Selecting an Appropriate Medication for Treating Neuropathic Pain in Patients with Diabetes: A Study Using the U.K. and Germany Mediplus Databases

Objective:   To evaluate the appropriateness of prescribing select neuropathic pain medications to diabetes patients based on the potential for drug–drug interactions with medications diabetes patients were prescribed continuously for ≥ 3 months (chronic use).
Methods:   Medical records of patients with a diagnosis of diabetes or use of antidiabetic medications between January 1, 2002 and September 30, 2005 in the U.K. and Germany Mediplus databases were obtained.
Patients:   Medication use profiles were evaluated between April 2004 and September 2005. The metabolic pathways associated with medications that were prescribed chronically to at least 10% of study patients were compared with the metabolic pathways of neuropathic pain medications to identify potential drug–drug interactions.
Results:   A total of 40,448 patients in the U.K. (63.6 ± 16.6 years, 51% male) and 31,930 patients in Germany (68.9 ± 12.7 years, 46% male) were identified. Frequently prescribed medications in the U.K. included aspirin (33.7%), metformin (32.7%), simvastatin (25.5%), atorvastatin (19.4%), atenolol (18.1%), and in Germany hydrochlorothiazide (35.8%), aspirin (25.2%), metformin (21.6%), metoprolol (20.3%), and simvastatin (18.3%). Several neuropathic pain medications have potential for drug–drug interactions with medications prescribed to diabetes patients. Examples include (neuropathic pain medications vs. diabetes medications): duloxetine, paroxetine, and methadone (CYP2D6 inhibitors) and oxycodone HCL, hydrocodone (CYP2D6 substrates) vs. metoprolol and bisoprolol (CYP2D6 substrates); and carbamazepine (CYP3A4 inducer) vs. simvastatin, and atorvastatin (CYP3A4 substrates).
Conclusions/Interpretation:   Our findings underscore the need for medical vigilance when selecting medications for treating neuropathic pain in diabetes patients. ▪     

Natural killer-like T-cell lymphomas: aggressive lymphomas of T-large granular lymphocytes [see comments]

Natural killer (NK)-like T cells are major histocompatibility complex- unrestricted cytotoxic T cells that are surface CD3-positive, express NK-cell antigens, and rearrange their T-cell receptor. Most neoplasms arising from this T-cell subpopulation have been a chronic lymphoproliferative disease referred to as T-large granular lymphocyte (LGL) leukemia. Only 10 NK-like T-cell lymphomas have been described in detail previously; this study presents the clinicopathologic features of six others and distinguishes these lymphomas from T-LGL leukemia. All patients presented with B-symptoms and often had marked hepatosplenomegaly without significant peripheral lymphadenopathy. Four of the six patients were immunosuppressed. All had CD3, CD8, CD56- positive tumors, presumably of hepatosplenic (n = 3), intestinal (n = 1), pulmonary (n = 1), or nodal (n = 1) origin. Three patients had lymphomatous bone marrow infiltrates, and four had peripheral blood involvement by neoplastic large lymphocytes, some of which had a blastic appearance or resembled virocytes. Azurophilic granules, ultrastructurally corresponding to cytoplasmic dense core and/or double density granules, were seen in all cases. T-cell clonality was shown in five tumors by Southern blot analysis, and three had abnormal karyotypes. Two untreated patients died 20 days after presentation, and three patients who received combination chemotherapy died within 5 months of presentation. One patient remains in complete remission 22 months after treatment. These findings suggest NK-like T-cell lymphomas are aggressive, are clinicopathologically distinct from T-LGL leukemia, and should be in the differential diagnosis of extranodal T-cell lymphoproliferations, including those in immunosuppressed patients. Furthermore, the LGL morphology, phenotype, and tissue distribution of some NK-like T-cell lymphomas suggest they arise from thymic- independent T cells of the hepatic sinusoids and intestinal mucosa.     

Evaluation of Apaf-1 and procaspases-2, -3, -7, -8, and -9 as potential prognostic markers in acute leukemia

Recent studies have suggested that variations in levels of caspases, a family of intracellular cysteine proteases, can profoundly affect the ability of cells to undergo apoptosis. In this study, immunoblotting was used to examine levels of apoptotic protease activating factor-1 (Apaf-1) and procaspases-2, -3, -7, -8, and -9 in bone marrow samples (at least 80% leukemia) harvested before chemotherapy from adults with newly diagnosed acute myelogenous leukemia (AML, 42 patients) and acute lymphocytic leukemia (ALL, 18 patients). Levels of each of these polypeptides varied over a more than 10-fold range between specimens. In AML samples, expression of procaspase-2 correlated with levels of Apaf-1 (R(s) = 0.52, P <.02), procaspase-3 (R(s) = 0.56, P <.006) and procaspase-8 (R(s) = 0.64, P <.002). In ALL samples, expression of procaspases-7 and -9 was highly correlated (R(s) = 0.90, P <.003). Levels of these polypeptides did not correlate with prognostic factors or response to induction chemotherapy. In further studies, 16 paired samples (13 AML, 3 ALL), the first harvested before induction therapy and the second harvested at the time of leukemia regrowth, were also examined. There were no systematic alterations in levels of Apaf-1 or procaspases at relapse compared with diagnosis. These results indicate that levels of initiator caspases vary widely among different leukemia specimens but cast doubt on the hypothesis that this variation is a major determinant of drug sensitivity for acute leukemia in the clinical setting. (Blood. 2000;96:3922-3931)     

Inhibitors of signaling in myelodysplastic syndrome

Treatment of myelodysplastic syndrome (MDS) has been hampered by the lack of understanding of the molecular and biological abnormalities associated with this disease. Biological abnormalities may lead to typical phenotypic changes in more differentiated cells. Recent developments in the natural history and underlying molecular mechanisms of MDS and acute myeloid leukemia (AML) have identified new molecular therapeutic targets. Several new classes of drugs have shown promise in early clinical trials and may alter the standard of care of these patients. Among these new drugs are farnesyltransferase inhibitors, receptor tyrosine kinase inhibitors, protein kinase C inhibitors, and VEGF inhibitors. These agents have been tested in patients with solid tumors and hematological malignancies such as AML and MDS. Most of the studies in MDS are in early stages of development, where doses are being determined based on the experience in refractory or relapsed AML or solid tumors. Future therapies in MDS will attempt to resolve cytopenias, eliminate malignant clones and allow differentiation by attacking specific mechanisms of the disease.     

Vessel co‐option is common in human lung metastases and mediates resistance to anti‐angiogenic therapy in preclinical lung metastasis models

Anti‐angiogenic therapies have shown limited efficacy in the clinical management of metastatic disease, including lung metastases. Moreover, the mechanisms via which tumours resist anti‐angiogenic therapies are poorly understood. Importantly, rather than utilizing angiogenesis, some metastases may instead incorporate pre‐existing vessels from surrounding tissue (vessel co‐option). As anti‐angiogenic therapies were designed to target only new blood vessel growth, vessel co‐option has been proposed as a mechanism that could drive resistance to anti‐angiogenic therapy. However, vessel co‐option has not been extensively studied in lung metastases, and its potential to mediate resistance to anti‐angiogenic therapy in lung metastases is not established. Here, we examined the mechanism of tumour vascularization in 164 human lung metastasis specimens (composed of breast, colorectal and renal cancer lung metastasis cases). We identified four distinct histopathological growth patterns (HGPs) of lung metastasis (alveolar, interstitial, perivascular cuffing, and pushing), each of which vascularized via a different mechanism. In the alveolar HGP, cancer cells invaded the alveolar air spaces, facilitating the co‐option of alveolar capillaries. In the interstitial HGP, cancer cells invaded the alveolar walls to co‐opt alveolar capillaries. In the perivascular cuffing HGP, cancer cells grew by co‐opting larger vessels of the lung. Only in the pushing HGP did the tumours vascularize by angiogenesis. Importantly, vessel co‐option occurred with high frequency, being present in >80% of the cases examined. Moreover, we provide evidence that vessel co‐option mediates resistance to the anti‐angiogenic drug sunitinib in preclinical lung metastasis models. Assuming that our interpretation of the data is correct, we conclude that vessel co‐option in lung metastases occurs through at least three distinct mechanisms, that vessel co‐option occurs frequently in lung metastases, and that vessel co‐option could mediate resistance to anti‐angiogenic therapy in lung metastases. Novel therapies designed to target both angiogenesis and vessel co‐option are therefore warranted. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Whole-exome sequencing identifies ALMS1, IQCB1, CNGA3, and MYO7A mutations in patients with Leber congenital amaurosis

It has been well documented that mutations in the same retinal disease gene can result in different clinical phenotypes due to difference in the mutant allele and/or genetic background. To evaluate this, a set of consanguineous patient families with Leber congenital amaurosis (LCA) that do not carry mutations in known LCA disease genes was characterized through homozygosity mapping followed by targeted exon/whole-exome sequencing to identify genetic variations. Among these families, a total of five putative disease-causing mutations, including four novel alleles, were found for six families. These five mutations are located in four genes, ALMS1, IQCB1, CNGA3, and MYO7A. Therefore, in our LCA collection from Saudi Arabia, three of the 37 unassigned families carry mutations in retinal disease genes ALMS1, CNGA3, and MYO7A, which have not been previously associated with LCA, and 3 of the 37 carry novel mutations in IQCB1, which has been recently associated with LCA. Together with other reports, our results emphasize that the molecular heterogeneity underlying LCA, and likely other retinal diseases, may be highly complex. Thus, to obtain accurate diagnosis and gain a complete picture of the disease, it is essential to sequence a larger set of retinal disease genes and combine the clinical phenotype with molecular diagnosis.     

One‐Year Follow‐Up of Nonrandomized Comparison between Coronary Artery Bypass Grafting Surgery and Drug‐Eluting Stent for the Treatment of Unprotected Left Main Coronary Artery Disease in Elderly Patients (Aged ≥75 Years)

Purpose: The present observational study compares in‐hospital and 12‐month clinical outcomes in elderly patients with unprotected left main coronary artery disease treated either with coronary artery bypass grafting or drug‐eluting stent. Methods: From January 2004 to December 2007, 211 patients (pts) with unprotected left main coronary artery (ULMCA) stenosis, aged 75 or older, underwent coronary revascularization either with coronary artery bypass graft (CABG) (106 pts) or drug‐eluting stent (DES) (105 pts). The decision to treat with CABG or percutaneous coronary intervention (PCI) was dependent on the patient's and the physician's choice. The occurrence of major adverse cardiac or cerebrovascular events (MACCE: death, nonfatal myocardial infarction, or stroke) and revascularizations was recorded after 1 year of follow‐up. A multivariate logistic regression analysis was performed using a propensity score method to take potential baseline differences between groups into account. Results: In‐hospital MACCE rates were 5.7% and 3.8% in the CABG and PCI groups, respectively (P = 0.748). After 1 year of follow‐up, these rates were, respectively, 13.9% and 14.9% (P = 0.841), and rates for target vessel revascularization at 12 months were 1.0% and 13.9% (P < 0.001). The PCI group was significantly associated with older age, dyslipidemia, history of cancer, high Euroscore, elevated creatininemia, single‐vessel disease, fewer chronic occlusions of the left anterior descending artery, and more LMCA stenosis ≥70%. The multivariate logistic regression analysis was adjusted for age, diabetes, left ventricular ejection fraction, Euroscore, and plasma creatininemia and stratified on the score of propensity to be treated with PCI. In the subgroup below median propensity score, the adjusted odds ratio for 1‐year MACCE was OR = 0.91 (95% confidence interval: 0.14 to 5.98; P = 0.924) whereas OR was 0.16 (0.04–0.69; P = 0.013) in the subgroup above median propensity score. Conclusions: In patients with a high probability of being treated with PCI (older age, high Euroscore, high creatininemia, single‐vessel disease, …), the 1‐year risk of MACCE was significantly lower in PCI‐ than in CABG‐treated subjects. No significant difference was found in other cases.