Plasma cytokines in polycythemia vera: Phenotypic correlates,prognostic relevance,and comparison with myelofibrosis

Plasma cytokine milieu is abnormal in primary myelofibrosis (PMF) and correlates with disease phenotype and prognosis. In this study, we show that several plasma cytokines are also abnormally expressed in polycythemia vera (PV; n = 65), compared to normal controls (n = 35), but with a significantly different pattern than that of PMF (n = 127). Direct phenotypic correlation in PV included levels of IL‐12 with hematocrit; IL‐1b, IL‐2, IL‐7, FGF‐b, and HGF with leukocytosis; and IFN‐α and IFN‐γ with thrombocytosis. In univariate analysis, levels of 13 cytokines (out of 30 analyzed) correlated with survival but only MIP‐1β remained significant on multivariable analysis that included the other cytokines as covariates. Increased level of MIP‐1β (P < 0.01), older age (P < 0.01), and leukocytosis (P = 0.03) maintained their association with shortened survival, on multivariable analysis. This study provides preliminary observations that warrant a larger scale study and suggests the value of plasma cytokines as prognostic biomarkers in PV. Am. J. Hematol., 2012. © 2012 Wiley Periodicals, Inc.     

Risk stratification for survival and leukemic transformation in essential thrombocythemia: a single institutional study of 605 patients.

Unlike the case with thrombosis, prognostic models for survival and leukemic transformation (LT) in essential thrombocythemia (ET) are not available. Among 605 patients with ET seen at our institution and followed for a median of 84 months, 155 died and LT was documented in 20 patients (3.3%). In a multivariable analysis, hemoglobin level below normal (females<120 g/l; males<135 g/l) was identified as an independent risk factor for both inferior survival and LT. Additional risk factors for survival included age > or =60 years, leukocyte count> or =15 x 10(9)/l, smoking, diabetes mellitus and thrombosis. For LT, platelet count> or =1000 x 10(9)/l but not cytoreductive therapy was flagged as an additional independent risk factor. In fact, four of the 20 patients (20%) with LT were untreated previously. We used the above information to construct prognostic models that effectively discriminated among low-, intermediate- and high-risk groups with respective median survivals of 278, 200 and 111 months (P<0.0001), and LT rates of 0.4, 4.8 and 6.5% (P=0.0009) respectively. Presence of JAK2V617F did not impact either survival or LT and mutational frequency was similar among the different risk groups.     

Intravenous morphine for emergency treatment of cancer pain

Despite the wide use of the World Health Organization (WHO) analgesic ladder for the relief of cancer pain, it is not uncommon to find patients presenting with severe pain to palliative care centres. This is more so in the developing world, where facilities for pain relief are few and the health care system is not well organized. It has been the practice in a pain and palliative care clinic in south India to give repeated boluses of 1.5 mg of morphine intravenously every 10 min to patients presenting with severe pain. An audit of the procedure was undertaken by a retrospective study of 793 case notes. Seventy-nine per cent of patients had total relief of their pain with intravenous morphine. Three per cent of patients experienced side-effects during the procedure. These included nausea and vomiting, itching, giddiness, restlessness, dyspnoea, chest pain, disorientation and a feeling of uneasiness. Thirty-two per cent of patients had drowsiness, which was one of the end-points of the procedure. It is concluded that intravenous morphine in repeated boluses of 1.5 mg every 10 min is a safe and effective method of managing cancer pain emergencies in a clinical setting in a developing country.     

Voltage-gated potassium ion channels in colon cancer

Voltage-gated potassium channels (VGPCs) have been previously implicated in cellular proliferation. In this study, the expression of VGPCs was examined by immunohistochemistry in seventy-four human colonic carcinoma specimens. Immunostaining for the Kv1.3 type VGPC was absent in two normal human colon specimens. Kv1.3 staining in the 74 colon cancer specimens was low in 9% (7/74), moderate in 61% (45/74) and high in 30% (22/74). Potassium channel (PC) openers, minoxidil and diazoxide (5-50 microg/ml), increased growth of SW1116, LoVo, Colo320DM and LS174t human colon cancer cell lines by 20-40%. PC-blockers, dequalinium and amiodarone, caused marked growth-inhibition of the four cell lines, at concentrations between 1 to 3 microg/ml. PC-blockers such as glibenclamide inhibited cellular proliferation at concentrations above 50 microg/ml while tetraethylammonium and 4-aminopyridine (up to 100 microg/ml) did not have significant growth-suppressive effects. Our results indicate the presence of VGPCs in colon cancer and suggest that PCs could serve as therapeutic targets.     

Potentiation of the antiproliferative activity of MKT-077 by loperamide, diltiazem and tamoxifen

MKT-077, a delocalized lipophilic cation, selectively targets cancer cells. MKT-077 has been reported to inhibit the growth of several tumor types and has undergone phase I clinical testing. We have examined the effect of MKT-077, alone and in combination with the antidiarrheal drug loperamide. Ten human cancer cell lines, four prostate (PC3, DU145, LNCaP, MDA-PCA-2B), two breast (MCF-7 and MDA-MB-231) and four colon (LoVo, Colo320DM, SW1116 and LS174t) were tested in vitro. Cells were grown to confluency prior to treatment. Loperamide potentiated the antiproliferative effect of MKT-077 in all ten cell lines, in a dose-dependent manner. The sensitivity of MDA-PCA-2B cells, the two breast and four colon cancer cell lines to MKT-077 was relatively low (>2.5 microg/ml MKT-077 required to inhibit growth by 95%). In these cell lines, 0.5-5 microg/ml (1-10 microM) loperamide caused a marked increase in the response to MKT-077. Loperamide is known to activate micro-opioid receptors at nanomolar concentrations and block voltage-gated calcium channels at micromolar doses. We found that calcium channel-blockers diltiazem and nifedipine (10-20 microg/ml), as well as tamoxifen (1.5-2.5 microg/ml) can also potentiate the growth-inhibitory effects of MKT-077. These synergistic interactions could be exploited for therapeutic benefit.