Spleen Length Research Articles

Effect of Rapamycin on Spleen Size in Longstanding Renal Transplant Recipients

BackgroundBased on evidence available in the literature, rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, but not calcineurin inhibitors (CNIs), has been shown to decrease spleen size. Small spleen, in some instances, is associated with hyposplenism, a condition recently reported in patients with longstanding renal transplant. Accordingly, the effect of immunosuppressive drugs on spleen size was evaluated. MethodsRenal transplant recipients (35 taking mTOR and 68 CNI) were included, in whom a standardized investigation of the kidney allograft and spleen with the use of color Doppler ultrasound was performed and a peripheral smear were reviewed for the presence of Howell-Jolly bodies (HJBs). ResultsWe enrolled 103 patients (64 men; 66 from a deceased donor). The mean age was 47.7 years (range, 23.0–74.0 y). Mean transplant duration was 1,899 days (range, 181–6,883 d). According to the presence of HJBs, the prevalence of hyposplenism was 47.6% for the entire cohort. The differences between the mTOR and CNI groups regarding sex and the presence of HJBs were not statistically significant (P > .05). Age, creatinine, hemoglobin, leukocytes, platelets, and Doppler parameters in spleen and kidney were similar in both groups (P > .05). mTOR patients had a decreased spleen length size (90.09 ± 13.02 mm vs 111.95 ± 18.66 mm; P < .001), a longer transplant duration (3,576 ± 1,594 d vs 1,036 ± 1,369 d; P < .001) and higher serum cholesterol (227.50 ± 38.75 mg/dL vs 182.67 ± 37.74 mg/dL; P < .001) and triglycerides (194.23 ± 79.88 mg/dL vs 148.70 ± 55.54 mg/dL; P = .003) levels compared with the CNI group. A multivariate analysis showed mTOR inhibitor to be the most important predictor of spleen size. In both the mTOR and CNI groups, the comparison between the subgroups of present and absent HJBs did not show any difference. ConclusionsThe findings of this study suggest that small spleens in transplant recipients may be linked to treatment with an mTOR inhibitor, although this apparently does not compromise splenic function.

Efficacy of a vaccine for Angiostrongylus costaricensis against rat lungworm disease caused by A. cantonensis in wild Hawaiian Rats (Rattus rattus) (VAC7P.978)

Abstract The nematode Angiostrongylus cantonensis is a rat lungworm, a zoonotic pathogen which causes a global, emerging infectious disease known as rat lungworm disease (RLWD). RLWD has been reported in 30 countries, and Hawaii is the epicenter for RLWD in the United States. We conducted a study in wild Hawaiian rats (Rattus rattus) to determine the efficacy of a vaccine developed against a related species (A. costaricensis). Twenty-eight wild adult rats were captured from Waiakea Forest Reserve on the Island of Hawaii. Rats were mated and 41 F1 offspring were vaccinated with two doses of PP2A vaccine, a serine/threonine phosphatase 2A recombinant peptide (4 µg vaccine and 4 µg adjuvant/25 g body weight) at &amp;gt;3 mos. of age. Rats were gavaged with 50 L3 stage larvae at four weeks post-vaccination. Rats were euthanized and necropsies conducted at 51-53 days PI. Spleen weight, spleen length, and lung weight were recorded and number of worms in heart and lungs counted. Adult worms were found in all F1 rats. An average of 20.88 worms/rat reached adulthood with an infective dose of 50 L3 stage larvae. We found no significant differences between vaccinated rats (n=21) and unvaccinated rats (n=20) in spleen weight (p=0.963), spleen length (p=0.830), lung weight (p=0.830) or number of worms collected from the heart and lungs (p=0.882), suggesting the vaccine does not provide adequate protective immunity to guard against infection by A. cantonensis in wild Hawaiian rats.

Prediction of Esophageal Varices in Patients with Cirrhosis: Usefulness of Three-dimensional MR Elastography with Echo-planar Imaging Technique

To determine the diagnostic performance of magnetic resonance (MR) elastography in comparison to spleen length and dynamic contrast material-enhanced (DCE) MR imaging in association with esophageal varices in patients with liver cirrhosis by using endoscopy as the reference standard. This retrospective study received institutional review board approval, and informed consent was waived. One hundred thirty-nine patients with liver cirrhosis who underwent liver DCE MR imaging, including MR elastography, were included. Hepatic stiffness (HS) and spleen stiffness (SS) values assessed with MR elastography, as well as spleen length, were correlated with the presence of esophageal varices and high-risk varices by using Spearman correlation analysis. The diagnostic performance of MR elastography was compared with that of DCE MR imaging and combined assessment of MR elastography and DCE MR imaging by using receiver operating characteristic analysis. MR elastography reproducibility was assessed prospectively, with informed consent, in another 15 patients by using intraclass correlation coefficients. There were significant positive linear correlations between HS, SS, and spleen length and the grade of esophageal varices (r = 0.46, r = 0.48, and r = 0.36, respectively; all P < .0001). HS and SS values (>4.81 kPa and >7.60 kPa, respectively) showed better performance than did spleen length in the association with esophageal varices (P = .0306 and P = .0064, respectively). Diagnostic performance of HS and SS in predicting high-risk varices was comparable to that of DCE MR imaging (P = .1282 and P = .1371, respectively). When MR elastography and DCE MR imaging were combined, sensitivity improved significantly (P = .0004). MR elastography was highly reproducible (intraclass correlation coefficient > 0.9). HS and SS are associated with esophageal varices and showed better performance than did spleen length in assessing the presence of esophageal varices. MR elastography is comparable to DCE MR imaging in predicting the presence of esophageal varices and high-risk varices, but, when assessed in combination, sensitivity is higher.

Quantitative assessment of the presence and severity of cirrhosis in patients with hepatitis B using right liver lobe volume and spleen size measured at magnetic resonance imaging.

ObjectiveTo determine whether right liver lobe volume (RV) and spleen size measured utilizing magnetic resonance (MR) imaging could identify the presence and severity of cirrhosis in patients with hepatitis B.MethodsTwo hundred and five consecutive patients with clinically confirmed diagnosis of cirrhosis due to hepatitis B and 40 healthy control individuals were enrolled in this study and underwent abdominal triphasic enhanced scans using MR imaging. Spleen maximal width (W), thickness (T) and length (L), together with RV and spleen volume (SV), were measured utilizing MR imaging. Spleen multidimensional index (SI) was obtained by multiplying previously acquired parameters W×T×L. Then statistical assessment was performed to evaluate the ability of these parameters, including RV, SV, RV/SV and SI, to identify the presence of cirrhosis and define Child-Pugh class of this disease.ResultsSV and SI tended to increase (r = 0.557 and 0.622, respectively; all P<0.001), and RV and RV/SV tended to decrease (r = −0.749 and −0.699, respectively; all P<0.001) with increasing Child-Pugh class of cirrhosis. All the parameters, including RV, SV, RV/SV and SI, might be the indicators used to discriminate the patients with liver cirrhosis from the control group, and to distinguish these patients between Child-Pugh class A and B, between B and C, and between A and C (area under receiver operating characteristic curve [AUC] = 0.609–0.975, all P<0.05). Among these parameters, RV/SV was the best noninvasive factor for the discrimination of liver cirrhosis between Child-Pugh class A and B (AUC = 0.725), between A and C (AUC = 0.975), and between B and C (AUC = 0.876), while SI was the best variable to distinguish the cirrhosis patients from the control group (AUC = 0.960, P<0.05).ConclusionRV/SV should be used to identify the severity of cirrhosis, while SI can be recommended to determine the presence of this disease.

WHO Clinical Molecular and Pathological (WHO-CMP) Features of Congenital MPLS505N and the Acquired MPLW515l/K Mutated Essential Thrombocythemia and Myelofibrosis

We analysed the clinical and hematological features in 41 patients of seven families, including 21 ET patients with a proven MPLS505N mutation and 20 relatives with thrombocythemia reported in the medical records. Out of the 41 MPL S505N mutated individuals 15 major thrombotic episodes in 14 members (34%) were reported as Budd-Chiari syndrome age 17 in 1, deep vein thrombosis leg age 41 in 1,ecclampsia and fetal in 1, stroke at ages 43, 72, 76 and 80 in 4 and myocardial infarction at ages between 31-81 years, median 52 years. Fourteen out of 21 well documented MPLS505N mutated ET patients had no splenomegaly and were free of major thrombosis during follow-up at ages between 2 and 76 years (mean 31 years). Eight MPLS505N mutated patients had myelofibrosis (MF) from grade MF1 in 5 to grade MF2 in 3 at ages between 28-80 years (mean 48 years), which was associated with mild to moderate splenomegaly (spleen length diameter 14.5 to 18 cm). Six anemic cases at hemoglobin levels between 10 and 11.9 g/dL had platelet counts between 317 and 963 × 10 9 /L. Among 15 family members 9 died from thrombosis in 3, hypocellular myelofibrosis (two of them at age 76 and 80 years) in 3, and cancer or undefined in 3 cases. The maximum life expectancy of MPLS505N family members with thrombocythemia was 50% at 80 years, and 90% at 80 years of non-affected family members without thrombocythemia. The clinical presentation in 30 ET patients with acquired MPL 505N mutation (9 males and 21 females, age 22-84 (mean 56 years of whom 18 had the W 515L and 12 the W 515K ) was featured by a high incidence of major arterial event in 23%, venous thrombosis in 10%, aspirin responsive microvessel disturbances in 60%, and major hemorrhage in 7%. The only abnormal laboratory finding in MPL mutated ET was increased platelet counts, 956+331 × 109/L in all and slight splenomegaly in 5 (17%). Bone marrow histology from patients ET carrying the MPL 505N mutation consistently displayed a normocellular bone marrow with clustered small and large to giant megakaryocytes with hyperlobulated stag-horn nuclei and no features of polycythemia vera (PV) in blood and bone marrow.

Sonographic assessment of the normal limits of the spleen in healthy school children in South-East Nigeria.

Ultrasonogrphy is a good modality for the detection of splenomegaly even when it is not clinically palpable. The objective of this study was to establish the normal values of splenic length in healthy school children in South-East, Nigeria and to correlate them with body indices. This is a cross-sectional prospective study of 1315 children (633 boys and 682 girls) between the ages of 5 and 17 years. The splenic length was measured between the most superiomedial and the most inferiolateral margins, at the level of the hilum. Only the spleens that had normal shape and echotexture were measured. The mean splenic length and the 5 th and 95 th percentiles were determined for each age. The length was correlated with the sex, age, weight (WT), height, body mass index (BMI) and body surface area (BSA) of the subjects. A regression model for prediction of spleen dimension from age and body habitus was computed. There was a significant correlation between splenic length and age, P < 0.001. Males had statistically significant longer spleen length than females. The splenic length correlated best with BSA, followed by body WT and least with BMI. This study noted racial variation between the established Nigerian values and results from other countries of the world. For the first time, a baseline value for splenic size for the Nigerian Children of various ages has been established with a regression model for predicting the splenic sizes.

Clinical study of free auxiliary device of hand assisted laparoscopic splenectomy and intraoperative autologous splenic blood transfusion

Objective To investigate the feasibility and advantage of hand assisted laparoscopic splenectomy for giant spleens without auxiliary device and the clinical value of intraoperative autologous splenic blood transfusion.Methods From October 2007 to October 2011,48 cases of liver cirrhosis splenomegaly were analyzed retrospectively according to operation method including hand assisted laparoscopic splenectomy group with free auxiliary device (HALS) (n =30) and conventional laparoscopic splenectomy (CLS) (n =12),and they were divided into two groups:severe splenomegaly group (the length of the spleen more than 20 cm) and moderate splenomegaly (the length of the spleen less than 20 cm).The intraoperative bleeding,operation time,the spleen removal time and transit operation rate were compared in these patients.The blood transfusion machine was used for autologous splenic blood transfusion.Results Free auxiliary device saved at least 2000 yuan without affecting the maintenance of pneumoperitoneum during operation.There was no significant difference in the average blood loss between HALS group and CLS group [(88.1 ± 16.3) ml vs.(107.5 ± 11.6) ml,P ＞0.05].The average operation time was significantly shorter [(75.2 ± 13.3) min vs.(120.7 ± 20.5) min,P ＜ 0.05],and the spleen removal time was markedly shorter [(8.0 ±3.1) min vs.(25.2 ±2.8) min,P ＜0.05] in HALS group than in CLS group.The transit operation rate of severe splenomegaly (50％) was significantly higher than moderate splenomegaly (20％) (P ＜ 0.01),and the intraoperative bleeding too [(103.8 ± 25.0) ml vs.(70.4 ± 10.3) ml,P ＜0.01].Intraoperative autologous splenic blood transfusion significantly elevatedf hemoglobin level on the first day after operation [(2.07 ± 0.25) g/L,P ＜ 0.05].Conclusion HALS significantly facilitates the surgical procedure and reduces the operational risk,while maintaining the advantages of CLS.Hand-assisted laparoscopic splenectomy is a safe and effective technique especially for the management of severe splenomegaly.Intraoperative autologous splenic blood transfusion shows obvious special advantage in ascending hemoglobin. Key words: Hand-assisted laparoscopic splenectomy; Splenomegaly; Splenic blood transfusion

Efficacy Of Ruxolitinib In Korean Myelofibrosis Patients and Cases Complicated TB Lymphadenitis During The Treatment

IntroductionRuxolitinib is a selective JAK 1/2 inhibitor, which shows an excellent treatment outcome in myelofibrosis (MF) patients. Main side effect of JAK 1/2 inhibitors is an increased risk of infection. JAK1/2 inhibition may interfere with the differentiation of interferon-γ (IFN-γ) producing Th1 cells and IFN-γ is a key cytokine involved in protective immunity against Mycobacterium tuberculosis(TB). During COMPORT-II trial, a case of disseminated TB with ruxolitinib was reported. Here, we analyze the efficacy and safety of ruxolitinib in Korean MF patients and report cases of TB lymphadenitis during the treatment. MethodsForty-nine patients diagnosed with PMF, PPV-MF or PET-MF have been enrolled and at this time twenty patients are evaluable (median age; 63 years, 37-80). Starting dose of ruxolitinib was determined based on each patient's baseline platelet count (20 mg bid/d for a baseline platelet more than 200,000/µL, 15 mg bid/d for 100,000-200,000/uL). To determine the efficacy of ruxolitinib, we serially assessed the spleen size by palpation, myelofibrosis symptom assessment using MFSAF and BM examination with JAK2V617Fmutation allele burden. Among 20 evaluable patients, 16 assessed IFN-γ release assays (IGRAs, quantiFERON-TB Gold test) before starting ruxolitinib. ResultsOf total twenty patients, 12 (60.0%), 3 (15.0%) and 5 (25.0%) were PMF, PPV-MF and PET-MF, respectively. By DIPSS, 13 (65.0%) was Int-2 risk, 3 (15.0%) and 4 (20.0%) were Int-1 and high risk. Eleven patients started with 20 mg bid/d (median baseline platelet: 302,000/uL, 206,000-814,000) and nine were 15 mg bid/d (median; 139,000/uL, 100,000-194,000). Median baseline total symptom score (TSS) was 12 (1-36) and palpable spleen length was 19 cm (1-30). JAK2V617Fmutation was positive in 13 (65.0%) patients (median allele burden; 87.1%, 26.2-93.7). Median time of ruxolitinib exposure was 2.0 ms. (0.8-6.2). Two patients increased TSS following ruxolitinib treatment, however, median maximal reduction in TSS was above 90.9% (27.8-100) and 64.7% of patients showed more than 50% reduction of TSS with ruxolitinib. In an aspect of spleen length, all except two patients showed decreased palpable spleen length. Median maximal reduction in spleen length was 70.2% (0-100) and 72.2% of patients showed more than 35% reduction in spleen length with ruxolitinib. Three patients (15.0%) experienced gr. 3/4 thrombocytopenia and one (5.0%) gr. 3 neutropenia. Among patients who assessed pre-treatment IGRAs, only one revealed positive IGRAs. Since there was no evidence of active TB in symptom and radiologic examination, he was diagnosed as latent TB infection (LTBI) and started 9 ms.-isoniazid (INH) treatment. He had a huge hepatosplenomegaly combined with large amount of ascites which needed frequent paracentesis, hence, we started ruxolitinib with INH treatment. He showed no evidence of active TB and achieved negative IGRAs result on 5 ms. of ruxolitinib treatment. On 1 m. and 5 ms. of ruxolirinib treatment, two patients developed pyrexia and neck masses which were diagnosed as TB lymphadenitis. All of them had no previous history of TB and showed negative results in pre-treatment IGRAs and radiologic examinations. First patient discontinued ruxolitinib by herself and eventually died of MF progression 2 ms. later. Second patient continued ruxolitinib treatment with TB medication and there was no evidence of active TB or MF progression on 5 ms. of ruxolitinib treatment. ConclusionsRuxolitinib was generally well tolerated and showed an excellent treatment outcome in Korean MF patients. By 2008 WHO report, intermediate burden of TB cases exist in Korea, hence, TB is still endemic in Korea. According to 2011 Korean Guidelines for TB, LTBI should be treated in patients receiving immunosupressive agents including TNF-α inhibitors. Although further prospective investigations on the incidence of TB with JAK 1/2 inhibitors in TB endemic countries are warranted, it seems to be reasonable to check the possibility of LTBI before starting JAK 1/2 inhibitors. LTBI confirmed patients receiving JAK 1/2 inhibitors may be deemed a high risk of active TB and consider LTBI treatment. Furthermore, it is necessary to use a caution for active TB infection during the treatment of JAK 1/2 inhibitors in such countries. Disclosures:No relevant conflicts of interest to declare.

A Phase 2 Study Of Ruxolitinib In Patients With Splanchnic Vein Thrombosis Associated With Myeloproliferative Neoplasm. Preliminary Results

Philadelphia-negative Myeloproliferative Neoplasms (MPN) include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Myelofibrosis, both Primary (PMF) and secondary to PV or ET (PPV-MF and PET-MF). A MPN is frequently the underlying cause of splanchnic vein thrombosis (SVT), accounting for 31.5% of portal vein thrombosis (PVT) and 40.9% of Budd Chiari syndrome (BCS). In patients (pts) with MPN and SVT, splenomegaly can arise as the consequence of the hematological disease and/or blood flow abnormalities consequent to the thrombosis itself. Splenomegaly and the compensatory enlarged splanchnic vessels are responsible for several complications including esophageal and gastric varices. Splenomegaly may cause abdominal discomfort; furthermore pts may present symptomatic burden due to the MPN. Current treatment strategies for MPN pts with SVT include anticoagulants and cytoreductive therapy (ie hydroxyurea, interferon) that have little influence in the control of splenomegaly and symptoms and do not improve flow abnormalities. Ruxolitinib, a JAK1/2 inhibitor, was highly effective in reducing spleen volume and improving symptoms in patients with MF and PV in phase II and III studies. We hypothesized that the decrease of the enlarged spleen determined by Ruxolitinib could result in a reduction of the local pressure in splanchnic vessels, producing both symptomatic improvement of splenomegaly-related symptoms and of splanchnic circulation. We designed an investigator-initiated multicentre phase 2 study of Ruxolitinib in pts with splenomegaly due to an underlying MPN associated with SVT. The drug was provided free of charge by Novartis, that had no role in trial design nor in data analysis. The primary study objective was to evaluate the proportion of subjects achieving ≥ 50% reduction in spleen length from left costal margin (LCM) measured by palpation at any time from baseline to week 24 (w24) and at w24, or a ≥ 35% reduction in spleen volume by MRI or CT at week 24. The secondary objectives included: evaluation of safety of Ruxolitinib in MPN-associated SVT; assessment of splanchnic circulation through Doppler analysis, measurement of hyperdynamic arterial circulation by echocardiography and stiffness of hepatic/splenic parenchyma by fibroscan; status of esophageal varices at w24 compared to baseline. Quality of Life assessment was performed using MPN-SAF questionnaire. Exploratory objectives include evaluations of changes in JAK2V617F or MPLW515 allelic burden, association of baseline mutations with response to treatment, changes in cytokine and microRNAs profiles, quantification of circulating endothelial cells. At the time of abstract submission 7 out of 21 pts have been enrolled, of which 5 completed the 24 weeks of treatment; two additional pts are in screening phase. Three pts had PMF, two ET, one PV and one PPV-MF, associated to spleno-porto-mesenteric thrombosis (5 pts) and Budd Chiari syndrome (2 pts). All pts were under oral anticoagulation therapy. Initial dose of Ruxolitinib was 10 mg BID for PV, 25 mg BID for ET, 15 mg BID for MF pts with baseline platelet count of 100 to 200x109/L and 20 mg BID for those with baseline platelet count >200x109/L. A palpable splenomegaly greater than 5 cm below LCM was a criterion for enrollment; the 5 patients who completed the 24 weeks of treatment had a median splenomegaly of 8 cm below LCM at baseline, and obtained a median reduction of 69% measured by palpation at week 24, associated with a significant reduction in abdominal discomfort as measured by MPN-SAF questionnaire (median score at screening 5 vs 1.5 at week 24). The total symptom score calculated by using BFI and MPN-SAF was reduced from 50 at screening to 35 at week 24. Instrumental evaluations of splanchnic and systemic circulation showed that 3 pts obtained a reduction of the spleen stiffness from a median value of 66 to 49.6 kilopascals (KPa), 2 pts had a reduction of the liver stiffness from a median value of 23.85 to 18.2 KPa and 1 pt a reduction of the cardiac output from 5.871 to 4.6 L/min. Evaluation of esophageal varices at week 24 showed stabilization with neither worsening nor need of banding. Ruxolitinib was well tolerated, with no SAE reported; one pt developed anemia G2 and one G3 leading to dose reduction. Other adverse events include G1 asthenia and G≤2 AST/ALT increase in 3 pts, one case of Herpes Zoster and one case of abdominal pain both G1. Updated results will be presented at the meeting. Disclosures:Marchioli:Novartis: Research Funding; Ospedali Riuniti di Bergamo: Research Funding; AIFA (Italian Regulatory Agency): Research Funding; AMGEN S.p.A.: Research Funding; Genzyme Olanda: Research Funding; Gruppo Italiano Trapianti di Midollo (GITMO): Research Funding; Pierre Fabre Italia S.p.A.: Research Funding; Università Cattolica del Sacro Cuore, Roma: Research Funding; Sigma-Tau: Research Funding; Myeloproliferative disorder Research Consortium: Research Funding; Celgene: Research Funding; Associazione Italiana Linfomi (AIL): Research Funding; Fondazione Italiana Linfomi (FIL): Research Funding; LaRoche: Research Funding; Università degli Studi di Firenze: Research Funding. Vannucchi:NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Rapid Clearance Of JAK2 V617F Allele Burden In Patient With Advanced Polycythemia Vera (PV) During Combination Therapy With Ruxolitinib and Peg-Interferon Alpha-2a

BackgroundTreatment with pegylated interferon-alpha2 (IFN) is associated with complete hematologic remissions (CHR) in a large majority of patients with essential thrombocythemia (ET) and PV. In a subset of patients, IFN can induce major molecular remissions that can be sustained for up to 4 years after discontinuation of therapy. In hypercellular myelofibrosis (MF), IFN may also induce regression of bone marrow fibrosis. To this end, long-term IFN treatment with normalization of elevated blood counts is accompanied by a reduced risk of thrombosis and hemorrhage. When initiated at the early disease stage, IFN may have the greatest chance to induce “minimal residual disease” with a low JAK2 V617F allele burden. For these reasons, IFN is foreseen to be a cornerstone in the treatment of these neoplasms. Ruxolitinib (RUX) is a JAK1-2 inhibitor that is highly efficacious in alleviating hypermetabolic symptoms and enlarged spleens in patients with MF. Although the earliest reports suggested that RUX did not significantly lower JAK2 V617F mutational load, newer findings clearly show that in a subset of patients RUX may indeed profoundly decrease JAK2 V617F allele burden; these reductions could be even larger if treatment is instituted in early stages of MF or PV. Preliminary data show RUX to be highly efficacious in PV as well. With both drugs having potent antiproliferative and anti-inflammatory effects, combination therapy with IFN and RUX may potentially promote tumor regression in MPNs, as assessed by rapid induction of CHR, reduction in spleen size, and enhanced reduction of JAK2 V617F allele burden. Case reportA 55-year-old woman with PV diagnosed in the precursor stage of ET 12 years ago was referred for a second opinion due to intolerance of hydroxyurea (HU; monosymptomatic fever) and pegylated interferon-alpha2b (PEG-Intron; exanthema). The patient had suffered 2 episodes of transitory ischemic attack (TIA) since 2009, and therefore, permanent treatment with clopidogrel had been instituted. Several CT scans were normal. At the time of referral, the patient was receiving anagrelide and clopidogrel. The patient's hemoglobin was 11.9 g/dL, her leukocyte count was 21.9 x 109/L, and platelets were elevated at 526 x 109/L. CRP levels were normal. An abdominal ultrasound revealed a spleen length of 20 cm, causing intermittent pain and abdominal discomfort. Because of hypermetabolic symptoms, pronounced abdominal discomfort, and intolerance of PEG-Intron and HU, treatment with RUX was initiated at a dose of 20 mg twice daily. Within the first 3 days of RUX therapy, the patient experienced remarkable clinical improvement with resolution of severe fatigue, night sweats, abdominal pain, and pruritus, which had negatively impacted the patient's quality of life during the past 2 to 3 years. Four days after starting RUX, the patient experienced acute TIA-like symptoms with transient decrease of strength in the left arm and abnormal sensations in the left half of the tongue and neck. The symptoms were similar to those that the patient experienced during previous TIAs. The blood values disclosed a slight decrease in the leukocyte count (17.6 x 109/L) and an increase in the platelet count (573 x 109/L). A CT scan was normal. Consequently, RUX therapy was combined with PEG-IFN-alpha2a (Pegasys) at a very low dose of 45 µg every second week. After 1 month, a CHR was achieved (Figure 1), and after 2.5 months, an abdominal ultrasound showed a spleen length reduction from 20 to 13.8 cm. After 6 months, the spleen was no longer palpable. The patient had no need of phlebotomies during treatment with RUX and Pegasys. The combination therapy was exceedingly well tolerated without any side effects to either drug. Remarkably, despite an advanced PV stage, JAK2 V617F allele burden was rapidly lowered from 90% mutated alleles at referral to 59% at 6 months and 20% within 1 year (Figure 2). [Display omitted] ConclusionThis case report demonstrates for the first time that combination therapy with RUX and “low–low-dose” Pegasys is highly efficacious in rapidly reducing JAK2 V617F allele burden in concert with achieving CHR and resolution of splenomegaly. This observation warrants prospective trials of this combinatorial approach in patients with PV and hyperproliferative MF to assess whether combination therapy induces a more rapid decline in the JAK2 V617F allele burden than monotherapy with either drug. Disclosures:Hasselbalch:Novartis: Consultancy, Honoraria, Speakers Bureau. Off Label Use: Interferon-alpha2a is used routinely in Denmark for treatment of essential thrombocythemia polycythemia vera and in some myelofrbrosis patients , as well. Ruxolitinib is being used routinely in myelofibrosis patients on strict indications including hypermetabolic symptoms and abdominaldiscomfort due to large splenomegaly ln rare cases Ruxolitinib is being used in the transitional stage of PV towards myelofibrosis when other options are not available due to intolerance to eg. interferonlor hydroryurea.

A Phase 1b, Dose-Finding Study Of Ruxolitinib Plus Panobinostat In Patients With Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (PPV-MF), Or Post–Essential Thrombocythemia MF (PET-MF): Identification Of The Recommended Phase 2 Dose

A Phase 1b, Dose-Finding Study Of Ruxolitinib Plus Panobinostat In Patients With Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (PPV-MF), Or Post–Essential Thrombocythemia MF (PET-MF): Identification Of The Recommended Phase 2 Dose

Phase I Study Of LY2784544, a JAK2 Selective Inhibitor, In Patients With Myelofibrosis (MF), Polycythemia Vera (PV), and Essential Thrombocythemia (ET)

BackgroundMF, PV, and ET are neoplasms characterized by activation of JAK2 signaling, and the majority of cases are associated with the gain of function JAK2 V617F mutation. Given that wild-type JAK2 plays a pivotal role in multiple stages of hematopoiesis it is desirable to treat JAK2V617F-positive cases by selectively inhibiting JAK2 V617F while minimizing inhibition of wild-type JAK2 in order not to impede normal marrow function. LY2784544 is a selective inhibitor of JAK2 which demonstrates dose dependent selectivity for JAK2 V617F/STAT5 signaling. LY2784544 entered clinical testing in a Phase I trial in MF, PV, and ET patients (I3X-MC-JHTA, NCT01134120). We have previously reported early interim analysis from this study and provide here an update following completion of study enrollment. MethodsThe study's primary objectives were to determine the safety and tolerability of LY2784544 and define a recommended oral daily dose for further study in patients with JAK2 V617F-positive MF, ET, or PV. Secondary objectives included determination of pharmacokinetics and evaluation of response using the IWG-MRT response criteria (2006), European Leukemia Net response criteria for PV and ET (EULN 2009), and symptom burden using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) (Scherber et. al. Blood 2011). Study design included a standard 3+3 dose-escalation to define the maximum tolerated dose (MTD) and was amended to allow cohort expansions at multiple doses demonstrating potential clinical merit. ResultsPatients Prior to closing to enrollment, 47 patients were consented; 9 did not meet eligibility screening. The 38 treated patients included 31 MF (22 pMF, 6 post-PV MF and 3 post-ET MF), 6 PVs, and 1 ET patient(s), and 86% had received prior systemic therapy for their MPN.Dosing and tolerability of LY2784544: Systemic exposures were approximately dose proportional across the tested range from 30 to 300 mg. Daily doses of 200 mg or greater were associated with CTCAE Grade 3 increases in serum creatinine. In general, increases in serum creatinine occurred within the first 2 weeks of either starting treatment or after an increase in study drug dose. With the available data, the elevations in serum creatinine appear to be fully reversible after dose reduction or drug holiday in the majority of patients. The maximum tolerated daily dose of LY2784544 when given on a continuous daily basis was determined to be 120 mg per day.Serious AEs, across all grades and doses, included increased creatinine/acute renal insufficiency (4 grade 3, 5 grade 2, 1 grade 1), hyperuricemia (2 grade 4, 1 grade 1), hyperkalemia (1 grade 1), and anemia (1 grade 3). This study allowed intrapatient dose escalation, and 34 patients received 120 mg during their study participation. There were 4 patients dosed at 120 mg with SAEs but all were unrelated to study drug treatment (anemia, influenza, enterococcal bacteremia, hematuria and pneumonia). At 120 mg, the most frequently reported drug-related AEs across all grades were diarrhea (44%), nausea (29%), increased creatinine (21%), and anemia, vomiting, fatigue (9% each). Of these related AEs at 120 mg, there was 1 Grade 3 anemia, 3 Grade 3 increased creatinine, and 2 Grade 3 fatigue. There were no Grade 4 AEs. EfficacyAmong a cohort of 10 MF patients who only received 120 mg, 3 achieved a clinical improvement. Analyzing across dose levels, a palpable spleen length reduction of ≥50% was seen in 15 of 27 evaluable patients (56%) at any time. The median duration of these responses was 18.3 weeks (range from 0.7 to 148.1 weeks). At 12 weeks, 56% of patients (15/27) reported a ≥50% improvement in Total Symptom Score on the MPN-SAF. Of the 6 PV patients, 3 achieved a clinicohematologic PR. Findings from a central pathology review of serial bone marrow samples will be presented at the meeting. ConclusionsA recommended phase II dose for daily dosing of LY2784544 was identified as 120 mg. This dose has been well tolerated and associated with clinical improvements, supporting ongoing Phase II testing of LY2784544 in MPNs. Disclosures:Verstovsek:Eli Lilly and Co: Research Funding. Mesa:Eli Lilly and Co: Research Funding; Genetech: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Sanofi: Research Funding; NS pharma: Research Funding; Celgene: Research Funding. Salama:Eli Lilly and Co: Research Funding. Giles:Eli Lilly and Co: Employment. Pitou:Eli Lilly and Co: Employment. Hayden Zimmermann:Eli Lilly and Co: Employment. Price:Eli Lilly and Co: Employment. Walgreen:Eli Lilly and Co: Employment. Prchal:Eli Lilly and Co: Research Funding.

Prognostic Factors For Outcome In Patients (pts) With Myelofibrosis (MF) Treated With Ruxolitinib (Rux)

BackgroundRux is a potent and specific oral JAK1 & 2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of MF. In two phase 3 randomized studies, Rux demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life. In addition, Rux-treated pts demonstrated longer survival than those receiving placebo or best available therapy. AimsTo assess prognostic factors for response and survival in pts with MF treated at MDACC with Rux. MethodsThe details of the study design have been previously published (Verstovsek et al. NEJM 2010;363:1117-1127): 107 consecutive pts were treated between 6/07 and 9/11 and thus were evaluable. ResultsMedian age was 66 years (range, 41-84), with 52% of pts being > 65 years. 66 pts (56%) had primary MF. By the International Prognostic Scoring System (IPSS) at the start of therapy, 10 (9%) had intermediate (int)-1, 34 (32%) int-2, and 63 (59%) high-risk MF. Karyotype was diploid in 59 (51%) pts. The JAK2V617F mutation was identified in 84 pts (78%) with a median allele burden of 65%. At baseline (BL), median spleen size was 19 cm (range, 0-36); 28 pts (26%) were RBC transfusion-dependent. Median BL platelets count was 277 x 109/L (range, 100-1195). At BL, median hemoglobin was 10.3 g/dL (range, 7.2-16.9) and median WBC was 18 x 109/L (range, 2.5-159): 65% of pts having WBC > 25 x 109/L. 48 (45%) pts had peripheral blood blasts of >1%. Median follow-up was 47 months (mo; range, 2-72+). Rux was given for a median of 37 mo (range, 2-72+); 26 (24%) pts are still receiving Rux at the time of this analysis. Clinical improvement (defined as 50% reduction of spleen length per IWG) at any time was observed in 67 pts (63%) for a median of 40 mo (range 1-62+); 35 additional pts (33%) with post-BL assessments experienced a clinical benefit with noticeable reduction in spleen volume and improvement in symptoms. Only 3 pts had primary “refractory” disease and progressed while on Rux, and 2 pts were not evaluable for response. By univariate analysis, none of the BL pts' characteristics was found to have a statistically significant effect on clinical improvement and clinical benefit. Nine pts (8%) experienced transformation into acute myeloid leukemia. Median overall survival (OS) and transformation-free survival (TFS) were 57 and 52 mo, respectively, while 3-year TFS and OS rates were 64% and 66%, respectively. By univariate analysis, higher platelets count, lower bone marrow blasts, and transfusion independency at BL were associated with better TFS. Similarly, higher platelets count, and transfusion independency were associated with better OS. By multivariate analysis, only higher platelets count, and transfusion independency at BL were positive independent prognostic factors for TFS and OS. ConclusionEven in the presence of poor disease characteristics, Rux provided significant clinical benefit in the great majority of pts with MF, including int-1 pts. Pts with low platelets counts and transfusion dependency at BL have suboptimal outcome. These poor prognostic factors could serve to advise pts of their prognosis and additional treatment options. Disclosures:Off Label Use: Clofarabine use in AML. Cortes:Incyte: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding. Ravandi:Sunesis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Teva: Consultancy, Honoraria; Pfizer: Honoraria; Merck: Research Funding; Bayer/Onyx: Consultancy, Honoraria; EMD Serono: Research Funding; Medimmune: Research Funding; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Verstovsek:Incyte: Research Funding.

Sonographic biometry of spleen among school age children in Nsukka, Southeast, Nigeria

Normative value of spleen size among school age children is important for objective assessment of the spleen. This study was aimed at determining sonographically the normal limits of the spleen size according to age, sex, and somatometric parameters among school age children. A cross sectional study was done on 947 apparently healthy subjects (496 boys and 451 girls) aged 6 - 17 years. The subjects were recruited from some primary and secondary schools within Nsukka metropolis and also from out patients in the study centre. A pilot study was done to determine the intra- and inter rater reliability of sonographic measurements of the spleen. The sonographic examination was performed on Shenzhen DP-1100 machine with 3.5 and 5 MHz convex transducers. Spleen sizes were obtained with the subject in a right lateral decubitus position. Measurement of spleen length was reliable while measurement of spleen width was less reliable within and between sonographers. Dimensions of the spleen were not statistically different in boys and girls (p > 0.05). Height correlated best with spleen dimensions. Normogram of the spleen size with respect to height is important in the determination of some pathology associated with changes in its size.

Comparison of placebo and best available therapy for the treatment of myelofibrosis in the phase 3 COMFORT studies

Prior to Janus kinase inhibitors, available therapies for myelofibrosis were generally supportive and did not improve survival. This analysis compares efficacy outcomes of patients with myelofibrosis in the control arms (placebo [n=154] and best available therapy [n=73]) from the two phase 3 COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (COMFORT) studies. Spleen volume was assessed by magnetic resonance imaging/computed tomography at baseline and every 12 weeks through week 72; spleen length was assessed by palpation at each study visit. Health-related quality of life and symptoms were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items at baseline and in weeks 4, 8, 12, 16 and 24 in COMFORT-I and in weeks 8, 16, 24 and 48 in COMFORT-II. The demographic and baseline characteristics were similar between the control arms of the two studies. One patient who received placebo and no patients who received best available therapy had a ≥35% reduction in spleen volume from baseline at week 24. At 24 weeks, neither placebo nor best available therapy had produced clinically meaningful changes in global quality of life or symptom scales. Non-hematologic adverse events were mostly grade 1/2; the most frequently reported adverse events in each group were abdominal pain, fatigue, peripheral edema and diarrhea. These data suggest that non-Janus kinase inhibitor therapies provide little improvement in splenomegaly, symptoms or quality of life as compared with placebo. Both COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) studies have been appropriately registered with clinicaltrials.gov.

A Very High Infection Intensity of Schistosoma mansoni in a Ugandan Lake Victoria Fishing Community Is Required for Association with Highly Prevalent Organ Related Morbidity

BackgroundIn schistosomiasis control programmes using mass chemotherapy, epidemiological and morbidity aspects of the disease need to be studied so as to monitor the impact of treatment, and make recommendations accordingly. These aspects were examined in the community of Musoli village along Lake Victoria in Mayuge district, highly endemic for Schistosoma mansoni infection.Methodology and Principal FindingsA cross sectional descriptive study was undertaken in a randomly selected sample of 217 females and 229 males, with a mean age of 26 years (SD ±16, range 7–76 years). The prevalence of S. mansoni was 88.6% (95% CI: 85.6–91.5). The geometric mean intensity (GMI) of S. mansoni was 236.2 (95% CI: 198.5–460.9) eggs per gram (epg) faeces. Males had significantly higher GMI (370.2 epg) than females (132.6 epg) and age was also significantly associated with intensity of infection. Levels of water contact activities significantly influenced intensity of infection and the highest intensity of infection was found among people involved in fishing. However, organomegaly was not significantly associated with S. mansoni except for very heavy infection (>2000 epg). Liver image patterns C and D indicative of fibrosis were found in only 2.2% and 0.2%, respectively. S. mansoni intensity of infection was associated with portal vein dilation and abnormal spleen length. Anaemia was observed in 36.4% of the participants but it was not associated with S. mansoni infection intensity. Considering growth in children as one of the morbidity indicators of schistosomiasis, intensity of S. mansoni was significantly associated with stunting.ConclusionAlthough organ-related morbidity, with the exception of periportal fibrosis, and S. mansoni infections were highly prevalent, the two were only associated for individuals with very high infection intensities. These results contrast starkly with reports from Ugandan Lake Albert fishing communities in which periportal fibrosis is more prevalent.

Stapleless Laparoscopic Splenectomy with Individual Vessel Dissection in Patients with Splenomegaly

Mechanical stapling devices have been established as a mainstay in laparoscopic splenectomy (LS), but limited data are available regarding stapleless LS for splenomegaly with individual vessel dissection (IVD). This study aimed to investigate the feasibility of stapleless LS for splenomegaly and its potential advantage over staple-based LS. A total of 51 patients with splenomegaly underwent stapleless LS and were subsequently reviewed. The data collected include the patients' demographics, operative outcomes, and the rates of conversion to open surgery, complications, and mortality. Multiple linear and logistic regression analyses were used to assess the impact of the primary diagnosis, body mass index (BMI), and massive splenomegaly on the perioperative conversion rate. There were no deaths. The mean for various parameters are as follows: spleen length 21.6 cm; spleen weight 1,184 g, operating time 148 min, hospital stay 5.2 days, estimated blood loss 245 ml. The total conversion rate was 9.8 % (including one reoperation for bleeding). The presence of a BMI >30 % and hematologic malignancy-cofactors of portal hypertension (PH)-and a spleen weight >1,000 g were independent predictors of conversion to open surgery. Stapleless LS for splenomegaly is feasible and safe in selected patients. It has advantages over traditional procedures using staples, at least in patients with benign splenomegaly. Patients with hematologic malignancy, BMI >30 %, coexistence of PH, and spleen weight >1,000 g are susceptible to bleeding during dissection of the splenic hilum, with use of IVD being relatively limited.

Sonographic measurement of the spleen: splenic length in adults and its correlation with different parameters

Aim: The purpose of this study was to establish guidelines for normal splenic length at different ages by using a simple and reproducible sonographic method and to find out a relation between spleen length, age, height, weight, and surface area. Materials and methods: One hundred sixty subjects, from 21 years to 60 years old, had sonography because of abdominal and/or pelvic problems unrelated to the spleen. The splenic size was measured by obtaining a coronal view that included the hilum during deep inspiration to minimize masking by lung. The greatest longitudinal distance between the dome of the spleen and the tip (splenic length) was measured and correlated with age, height, and weight. Results: The results show that the splenic length decreased with increase in age in both males and females. The length of the spleen increased with increase in the body height, body weight, and body surface area in both males and females. In most of the subjects, the splenic length was found to be <11 cm. The splenic size in males was greater than that in females. Discussion: The findings of present study that the splenic length decreases with age are similar to the findings of Loftus and Metreweli. Konus et al in 1998 proposed that the splenic length correlated best with the body height. This is similar to the findings of the present study. The finding of present study that the splenic length has positive correlation with the body height, weight, and surface area is similar to the finding of Megremis et al. Conclusion: On the basis of the above study, it was concluded that the splenic length decreased with increase in age in both males and females. The length of the spleen has positive correlations with increase in the body height, body weight, and body surface area in both males and females. The splenic length was less in females than that in males with the corresponding age, body height, body weight, and body surface area. In most of the subjects, the splenic length was found to be <11 cm.

Sonological Evaluation of the Liver, Spleen and the Kineys in an Adult Southern Nigerian Population

The objective of this study was to determine the normal range of dimensions for the liver, spleen and kidneys and see how they correlate with some physical parameters in healthy adult Nigerians. A total of 723 Ijaw (Southern Nigerian) students of the University of Port Harcourt (363 males and 360 females) ages ranging from 18 to 40 years were utilized for the study. The liver, spleen and the kidneys were scanned and measurements taken, the corresponding age, weight, height and body mass index of each subject were also noted. The mean liver length was 13.13±1.09 cm; spleen length was 9.23±1.53 cm. The mean bipolar length and transverse diameter of the left kidney was 10.31±1.10 cm and 5.04±0.63 cm respectively, while the bipolar length and transverse diameter of the right kidney was 10.02±0.97 cm and 5.12±0.68 cm respectively. There was significant difference in organ dimensions with respect to sex (p<0.05). The organs dimensions however showed weak correlations with age, sex, weight, length and body mass index.

Liver Dysfunction and Early Mortality after Heart Transplant

Purpose Mortality after cardiac transplant is predicted by The Model for End-Stage Liver Disease (MELD) score. The score is derived from serum bilirubin, creatinine and International Normalized Ratio (INR); abnormalities in each occurs with advanced liver disease. Given the hemodynamic burden experienced during cardiac transplant, we hypothesized that markers of milder pre-transplant liver dysfunction also predict early mortality after cardiac transplant. Methods and Materials We conducted a retrospective cohort study of adult patients at our institution that underwent their first heart transplant from 2007 to 2012. We evaluated the utility of pre-transplant aspartate aminotransferase (AST), bilirubin, albumin, INR, platelets and imaging evidence of cirrhosis and splenomegaly in predicting 30-day mortality post transplant. We used univariable logistic regression to identify hepatic predictors of mortality post transplant. We then compared a risk score that integrated these predictors to the MELD score using receiver operating characteristic (ROC) curve analysis. Results The study population consisted of 126 heart transplant recipients (Age 49±13,male 66%,ischemic etiology 27%). Mortality rate was 10.3% at 30 days. Patients that died had more sternotomies, higher pre-transplant creatinine levels and were more likely to have congenital heart disease. Univariate hepatic predictors of 30-day post-operative mortality were pre-transplant: platelet count Conclusions In our cohort, pre-transplant spleen length and platelet count, parameters not included in the MELD score, predicted mortality post heart transplant. These markers of milder liver dysfunction enhanced the MELD score’s ability to predict early mortality after cardiac transplant.