Multiple Myeloma with Foamy Mott Cells.

Intracytoplasmic assorted vacuoles containing immunoglobulin collections are occasionally seen in multiple myeloma. When abundant, they impart a foamy appearance to the tumor cells, which is a potential source for diagnostic pitfalls. Herein, we report the case of a patient who presented with skeletal pain and CT confirmed lytic lesions. A bone marrow biopsy revealed multiple myeloma with unusual foamy Mott cells. The patient was subsequently treated with four cycles of cyclophosphamide, bortezomib, and dexamethasone induction therapy, followed by 3 cycles of lenalidomide with dexamethasone. A biopsy performed following initial biological and immunomodulatory drugs revealed different morphological and clonal characteristics. These features were modified again, five years later, and again, after two years of close monitoring. Hematopathologists should be aware of this morphologic variant of myeloma as well as for the capacity of clonal characteristics, such as light chain monotype, to fluctuate subsequent to treatment.

Relapsing Fever: Diagnosis Thanks to a Vigilant Hematology Laboratory.

Three cases of relapsing fever from southern Israel were diagnosed promptly thanks to vigilance of the hematology laboratory technicians. In this region of Israel, patients presenting with prolonged fever and leukopenia without localizing symptoms are generally suspected of having brucellosis or a rickettsial disease. Pediatric patients with prolonged fever, cytopenias, and negative aforementioned serologies are often hospitalized for further work-up. Because of the policy of performing a manual blood smear when results of the automated blood count demonstrate severe anemia and abnormal platelet and/or white blood cell counts, a diagnosis of tick-borne relapsing fever was confirmed and promptly relayed to the physician. This routine prevented unnecessary examinations and hospitalization days and provided important information to regional epidemiology and public health authorities.

The MAPK ERK5, but not ERK1/2, inhibits the progression of monocytic phenotype to the functioning macrophage.

Intracellular signaling pathways present targets for pharmacological agents with potential for treatment of neoplastic diseases, with some disease remissions already recorded. However, cellular compensatory mechanisms usually negate the initial success. For instance, attempts to interrupt aberrant signaling downstream of the frequently mutated ras by inhibiting ERK1/2 has shown only limited usefulness for cancer therapy. Here, we examined how ERK5, that overlaps the functions of ERK1/2 in cell proliferation and survival, functions in a manner distinct from ERK1/2 in human AML cells induced to differentiate by 1,25D-dihydroxyvitamin D3 (1,25D). Using inhibitors of ERK1/2 and of MEK5/ERK5 at concentrations specific for each kinase in HL60 and U937 cells, we observed that selective inhibition of the kinase activity of ERK5, but not of ERK1/2, in the presence of 1,25D resulted in macrophage-like cell morphology and enhancement of phagocytic activity. Importantly, this was associated with increased expression of the macrophage colony stimulating factor receptor (M-CSFR), but was not seen when M-CSFR expression was knocked down. Interestingly, inhibition of ERK1/2 led to activation of ERK5 in these cells. Our results support the hypothesis that ERK5 negatively regulates the expression of M-CSFR, and thus has a restraining function on macrophage differentiation. The addition of pharmacological inhibitors of ERK5 may influence trials of differentiation therapy of AML.

ERK 5/MAPK pathway has a major role in 1α,25-(OH)2 vitamin D3-induced terminal differentiation of myeloid leukemia cells.

Vitamin D derivatives, including its physiological form 1α,25(OH)2 vitamin D3 (1,25D), have anti-tumor actions demonstrated in cell culture and confirmatory epidemiological associations are frequently reported. However, their promise for use in the cancer clinic is still incompletely fulfilled, suggesting that a better understanding of the molecular events initiated by these compounds is needed for therapeutic advances. While ERK1/2 has been intensely investigated and is known to transmit signals for cell survival, growth, and differentiation, the role of other MAPK pathways has been studied sporadically. Therefore, we utilized acute myeloid leukemia (AML) cells in culture (HL60 and U937), to determine if ERK5 has a role in 1,25D-induced terminal differentiation which is distinct from the previously shown involvement of ERK1/2. We previously found that inhibition of kinase activity of ERK5 by specific pharmacological inhibitors BIX02189 or XMD8-92 results in higher expression of general myeloid marker CD11b, but a lower expression of the monocytic marker CD14. In contrast, the inhibition of the ERK1/2 pathway by PD98059 or U0126 reduced the expression of all differentiation markers studied. We report here for the first time that the differentiation changes induced by ERK5 inhibitors are accompanied by the inhibition of cell proliferation, and this occurs in the both G1 and G2 phases of the cell cycle. Of note, inhibition of ERK5 auto-phosphorylation by XMD8-92 results in a particularly robust cell cycle arrest in G2 phase in AML cells. This study provides a link between the 1,25D-elevated ERK5 pathway and changes in the cell cycle phase transitions in AML cells. Thus, combinations of vitamin D derivatives and ERK5 inhibitors may be more successful in cancer clinics than 1,25D or analogs alone. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.

Terrorist suicide bombings: lessons learned in Metropolitan Haifa from September 2000 to January 2006.

BACKGROUND: The threat of suicide bombing attacks has become a worldwide problem. This special type of multiple casualty incidents (MCI) seriously challenges the most experienced medical facilities. METHODS: The authors concluded a retrospective analysis of the medical management of victims from the six suicide bombing attacks that occurred in Metropolitan Haifa from 2000 to 2006. RESULTS: The six terrorist suicide bombing attacks resulted in 411 victims with 69 dead (16.8 percent) and 342 injured. Of the 342 injured, there were 31 (9.1 percent) severely injured, seven (2.4 percent) moderately severely injured, and 304 (88.9 percent) mildly injured patients. Twenty four (77 percent) of the 31 severely injured victims were evacuated to the level I trauma center at Rambam Medical Center (RMC). Of the seven severely injured victims who were evacuated to the level II trauma centers (Bnai-Zion Medical Center and Carmel Medical Center) because of proximity to the detonation site, three were secondarily transferred to RMC after initial resuscitation. Eight of the 24 severely injured casualties, admitted to RMC, eventually died of their wounds. There was no in-hospital mortality in the level II trauma centers. CONCLUSIONS: A predetermined metropolitan triage system which directs trauma victims of a MCI to the appropriate medical center and prevents overcrowding of the level I facility with less severe injured patients will assure that critically injured patients of a suicide bombing attack will receive a level of care that is comparable with the care given to similar patients under normal circumstances. Severe blast injury victims without penetrating injuries but with significant pulmonary damage can be effectively managed in ICUs of level II trauma centers.

Polymeric nanoparticles for sustained down-regulation of annexin A2 inhibit prostate tumor growth.

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer related death in Western men. In prostate intraepithelial neoplasia annexin A2 expression is absent however upon loss of androgen dependence annexin A2 is subsequently over-expressed. Regaining regulatory control of annexin A2 presents a means of therapy in the treatment of hormone refractory prostate cancers. In an effort to regain control of aberrant annexin A2 expression we have formulated poly lactide-co-glycolide (PLGA) nanoparticles loaded with pDrive-sh AnxA2 plasmid DNA. These nanoparticles are capable of sustained intracellular delivery of pDrive-sh AnxA2 plasmid DNA vector for long-term siRNA mediated down-regulation of annexin A2. Intra-tumoral administration of pDrive-sh AnxA2 loaded nanoparticles to xenograft prostate tumors in nude mice demonstrates an overall decrease in tumor growth. The decrease in tumor growth is through a reduction of annexin A2 and VEGF mRNA and protein levels within the tumor mass. Administration of blank nanoparticles demonstrated no alteration in tumor growth or annexin A2 and VEGF at either the mRNA or protein levels. Our findings suggest that the use of sustained-release polymeric nanoparticles for down-regulation of annexin A2 expression may serve as an effective adjuvant treatment option for prostate cancer.

Synergistic antileukemic activity of carnosic acid-rich rosemary extract and the 19-nor Gemini vitamin D analogue in a mouse model of systemic acute myeloid leukemia.

OBJECTIVE: Differentiation therapy with the hormonal form of vitamin D, 1alpha,25-dihydroxyvitamin D(3) (1,25D(3)), is a promising approach to treatment of acute myeloid leukemia (AML); however, 1,25D(3) induces hypercalcemia at pharmacologically active doses. We investigated the in vitro and in vivoantileukemic efficacy of combined treatment with non-toxic doses of a low-calcemic 1,25D(3) analogue, 1,25-dihydroxy-21(3-hydroxy-3-methyl-butyl)-19-nor-cholecalciferol (19-nor-Gemini; Ro27-5646), and rosemary plant agents in a mouse model of AML. METHODS: Proliferation and differentiation of WEHI-3B D- (WEHI) murine myelomonocytic leukemia cellsin vitro were determined by standard assays. Reactive oxygen species, glutathione and protein expression levels were measured by flow cytometry, enzymatic assay and Western blotting, respectively. Systemic AML was developed by intravenous injection of WEHI cells in syngeneic Balb/c mice. RESULTS: 19-nor-Gemini had a higher potency than its parent compounds, Gemini (Ro27-2310) and 1,25D(3), in the induction of differentiation (EC(50) = 0.059 +/- 0.011, 0.275 +/- 0.093 and 0.652 +/- 0.085 nM, respectively) and growth arrest (IC(50) = 0.072 +/- 0.018, 0.165 +/- 0.061 and 0.895 +/- 0.144 nM, respectively) in WEHI cells in vitro, and lower in vivo toxicity. Combined treatment of leukemia-bearing mice with 19-nor-Gemini (injected intraperitoneally) and standardized rosemary extract (mixed with food) resulted in a synergistic increase in survival (from 42.2 +/- 2.5 days in untreated mice to 66.5 +/- 4.2 days, n = 3) and normalization of white blood cell and differential counts. This was consistent with strong cooperative antiproliferative and differentiation effects of low concentrations of 19-nor-Gemini or 1,25D(3) combined with rosemary extract or its major polyphenolic component, carnosic acid, as well as with the antioxidant action of rosemary agents and vitamin D derivatives in WEHI cell cultures. CONCLUSION: Combined effectiveness of 1,25D(3) analogues and rosemary agents against mouse AML warrants further exploration of this therapeutic approach in translational models of human leukemia.

Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia.

1alpha,25-dihydroxyvitamin D(3) (1,25D(3)) is a powerful differentiation agent, which has potential for treatment of myeloid leukemias and other types of cancer, but the calcemia produced by pharmacologically active doses precludes the use of this agent in the clinic. We have shown that carnosic acid, the major rosemary polyphenol, enhances the differentiating and antiproliferative effects of low concentrations of 1,25D(3) in human myeloid leukemia cell lines (HL60, U937). Here we translated these findings to in vivo conditions using a syngeneic mouse leukemia tumor model. To this end, we first demonstrated that as in HL60 cells, differentiation of WEHI-3B D(-) murine myelomonocytic leukemia cells induced by 1 nM 1,25D(3) or its low-calcemic analog, 1,25-dihydroxy-16-ene-5,6-trans-cholecalciferol (Ro25-4020), can be synergistically potentiated by carnosic acid (10 microM) or the carnosic acid-rich ethanolic extract of rosemary leaves. This effect was accompanied by cell cycle arrest in G0 + G1 phase and a marked inhibition of cell growth. In the in vivo studies, i.p. injections of 2 microg Ro25-4020 in Balb/c mice bearing WEHI-3B D(-) tumors produced a significant delay in tumor appearance and reduction in tumor size, without significant toxicity. Another analog, 1,25-dihydroxy-16,23Z-diene-20-epi-26,27-hexafluoro-19-nor-cholecalciferol (Ro26-3884) administered at the same dose was less effective than Ro25-4020 and profoundly toxic. Importantly, combined treatment with 1% dry rosemary extract (mixed with food) and 1 microg Ro25-4020 resulted in a strong cooperative antitumor effect, without inducing hypercalcemia. These results indicate for the first time that a plant polyphenolic preparation and a vitamin D derivative can cooperate not only in inducing leukemia cell differentiation in vitro, but also in the antileukemic activity in vivo. These data may suggest novel protocols for chemoprevention or differentiation therapy of myeloid leukemia.

Rizatriptan RPD for severe migraine in the emergency department--a multicenter study.

Many patients with severe migraine come to the Emergency Department (ED) due to failure of different drug regimens to stop their headache. We treated 98 patients with severe migraine who were seen in three different EDs. We used rizatriptan RPD wafers 10 mg and observed the patients for 2 h. We found that at 2 h, 92.9% (91/98) of the patients had pain relief, and 73.5% were pain free. The mean time to pain relief was 26.9 +/- 29.6 min with a median of 15 min, and the time to pain free was 70.2 +/- 47.3 min with a median of 75 min. Eighty-five percent of the patients were free of associated symptoms, such as nausea and vomiting, at 2 h with a mean time to symptom free of 55 +/- 47.5 min and a median of 45 min. Rizatriptan was reported to be much better than other drugs by 74.4% of the patients. Side effects were minor and transient. Recurrence of migraine occurred part of the day in 17.1% of the patients and all day or almost all day in 8.6% of the patients only. The results were consistent in all three EDs. We conclude that rizatriptan RPD is very effective and reliable as a first-line therapy for acute migraine in the ED. It dissolves immediately in the mouth without the inconvenience of an injection. It works fast and has few side effects and low headache recurrence.

Cytology of middle ear fluid during acute otitis media.

BACKGROUND: Limited information is available on the cellular characteristics of the middle ear fluid (MEF) during acute otitis media (AOM). OBJECTIVES: To determine the white blood cell (WBC) composition of the MEF in AOM before and during antibiotic therapy. MATERIALS AND METHODS: Total WBC and differential counts were determined in the MEF of 96 infants and children (ages 2 weeks to 3 years) with AOM who were receiving antibiotics. WBC counts were reported as number of WBC/mg MEF (mean +/- sd). RESULTS: One hundred forty-five MEF samples were obtained by tympanocentesis at enrollment (Day 1), and 36 samples were collected on Days 4 to 5 after initiation of antibiotic therapy. Sixty-one percent of the patients were <1 year of age, and 38% were receiving antibiotic therapy at enrollment. Twenty-eight MEF samples were paired (same ear, Day 1 and Days 4 to 5). One hundred twelve pathogens were isolated from 95 of 145 (66%) culture-positive samples obtained on Day 1: 67 Haemophilus influenzae, 40 Streptococcus pneumoniae and 5 others. MEF WBC counts were lower on Day 1 in patients who had received previous antibiotic therapy than in those who had not (432.4+/- 412.8 vs. 590.5 +/- 436.8, P = 0.03). WBC counts were higher on Day 1 in culture-positive than in culture-negative samples (603.9 +/- 504.9 vs.421.4 +/- 373.4, P = 0.02). WBC counts were higher on Day 1 in MEF samples positive for S. pneumoniae than in those positive for H. influenzae (799.2 +/- 641.5 vs.506.4 +/- 401.9, P = 0.04). There were no differences in the number of neutrophil WBC present in the samples obtained on Day 1 vs. Days 4 to 5 or between samples positive vs.samples negative for bacterial pathogens. CONCLUSIONS: WBC counts were higher in the MEF of patients with culture-positive AOM than in those with culture-negative AOM and in those with AOM caused by S. pneumoniae.