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Ibrutinib and other targeted inhibitors of B-cell receptor signaling achieve impressive clinical results for patients with chronic lymphocytic leukemia (CLL). A treatment-induced rise in absolute lymphocyte count (ALC) has emerged as a class effect of kinase inhibitors in CLL and warrants further investigation. Here we report correlative studies in 64 patients with CLL treated with ibrutinib. We quantified tumor burden in blood, lymph nodes (LNs), spleen and bone marrow, assessed phenotypic changes of circulating cells and measured whole-blood viscosity. With just one dose of ibrutinib, the average increase in ALC was 66%, and in>40% of patients the ALC peaked within 24 h of initiating treatment. Circulating CLL cells on day 2 showed increased Ki67 and CD38 expression, indicating an efflux of tumor cells from the tissue compartments into the blood. The kinetics and degree of the treatment-induced lymphocytosis was highly variable; interestingly, in patients with a high baseline ALC the relative increase was mild and resolution rapid. After two cycles of treatment the disease burden in the LN, bone marrow and spleen decreased irrespective of the relative change in ALC. Whole-blood viscosity was dependent on both ALC and hemoglobin. No adverse events were attributed to the lymphocytosis.

Dasatinib, a broad-spectrum tyrosine kinase inhibitor (TKI), predominantly targets BCR-ABL and SRC oncoproteins and also inhibits off-target kinases, which may result in unexpected drug responses. We identified 22 patients with marked lymphoproliferation in blood while on dasatinib therapy. Clonality and immunophenotype were analyzed and related clinical information was collected. An abrupt lymphocytosis (peak count range 4–20 × 10 9 /l) with large granular lymphocyte (LGL) morphology was observed after a median of 3 months from the start of therapy and it persisted throughout the therapy. Fifteen patients had a cytotoxic T-cell and seven patients had an NK-cell phenotype. All T-cell expansions were clonal. Adverse effects, such as colitis and pleuritis, were common (18 of 22 patients) and were preceded by LGL lymphocytosis. Accumulation of identical cytotoxic T cells was also detected in pleural effusion and colon biopsy samples. Responses to dasatinib were good and included complete, unexpectedly long-lasting remissions in patients with advanced leukemia. In a phase II clinical study on 46 Philadelphia chromosome-positive acute lymphoblastic leukemia, patients with lymphocytosis had superior survival compared with patients without lymphocytosis. By inhibiting immunoregulatory kinases, dasatinib may induce a reversible state of aberrant immune reactivity associated with good clinical responses and a distinct adverse effect profile.

The nucleoside analogue GS-441524 is a common treatment for cats with feline infectious peritonitis (FIP). In a previous study, 40 cats with FIP with effusion were treated with 15 mg/kg GS-441524 orally once daily for either 42 days or 84 days, and a 42-day treatment was as effective as the earlier recommended 84-day treatment. The aim of the present study was to describe unexpected clinical and laboratory observations occurring during and after treatment (within one year) in these cats and to compare them regarding the different treatment durations. Thirty-eight cats recovered rapidly during treatment, two cats had to be euthanized, and one cat was lost to follow-up. During treatment, 25 cats developed diarrhea. Lymphocytosis occurred in 26/40 cats during treatment, eosinophilia in 25/40 during treatment, increased alanine aminotransferase activity in 22/40, alkaline phosphatase activity in 7/40, and symmetric dimethylarginine levels in 25/40. These unexpected observations occurred equally in both treatment duration groups, but statistically significantly more cats developed lymphocytosis and eosinophilia when treated for 84 days. Although most of the unexpected observations during GS-441524 treatment improved or disappeared after treatment termination, these conditions have to be monitored, and treatment should not be given for longer than necessary.

During follow-up of leukocyte counts in 20 consecutive patients (age range 29–81 years) treated with dasatinib, 9 patients (7 chronic myeloid leukemia in chronic phase, 2 Philadelphia chromosome-positive acute lymphoid leukemia in complete remission) developed lymphocytosis (>3,000/μl). Peripheral blood smears revealed a population of large granular lymphocytes. Large granular lymphocytosis (LGL) was first noted between 1 and 8 months after initiation of dasatinib, and it has persisted up to 33 months from the onset of LGL in one patient. Peak numbers of large granular lymphocytes ranged from 2,915 to 17,425/μl. The occurrence of LGL might interfere with achieving molecular response (MR, real-time quantification of major BCR - ABL1 mRNA less than 50 copies/μg RNA) in our small cohort; 8 (89%) of 9 patients with LGL attained MR, while only 6 (55%) of 11 patients without LGL eventually achieved MR. With respect to the relationship between LGL and pleural effusion (PE), 3 (27%) of 11 patients without LGL developed PE, while 5 (56%) of 9 patients with LGL developed PE. Moreover, the mean peak number of LGL was 9,215/μl, which was much higher than the mean peak number (4,635/μl) of LGL in patients without PE. These results may suggest possible association of both events in our cohorts.

There are no reports of the clinical features or treatment outcomes in large series of patients with lymphocytic colitis, and it is not known whether treatments that appear to be beneficial in patients with collagenous colitis are also beneficial in lymphocytic colitis. We sought to analyze these issues in our patients with lymphocytic colitis. All patients with biopsy-proven lymphocytic colitis evaluated at our institution between January 1, 1997, and December 31, 1999, were identified. Clinical features on presentation and treatment outcomes were abstracted from the medical records. A total of 170 patients with lymphocytic colitis were identified (median age 67 yr, 61% female). Diarrhea, bloating, rectal urgency, fecal incontinence, weight loss, concomitant autoimmune disorders, and aspirin or nonsteroidal anti-inflammatory drug use were common. Loperamide, diphenoxylate/atropine, and bismuth subsalicylate were effective therapies and were well tolerated. However, no therapy produced a complete response in more than 40% of patients. Lymphocytic colitis typically presents in elderly patients as chronic diarrhea. Nocturnal stools, urgency, and abdominal pain occur frequently, as do weight loss, fecal incontinence, and concomitant autoimmune disorders. Many empiric treatment options are used, but overall response rates are disappointing. Randomized controlled trials are needed to determine the optimum therapeutic approach to these patients.

Background: Multiple sclerosis (MS) patients discontinuing natalizumab treatment are at risk of disease reactivation. No clinical or surrogate parameters exist to identify patients at risk of post-natalizumab MS reactivation. Objective: To determine the role of natalizumab-induced lymphocytosis and of Akt polymorphisms in disease reactivation after natalizumab discontinuation. Methods: Peripheral leukocyte count and composition were monitored in 93 MS patients during natalizumab treatment, and in 56 of these subjects who discontinued the treatment. Genetic variants of the anti-apoptotic protein Akt were determined in all subjects because natalizumab modulates the apoptotic pathway and lymphocyte survival is regulated by the apoptotic cascade. Results: Natalizumab-induced peripheral lymphocytosis protected from post-natalizumab MS reactivation. Subjects who relapsed or had magnetic resonance imaging (MRI) worsening after treatment cessation, in fact, had milder peripheral lymphocyte increases during the treatment, largely caused by less marked T cell increase. Furthermore, subjects carrying a variant of the gene coding for Akt associated with reduced anti-apoptotic efficiency (rs2498804T) had lower lymphocytosis and higher risk of disease reactivation. Conclusion: This study identified one functionally meaningful genetic variant within the Akt signaling pathway that is associated with both lymphocyte count and composition alterations during natalizumab treatment, and with the risk of disease reactivation after natalizumab discontinuation.

The cellular profile of bronchoalveolar lavage fluid (BALF) in asbestos-exposed population remains controversial. We, therefore, aimed to investigate BALF in apparently healthy individuals that were exposed in asbestos-related work for a long period of time. Participants were selected among employees of a car brakes and clutches factory that used chrysotile asbestos. Selection criteria were an employment history of ≥15 years and the absence of severe respiratory disease. The total number and type of BALF cells, the existence of dust cells, iron-laden macrophages and asbestos bodies were assessed. Thirty-nine workers (25 men), with a mean age of 46.2 ± 4.2 years and a mean employment time of 23.5 ± 4 years, participated. Asbestos bodies were observed in 14 out of 39 (36%) specimens, dust cells in 37 and iron-laden macrophages in all. Those with asbestos bodies had at least 3 times higher probability to have lymphocytosis (lymphocytes > 11%: 64% vs 28%, p = 0.027) and had an increased percentage of iron-laden macrophages compared to those without asbestos bodies (median values: 42% vs 13%, p = 0.08). Smokers (36%) had less lymphocytes compared to non and ex-smokers (median values: 6% vs. 13%, p = 0.002), and iron-laden macrophages count had a positive relation (r = 0.31, p = 0.05) to lymphocyte count. Asbestos-exposed asymptomatic individuals with the presence of asbestos bodies in the BALF are more likely to have lymphocytic alveolitis while concurrent dust exposure and smoking habits hold a significant role.

A diagnosis of DRESS requires three criteria: cutaneous eruption, hematologic abnormalities with either eosinophilia (more than 50% of patients) or atypical lymphocytosis (10%-60% of patients, depending on the causative drug), and systemic symptoms (adenopathy, hepatitis, interstitial nephritis, interstitial pneumonitis or carditis). Fever and skin eruption are usually the presenting symptoms.3 Erythematous and maculopapular lesions typically appear first on the trunk, face and upper extremities, and may progress to blisters, vesicles, pustules or purpura.3 Exfoliative dermatitis may result. The pathogenesis of DRESS syndrome is not clear. Patients may have a genetic predisposition characterized by an inability to detoxify the active metabolites. Alternatively, an immuno-allergic mechanism triggered by human herpes virus 6 primary infection or reactivation may be involved.3,4 Treatment involves discontinuation of the offending drug. Although steroids are often given, the evidence for their efficacy is lacking and symptoms may worsen on tapering them.5 When DRESS is caused by aromatic anticonvulsants, crossreactivity is common; the entire class of medications should be avoided.2 Family members of patients should be counselled for possible genetic susceptibility to DRESS.3,4