Radioimmunotherapy versus autologous hematopoietic stem cell transplantation in relapsed/refractory follicular lymphoma: a Fondazione Italiana Linfomi multicenter, randomized, phase III trial.

BACKGROUND: Optimal consolidation for young patilents with relapsed/refractory (R/R) follicular lymphoma (FL) remains uncertain in the rituximab era, with an unclear benefit of autologous stem cell transplantation (ASCT). The multicenter, randomized, phase III FLAZ12 (NCT01827605) trial compared anti-CD20 radioimmunotherapy (RIT) with ASCT as consolidation after chemoimmunotherapy, both followed by rituximab maintenance. PATIENTS AND METHODS: Patients (age 18-65 years) with R/R FL and without significant comorbidities were enrolled and treated with three courses of conventional, investigator-chosen chemoimmunotherapies. Those experiencing at least a partial response were randomized 1 : 1 to ASCT or RIT before CD34+ collection, and all received postconsolidation rituximab maintenance. Progression-free survival (PFS) was the primary endpoint. The target sample size was 210 (105/group). RESULTS: Between August 2012 and September 2019, of 164 screened patients, 159 were enrolled [median age 57 (interquartile range 49-62) years, 55% male, 57% stage IV, 20% bulky disease]. The study was closed prematurely because of low accrual. Data were analyzed on 8 June 2023, on an intention-to-treat basis, with a 77-month median follow-up from enrollment. Of the 141 patients (89%), 70 were randomized to ASCT and 71 to RIT. The estimated 3-year PFS in both groups was 62% (hazard ratio 1.11, 95% confidence interval 0.69-1.80, P = 0.6662). The 3-year overall survival also was similar between the two groups. Rates of grade ≥3 hematological toxicity were 94% with ASCT versus 46% with RIT (P < 0.001), and grade ≥3 neutropenia occurred in 94% versus 41%, respectively (P < 0.001). Second cancers occurred in nine patients after ASCT and three after radioimmunotherapy (P = 0.189). CONCLUSIONS: Even if prematurely discontinued, our study did not demonstrate the superiority of ASCT versus RIT. ASCT was more toxic and demanding for patients and health services. Both strategies yielded similar, favorable long-term outcomes, suggesting that consolidation programs milder than ASCT require further investigation in R/R FL.

Sphingolipid composition of circulating extracellular vesicles after myocardial ischemia.

Sphingolipids are structural components of cell membrane, displaying several functions in cell signalling. Extracellular vesicles (EV) are lipid bilayer membrane nanoparticle and their lipid composition may be different from parental cells, with a significant enrichment in sphingolipid species, especially in pathological conditions. We aimed at optimizing EV isolation from plasma and describing the differential lipid content of EV, as compared to whole plasma. As pilot study, we evaluated the diagnostic potential of lipidomic signature of circulating EV in patients with a diagnosis of ST-segment-elevation myocardial infarction (STEMI). STEMI patients were evaluated before reperfusion and 24-h after primary percutaneous coronary intervention. Twenty sphingolipid species were quantified by liquid-chromatography tandem-mass-spectrometry. EV-ceramides, -dihydroceramides, and -sphingomyelins increased in STEMI vs. matched controls and decreased after reperfusion. Their levels correlated to hs-troponin, leucocyte count, and ejection fraction. Plasma sphingolipids levels were 500-to-700-fold higher as compared to EV content; nevertheless, only sphingomyelins differed in STEMI vs. control patients. Different sphingolipid species were enriched in EV and their linear combination by machine learning algorithms accurately classified STEMI patients at pre-PCI evaluation. In conclusion, EV lipid signature discriminates STEMI patients. These findings may contribute to the identification of novel biomarkers and signaling mechanisms related to cardiac ischemia.

Aryl hydrocarbon receptor (AhR) rs2066853 gene polymorphism association with infertile oligoasthenoteratozoospermic men and seminal oxidative stress.

This study aimed to assess the association between aryl hydrocarbon receptor (AhR) rs2066853 gene polymorphism with infertile oligoasthenoteratozoospermic (OAT) men and seminal oxidative stress (OS). A total of 170 Egyptian men were allocated according to their semen analysis into fertile normozoospermic controls (n = 50) and infertile OAT men (n = 120). They were subjected to history taking, clinical examination, semen analysis, estimation of seminal glutathione peroxidase (GPx), and malondialdehyde (MDA). AhR rs2066853 gene polymorphism was identified in the blood by PCR-RFLP. Comparing infertile OAT men with fertile controls, AhR rs2066853 genotypes showed decreased prevalence for wild homozygous genotype GG (35.8 vs 56%) and for heterozygous genotype GA (17.5 vs 30%) and an increased prevalence for homozygous genotype AA (46.7 vs 14%). Distribution of alleles of AhR rs2066853 among OAT men compared with fertile men showed decreased prevalence of G allele (44.6 vs 71%) and an increased prevalence of A allele (55.4 vs 29%). Seminal MDA demonstrated significant increase whereas seminal GPx demonstrated significant decrease in cases with AA and GA/AA genotypes compared to cases with GG genotype. It is concluded that there is a significant association between AhR rs2066853 genotype polymorphism with decreased sperm parameters as well as increased seminal oxidative stress in infertile OAT men.

Optical gain from polyfluorene keto defects in a liquid crystal mixture.

By means of confocal photoluminescence measurements and fs pump-probe spectroscopy, we observe the optical properties of phase separation in a mixture of polyfluorene and Liquid Crystals (LCs). The boundaries of LC-rich micro-domains display a large polarized gain region from keto defects stemming from the single-chain nature of this defect.

Monte Carlo simulation for the prediction of precision of absorbance measurements with a miniature CCD spectrometer.

The precision characteristics of the absorbance measurements obtained with a low-cost miniature spectrometer incorporating an array detector were evaluated. Uncertainties in absorbance measurements were due to a combination of non-uniform light intensity and detector response over the wavelength range examined (350-850 nm), in conjunction with the digitization of the intensity indications and the intrinsic noise of the detecting elements. The precision characteristics are presented as contour plots displaying the expected RSD% of absorbances on the absorbance versus wavelength plane. The minimum RSD% for the spectrometer configuration tested was observed within the 0.2-1.5 absorbance units and 500-750 nm wavelength range. Without invoking signal enhancement features of the data-acquisition program (scan average, higher integration times, smoothing based on averaging the signal detected by adjacent pixels), the attainable precision within this range was 0.4-0.8%. A computer program based on Monte Carlo simulations was developed for the prediction of absorbance precision characteristics under various conditions of measurements.

Short term wear of high Dk soft contact lenses does not alter corneal epithelial cell size or viability.

BACKGROUND/AIMS: Current contact lenses (CLs) when worn on an extended wear basis cause corneal epithelial alterations. The aim of this study was to evaluate changes in corneal epithelial cell morphology and physiology following short term (3 months) wear of highly oxygen permeable CLs and to compare this with disposable CLs. METHODS: Subjects were wearers of highly oxygen permeable CLs (n=11, wearing CLs on a 30 night schedule), disposable CL users (n=6, wearing CLs on a 6 night schedule), and non-CL wearers (n=20). Mean CL wear experience was 3 months. Epithelial cells were harvested using corneal cytology and were stained using acridine orange and ethidium bromide. Epithelial cell size and viability were determined. RESULTS: The majority of epithelial cells recovered were non-viable (71%), and the mean longest cell diameter was 38 (SD 8) microm. Disposable CLs caused an increase in cell size (42 (7) microm) compared with both non-wear (39 (7) microm, p=0.01) and wear of highly oxygen permeable CLs (37 (10) microm, p=0.0049). There was no difference in cell viability between groups. CONCLUSIONS: Extended wear of disposable CLs caused an 8% increase in cell diameter in harvested corneal epithelial cells following 3 months of CL wear. Cells harvested following 3 months' wear of highly oxygen permeable CLs were indistinguishable from those recovered from non-CL wearers.

A phase II study of neuroimmunotherapy with subcutaneous low-dose IL-2 plus the pineal hormone melatonin in untreatable advanced hematologic malignancies.

Interleukin-2 (IL-2) has proven to be able to generate an effective anticancer immunity against both solid and hematologic malignancies. Moreover, recent advances in the knowledge of psychoneuroimmunology have demonstrated that anticancer immunity is under neuroendocrine control and that the pineal hormone melatonin (MLT) may stimulate the IL-2-dependent anticancer reaction. Finally, preliminary clinical studies have already shown that the concommitant administration of MLT may amplify the efficacy of IL-2 in the treatment of advanced solid neoplasms, whereas there are no data about MLT influence on IL-2 activity in hematologic malignancies. The aim of the present study was to evaluate the efficacy and tolerability of a neuroimmunotherapeutic combination of low-dose IL-2 plus MLT in advanced hematologic malignancies which did not respond to previous standard therapies. The study included 12 evaluable patients. Tumor histotypes were as follows: non-Hodgkin's lymphoma (NHL) 6; Hodgkin's disease (HD), 2; multiple myeloma, 2; acute myelogenous leukemia (ALM), 1 and chronic myelomonocytic leukemia (CMML), 1. IL-2 was injected subcutaneously at a dose of 3 million IU/day for 6 days per week for 4 weeks, corresponding to one cycle. MLT was given orally at 20 mg/day in the evening, without interruption. In non-progressing patients, a second IL-2 cycle was planned after a 3 week-rest period. A partial response was achieved in one patient with multiple myeloma. Stable disease occurred in 7 other patients (NHL, 3; HD, 1; AML, 1; CLLM, 1; multiple myeloma, 1), whereas the other 4 patients progressed. Therefore, lack of progression was obtained in 8 out of 12 (67%) patients, with a median duration of 21+ months (14-30+ months). The treatment was well tolerated in all patients. These preliminary results would suggest that the concomitant administration of low-dose IL-2 plus the pineal hormone MLT may prolong the survival time in untreatable advanced hematologic malignancies, with results comparable to those previously reported using a more toxic immunotherapy, consisting of high-dose IL-2 alone.

Blood concentrations of tumor necrosis factor-alpha in malignant lymphomas and their decrease as a predictor of disease control in response to low-dose subcutaneous immunotherapy with interleukin-2.

Tumor necrosis factor-alpha (TNF-alpha), a cytokine provided by both immunomodulating and inflammatory activities, has been described to be abnormally increased in the blood of patients affected by malignant lymphomas, particularly NHL. However, the biological and clinical significance of TNF-alpha secretion in malignant lymphomas is still controversial. The present study was carried out to further define TNF-alpha secretion in untreated malignant lymphomas and during low-dose IL-2 immunotherapy. The study included 80 malignant lymphoma patients, 54 of whom were affected by HD and the other 26 by NHL. The mean TNF-alpha serum concentrations observed in untreated lymphoma patients were significantly higher than those seen in the healthy controls, without significant differences between HD and NHL. Moreover, both HD and NHL lymphoma patients at clinical stage III-IV showed significantly higher mean TNF-alpha levels than those at clinical stage I-II. Finally, patients with systemic symptoms had higher mean TNF-alpha concentrations than those without any systemic symptoms, even though statistical significance was observed only for NHL patients. In a second study we have evaluated changes in TNF-alpha levels in seven evaluable lymphoma patients (NHL: 6; HD: 1)--who did not respond to conventional therapies--during subcutaneous low-dose IL-2 (3 MIU/day, 6 days/week for 4 weeks). Long-term stable disease was achieved in four patients with NHL, whereas the other three progressed. In patients with stable disease the mean TNF-alpha concentrations significantly decreased during treatment, whereas they increased in progressing patients. This study, by showing an abnormally enhanced TNF-alpha secretion in both NHL and HD patients with advanced disease and systemic symptoms and a decrease in its levels in patients who achieved disease control on IL-2 immunotherapy, appears to confirm the unfavorable prognostic significance of enhanced TNF-alpha levels in malignant lymphomas.

Ceftriaxone/Amikacin vs Ceftazidime/Amikacin as Empirical Therapy for Fever in Patients with Haematological Malignancy and Severe Granulocytopenia: Clinical and Economic Outcomes.

To assess the economic outcomes produced when a conventional antibiotic treatment regimen requiring three administrations per day was replaced with a treatment regimen requiring only one daily administration, the efficacy, tolerability and cost of ceftazidime was compared with that of ceftriaxone (both drugs in combination with amikacin) for the empirical treatment of febrile granulocytopenic patients with haematological malignancy. 102 febrile patient-episodes were randomly assigned to receive ceftazidime (6g in three divided doses) or ceftriaxone (2g as a single daily dose), both in combination with amikacin. The response was evaluable in 94 patients (47 in each group). 75 (80%) patients had an absolute granulocyte count lower than 100/mm(3) at the onset of fever or during the first week of antibiotic therapy. 61 (64.9%) were affected by acute leukaemia. Multiple daily ceftazidime plus amikacin was effective in 33 of 47 (70.2%) patients, and single daily ceftriaxone plus amikacin in 31 of 47 (66%) patients (p > 0.2). Among patients successfully treated, median time to defervescence was 3.3 days (range 1 to 11) for ceftazidime plus amikacin and 4.5 days for ceftriaxone plus amikacin (range 1 to 15) [p = 0.14]; study drugs were continued for 12 (range 7 to 26) and 12.3 days (range 7 to 28), respectively. Our study demonstrated that single daily administration of ceftriaxone was as effective and well tolerated as multiple daily administration of ceftazidime when both were administered in combination with amikacin. Cost analysis showed that compared with the thrice daily regimen, administration of single daily doses of ceftriaxone for a 12-day treatment period would result in a net cost saving of $US392 (626 940 Italian lire).

Establishment of the human reflex tear two-dimensional polyacrylamide gel electrophoresis reference map: new proteins of potential diagnostic value.

To understand the changes in protein expression associated with various physiological states as well as the development of pathological eye disease, we have begun to map the protein components of normal human reflex tears. An analytical reference map of normal human reflex tears was created using two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) with pH 3.5-10 immobilized pH gradients (IPGs). Micropreparatively loaded gels were transferred to polyvinylidene difluoride (PVDF) and analysed by a combination of N-terminal sequence tagging and amino acid compositional analysis. Thirty spots were sequence tagged, resulting in identification of six different proteins (lipocalin, lysozyme, lactotransferrin, zinc-alpha-2 glycoprotein, cystatin S, cystatin SN) that matched to entries in the SWISS-PROT database. A group of N-terminally blocked proteins was clearly identified from SWISS-PROT by amino acid analysis, isoelectric point (pI) and molecular weight (Mr). A number of highly expressed protein components remain unidentified despite being subjected to amino acid analysis and Edman sequencing. A majority of the abundant proteins showed varying degrees of charge heterogeneity attributed to post-translational processing such as glycosylation and N-terminal truncation. We have identified a previously undescribed protein that we have named lacryglobin. This protein displays strong homology with mammaglobin, a protein overexpressed in breast cancer. The discovery of this homologue in tears offers the potential for disease diagnosis by screening tear fluid proteins.

Alpha interferon as initial treatment of essential thrombocythemia. Analysis after two years of follow-up.

AIMS AND BACKGROUND: Recombinant alpha-interferon has been shown to be effective in essential thrombocythemia and in thrombocytosis associated with other myeloproliferative disorders. PATIENTS AND METHODS: Twenty-five untreated patients were enrolled in our study from May 1989 to April 1992. Recombinant alpha interferon-2b was administered at an initial dose of 2 megaunits (MU)/m2 three times a week at escalating doses to 5 MU/m2 or the maximum tolerated dose. The mean follow-up for patients still in treatment at the time of this report was 35.9 months (range, 24-63). RESULTS: Fourteen patients (56%) had achieved a complete remission by a mean time of 152 days; 6 patients (24%) had achieved a good partial remission by a mean of 180 days. In addition to the favorable effect on platelet count, a marked improvement in clinical symptoms was observed. Treatment had to be discontinued in 9 patients (36%), 5 for toxicity (3 neurologic, 1 anemia and 1 severe hypertriglyceridemia) at a median of 155 days from the beginning of therapy (range, 30-400). Four patients refused to continue therapy because of low tolerance (flu-like syndrome) at mean of 160 days from the beginning of therapy (range, 34-301). CONCLUSIONS: In our study, lower doses were administered compared with previous short-time trials. The present data show that interferon is an effective alternative to cytostatic agents in long-term treatment of patients with essential thrombocythemia, even when used at lower dosages.

Effect of exogenous hyaluronan and hyaluronan oligosaccharides on hyaluronan and aggrecan synthesis and catabolism in adult articular cartilage explants.

The addition of hyaluronan to the culture medium of explant cultures of articular cartilage was shown to suppress the synthesis of hyaluronan and aggrecan, the major proteoglycan present in cartilage, and resulted in a greater proportion of the newly synthesized aggrecan and hyaluronan appearing in the culture medium. This effect of exogenous hyaluronan on aggrecan and hyaluronan synthesis was concentration-dependent and reversible on removal of the glycosaminoglycan from the culture medium. The addition of tetra- and hexasaccharides derived from Streptomyces sp. hyaluronidase digestion of hyaluronan to explant cultures of articular cartilage did not change the rate of synthesis of aggrecan or hyaluronan or their ultimate distribution between tissue and medium. However, the addition of tetra- and hexasaccharides of hyaluronan resulted in a decrease in the rate of loss of hyaluronan from the tissue but not that of aggrecan, which remained the same as in control cultures. This suppression of the rate of loss of hyaluronan was eliminated on removal of the hyaluronan oligosaccharides from the culture medium. Analysis of the hydrodynamic size of the newly synthesized hyaluronan indicated that the presence of hyaluronan tetra- and hexasaccharides brought about an accumulation of hyaluronan of intermediate molecular mass. Since no radiolabeled hyaluronan was detected in the culture medium, it was concluded that the tetra- and hexasaccharides inhibited the internalization and intracellular catabolism of hyaluronan by the cartilage explant cultures. Regardless of whether hyaluronan or tetra- and hexasaccharides of hyaluronan were added to the culture medium, newly synthesized hyaluronan underwent depolymerization at a rate consistent with a mechanism involving oxygen-derived radicals.

Amikacin and ceftazidime as empirical antibiotic therapy in severely neutropenic patients: analysis of prognostic factors.

This study aimed to evaluate the efficacy of amikacine and ceftazidime as an empirical antibiotic therapy for neutropenic patients affected by haematological neoplasms and to investigate the presence of prognostic features suggesting a poor outcome with this antibiotic combination at the onset of infection. This could allow the identification of subgroups of patients with a low rate of response to amikacin/ceftazidime therapy; in these patients different initial empirical therapy may be indicated. The study population comprised 166 severely neutropenic (absolute neutrophil count below 500/microliters) oncohaematological patients with fever or clinical signs of infection. Multivariate analysis confirmed four negative prognostic factors: 3 or more days of hospitalization at the onset of an infectious episode, a diagnosis of acute myelmany factors are present, cases can be stratified into three groups, of significantly different prognosis: favourable (0 or 1 factor) 76% success; intermediate (2 factors) 52% success; unfavourable (3 or 4 factors) 19% success. At the onset of an infectious episode a subgroup of patients with a very low response rate to empirical amikacin/ceftazidime antibiotic therapy is identifiable, for whom a different therapy is indicated. Because of the high rate of proven or probable fungal infections in this group, the immediate administration of a systemic antifungal therapy, in addition to antibacterial agents, could be considered in these high-risk patients. Studies should be specifically addressed to evaluating a stratification of empirical antibiotic therapy according to risk factors present at the onset of infection.

[Multiple myeloma. Role of prognostic factors and staging in a therapeutic program]. / Il mieloma multiplo. Ruolo dei fattori prognostici e della stadiazione in un programma terapeutico.

Patients affected with multiple myeloma constitute an heterogeneous population with very different clinical patterns, varying from asymptomatic to very compromised patients with severe and uncontrolled disease. Most common clinical and biological staging systems have been in use for many years. Recently new prognostic factors have been identified; among them, serum levels of beta-2 microglobulin, C-reactive protein and interleukin-6 employed with already known parameters have been useful in the new staging system, permitting a more focalized therapy. As today is not yet possible to define the best treatment schedule, as the most common treatments are incapable to eradicate myeloma neoplastic clone even in responsive patients. Nevertheless extensive use of biologic response modifiers in the last years, as alpha interferon, have added new powerful and hopeful therapeutic tools even if the results need to be confirmed in future trials. It is important to remind the primary role of bone marrow transplantation associated with high dose polychemotherapy even if just a minority of patients is eligible for this therapeutic chance.

Atrial flutter followed by sick sinus syndrome as presenting symptoms of B-cell malignant non-Hodgkin lymphoma involving the heart.

A case of non-Hodgkin lymphoma involving the heart is described; the patient suffered for atrial flutter, followed by sick sinus syndrome for one year before diagnosis was made. Although it is not possible to demonstrate primary cardiac onset, the clinical history is highly suggestive. Most recent cases described occurred in immunodeficient patients. Interestingly our patient showed no evidence of immunodeficiency. Our patient received conventional chemotherapy followed by radiotherapy, obtaining complete remission without complications, and remains in this condition after a 3-year follow-up. The patient's good condition may be responsible for this successful outcome.