Thymic anti-tumor effectors in mice cured of lymphoma by cyclophosphamide plus TNF-α therapy: Phenotypic and functional characterization up to 20 months after initial tumor inoculation

As reported previously, cyclophosphamide plus tumor necrosis factor-α treatment of C57BL/6 mice bearing advanced EL4 lymphoma induced approx. 60% long-term (i.e., >60 days) survivors. These mice developed protective immunity, as evidenced by 1) rejection (100% survival) of EL4 tumor re-implanted on day 60 (day 0 = initial tumor implantation); and 2) development of significant levels of specific EL4 tumor cell killing activity by both splenocytes and thymocytes. Using this model, age-related changes in functionally and phenotypically definable thymocyte subsets were assessed. In thymocytes from 90 to 308 day survivors, specific immune memory was long term; both CD4⁺ and CD8⁺ cells were required for the ex vivo stimulation of lytic activity, but the specific anti-EL4 cytotoxic effector was CD4⁻CD8⁺. On day 520, the surviving mice were randomized into 2 groups. One group received a second re-challenge with EL4 tumor cells and all survived. The other group was sacrificed on day 520. Their thymocytes, exposed to X-irradiated EL4, developed anti-EL4 lytic activity and, in comparison with thymocytes of young and age-matched control mice, were markedly enriched in CD4⁻CD8⁺CD44⁺ cells. On day 625, thymocytes from the survivors of the day 520 re-challenge were evaluated and were found to have developed specific anti-EL4 lytic activity. Phenotypically, they had returned toward the pattern seen in age-matched control mice although CD4⁻CD8⁺CD44⁺ cells remained increased. These mice were ≥2 years old, the median life span of C57BL/6 mice. Thus, mice cured of tumor by an immuno-modulating regimen rejected re-implanted primary tumor and maintained specific thymic anti-tumor immune memory for life. Int. J. Cancer 76:579–586, 1998.© 1998 Wiley-Liss, Inc.     

Emerging translational science discoveries,clonal approaches,and treatment trends in chronic myeloproliferative neoplasms

The 60th American Society of Hematology (ASH) held in San Diego in December 2018 was followed by the 13th Post‐ASH chronic myeloproliferative neoplasms (MPNs) workshop on December 4 and 5, 2018. This closed annual workshop, first introduced in 2006 by Goldman and Mughal, was organized in collaboration with Alpine Oncology Foundation and allowed experts in preclinical and clinical research in the chronic MPNs to discuss the current scenario, including relevant presentations at ASH, and address pivotal open questions that impact translational research and clinical management. This review is based on the presentations and deliberations at this workshop, and rather than provide a resume of the proceedings, we have selected some of the important translational science and treatment issues that require clarity. We discuss the experimental and observational evidence to support the intimate interaction between aging, inflammation, and clonal evolution of MPNs, the clinical impact of the unfolding mutational landscape on the emerging targets and treatment of MPNs, new methods to detect clonal heterogeneity, the challenges in managing childhood and adolescent MPN, and reflect on the treatment of systemic mastocytosis (SM) following the licensing of midostaurin.     

The underappreciated risk of thrombosis and bleeding in patients with myelofibrosis: a review

Bleeding and thrombosis are long recognized complications of myelofibrosis (MF) and contribute significantly to its morbidity and mortality. However, so far, few studies have evaluated the frequency of these events, their characteristics, and their prognostic impact. Based on these studies, thrombotic events in MF are about as common as in essential thrombocytemia (ET) but less common than in polycythemia vera (PV), while bleeding events are relatively more common in MF than in ET or PV. The emergence of the concept of prefibrotic primary MF (PMF), which is associated with a higher frequency of thrombohemorrhagic complications than ET, and the growing evidence that prefibrotic PMF may also have a different thrombotic and bleeding risk profiles than fibrotic (overt) PMF have emphasized the need for a reappraisal of the risk of thrombosis and hemorrhage in patients with MF. In this review, we discuss the frequency of thrombosis and bleeding in patients with MF, including prefibrotic PMF and their established and potential risk factors.     

Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond

Recent advances in our understanding of the pathogenesis of the Philadelphia chromosome-negative myeloproliferative neoplasms, polycythaemia vera, essential thrombocythaemia and myelofibrosis have led to the identification of the mutation V617F in Janus kinase (JAK) as a potential therapeutic target. This information has prompted the development of ATP-competitive JAK2 inhibitors. Therapy with JAK2 inhibitors may induce rapid and marked reductions in spleen size and can lead to remarkable improvements in constitutional symptoms and overall quality of life. Because JAKs are involved in the pathogenesis of inflammatory and immune-mediated disorders, JAK inhibitors are also being tested in clinical trials in patients with rheumatoid arthritis and psoriasis, as well as for the treatment of other autoimmune diseases and for the prevention of allograft rejection. Preliminary results indicate that these agents hold great promise for the treatment of JAK-driven disorders.     

Guidelines of the Croatian Society for Rheumatology for the treatment of knee and hip osteoarthritis

Osteoarthritis of the hip and the knee belongs to one of the most disabiliting conditions. Treatment goals for these patients include a reduction in pain, an improvement in joint mobility and to limit functional impairment. To properly manage osteoarthritis, both nonpharmacologic (non-interventional) and pharmacologic modalities may be employed, while minority of patients will require surgery. According to the available evidence for available therapies and experts' opinion here we present guidelines for the treatment of hip and the knee osteoarthritis in Croatia.     

Phase II Study of Obatoclax Mesylate (GX15-070), a Small-Molecule BCL-2 Family Antagonist,for Patients With Myelofibrosis

BackgroundMyelofibrosis (MF) is a disease characterized by the overexpression of the antiapoptotic BCL-2 family of proteins (eg, BCL-X_L and MCL-1).Patients and MethodsWe conducted a multicenter, open-label, noncomparative phase II study of obatoclax mesylate, a small-molecule pan–BCL-2 antagonist, in patients with MF. Obatoclax was administered as a 24-hour infusion (on an outpatient basis) every 2 weeks at a fixed dose of 60 mg.ResultsA total of 22 patients were enrolled, with a median age of 63 years (range, 43-89 years). Twelve were men, and all 22 patients were previously treated (median of 2 previous therapies). Ten patients (45%) had a Lille score of 1, and 9 patients (41%) had a Lille score of 2. Thirteen (59%) were red blood cell transfusion dependent. A median of 7 cycles of obatoclax were administered. No patient achieved complete or partial response according to International Working Group criteria. One patient (4%) demonstrated a clinical improvement (in terms of hemoglobin and platelet count) after 7 cycles of therapy. The improvement was sustained for 4 cycles of therapy, after which he underwent allogeneic stem cell transplantation. The most common adverse events included low-grade ataxia and fatigue in 50% of the patients. Dose reduction because of toxicity was required in 1 patient, whereas 2 patients were taken off the study because of grade 3 ataxia and grade 3 heart failure. Grade 3/4 anemia and thrombocytopenia were evident in 6 (27%) and 4 (18%) patients, respectively.ConclusionObatoclax exhibits no significant clinical activity in patients with MF at the dose and schedule evaluated.     

The BH3-mimetic GX15-070 induces autophagy,potentiates the cytotoxicity of carboplatin and 5-fluorouracil in esophageal carcinoma cells

Despite improvements in both surgical techniques and radio- and chemo-therapy regimens, the prognosis of esophageal cancer is poor. In pursuit of novel effective strategy, this study examined the effect of the BH3-mimetic GX15-070 on esophageal carcinoma cells. We discovered that GX15-070 inhibited the growth of esophageal cancer cells. There was synergism between GX15-070 and carboplatin or 5-fluorouracil. GX15-070 induced autophagy in esophagus cancer cell line EC9706 and osteosarcoma cancer cell line U2OS. 3-methyladenine and chloroquine, inhibitors of autophagy with distinct mechanisms, potentiated the cytotoxicity of GX15-070. In conclusion, GX15-070 inhibits growth of esophageal cancer cells.     

Epidemiological importance of humans and domestic animals as reservoirs of verocytotoxin-producing Escherichia coli

BACKGROUND/AIM: A "new" pathogenic agent, verocytotoxin--producing Escherichia coli (VTEC) emerged in the last 20 years, causing an increased number of sporadic cases, as well as of outbreaks of diarrhoeal diseases. Humans and animals can be infected with VTEC, but their epidemiological importance as a reservoir of this agent is not quite clear, especially in the Balkan region. Therefore, the aim of this study was to investigate the frequency of isolation of VTEC from the intestinal tract of humans and animals and to determine the serogroups of the isolated strains. METHODS: A total of, 3 401 stool samples from humans and 2 660 samples from five different species of domestic animals were tested for the presence of this pathogen. RESULTS: VTEC was isolated from 20 (0.6%) humans stools and from 431 (16.2%) animal fecal samples (p < 0.001). Only 15 (3.3%) VTEC strains belonged to human infection-associated serogroups (O26, O55, O111, O128 and O157), designated as enterohaemorrhagic E. coli (EHEC). The most known serogroup-O157 was identified in 6 (1.3%) of the isolated VTEC strains; of them, 1 (5%) was of human origin and 5 (1.2%) were animal strains. CONCLUSION: This study revealed that domestic animals were a more important reservoir of VTEC than humans, and that the isolated VTEC strains rarely belonged to O157, as well as to other EHEC serogroups that might explain rare sporadic cases and the absence of epidemic occurrence of diarrhoeal diseases caused by VTEC in this geographic region.     

Prognostic Model to Identify Patients With Myelofibrosis at the Highest Risk of Transformation to Acute Myeloid Leukemia

BackgroundSome patients with myelofibrosis (MF) progress to acute myeloid leukemia (AML). Current prognostic tools were not devised to assess risk of AML transformation.MethodsMultivariate analysis in 649 patients followed for a median of 19 months (range, 1-180 months).ResultsWe identified age > 60 (P = .004; hazard ratio [HR], 1.63), platelets <100 × 10⁹/L (P < .001; HR, 1.62), bone marrow blast > 10% (P = .002; HR, 2.18), high-risk karyotype (P < .001; HR, 2.44), transfusion dependency (P < .001; HR, 2.64), performance status > 1 (P = .003; HR, 1.47), lactate dehydrogenase > 2000 U/L (P < .001; HR, 1.62), previous hydroxyurea (P < .001; HR, 1.69), and male sex (P = .005; HR, 1.41) as independent poor prognostic factors for survival. Using the same baseline variables we identified bone marrow blasts >10% and worst karyotype as independent risk factors for AML transformation. Patients with 1 or both of these risk factors (n = 80; 12%) had a median survival of 10 months and a 1-year AML transformation rate of 13% (2% if none of those factors, P = .001).ConclusionWe have identified risk factors that predict high risk of transformation from MF to AML.     

Superior outcome with hypomethylating therapy in patients with acute myeloid leukemia and high‐risk myelodysplastic syndrome and chromosome 5 and 7 abnormalities

BACKGROUND:

Outcome of patients with acute myeloid leukemia (AML) and high‐risk myelodysplastic syndrome (MDS) with chromosome 5 and 7 abnormalities (excluding del 5[q]) has been poor, with <10% of patients alive at 2 years.

METHODS:

The authors investigated whether treatment with hypomethylating agents (5‐azacytidine/decitabine) leads to an improved outcome. Between January 2004 and December 2007, 81 patients (37 [46%] with AML [≥20% blasts]; 44 [54%] with high‐risk MDS) with chromosome 5 and 7 abnormalities were treated with hypomethylating agents as their initial therapy. These included 68 patients with complex (≥3) abnormalities and 13 with <3 aberrations. During the same period, 151 patients (126 with AML, 25 with MDS) with chromosome 5 and 7 abnormalities (128 complex, 23 noncomplex) were treated with intensive chemotherapy (including cytarabine‐based regimens in 72% and other regimes in 28%).

RESULTS:

The median ages for the 2 groups were 66 years and 61 years, respectively (ranges, 37‐85 years and 19‐89 years). Thirty‐three (41%) patients in the hypomethylating group achieved complete remission (CR) versus 53 (35%) in the chemotherapy group (P = .395). With a median follow‐up of 51 weeks (range, 12‐101 weeks) and 40 weeks (range, 5–128 weeks), 22 of 33 patients in the hypomethylating group and 33 of 53 patients in the chemotherapy group had developed disease recurrence. The median CR duration was 45 weeks and 23 weeks, respectively (P = .153). The overall survival was superior for the hypomethylating group compared with the chemotherapy group (P = .019).

CONCLUSIONS:

Treatment with hypomethylating agents may be superior to chemotherapy in patients with chromosome 5 and 7 abnormalities. Cancer 2009. © 2009 American Cancer Society.