PD-1) is a crucial pathway in immune tolerance. Nivolumab is a PD-1 antagonist that was the first approved checkpoint inhibitor in hematological malignancies including HL.PD-1 blockade leads to the activation of T cells breaking immune tolerance. Nivolumab has an emerging role in the management of patients who have relapsed after autologous transplant. 2 However, the safety of novel PD-1 inhibitors administered before autologous transplantation is unknown. We report here a patient who received nivolumab prior to autologous stem cell mobilization and transplantation who subsequently developed cytokine storm. This was successfully managed using parenteral ascorbic acid. | C A S E REP ORTA 28-year-old female patient was diagnosed with cHL stage IV, mixed cellularity subtype. She underwent four cycles of frontline chemotherapy with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). On follow-up imaging, she showed disease progression. She then received three cycles of ifosfamide, carboplatin, and etoposide, followed by a single cycle of brentuximab, and complicated by pancreatitis. A single 240 mg dose of nivolumab was administered 26 days prior to stem cell mobilization and collection. Stem cells were mobilized using filgrastim 10 μg/kg/d for 4 days. Conditioning regimen for stem cell transplant (SCT) was carmustine, etoposide, cytarabine, and melphalan (BEAM), followed by an infusion of 4.1 × 10 6 CD34 + cells/kg on day 0. On day +1 post-SCT, she became febrile. Cefepime and vancomycin were initiated for febrile neutropenia. Chest imaging revealed mild basilar volume loss. On day +3, she developed diarrhea and was diagnosed with Clostridium difficile infection. Oral vancomycin was initiated. Day Abstract Checkpoint inhibitor therapy is effective in the treatment of relapsed classical Hodgkin's Lymphoma. Here, we report a patient with relapsed Hodgkin's Lymphoma who received nivolumab prior to autologous stem cell mobilization. She went on to develop cytokine storm shortly following transplantation, with marked T-cell proliferation coincident with myeloid engraftment. Non-cardiogenic pulmonary edema and alveolar hemorrhage developed despite corticosteroid therapy. There was rapid and complete resolution of these complications with parenteral ascorbic acid infusion. Our case illustrates the risk of cytokine release syndrome following infusion of stem cells mobilized after checkpoint inhibitor therapy and the role of ascorbic acid in its management. K E Y W O R D S bone marrow transplantation, Hodgkin's lymphoma, transplantation

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