Extracorporeal photopheresis (ECP) was given to 23 patients with steroid-refractory acute GVHD (aGVHD, grade II (n ¼ 10), III (n ¼ 7) or IV (n ¼ 6)). The median duration of ECP was 7 months (1-33) and the median number of ECP cycles in each patient was 10. Twelve patients (52%) had complete responses. Eleven patients (48%) survived and 12 died, 10 of GVHD with or without infections and two of leukaemia relapse. The average grade of GVHD was reduced from 2.8 (on the first day of ECP) to 1.4 (on day þ 90 from ECP) (P ¼ 0.08), and the average dose of i.v. methylprednisolone from 2.17 to 0.2 mg/kg/d (P ¼ 0.004). Complete responses were obtained in 70, 42 and 0% of patients, respectively, with grades II, III and IV aGVHD; complete responses in the skin, liver and gut were 66, 27 and 40%. Patients treated within 35 days from onset of aGVHD had higher responses (83 vs 47%; P ¼ 0.1). A trend for improved survival was seen in grade III-IV aGVHD treated with ECP as compared to matched controls (38 vs 16%; P 0.08). ECP is a treatment option for patients with steroid refractory aGVHD and should be considered early in the course of the disease.

Slow controlled breathing is associated with potentiation of both the depressor and the cardio-inhibitory components of the arterial baroreflex, the potentiation being largely similar regardless of the age of the individual.

No abstract

No abstract

Introduction Mantle-cell lymphoma (MCL) is a B-cell non-Hodgkin Lymphoma (NHL) characterized by heterogenous behavior, ranging from indolent phenotype to highly aggressive and drug resistant one with dismal prognosis. Drug resistance may be generated by Tumor Microenvironment (TME), owing that Tumor-Associated Macrophages (TAM) are pathologically functional in providing survival signals to MCL cells (Pham, Front Oncol. 2018). Recently, "Don't Eat Me" signal (DEMs) blockade with anti-CD47 monoclonal Antibody (moAb) showed promising activity in pretreated NHL, through increase of phagocytosis by TAM (Advani, NEJM. 2019). CD24 was also demonstrated to be involved in DEMs and, in a preclinical model of solid cancer, blocking the CD24/Siglec-10 interaction provided an improvement of M2-like TAM-mediated phagocytosis in vitro and an increase of survival in vivo (Barkal, Nature. 2019). CD24 can be expressed in some phases of B-cell differentiation and MCL derives from a B-cell precursor with upregulated CD24. To date, there are no functional studies showing an improvement of phagocytosis through CD24/Siglec-10 pathway inhibition in hematologic malignancies and MCL. Here, we present our in vitro results of CD24/Siglec-10 DEMs blockade in MCL subset. Methods A panel of MCL cell lines (Jeko-1, Granta-519, Mino) has been analyzed for CD24 surface expression by flow cytometry (FC) (clone SN3). Consequently, we performed co-culture experiments with MCL cell lines and macrophages from healthy donors. Briefly, Peripheral Blood Mononucleated Cells (PBMC) were collected from healthy volunteers through density gradient centrifugation technique. CD14+ monocytes were isolated through CD14 Microbeads isolation kit and cultured in plates with 50 ng/ml human GM-CSF for 7-9 days. In order to create M2-like Siglec-10+ TAM, 50 ng/ml human IL-10 and 50 ng/ml human TGF-β 1 were added on days 3-4 of differentiation until use on days 7-9. Siglec-10 expression on TAM was checked by FC (clone 5G6). M2-like macrophages were then collected and co-cultured with CFSE-labelled MCL target cells for 1-2 hours in a serum-free medium. Anti-CD24 moAb (clone SN3) or the appropriate IgG 1 isotype control were added at a concentration of 10 μg/ml. Phagocytosis was then stopped on ice and CD11b-PE staining (anti-CD11b moAb, clone REA713) was performed to identify human macrophages by FC. Phagocytosis was measured as the number of CD11b+/CFSE+ macrophages, quantified as a percentage of the total CD11b+ macrophages. Each phagocytosis reaction was performed in technical triplicate and phagocytosis was normalized to the highest technical replicate per donor in order to consider raw phagocytic level among donor-derived macrophages. Results MCL cell lines express surface CD24 by FC, with higher levels in Mino cell line (Figure 1A). Differentiated M2-like macrophages showed an upregulation of Siglec-10 expression after immunosuppressive stimuli, which is fundamental owing that Siglec-10 is the ligand of CD24 (Figure 1B). As pertains to the phagocytic assay, we documented an improvement of phagocytosis when M2-like macrophages and MCL cell lines were co-cultured together with anti-CD24 moAb (Figure 2 and Figure 3A). Furthermore, it is worth mentioning that phagocytosis seemed to be much higher in MCL cell lines with higher surface levels of CD24 (e.g., Mino), presenting increased number of CD11b+/CFSE+ M2-like TAM by FC (Figure 3B). Conclusions MCL was found to be sensitive to CD24/Siglec-10 DEMs blockade when co-cultured with M2-like macrophages in vitro. We can argue that most of the observed increase of phagocytosis after the addition of anti-CD24 moAb may be secondary to loss of CD24 signalling rather than Fc-mediated opsonization, as already documented in previous analysis about solid cancer (Barkal, Nature. 2019). We can therefore hypothesize that the blockade of this DEMs pathway can improve phagocytosis in a non-opsonization manner in NHL as well. Furthermore, CD24 surface density seemed to be positively correlated to the intensity of phagocytic activity, suggesting that MCL subtypes expressing higher CD24 levels are much more dependent on this DEMs pathway than others with low CD24 density. Overall, CD24 turned out to be a potential immunotherapeutic target in MCL, aiming at improving innate immune system through DEMs blockade. In vivo studies are needed to confirm the activity we documented in vitro in this NHL subset. Figure 1 Figure 1. Disclosures Gambacorti-Passerini: Bristol-Myers Squibb: Consultancy; Pfizer: Honoraria, Research Funding.

BACKGROUNDCyanide, a mitochondrial toxin is one among the most rapidly acting lethal poisons known to man. If untreated, exposure to cyanide can kill within minutes. Current treatment of cyanide poisoning includes the intravenous administration of hydroxocobalamin. This case report describes unusual cyanide poisoning due to ingestion of large quantities of apricot kernels containing amygdalin, a compound which forms hydrogen cyanide when metabolised in the intestine and thus induces typical symptoms observed with cyanide poisoning. CASE PRESENTATIONA 35-year-old mentally ill woman was admitted while conscious to our emergency department and clinical toxicology unit. The patient's parents reported that they found their daughter in the living room, surrounded by apricots from which she had extracted and eaten the cores. Further investigation revealed that the woman had swallowed 20-30 apricot kernels, with extrapolation from the remaining uneaten kernels suggesting that this equated to a total kernel consumption of 10-15 g. The approximate time of consumption was 30 min prior to admission, and on arrival, the patient was uncooperative and appeared asymptomatic. INVESTIGATIONSThe following measurements were taken: blood pressure 120/70 mm Hg, pulse rate 120 beats/min, respiratory rate 26 breaths/min, temperature 37.5°C and SpO 2 on room air 98%. Arterial blood gas analysis also revealed slight metabolic acidosis (pH 7.33, pO 2 90 mm Hg, pCO 2 35.5 mm Hg, and HCO 3− 20 mmol/l). The anion gap at admission was 19 mEq/l. Lactate and cyanide levels were not measured and no signifi cant ECG changes were noted. TREATMENTAfter consultation with the clinical toxicology unit, she was subjected to a gastric lavage. One hundred grams of activated charcoal and 30 g of magnesium sulphate were administered, followed by hydration therapy (1000 ml of normal saline) and ECG monitoring. Approximately 70 min postingestion, the patient experienced headache, nausea and dyspnoea. Her vital signs were: blood pressure 75/50 mm Hg, pulse rate 145 beats/min, respiratory rate 30 breaths/min and SpO 2 93% (with supplementary oxygen mask: 3l/min). Arterial blood gas analysis revealed metabolic acidosis (pH 7.20, pO 2 75 mm Hg, pCO 2 34.2 mm Hg and HCO 3− 16 mmol/l). The anion gap was now 23 mEq/l. Two 1 ml phials of 5% amyl nitrite via inhalation, and intravenous infusion of 50 ml of 25% sodium thiosulphate in 1000 ml of 5% glucose solution (infusion rate 5 ml/min) were subsequently administered as recommended by the toxicologist. Following this therapy, the patient's methaemoglobin level was 10%, prompting the administration of oxygen via a facemask. Electrolytic solution (1000 ml) was then administered. This slightly improved her vital signs and her blood pressure rose to 80/60 mm Hg. SummaryClinical experience with hydroxocobalamin in acute cyanide poisoning via ingestion remains limited. This case concerns a 35-year-old mentally ill woman who consumed more than 20 apricot kernels. Published literature suggests each kernel would have conta...

Tyrosine- kinase inhibitor imatinib (STI571) has become the first line therapy for most patients with chronic myelogenous leukemia (CML), due to its high efficacy and generally good tolerance. However, severe hepatotoxicity has been observed in 1–5 % of patients. While generally reversible after imatinib discontinuation, this complication often recurs with drug reintroduction and many patients are prevented from the use of a very effective drug (Deininger MW et al.: J Clin Oncol2003; 21: 1637–1647). Here we describe 5 CML patients displaying imatinib- induced hepatotoxicity that completely resolved after the introduction of corticosteroid for a few months, thus allowing imatinib resumption. Five patients (age 50 – 79, median 66), received imatinib treatment at 400 – 600 mg/day for CML in chronic (4 patients) or accelerated phase (1 patient). At the beginning of imatinib treatment one patient had serological evidence of previous hepatitis B (HBsAg negative, HBV-DNA negative, anti-HBcAg and anti-HBsAg positive); however, all patients evidenced normal values of liver enzymes and functions. After a median 6 months of therapy (range 2–8), a sharp increment of serum aminotransferase values was detected, featuring grade III (3 patients) or grade IV (2 patients) liver toxicity according to WHO grading. No cholostatic changes were detected, whereas a reduction of serum anti-thrombin III level (to 48% of normal activity) was observed in the first patient. This patient underwent a liver biopsy that documented areas of necrosis, fibrous scars and peri-portal inflammatory infiltrate. In all patients, markers of active viral or autoimmune hepatitis were negative at the time of aminotransferase increment and no other drug, except imatinib, might have been implicated in hepatotoxicity. In 2 patients signs of liver toxicities gradually disappeared after imatinib withdrawal but promptly reappeared with imatinib resumption at lower dosage. In the other 3 patients aminotransferase values remained stable or slightly increased for 1–3 weeks after imatinib withdrawal, until corticosteroid addition. In all patients the start of corticosteroid therapy with prednisone (25–37 mg/day) or methylprednisolone (40 mg/day) resulted in the normalisation of aminotransferase values in 2–4 weeks. Imatinib therapy was then resumed at increasing dosage from 200–300 mg/day to full therapeutical dosage of 400–800 mg /day, while corticosteroids were gradually tapered off in 2– 4 months, without recurrence of liver toxicity. All patients obtained a complete hematological response and 3 patients a durable complete cytogenetic remission. While the mechanism of imatinib- induced hepatotoxicity is not fully understood, istological evidences from others’ (James C et al. Leukemia2003;17:978–9; Ohyashiki K et al. Leukemia2002;16:2160–1) and our reports suggest an inflammatory reaction with lymphocyte infiltration playing a role in liver damage. Corticosteroids at low-intermediate dosage look as a very promising treatment in order to reverse imatinib-induced hepatotoxicity and to avoid the permanent discontinuation of the most effective anti- CML drug.

images in clinical medicineT h e ne w e ngl a nd jou r na l o f m e dic i ne n engl j med 355;1 www.nejm.org july 6, 2006 66A 30-year-old man had a pleomorphic adenoma removed from his left parotid gland. His postoperative course was uncomplicated. Two months later, he noted that his left cheek became wet while he was eating. Believing that saliva was being discharged from the parotidectomy scar, he went to the emergency department. An examination revealed that the wound had healed well: there were no signs of a fistula (arrow, Panel A). Frey's syndrome was suspected, and the lemon test was performed. As soon as the patient ate a lemon wedge, his left auricular and parotic regions became flushed and sweaty (arrow, Panel B), thus confirming the diagnosis. He opted for no treatment. Gustatory sweating, or Frey's syndrome, can develop after a variety of insults to the autonomic nervous system, such as trauma or radiation therapy, but is most commonly encountered as a complication of parotidectomy. The most widely accepted mechanism is aberrant neuronal regeneration resulting in parasympathetic cholinergic innervation of cutaneous sympathetic receptors.