Citations

Background and Study Aims. Endoscopic placement of self-expanding metal stents (SEMSs) is indicated for palliation of inoperable malignant biliary obstruction. A fully covered biliary SEMS (WallFlex Biliary RX Boston Scientific, Natick, USA) was assessed for palliation of extrahepatic malignant biliary obstruction.Patients and Methods. 58 patients were included in this prospective, multicenter series conducted under an FDA-approved IDE. Main outcome measurements included (1) absence of stent occlusion within six months or until death, whichever occurred first and (2) technical success, need for reintervention, bilirubin levels, stent patency, time to stent occlusion, and adverse events.Results. Technical success was achieved in 98% (57/58), with demonstrated acute removability in two patients. Adequate clinical palliation until completion of followup was achievedin 98% (54/55) ofevaluablepatients, with 1 reintervention due to stent obstruction after 142 days. Mean total bilirubin decreased from 8.9 mg/dL to 1.2 mg/dL at 1 month. Device-related adverse events were limited and included 2 cases of cholecystitis. One stent migrated following radiation therapy.Conclusions. The WallFlex Biliary fully covered stent yielded technically successful placement with uncomplicated acute removal where required, appropriate reduction in bilirubin levels, and low rates of stent migration and occlusion. This SEMS allows successful palliation of malignant extrahepatic biliary obstruction.

SummaryMyelofibrosis (MF) patients can present with a wide spectrum of disease characteristics. We analysed the consistency of ruxolitinib efficacy across patient subgroups in the COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment (COMFORT‐I,) a double‐blind trial, where patients with intermediate‐2 or high‐risk MF were randomized to twice‐daily oral ruxolitinib (n = 155) or placebo (n = 154). Subgroups analysed included MF subtype (primary, post‐polycythaemia vera, post‐essential thrombocythaemia), age (≤65, > 65 years), International Prognostic Scoring System risk group, baseline Eastern Cooperative Oncology Group performance status (0, 1, ≥2), JAK2 V617F mutation (positive, negative), baseline haemoglobin level (≥100, <100 g/l), baseline platelet count (100–200 × 109/l, >200 × 109/l), baseline palpable spleen size (≤10, >10 cm), and baseline quartile of spleen volume and Total Symptom Score (TSS; Q1 = lowest, Q4 = highest). Mean percentage change from baseline to week 24 in spleen volume and TSS were calculated for ruxolitinib and placebo in each subgroup. Overall survival was estimated by Kaplan–Meier method according to original randomization group. In ruxolitinib‐treated patients, reductions in spleen volume and TSS and evidence of improved survival relative to placebo across subgroups were consistent with those seen in the COMFORT‐I population, confirming that ruxolitinib is an effective therapy for the spectrum of MF patients studied in COMFORT‐I.

Purpose To assess the effects of ruxolitinib on symptom burden and quality of life (QoL) and to evaluate the ability of the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 to measure meaningful changes in myelofibrosis-related symptoms in patients with myelofibrosis. Patients and Methods COMFORT-I (Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment–I) is a double-blind, placebo-controlled phase III study evaluating ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis. Exploratory analyses were conducted on the following patient-reported outcomes (PROs) assessments: modified MFSAF v2.0 (individual symptoms and Total Symptom Score [TSS]), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and Patient Global Impression of Change (PGIC). Results Patients receiving ruxolitinib experienced improvements in individual myelofibrosis-related symptoms, although patients receiving placebo experienced worsening (P < .001). The majority (91%) of ruxolitinib-treated patients designated as ≥ 50% TSS responders (≥ 50% TSS improvement) self-reported their condition as either “Much improved” or “Very much improved” on the PGIC. These patients achieved significant improvements in the EORTC QLQ-C30 functional domains and Global Health Status/QoL versus patients receiving placebo, who experienced worsening on these measures (P ≤ .0135). Ruxolitinib-treated patients with a lesser degree of symptom improvement (< 50% TSS responders) also achieved improvements over placebo on these measures. The degree of spleen volume reduction with ruxolitinib correlated with improvements in TSS, PGIC, PROMIS Fatigue Scale, and EORTC Global Health Status/QoL. Ruxolitinib-treated patients who achieved a ≥ 35% reduction in spleen volume experienced the greatest improvements in these PROs. Conclusion Ruxolitinib-treated patients achieved clinically meaningful improvements in myelofibrosis-related symptoms and QoL, but patients receiving placebo reported worsening of symptoms and other PROs.

We report the case of a 66-year-old woman with tumor-induced osteomalacia (TIO) caused by fibroblast growth factor 23 (FGF-23) secreting mesenchymal tumor localized in a lumbar vertebra and review other cases localized to the axial skeleton. She presented with nontraumatic low back pain and spontaneous bilateral femur fractures. Laboratory testing was remarkable for low serum phosphorus, phosphaturia, and significantly elevated serum FGF-23 level. Magnetic resonance imaging (MRI) of the lumbar spine showed a focal lesion in the L-4 vertebra which was hypermetabolic on positron emission tomography (PET) scan. A computed tomography (CT) guided needle biopsy showed a low grade spindle cell neoplasm with positive FGF-23 mRNA expression by reverse transcriptase polymerase chain reaction (RT-PCR), confirming the diagnosis of a phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT). The patient elected to have surgery involving anterior resection of L-4 vertebra with subsequent normalization of serum phosphorus. Including the present case, we identified 12 cases of neoplasms localized to spine causing TIO. To our knowledge, this paper represents the first documented case of lumbar vertebra PMT causing TIO. TIO is a rare metabolic bone disorder that carries a favorable prognosis. When a lesion is identifiable, surgical intervention is typically curative.

AbstractSTAT3 regulates cell growth by up-regulating downstream targets, such as Myc. The frequency of phosphorylated STAT3 (pSTAT3) and Myc expression and their prognostic relevance is unknown within diffuse large B-cell lymphoma (DLBCL) germinal center B-cell (GCB) and non-GCB subtypes. pSTAT3 and Myc were studied by immunohistochemistry (IHC) on tumors from 40 DLBCL patients uniformly treated on a clinical trial of epratuzumab/rituximab-CHOP. A total of 35% of cases were pSTAT3-positive, and pSTAT3 positivity was more frequent in the non-GCB (P = .06) type but did not correlate with event-free survival (EFS). Myc expression was observed in 50% of cases and was more frequent in non-GCB type (P = .07). Myc-positive cases had inferior EFS in all patients, including the GCB and pSTAT3-positive cases, were more likely to express Myc (P = .06). Myc translocations involving the major breakpoint regions were found in 10% (3 of 29) of cases, and all 3 cases were GCB and had an inferior EFS (P = .09). pSTAT3, but not Myc expression, was correlated with elevated pretreatment serum cytokines, such as IL-10 (P = .05), G-CSF (P = .03), and TNF-α (P = .04). pSTAT3 IHC in DLBCL tumors has the potential to identify patients for STAT3 pathway–directed therapy; Myc IHC is a potential marker for inferior EFS in GCB patients.

AbstractGenetic aberrations, including trisomies 3 and 18, and well-defined IGH translocations, have been described in marginal zone lymphomas (MZLs); however, these known genetic events are present in only a subset of cases. Here, we report the cloning of an IGH translocation partner on chromosome X, t(X;14)(p11.4;q32) that deregulates expression of an poorly characterized orphan G-protein–coupled receptor, GPR34. Elevated GPR34 gene expression was detected independent of the translocation in multiple subtypes of non-Hodgkin lymphoma and distinguished a unique molecular subtype of MZL. Increased expression of GPR34 was also detected in tissue from brain tumors and surface expression of GPR34 was detected on human MZL tumor cells and normal immune cells. Overexpression of GPR34 in lymphoma and HeLa cells resulted in phosphorylation of ERK, PKC, and CREB; induced CRE, AP1, and NF-κB–mediated gene transcription; and increased cell proliferation. In summary, these results are the first to identify a role for a GPR34 in lymphoma cell growth, provide insight into GPR34-mediated signaling, identify a genetically unique subset of MZLs that express high levels of GPR34, and suggest that MEK inhibitors may be useful for treatment of GPR34-expressing tumors.

A Fine Balance Intellectual and neurological disabilities can arise from diverse developmental aberrations. Novarino et al. (p. 394 , published online 6 September; see the Perspective by Beaudet ) have now determined the genetic basis for one such disorder for a small group of patients. Exome sequencing led to identification of mutations in a kinase BCKDK ( Branched Chain Ketoacid Dehydrogenase Kinase ) that regulates metabolism of branched-chain amino acids such as valine, leucine, and isoleucine. Mice with homozygous mutations in the BCKDK gene showed developmental and neurological abnormalities resembling those in certain mouse autism models. Analysis of transport mechanisms responsible for carrying amino acids across the blood-brain barrier revealed competition between the branched-chain amino acids and large neutral amino acids. Nutritional supplementation with extra branched-chain amino acids in the diet of mice carrying homozygous mutations in the BCKDK gene normalized their phenotype.

Abstract Diffuse Large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma, and is associated with variable clinical presentation as well as variable response to standard chemotherapy regimens. Most significant advances in the treatment of DLBCL over the last 15 years, has been the addition of rituximab to standard chemotherapy. However, still 40% of patients relapse and succumbing to the disease. To improve clinical outcomes for DLBCL patients, it is urgent to identify novel molecular targets and stratify patients according to the expression of specific biomarkers that predict outcomes for the individual patient. Recently, it has been reported that the Signal transducer and activator of transcription 3 (STAT3) is over expressed in DLBCL human cell lines. However, no study has reported the STAT3 expression in DLBCL patient samples or its molecular subtypes (germinal centre B cell type (GCB) and Non-GCB cell type). The phosphorylation of STAT3 (pSTAT3) at its Tyr-705 residue (pSTAT3Tyr705) leads to its activation, followed by dimerization and translocation to the nucleus. Constitutively active STATs (particularly STAT3 and STAT5) contribute to the malignant phenotype in both human cancer cell lines and primary tumors. We hypothesize that constitutive STAT3 activity might be associated with drug resistance and adverse outcome in DLBCL patients. We determined whether STAT3 is constitutively active in patients with DLBCL, and whether activated STAT3 levels correlate with disease severity. Expression of total (tSTAT3) or tyrosine phosphorylated STAT3 (pSTAT3) was determined by in 40 DLBCL tumors. pSTAT3 was found in 52% (21/40) of cases with variable expression {18% low, (+); 25% moderate, (++); and 10% very high (+++)}. However 80% (32/40) of patients expressed tSTAT3. pSTAT3 was expressed in both germinal centre B cells (GCB) (46%) and Non-GCB (69%) DLBCL cases which were molecular subtyped by the Hans method. Furthermore in-vitro inhibition of STAT3 dephosphorylated STAT3 and caused an inhibitory effect on phospho-STAT3 positive DLBCL cells; there was minimal effect on phospho-STAT3 negative cells. Event free survival was lower in pSTAT3 positive compared to pSTAT3 negative DLBCL patients. In summary, our data provide the first evidence that over-expression of pSTAT3 is common in DLBCL, this expression does not clearly relate only to non-GCB tumors and therefore STAT3 inhibitors should be tested in all DLBCL. Pre-treatment assessment of pSTAT3 tumor status will be important to understand whether this IHC marker can preselect patients for response or lack of response to new JAK/STAT targeted agents such as TG101348 (Sanofi Aventis) and BMS-911543 (Bristol-Myers Squibb). Our findings suggest a potential novel therapeutic approach of targeting the inhibition of STAT3 activity in a majority of DLBCL patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2576. doi:1538-7445.AM2012-2576