Additional booster doses in patients with chronic lymphocytic leukemia induce humoral and cellular immune responses to SARS-CoV-2 similar to natural infection regardless ongoing treatments: A study by ERIC, the European Research Initiative on CLL.

Profound immune dysregulation and impaired response to the SARS-CoV-2 vaccine put patients with chronic lymphocytic leukemia (CLL) at risk of severe COVID-19. We compared humoral memory and T-cell responses after booster dose vaccination or breakthrough infection. (Green) Quantitative determination of anti-Spike specific antibodies. Booster doses increased seroconversion rate and antibody titers in all patient categories, ultimately generating humoral responses similar to those observed in the postinfection cohort. In detail, humoral response with overscale median antibody titers arose in >80% of patients in watch and wait, off-therapy in remission, or under treatment with venetoclax single-agent. Anti-CD20 antibodies and active treatment with BTK inhibitors (BTKi) represent limiting factors of humoral response, still memory mounted in ~40% of cases following booster doses or infection. (Blue) Evaluation of SARS-CoV-2-specific T-cell responses. Number of T-cell functional activation markers documented in each patient. The vast majority of patients, including those seronegative, developed T-cell responses, qualitatively similar between treatment groups or between vaccination alone and infection cases. These data highlight the efficacy of booster doses in eliciting T-cell immunity independently of treatment status and support the use of additional vaccination boosters to stimulate humoral immunity in patients on active CLL-directed treatments.

Interim PET-CT-guided therapy in elderly patients with Hodgkin lymphoma-a retrospective national multi-center study.

Hodgkin lymphoma (HL), a disease of mostly young patients, also peaks in the elderly. Despite the profound improvement in the outcome of young patients, in the elderly, 5-year progression-free survival (PFS) rates are under 70%. Interim PET-CT (iPET) is known to be highly predictive for PFS in young HL patients, but it has not been sufficiently validated in the elderly patient population. In this multi-center collaboration, all consecutive elderly patients (age ≥ 60) diagnosed with HL between 1998 and 2016 were retrospectively reviewed. Baseline characteristics, outcome measures, and iPET results, classified according to the Deauville score, were recorded and analyzed. We identified 78 elderly HL patients (median age 69) who underwent iPET. ABVD was the treatment regimen in 52 (67%) patients. Eighty-three percent of patients had iPET scores of 1-3 while 17% had scores of 4-5. Patients with iPET scores of 1-3 had 5-year PFS and OS rates of 72% and 82% compared with 25% and 45%, respectively, in patients with scores of 4-5 (p < 0.001). Our findings show that iPET is highly predictive of outcome in elderly HL patients and provide evidence that iPET-guided therapy in this patient population may be key to achieving superior treatment outcome.

Novel agents for the treatment of lymphomas during pregnancy: A comprehensive literature review.

Lymphoproliferative diseases occurring during pregnancy present unique diagnostic and therapeutic challenges aiming to achieve maternal cure without impairing fetal health, growth, and survival. These goals are further complicated by the fast-paced emergence of novel therapies and their introduction as standard of care, even in newly diagnosed patients. Due to the rarity of hematological malignancies in pregnancy and the exclusion of pregnancy in almost all clinical trials, available data on the fetal effects of novel drugs are limited to animal models and case reports. The current review addresses the entire multidisciplinary team involved in treating pregnant patients with lymphoproliferative diseases. We describe novel agents according to their mechanism of action, and summarize our knowledge of their effects during the gestational period, particularly those associated with fetotoxicity. Therapeutic dilemmas associated with the employment of these new agents are also discussed.

Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with B-cell non-Hodgkin lymphoma.

Patients diagnosed with B-cell non-Hodgkin lymphoma (B-NHL), particularly if recently treated with anti-CD20 antibodies, are at risk of severe COVID-19 disease. Because studies evaluating humoral response to COVID-19 vaccine in these patients are lacking, recommendations regarding vaccination strategy remain unclear. The humoral immune response to BNT162b2 messenger RNA (mRNA) COVID-19 vaccine was evaluated in patients with B-NHL who received 2 vaccine doses 21 days apart and compared with the response in healthy controls. Antibody titer, measured by the Elecsys Anti-SARS-CoV-2S assay, was evaluated 2 to 3 weeks after the second vaccine dose. Patients with B-NHL (n = 149), aggressive B-NHL (a-B-NHL; 47%), or indolent B-NHL (i-B-NHL; 53%) were evaluated. Twenty-eight (19%) were treatment naïve, 37% were actively treated with a rituximab/obinutuzumab (R/Obi)-based induction regimen or R/Obi maintenance, and 44% had last been treated with R/Obi >6 months before vaccination. A seropositive response was achieved in 89%, 7.3%, and 66.7%, respectively, with response rates of 49% in patients with B-NHL vs 98.5% in 65 healthy controls (P < .001). Multivariate analysis revealed that longer time since exposure to R/Obi and absolute lymphocyte count ≥0.9 × 103/µL predicted a positive serological response. Median time to achieve positive serology among anti-CD20 antibody-treated patients was longer in i-B-NHL vs a-B-NHL. The humoral response to BNT162b2 mRNA COVID-19 vaccine is impaired in patients with B-NHL who are undergoing R/Obi treatment. Longer time since exposure to R/Obi is associated with improved response rates to the COVID-19 vaccine. This study is registered at www.clinicaltrials.gov as #NCT04746092.

Replacing carmustine by thiotepa and cyclophosphamide for autologous stem cell transplantation in Hodgkin's and non-Hodgkin's B-cell lymphoma.

This study aimed to compare the real-life results of TECAM, a thiotepa-based conditioning regimen consisting of thiotepa (40 mg/m2 days -5 to -2), etoposide (200 mg/m2 days -6 to -3), cytarabine (200 mg/m2 days -4 to -1), cyclophosphamide (60 mg/kg day -3), and melphalan (60 mg/m2 days -2 to -1) with that of the conventional carmustine-based regimen BEAM. We reviewed 125 consecutive patients who underwent a first autologous transplantation (ASCT) for B-cell lymphomas at a large tertiary transplantation center between 1999 and 2014. TECAM (n=65) and BEAM (n=60) had comparable results (3yPFS 49 vs 62%, P=0.16; 3yOS 64 vs 71%, P=0.44; TRM 1.6 vs 5%, P=0.35) without a difference in toxicity or time to engraftment. Notably, comparable outcomes were observed even though patients treated with TECAM were older (55 vs 44) and had a trend towards more prior lines of therapy (>2 prior lines: 43 vs 27%, P=0.08). In this regard, 23% of TECAM patients were over the age of 65 yet could withstand therapy with similar results to younger patients. We conclude that, replacing carmustine by thiotepa and cyclophosphamide for ASCT conditioning, has comparable efficacy and safety profiles with a possible advantage in older patients.

CD84 mediates CLL-microenvironment interactions.

Chronic lymphocytic leukemia (CLL) is a malignant disease of small mature lymphocytes. Signals from the CLL microenvironment promote progression of the disease and induce drug resistance. This phenomenon is largely dependent on direct contact between the malignant B cells and stromal cells. CD84 belongs to the signaling lymphocyte activation molecule family of immunoreceptors, which self-associates, forming an orthogonal homophilic dimer. We therefore hypothesized that CD84 may bridge between CLL cells and their microenvironment, promoting cell survival. Our in vitro results show that CD84 expressed on CLL cells interact with CD84 expressed on cells in their microenvironment, inducing cell survival in both sides. Blocking CD84 in vitro and in vivo disrupt the interaction of CLL cells with their microenvironment, resulting in induced cell death. Thus, our findings suggest novel therapeutic strategies based on the blockade of this CD84-dependent survival pathway.

Trihexyphenidyl treatment of vertical pendular nystagmus.

Vertical pendular nystagmus developed 4 months after massive brainstem hemorrhage due to eclampsia. The symptom markedly improved with chronic trihexyphenidyl treatment.

Cerebral square wave jerks.

Abnormal saccadic intrusions consisting of frequent sporadic horizontal saccades followed, after an interval, by corrective saccades occurred in 70% of 17 patients with acute or chronic focal cerebral lesions. These square wave jerks were significantly lower in amplitude than those in cerebellar system disease. The metrics of these jerks were uniform regardless of the site of cerebral damage. Mean durations approximated the reaction time for saccadic refixations triggered by visual feedback. Very short-latency corrective saccades in some patients are attributed to internal (nonretinal) feedback of eye position errors. Low-amplitude cerebral square wave jerks can be detected clinically by funduscopy.

Myophosphorylase deficiency: the course of an unusual congenital myopathy.

A 59-year-old man had proximal weakness and wasting that started in early childhood. EMG was "myopathic," serum CK activity was increased, and muscle biopsy showed accumulations of glycogen. Biochemical studies revealed elevated glycogen concentration and absence of myophosphorylase activity. This unusual presentation of a long-standing, painless, and quite static weakness due to myophosphorylase deficiency represents another example of clinical heterogeneity.

Visual-vestibular interaction in multiple sclerosis.

Visual modulation of the vestibuloocular reflex (VOR) was analyzed in 20 patients with multiple sclerosis who had no vestibular or ocular motor symptoms. Visual suppression of the VOR was impaired in 75% of patients. VOR gains in darkness were elevated in 35% of patients. Elevated VOR gain in darkness is attributed to vestibular adaptation to defective smooth pursuit. This vestibular plasticity achieved retinal image stability by matching eye velocity to head velocity when stationary targets were viewed. The high incidence of impaired visual suppression of the VOR rivals the sensitivity of other physiologic tests used to identify multiple sclerosis.

Cefuroxime-induced encephalopathy.

We describe four patients who developed an encephalopathic syndrome characterized by obtundation or stupor, myoclonic jerks, and asterixis in association with cefuroxime therapy. Three patients had renal failure. These cases suggest that cefuroxime in overdose or in conventional doses in patients with renal failure can cause a reversible encephalopathy. This syndrome may have been unrecognized because it usually occurs in severely ill patients with additional causes for encephalopathy.

Adult muscle phosphorylase "b" kinase deficiency.

A 35-year-old man had severe exercise intolerance and cramps. Venous blood lactate did not rise after ischemic exercise, and electromyographically silent contracture of hand muscles appeared. Histochemistry and electronmicroscopy of a muscle biopsy revealed subsarcolemmal and intermyofibrillar accumulation of glycogen. Biochemical studies showed moderately increased amount of glycogen. Total phosphorylase activity was normal, but the active form "a" was 27% of normal. Phosphorylase kinase activity was 12% of the normal value and was normal in leukocytes and erythrocytes.

Normal square wave jerks.

Fixation stability of the saccadic system was investigated by infrared reflection oculography in 29 normal subjects, young and elderly. Square wave jerks consisting of spontaneous horizontal saccadic excursions of 0.5 degree and over, followed some 200 msec later by corrective saccades, were recorded in 24% of subjects. The frequency of square wave jerks in the elderly was significantly higher than in young subjects. The results suggest that square wave jerks more frequent than 9/min in young patients can be considered abnormal.

Effect of L-dopa on polycythemia.

A patient with Parkinson's disease, in whom polycythemia vera was known to be present for several years prior to the onset of parkinsonian symptoms, received treatment with a preparation consisting of L-dopa plus a decarboxylase inhibitor (Madopar). Improvement in the parkinsonian symptoms was associated with marked improvement in the polycythemia. A therapeutic trial of the same L-dopa preparation in 2 other patients with polycythemia had similar effects. The cases are presented and the possible central therapeutic effect of L-dopa is discussed.

Myasthenia gravis in the elderly.

During a 15-year period in Jerusalem, myasthenia gravis was diagnosed in 15 patients aged 60 or older. At this age, diagnosis is difficult because of such possible associated conditions as cerebrovascular and cardiovascular arteriosclerotic diseases or bronchopulmonary disorders. The clinical course often is complicated by these associated conditions, and also by their treatment. Seven of the patients died within 4 years of the onset of their illness, but only 5 because of myasthenia gravis. This disease represents an important diagnostic and therapeutic problem in elderly patients.

Increased appetite (bulimia) in Parkinson's disease.

Five patients with Parkinson's disease, when first seen, manifested an abnormal increase in appetite. This bulimia decreased concomitantly with clinical improvement in the parkinsonism during treatment with L-dopa plus a decarboxylase inhibitor. A possible role of dopamine in the central control of appetite is discussed. Abnormally increased appetite (bulimia) is proposed as a new autonomic sign in Parkinson's disease.

Comparative genomic hybridization in polycythemia vera and essential thrombocytosis patients.

Polycythemia vera (PV) and essential thrombocytosis (ET) are clonal chronic myeloproliferative disorders originating from a multipotent stem cell. Bone marrow examinations reveal chromosomal abnormalities in 15-43% of PV patients and 5% of ET patients, but no specific recurring abnormality has been found to date. We aimed to find cytogenetic aberrations in PV and ET by comparative genomic hybridization (CGH), a relatively new molecular cytogenetic technique. In this study, CGH analysis was performed on peripheral blood leukocytes of 12 PV patients and 8 ET patients. One patient (8.3%) with PV had an abnormal karyotype with a deletion in 7q11.2 and one patient with ET (12.5%) had a gain in 18p. Peripheral blood analysis by CGH revealed a low frequency of cytogenetic abnormalities in PV and ET patients. However, using CGH we were able to detect two cytogenetic aberrations that were not reported previously in these disorders.

Analysis of chromosomal aberrations in large hepatocellular carcinomas by comparative genomic hybridization.

Hepatocellular carcinoma (HCC) is a very common and highly malignant tumor, associated mainly with chronic viral hepatitis, cirrhosis of any cause, aflatoxin exposure and ethanol consumption. The aim of this study was to map genomic aberrations in HCC by a recently developed technique: comparative genomic hybridization (CGH). We applied CGH on 17 liver specimens, of which seven were HCCs. The rest were benign liver tumors, cirrhotic and normal livers, and other liver malignancies. Our study included mainly large tumors (mean size 10.5 cm) unrelated to viral hepatitis or cirrhosis. Our CGH analysis detected genomic imbalances in 42% of HCCs. The common aberrations included DNA gains of 1q, 9p, and 8q and DNA losses of 17p, 13q, 9q, 4q, and 11q. Also, we detected trisomies 8, 9, 18 and 21, which have not been reported previously. Gains and losses of DNA found in this study probably involve oncogenes and tumor suppressor genes that play a role in the puzzle of hepatocarcinogenesis. This study also suggests a possible link between the size of the tumor and the burden of genetic changes.

Selective dopamine neurotoxicity by an industrial chemical: an environmental cause of Parkinson's disease?

While unproved, environmental toxins of industrial and or agricultural origin represent an attractive theory to explain the increasing incidence of degenerative diseases of the nervous system such as Parkinson's disease (PD). We have examined several chemicals utilized in an area of Israel previously demonstrated to contain a statistically greater than average number of people with Parkinson's disease. One of these agents, a light stabilizer employed universally in the production of polyolifins used in plastics, depleted primary mesencephalic cultures of dopamine neurons, and produced a dopamine-specific lesion of the substantia nigra pars compacta when injected stereotactically into the ventral midbrain of adult rats. The observed effects were dose-dependent. These findings represent a potentially significant development in the search for industrial/environmental causes of neurodegenerative disease.

In vivo interaction of anticonvulsant drugs. The mathematical correlation of plasma levels of anticonvulsant drugs in epileptic patients.

The phenytoin plasma levels were measured in 45 epileptic patients whose only treatment was phenytoin. The plasma of 20 other patients receiving both phenytoin and phenobarbital was also tested for concentration of these two drugs and 18 patients treated with phenytoin, phenobarbital and primidone were investigated in the same way. The results were used to calculate the plasma levels of phenytoin in relation to dosage and to measure the effect of the simultaneous use of phenobarbital on the phenytoin plasma levels and of primidone together with phenobarbital on phenytoin concentration. The results led to the following conclusions: The population of epileptic patients can be divided into 2 groups. In the first group the patients reach equilibrium at the relatively high phenytoin plasma level for a given dose of phenytoin, and in the second group the phenytoin plasma level tends to be significantly lower for parallel dosages. Both groups, in their behavior, obey mathematically an exponential graph specific for each group. Phenobarbital tends to lower the plasma phenytoin level when the two drugs are used simultaneously. It is also possible, by the graphs produced, to calculate the expected phenytoin plasma levels when using the drugs together. Primidone and phenobarbital together decrease the phenytoin level much more than expected from the effect of phenobarbital alone.