Abstract: The JAK1/2 inhibitor ruxolitinib (RUX) is effective in decreasing symptomatic splenomegaly, and constitutional symptoms in patients with myelofibrosis (MF). Long-term data suggest that treatment with RUX is associated with a survival benefit, and may delay/reverse bone marrow fibrosis. Further, a ≥ 20% reduction in JAK2 V617F allele burden with RUX has been described (Vannucchi et al. Blood. 2012). Yet, many uncertainties surrounding the full clinical potential of RUX persist. The conceivable disease-modifying impact including the achievement of a JAK2 V617F molecular remission under sustained JAK1/JAK2 inhibition in a patient with primary myelofibrosis (PMF) is presented. Patient and Methods: the diagnosis of JAK2 V617F-positive PMF according to the 2008 WHO criteria was made in a 50-years old caucasian male in February 2009. On the first consultation in November, 2009, he complained of fatigue and night sweats. Spleen was 12 cm below costal margin by palpation. Laboratory results were: Hb 153 g/L, WBC 18.9 x109/L, platelets 268 x109/L, peripheral blasts 2%, a leucoerythroblastic blood picture, LDH 10.6 µkat/L [2.8x upper limit of normal]. With an IPSS of 2 points (night sweats and peripheral blasts 〉 1%) the IPSS risk category for survival was intermediate-II. After signing informed consent, the patient was included in the phase 3, multicenter COMFORT-II trial and randomized to treatment with RUX at a dose of 20mg bid based on platelets count. By week (w) 4, the dose was increased to 25mg bid per protocol ( 〈 40% reduction is palpable spleen length). For efficacy and safety evaluations, serial clinical, spleen volume [by magnetic resonance imaging (MRI)], blood picture, blood chemistry, bone marrow trephine biopsy, and JAK2 V617F allele burden from both peripheral blood samples as well as bone marrow assessments were conducted. The histology of the biopsies was evaluated according to the WHO criteria by experienced pathologists (Table). The JAK2 V617F allele burden was measured from blood samples using allele-specific oligonucleotide quantitative real-time polymerase chain reaction (qPCR) with a dynamic detection range from 0.1 to100% mutated allele (Lange et al. Haematologica 2013) and from bone marrow samples via qPCR followed by pyrosequencing for determining the allelic burden with a sensitivity of 5% of mutated DNA. If necessary, blocking of the non-mutated allele for sensitivity enhancement from 5% up to 0,001% of mutated DNA was done (Siebolts et al. J Clin Pathol 2010). Results: After a follow-up of 240 weeks, treatment with 25mg bid is ongoing. No dose modification/interruption because of adverse events was required. Clinical response was rapid with a 52% reduction in baseline spleen volume from 3.77 L to 1.8 L and improvement in constitutional symptoms at w 12. This was followed by a further decline in spleen volume. By w 216, spleen volume was 0.5 L which corresponded to 85.5% reduction from baseline (Figure). WBC and LDH normalized by w 24 and w 84 respectively. Histologic improvement in marrow cellularity, megakaryocytic, and granulocytic lineages was first evident at w 126 with further reversal of MF-related abnormalities including marrow fibrosis by w 216 (Table). JAK2 V617F allele burden of 〈 10% in a peripheral blood sample and 〈 1% in the bone marrow were first documented at w 108 and w 132 respectively. As of w 216, an allele burden 〈 1% was sustained in both blood and marrow samples (Figure). Conclusions: The rapid symptomatic improvement with ruxolitinib could be followed by a considerable MF-modifying response with the potential to alter the course of disease and prognosis. Unlike targeted therapy for chronic myeloid leukemia, ruxolitinib-delivered molecular and histologic remissions could be gradual, and progressive. Whether such deep long-term responses are dose-dependent is not yet known. Thus, the full potential of a sustained JAK1/JAK2 inhibition needs to be elucidated by carefully analyzing the possible correlation between dose, short-term spleen responses and long-term molecular and histologic responses; both in retro- and prospective studies. Changes in marrow histology and spleen volume under ruxolitinib Table 1. Marrow Cellularity % Megakaryocyte Granulocytic ProliferationG:E Marrow Fibrosis (EUMNET) Spleen volume (L)ProliferationAtypiaBaseline100%+++++++++8:1PMF13.8Week 4880%+++++++5:1PMF21.2Week 12630%+++-1:3PMF10.6Week 21640%-+-3:1PMF00.5 Figure 1 Figure 1. Disclosures Al-Ali: Novartis: Honoraria, Research Funding. Lange:Novartis: Consultancy, Honoraria, Research Funding. Prashanth:Novartis: Employment. Niederwieser:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gentium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract: BACKGROUND: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor that has demonstrated improvements in splenomegaly, MF-related symptoms, and quality of life measures and prolonged survival in 2 phase 3 studies. JAK signaling can activate the PI3K/mTOR pathway, and constitutive PI3K activation has been implicated in numerous cancers. Preclinical and early clinical results indicate benefit with inhibition of PI3K in MF. Buparlisib is a pan-PI3K inhibitor with specific and potent activity against class I PI3Ks. The aims of HARMONY are to evaluate the safety of co-administration of RUX and buparlisib in patients (pts) with MF and determine a recommended phase 2 dose (RP2D). METHODS: This is a dose-finding, phase 1b study (NCT01730248) of RUX plus buparlisib in intermediate- or high-risk MF pts. Pts must have palpable splenomegaly ≥ 5 cm below the costal margin and MF symptoms. There are 2 treatment groups (JAK inhibitor–naive pts [arm A] and pts not benefiting from prior JAK inhibition [arm B] ) and 2 study phases (dose escalation and expansion). Dose escalation is guided by a Bayesian logistic regression model with overdose control and depends on dose-limiting toxicities in cycle 1 and other safety findings. Each dose level consists of ≥ 3 evaluable pts; the 5 dose levels are (RUX [mg bid]/buparlisib [mg qd] ) 10/60, 15/60, 15/80, 20/80, 20/100. 9 evaluable pts are required at the final dose level to determine an RP2D and proceed to the expansion phase; 10 additional pts per arm will be treated at the RP2D. PK of RUX was assessed by LC-MS/MS on day 1 after the first dose of RUX and on days 2 and 8 when administered in combination with buparlisib. RESULTS: To date, 33 pts (arm A, n = 20; arm B, n = 13) have been treated in the dose-escalation phase. Baseline characteristics were (arm A and arm B) median age, 64 y (range, 48-79 y; 45% ≥ 65 y) and 61 y (53-74 y; 31% ≥ 65 y); male, 50% and 62%. RP2D was selected based on tolerability in the investigated dose levels, with additional confirmation from dose-selection recommendations derived through a Bayesian model.Currently, RUX 15 mg bid/buparlisib 60 mg qd was determined as the RP2D in both arms; the study is proceeding into the expansion phase. At data cutoff (April 1, 2014), 15 (75%) and 8 (62%) pts were ongoing in arm A and arm B with a median exposure of 11.3 wk (range, 2.3-48.4 wk) and 19.0 wk (range, 0.6-50.9 wk), respectively. The primary reasons for discontinuation included lack of efficacy (10%) in arm A and AEs (15%) in arm B; all other reasons were in 1 pt each. There was 1 death (arm A) from duodenal ulcers/perforation, assessed as not related to study drugs by the investigator. Despite the short follow-up, a ≥ 50% reduction from baseline in palpable spleen length was achieved by 70% and 54% of pts in arms A and B; 7 pts had a resolution of splenomegaly (6 in arm A; 1 in arm B). All pts with prior JAK inhibitor treatment, including 5 who had no previous spleen length reductions, had reductions with the combination. Hematologic AEs included anemia (all grade [grade 3/4]: arm A, 30% [15%] ; arm B, 31% [23%]) and thrombocytopenia (40% [10%] ; 62% [39%]). Nonhematologic AEs were primarily grade 1/2 (Table). Overall, 20% and 23% of pts experienced serious AEs; these occurred in 1 pt each, with the exception of pyrexia (n = 2). PK parameters of RUX were comparable when administered alone or in combination with buparlisib, suggesting a lack of impact of buparlisib on RUX PK. CONCLUSIONS: The combination of RUX and buparlisib was well tolerated, with early signs indicating promising efficacy even in pts who have previously failed JAKi; preliminary RP2D was assessed as RUX 15 mg bid/buparlisib 60 mg qd for both arms. Updated efficacy and safety for the dose-escalation phase will be presented (July 1, 2014 data cutoff). Table Nonhematologic AEs in ≥ 2 Pts in Either Arm Pts, % Arm A n = 20 Arm B n = 13 All Grade Grade 3/4 All Grade Grade 3/4 Abdominal distension 15 0 8 0 Abdominal pain 10 0 15 0 Abdominal pain lower 0 0 15 0 Abdominal pain upper 5 0 15 0 Diarrhea 10 0 46 8 Dyspepsia 10 0 0 0 Nausea 10 0 31 0 Stomatitis 15 5 8 8 Vomiting 5 0 15 0 Asthenia 0 0 31 0 Fatigue 10 0 23 0 General health deterioration 0 0 15 0 Edema peripheral 10 0 0 0 Pyrexia 15 0 23 15 Nasopharyngitis 15 0 15 0 Decreased appetite 5 0 46 8 Hyperglycemia 15 5 0 0 Hyperkalemia 5 5 15 0 Arthralgia 20 5 8 0 Pain in extremity 10 0 8 0 Dizziness 5 0 23 0 Anxiety 20 5 15 0 Confusional state 10 0 8 0 Depressed mood 0 0 15 8 Depression 0 0 15 8 Insomnia 5 0 15 0 Epistaxis 5 0 15 0 Hyperhidrosis 0 0 31 0 Night sweats 0 0 23 0 Hypertension 10 5 0 0 Disclosures Durrant: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Yes; Ruxolitinib is a kinase inhibitor indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Buparlisib is an investigational agent. Koren-Michowitz:Novartis: Honoraria, Research Funding. Lavie:Novartis: Membership on an entity's Board of Directors or advisory committees. Martinez-Lopez:Novartis: Research Funding; BMS: Honoraria; Celgene: Honoraria. Vannucchi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. Stalbovskaya:Novartis: Employment, Equity Ownership. Atienza:Novartis: Employment. Iommazzo:Novartis: Employment. Gopalakrishna:Novartis: Employment. Gisslinger:AOP ORPHA: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy.

Abstract: A new species of Indian caecilian, Gegeneophis goaensis (Amphibia: Gymnophiona: Caeciliidae) is described from three specimens collected from the Western Ghats region of Goa. This species is distinguished from all other members of the genus in having more than 120 primary annuli with more than 75 of these having secondary annular grooves.

Abstract: Gauges used for dimension inspection of critical components in various assemblies need to be precise and accurate. At the same time, the rate of inspection should be as high as possible for increased production. This is more so with regard to steering assemblies of automobiles. In automotive lines, the dimension inspection of the steering assemblies (constant velocity assembly) by Coordinate Measuring Machine would not be feasible as the process is slow and productivity would be affected. The proposed constant velocity gauging system can be considered as an alternative. The constant velocity assembly has six opening windows whose height is extremely critical. The accuracy of the component and the criticality demand complete inspection of the window height and identification of oversized window parts. The proposed cost-effective gauging system has a separate replaceable probe for each window to check the window height. All six windows are checked simultaneously to save production time. The qualified components and rejected components have been checked by first principles and on Coordinate Measuring Machine. Both have been found to be in good agreement.

Abstract: Cryptococcus is an invasive encapsulated yeast-like fungus that most commonly affects immunocompromised patients. Cryptococcal central nervous system infections, though rare, have been reported in patients without apparent immunocompromised state and in chronic cannabis smokers. Case We present a case of a 30-year-old White man with no significant medical history presenting with fever and headache of 1-month duration. He was found to have cryptococcal meningitis with persistently elevated cerebrospinal fluid pressures requiring a lumbar drain. The only risk factor identified was chronic cannabis use. Conclusions Cryptococcal meningitis though rare can occur in immunocompetent hosts. One of the risk factors identified was contaminated cannabis use. Most of these cases go undiagnosed initially as the index of suspicion is low. This may lead to increased mortality in this group of patients. In the literature search, there is only one previous report of cryptococcal meningitis in a cannabis user so the present case adds further evidence of this association.