Citations

Vascular compression is a well-established cause of cranial nerve neuralgic syndromes. A unique case is presented that demonstrates that vascular compression may be a possible cause of occipital neuralgia. A 48-year-old woman with refractory left occipital neuralgia revealed on magnetic resonance imaging and computed tomographic imaging of the upper cervical spine an atypically low loop of the left posterior inferior cerebellar artery (PICA), clearly indenting the dorsal upper cervical roots. During surgery, the PICA loop was interdigitated with the C1 and C2 dorsal roots. Microvascular decompression alone has never been described for occipital neuralgia, despite the strong clinical correlation in this case. Therefore, both sectioning the dorsal roots of C2 and microvascular decompression of the PICA loop were performed. Postoperatively, the patient experienced complete cure of her neuralgia. Vascular compression as a cause of refractory occipital neuralgia should be considered when assessing surgical options.

Cholangiocytes, epithelial cells lining the biliary tree, have primary cilia extending from their apical membrane into the ductal lumen. Although important in disease, cilia also play a vital role in normal cellular functions. We reported that cholangiocyte cilia are sensory organelles responding to mechanical stimuli (i.e., luminal fluid flow) by alterations in intracellular Ca 2+ and cAMP. Because cholangiocyte cilia are also ideally positioned to detect changes in composition and tonicity of bile, we hypothesized that cilia also function as osmosensors. TRPV4, a Ca 2+ -permeable ion channel, has been implicated in signal transduction of osmotic stimuli. Using purified rat cholangiocytes and perfused intrahepatic bile duct units (IBDUs), we found that TRPV4 is expressed on cholangiocyte cilia, and that hypotonicity induces an increase in intracellular Ca 2+ in a TRPV4-, ciliary-, and extracellular calcium-dependent manner. The osmosensation of luminal tonicity by ciliary TRPV4 induces bicarbonate secretion, the main determinant of ductal bile formation, by a mechanism involving apical ATP release. Furthermore, the activation of TRPV4 in vivo , by its specific agonist, 4αPDD, induces an increase in bile flow as well as ATP release and bicarbonate secretion. Our results suggest that cholangiocyte primary cilia play an important role in ductal bile formation by acting as osmosensors.

Purpose The traditional end point for assessing efficacy of first-line chemotherapies for advanced cancer is overall survival (OS), but this end point requires prolonged follow-up and is potentially confounded by the effects of second-line therapies. We investigated whether progression-free survival (PFS) could be considered a valid surrogate for OS in advanced colorectal cancer. Patients and Methods Individual patient data were available from 10 historical trials comparing fluouracil (FU) + leucovorin with either FU alone (1,744 patients) or with raltitrexed (1,345 patients) and from three validation trials comparing FU + leucovorin with or without irinotecan or oxaliplatin (1,263 patients). Correlation coefficients were estimated in historical trials between the end points of PFS and OS, and between the treatment effects on these end points. Treatment effects on OS were predicted in validation trials, and compared with the observed effects. Results In historical trials, 1,760 patients (57%) had progressed or died at 6 months, and 1,622 (52%) had died at 12 months. The rank correlation coefficient between PFS and OS was equal to 0.82 (95% CI, 0.82 to 0.83). The correlation coefficient between treatment effects on PFS and on OS ranged from 0.99 (95% CI, 0.94 to 1.04) when all trials were considered to 0.74 (95% CI, 0.44 to 1.04) after exclusion of one highly influential trial. In the validation trials, the observed OS hazard ratios were within the 95% prediction intervals. A hazard ratio of 0.77 or lower in terms of PFS would predict a benefit in terms of OS. Conclusion PFS is an acceptable surrogate for OS in advanced colorectal cancer.

AbstractCentrosome amplification is common in myeloma and may be involved in disease pathogenesis. We have previously derived a gene expression–based centrosome index (CI) that correlated with centrosome amplification and was an independent prognostic factor in a small cohort of heterogeneously treated patients. In this study, we validated the prognostic significance of the CI in 2 large cohorts of patients entered into clinical trials and showed that a high CI is a powerful independent prognostic factor in both newly diagnosed and relapsed patients, whether treated by intensive therapy (total therapy II) or novel agents (bortezomib). Tumors with high CI overexpressed genes coding for proteins involved in cell cycle, proliferation, DNA damage, and G2-M checkpoints, and associated with the centrosome and kinetochore/ microtubules. In particular, aurora kinases are significantly overexpressed in patients with high CI, with concordant increase in protein expression. Human myeloma cell lines with higher CI are more responsive to treatment with a novel aurora kinase inhibitor. Aurora kinase may represent novel therapeutic targets in these patients with very poor prognosis.

JAK2V617F is an acquired mutation associated with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). We tested the hypothesis that the paradox of a single disease allele associated with 3 distinctive clinical phenotypes could be explained in part by host-modifying influences. We screened for genetic variation within 4 candidate genes involved in JAK-STAT signaling, including receptors for erythropoietin (EPOR), thrombopoietin (MPL), and granulocyte colony-stimulating factor (GCSFR), and JAK2. We genotyped 32 linkage disequilibrium tag single nucleotide polymorphism (SNP) loci in 179 white patients: 84 had PV, 58 had PMF, and 37 had ET. Genotype-phenotype analysis showed 3 JAK2 SNPs (rs7046736, rs10815148, and rs12342421) to be significantly but reciprocally associated with PV (P < .001 for all; odds ratio = 0.16, 2.72, and 2.46, respectively) and ET (P < .001 for all; odds ratio = 3.05, 0.29, and 0.30, respectively) but not with PMF. Three additional JAK2 SNPs (rs10758669, rs3808850, and rs10974947) and a single EPOR SNP (rs318699) were also significantly associated with PV but not with ET or PMF. Finally, intragene haplotypes in JAK2 were significantly associated with PV only. Thus, host genetic variation may contribute to phenotypic diversity among myeloproliferative disorders, including in the presence of a shared disease allele.

Abstract The frequency of colorectal cancer (CRC) among the Alaska Native people is the highest of any ethnic group in the United States. In this study, CRC from 329 Alaska Native people (165 Eskimo, 111 Indians, and 53 Aleut) were evaluated for evidence of defective DNA mismatch repair (MMR) by testing tumors for altered protein expression (hMLH1, hMSH2, and hMSH6) and for the presence of microsatellite instability. Of the 329 samples tested, 46 (14%) showed both microsatellite instability and altered protein expression; 42 (91%) with a loss of hMLH1, 3 (7%) hMSH2, and 1 (2%) hMLH1/hMSH6. Tumors with loss of hMLH1 were further evaluated for hMLH1 promoter hypermethylation and for the presence of the BRAF-V600E mutation. Among cases tested, all 19 (100%) tumors among the Eskimo patients showed hMLH1 promoter hypermethylation, whereas this was the case for only 3 of the 7 (42%) tumors among the Aleut (P = 0.002) and 5 of the 10 (50%) tumors from the Indians (P = 0.002). The majority of hypermethylated cases (23 of 27) tested positive for the V600E alteration. Of the nine tumors from the Aleut and Indian patients that did not exhibit hMLH1 hypermethylation, eight tested negative for V600E. Overall, the frequency of defective MMR among the three groups was not statistically different (P = 0.75). However, the data suggest that the pathogenesis of CRC may differ between the three groups. The CRC with defective MMR among the Eskimo sample fit the typical profile for hMLH1-related cancer associated with sporadic CRC, whereas the pattern in the Aleut and Indian suggests the possibility that germ line hMLH1 mutations may be present. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2344–50)

AbstractPrevious epidemiologic studies have reported that a history of allergy is associated with reduced risk of colorectal cancer and other malignancies. We studied the association between allergy history and incident colorectal cancer (n = 410) prospectively in 21,292 Iowa women followed for 8 years. Allergy was defined from four self-reported questions about physician-diagnosed asthma (a), hay fever (b), eczema or allergy of the skin (c), and other allergic conditions (d). A history of any allergy was inversely associated with incident colorectal cancer: after multivariate adjustment, the hazard ratio (HR) was 0.74 [95% confidence interval (95% CI), 0.59-0.94]. Compared with women with no allergy, women reporting only one of the four types of allergy and women reporting two or more types had HRs of 0.75 (95% CI, 0.56-1.01) and 0.58 (95% CI, 0.37-0.90), respectively (P trend = 0.02). The inverse association persisted in analyses restricted to any type of nonasthmatic allergy (HR, 0.73; 95% CI, 0.56-0.95). HRs were similar for rectal and colon cancers as well as for colon subsites: proximal and distal (HRs for any allergy ranged from 0.63 to 0.78 across these end points). Allergy history, which may reflect enhanced immunosurveillance, is associated with a reduced risk of colorectal cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2357–62)

The role of B-cell receptor (BCR)–mediated survival signals in diffuse large B-cell lymphoma (DLBCL) remains undefined. Ligand-induced BCR signaling induces receptor oligomerization, Igα/β immunoreceptor tyrosine-based activation motif (ITAM) phosphorylation, and activation of the spleen tyrosine kinase (SYK), which initiates downstream events and amplifies the initial BCR signal. BCRs also transmit low-level tonic survival signals in the absence of receptor engagement. Herein, we assess the role of SYK-dependent tonic BCR survival signals in DLBCL cell lines and primary tumors and evaluate the efficacy of an ATP-competitive inhibitor of SYK, R406, in vitro. R406 induced apoptosis of the majority of examined DLBCL cell lines. In R406-sensitive DLBCL cell lines, R406 specifically inhibited both tonic- and ligand-induced BCR signaling (autophosphorylation of SYK525/526 and SYK-dependent phosphorylation of the B-cell linker protein [BLNK]). The majority of examined primary DLBCLs also exhibited tonic- and ligand-induced BCR signaling; in these primary tumors, BCR signaling was also inhibited by R406. Of note, BCR-dependent and R406-sensitive DLBCL cell lines were independently identified as “BCR-type” tumors by transcriptional profiling. Therefore, SYK-dependent tonic BCR signaling is an important and potentially targetable survival pathway in some, but not all, DLBCLs. In addition, R406-sensitive DLBCLs can be identified by their transcriptional profiles.

Abstract Combination chemotherapy regimen incorporating CD20 antibodies are commonly used in the treatment of CD20-positive non–Hodgkin's lymphoma (NHL). Fludarabine phosphate (F-araAMP), cyclophosphamide, and CD20 antibodies (Rituximab) constitute the FCR regimen for treating selected NHL, including aggressive mantle cell lymphoma (MCL). As an alternative to the CD20 antibody, we generated a CD20-targeted measles virus (MV)–based vector. This vector was also armed with the prodrug convertase purine nucleoside phosphorylase (PNP) that locally converts the active metabolite of F-araAMP to a highly diffusible substance capable of efficiently killing bystander cells. We showed in infected cells that early prodrug administration controls vector spread, whereas late administration enhances cell killing. Control of spread by early prodrug administration was also shown in an animal model: F-araAMP protected genetically modified mice susceptible to MV infection from a potentially lethal intracerebral challenge. Enhanced oncolytic potency after extensive infection was shown in a Burkitt's lymphoma xenograft model (Raji cells): After systemic vector inoculation, prodrug administration enhanced the therapeutic effect synergistically. In a MCL xenograft model (Granta 519 cells), intratumoral (i.t.) vector administration alone had high oncolytic efficacy: All mice experienced complete but temporary tumor regression, and survival was two to four times longer than that of untreated mice. Cells from MCL patients were shown to be sensitive to infection. Thus, synergy of F-araAMP with a PNP-armed and CD20-targeted MV was shown in one lymphoma therapy model after systemic vector inoculation. [Cancer Res 2007;67(22):10939–47]