This Paper argues that despite the Israel High Court of Justice's prima facie holding in favor of Arabic being an official language, still the Court has failed to decisively resolve the question ...concerning the meaning, scope, and consequences of such recognition. Thus, the Court has missed an opportunity, which could have been faithfully addressed had the Court viewed the question at stake romantically, through the genesis of its legal-political premises, upon which it was established; namely, the 1947 Resolution 181 (II) of the United Nations General Assembly (the Partition Plan), wherein the collective rights, including linguistic rights, of the Arab minority citizen, were promised to be constitutionally protected.
All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic ...trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity.
We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%.
Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity.
ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).
High CD33 expression in acute myeloid leukemia (AML) with mutated
provides a rationale for the evaluation of gemtuzumab ozogamicin (GO) in this AML entity. We conducted a randomized trial to evaluate ...GO in combination with intensive induction and consolidation therapy in
-mutated AML.
Between May 2010 and September 2017, patients ≥ 18 years old and considered eligible for intensive therapy were randomly assigned up front for induction therapy with idarubicin, cytarabine, etoposide, and all-
-retinoic acid with or without GO. The early (
= .02) primary end point of event-free survival (EFS) was evaluated 6 months after completion of patient recruitment.
Five hundred eighty-eight patients were randomly assigned (standard arm, n = 296; GO arm, n = 292). EFS in the GO arm was not significantly different compared with that in the standard arm (hazard ratio, 0.83; 95% CI, 0.65 to 1.04;
= .10). The early death rate during induction therapy was 10.3% in the GO arm and 5.7% in the standard arm (
= .05). Causes of death in both arms were mainly infections. The cumulative incidence of relapse (CIR) in patients achieving a complete remission (CR) or CR with incomplete hematologic recovery (CRi) was significantly reduced in the GO arm compared with the standard arm (
= .005), with no difference in the cumulative incidence of death (
= .80). Subgroup analysis revealed a significant beneficial effect of GO in female, younger (≤ 70 years), and
internal tandem duplication-negative patients with respect to EFS and CIR.
The trial did not meet its early primary end point of EFS, mainly as a result of a higher early death rate in the GO arm. However, in patients achieving CR/CRi after induction therapy, significantly fewer relapses occurred in the GO compared with the standard arm.
To evaluate the prognostic value of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) with NPM1 mutation (NPM1(mut)).
RNA-based real-time quantitative polymerase chain ...reaction (RQ-PCR) specific for the detection of six different NPM1(mut) types was applied to 1,682 samples (bone marrow, n = 1,272; blood, n = 410) serially obtained from 245 intensively treated younger adult patients who were 16 to 60 years old.
NPM1(mut) transcript levels as a continuous variable were significantly associated with prognosis after each treatment cycle. Achievement of RQ-PCR negativity after double induction therapy identified patients with a low cumulative incidence of relapse (CIR; 6.5% after 4 years) compared with RQ-PCR-positive patients (53.0%; P < .001); this translated into significant differences in overall survival (90% v 51%, respectively; P = .001). After completion of therapy, CIR was 15.7% in RQ-PCR-negative patients compared with 66.5% in RQ-PCR-positive patients (P < .001). Multivariable analyses after double induction and after completion of consolidation therapy revealed higher NPM1(mut) transcript levels as a significant factor for a higher risk of relapse and death. Serial post-treatment assessment of MRD allowed early detection of relapse in patients exceeding more than 200 NPM1(mut)/10(4) ABL copies.
We defined clinically relevant time points for NPM1(mut) MRD assessment that allow for the identification of patients with AML who are at high risk of relapse. Monitoring of NPM1(mut) transcript levels should be incorporated in future clinical trials to guide therapeutic decisions.
In the recent decade, a very tempestuous discourse, concerning the interrelationship between the governmental branches--particularly the Judiciary on the one hand, and the Knesset and the Government ...on the other hand--is taking place in Israel. The nature of Israel's political regime as parliamentary democracy, and the absence of a written constitution have only intensified this rift to an unprecedented level. Underlying this tempestuous discourse is a controversy over the definition of democracy, its scope, and its limits; a controversy that reflects on the nature of the principle of separation of powers, as well as the essence, and the meaning, of the fundamental principle of the rule of law. Here, Wattad examines the process through which the principle of the rule of law has evolved in Israel through its 70 years of existence.
This Article examines the constitutionality of an Israeli bill that criminalizes the use of PA systems in prayer houses, punishable by a fine of 5000–10,000 NIS (the Muezzin Law). The Bill was ...presented to the Israeli Parliament (the Knesset) as a religiously-neutral environmental law. This Article asserts that a careful reading of the Bill’s language reveals that it is specifically tailored to apply precisely to Muslim prayer houses, thus criminalizing the Muslim call for prayer (the adhan), especially the call occurring between dawn and sunrise (the Fajer adhan). As such, we perceive the Muezzin law as violating the right to equality and the right to dignity of the Muslim minority in Israel, as well as infringing upon its religious feelings. Additionally, we contend that the Muezzin Law is not truly driven by environmental concern, but rather that it represents a conflict with religious dimension (a CRD)—namely, the perception that the adhan, as a Muslim symbol, poses a threat to the identity of Jews in Israel. Examining the constitutionality of the Muezzin Law introduces a crucial question relating to the interplay between constitutional law and criminal law. Our assertion is that in any constitutional democracy, in order for the legislature to validly classify conduct as a crime, such criminalization must befit the values of constitutional democracy, serve a proper purpose, and be proportionate. The requirement for proportionality consists of three subtests: (a) the rational connection test; (b) the necessity test; and (c) the balancing benefits test. It is our contention that the Muezzin Law comprises an unconstitutional criminalization of the Fajer adhan. It stands in contrast with the basic values of constitutional democracy, primarily that of tolerance towards a religious minority, particularly, the Muslim community. Additionally, we assert that the Muezzin Law’s purpose is improper as it aims at infringing upon the religious feelings of the Muslim minority in Israel, holding that the value of protecting religious feelings is a constitutional value. Finally, we view such criminalization as provided in the Muezzin Law as being unproportionate. In this latter regard, we hold the view that our CRD analysis provides a more delicate, proper, and proportionate solution to the question at stake.
Major histocompatibility complex class I polypeptide-related sequence A (MICA) is a highly polymorphic ligand of the activating NKG2D receptor on natural killer (NK) cells, γδ-T cells, and NKT cells. ...MICA incompatibilities have been associated with an increased graft-versus-host disease (GVHD) incidence, and the MICA-129 (met/val) dimorphism has been shown to influence NKG2D signaling in unrelated hematopoietic stem cell transplantation (uHSCT). We investigated the effect of MICA matching on survival after uHSCT. We sequenced 2172 patients and their respective donors for MICA. All patients and donors were high-resolution HLA-typed and matched for 10/10 (n = 1379), 9/10 (n = 636), or 8/10 (n = 157) HLA alleles. Within each HLA match group, cases matched and mismatched for MICA and MICA-129 were analyzed for the end points overall survival (OS), disease-free survival (DFS), nonrelapse mortality (NRM), relapse-incidence (RI), and GVHD. Mismatches at the MICA locus as well as MICA-129 increased with the number of HLA mismatches (MICA mismatched 10/10, 9.2% n = 127; 9/10, 22.3% n = 142; 8/10, 38.2% n = 60; MICA-129 mismatched 10/10, 3.9% n = 54; 9/10, 10.2% n = 65; 8/10, 17.2% n = 27). Adverse OS was observed in the 10/10 match group if MICA-129 was mismatched (10/10, hazard ratio HR, 1.77; confidence interval CI, 1.22-2.57; P = .003). MICA-129 mismatches correlated with a significantly worse outcome for DFS in the 10/10 HLA match group (HR, 1.77; CI, 1.26-2.50; P = .001). Higher rates of aGVHD were seen in MICA-129 mismatched cases. Our results indicate that MICA-129 matching is relevant in uHSCT. Prospective typing of patients and donors in unrelated donor search may identify mismatches for MICA-129, and compatible donor selection may improve outcome for this small but high-risk subgroup.
•MICA-129 matching improves survival in uHSCT.•MICA-129 mismatches were observed in 6.7% of all transplant patients.
Despite major advances in therapy, multiple myeloma is still an incurable malignancy in the majority of patients. To increase survival, deeper remissions (i.e. CR) translating into longer PFS need to ...be achieved. Incorporation of new drugs (i.e. bortezomib and lenalidomide) as induction and maintenance treatment in an intensified treatment concept, including high dose melphalan (200 mg/m
), has resulted in increased CR rates, and is considered the standard of care for younger patients. Elotuzumab in combination with lenalidomide and dexamethasone has given better results as lenalidomide and dexamethasone alone in a phase III trial. The GMMG-HD6 trial will be the first phase III trial investigating the role of elotuzumab in combination with bortezomib, lenalidomide and dexamethasone (VRD) induction/consolidation and lenalidomide maintenance within a high dose concept.
GMMG-HD6 is a randomized, open, multicenter phase III trial. The planned recruitment number is 564 NDMM patients. All patients will receive 4 VRD cycles as induction and undergo peripheral blood stem cell mobilization and harvesting. Thereafter they will be treated with high dose melphalan therapy plus autologous stem cell transplantation followed by 2 cycles of VRD consolidation and lenalidomide maintenance. Patients in arm B1 + B2 will additionally receive elotuzumab in the induction phase, whereas patients in A2 + B2 will be treated with elotuzumab added to consolidation and maintenance. The primary endpoint of the trial is PFS. Secondary objectives and endpoints are OS, CR rates after induction therapy comparing the two arms VRD (A1 + A2) vs VRD + elotuzumab (B1 + B2), CR rates after consolidation treatment, best response to treatment during the study, time to progression (TTP), duration of response (DOR), toxicity and quality of life.
Since this is the publication of a study protocol of an ongoing study, no results can be presented.
This phase III trial is designed to evaluate whether the addition of elotuzumab to an intensified treatment concept with high dose melphalan chemotherapy plus autologous stem cell transplantation and induction, consolidation and maintenance treatment with bortezomib and lenalidomide is able to improve PFS compared to the same concept without elotuzumab.
NCT02495922 on June 24th, 2015.
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