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.

Safety and efficacy of odronextamab in patients with relapsed or refractory follicular lymphoma.

BACKGROUND: Odronextamab, a CD20×CD3 bispecific antibody that engages cytotoxic T cells to destroy malignant B cells, has demonstrated encouraging activity across multiple subtypes of relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. PATIENTS AND METHODS: This phase II study (ELM-2; NCT03888105) evaluated odronextamab in patients with R/R follicular lymphoma (FL) after ≥2 lines of systemic therapy. Patients received intravenous odronextamab in 21-day cycles, with step-up dosing in Cycle 1 to help mitigate the risk of cytokine release syndrome (CRS), until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by independent central review. RESULTS: Among 128 patients evaluated, 95% completed Cycle 1, and 85% completed ≥4 cycles. At 20.1 months' efficacy follow-up, ORR was 80.0% and complete response rate was 73.4%. Median duration of complete response was 25.1 months. Median progression-free survival was 20.7 months, and median overall survival was not reached. Discontinuation of odronextamab due to adverse events (AEs) occurred in 16% of patients. The most common treatment-emergent AEs were CRS (56%; grade ≥3 1.7% [1/60] with 0.7/4/20 mg step-up), neutropenia (39%), and pyrexia (38%). CONCLUSIONS: Odronextamab achieved high complete response rates with generally manageable safety in patients with heavily pretreated R/R FL.

Noncollinear electro-optic sampling detection of terahertz pulses in a LiNbO3 crystal while avoiding the effect of intrinsic birefringence.

We propose and experimentally prove efficient high-resolution electro-optic sampling measurement of broadband terahertz waveforms in a LiNbO3 crystal in the configuration with the probe laser beam propagating along the optical axis of the crystal. This configuration allows one to avoid the detrimental effect of strong intrinsic birefringence of LiNbO3 without any additional optical elements. To achieve velocity matching of the terahertz wave and the probe beam, the terahertz wave is introduced into the crystal through a Si prism at the Cherenkov angle to the probe beam. The workability of the scheme at different wavelengths of the probe optical beam (800 and 1550 nm) is demonstrated.

First assessment of root biomass and root carbon and nitrogen stocks in Turkish floodplain forests.

Estimation of whole root biomass including coarse and larger roots and root balls can provide better understanding of carbon and nitrogen stocks in floodplain forests. Whole root systems of nine ash trees (Fraxinus angustifolia Vahl.) and six alder trees (Alnus glutinosa L.) trees ranging in diameter breast height (dbh) from 29.1 to 72.0 cm for ash and from 29.1 to 44.3 cm for alder were excavated, and their small < 1 cm, medium 1-4 cm, larger > 4 cm and root-ball biomass, and root carbon and nitrogen stocks were determined in Karacabey floodplain forest in Bursa, Turkey. In addition, for the method comparison, small root biomass (< 1 cm) was also determined using soil-core method. The whole root biomass of ash trees varied from 167.7 to 186.8 Mg ha-1. Alder trees had lower whole root biomass than ash trees ranging from 49.0 to 63.6 Mg ha-1. The determination of small root biomass by soil excavation method was nearly two-fold higher than by soil core method. Both root carbon and nitrogen stocks showed an increase with increasing root diameter. Among the tree characteristics (dbh, age, height, and volume), the dbh showed the highest correlation with whole root biomass and root carbon and nitrogen stocks for both tree species. It is concluded that young trees can have higher small, medium, and large root biomass and store more C and N in those roots, whereas older trees can have higher root-ball biomass and root-ball carbon and nitrogen stocks in Karacabey floodplain forests.

Elastocapillary adhesion of a soft cap on a rigid sphere.

We study the capillary adhesion of a spherical elastic cap on a rigid sphere of a different radius. Caps of small area accommodate the combination of flexural and in-plane strains induced by the mismatch in curvature, and fully adhere to the sphere. Conversely, wider caps delaminate and exhibit only partial contact. We determine the maximum size of the cap enabling full adhesion and describe its dependence on experimental parameters through a balance of stretching and adhesion energies. Beyond the maximum size, complex adhesion patterns such as blisters, bubbles or star shapes are observed. We rationalize these different states in configuration diagrams where stretching, bending and adhesion energies are compared through two dimensionless parameters.

Nonellipsometric electro-optic sampling of terahertz waves in GaAs.

We report efficient high-resolution electro-optic sampling detection of broadband terahertz radiation by measuring direct intensity modulation of a femtosecond fiber laser beam induced by terahertz field in a 1-cm thick GaAs crystal.

Constraints on new gravitylike forces in the nanometer range.

We report on a new constraint on gravitylike short-range forces, in which the interaction charge is mass, obtained by measuring the angular distribution of 5 Å neutrons scattering off atomic xenon gas. Around 10^{7} scattering events were collected at the 40 m small angle neutron scattering beam line located at the HANARO research reactor of the Korean Atomic Energy Research Institute. The extracted coupling strengths of new forces in the Yukawa-type parametrization are g[over ^]^{2}=(0.2±6.8±2.0)×10^{-15} GeV^{-2} and g[over ^]^{2}=(-5.3±9.0_{-2.8}^{+2.7})×10^{-17} GeV^{-2} for interaction ranges of 0.1 and 1.0 nm, respectively. These strengths correspond to 95% confidence level limits of g^{2}<(1.4±0.2)×10^{-14} GeV^{-2} and g^{2}<(1.3±0.2)×10^{-16} GeV^{-2}, improving the current limits for interaction ranges between 4 and 0.04 nm by a factor of up to 10.

Randomized clinical trial of isolated Roux-en-Y versus conventional reconstruction after pancreaticoduodenectomy.

BACKGROUND: Pancreaticoduodenectomy (PD) is associated with a high incidence of postoperative complications including pancreatic fistula. This randomized clinical trial compared the incidence of pancreatic fistula between the isolated Roux-en-Y (IsoRY) and conventional reconstruction (CR) methods. METHODS: Patients admitted for PD between June 2009 and September 2012 in a single centre were assigned randomly to CR or IsoRY. The primary endpoint was the incidence of pancreatic fistula (grade A-C) defined according to the International Study Group on Pancreatic Fistula. Secondary endpoints were complication rates, mortality and hospital stay. Multiple logistic regression analysis was performed to identify factors associated with pancreatic fistula. RESULTS: Some 153 patients were randomized, 76 to CR and 77 to IsoRY; two patients from the IsoRY group were excluded after randomization. Pancreatic fistula occurred in 26 patients (34 per cent) in the CR group and 25 (33 per cent) in the IsoRY group (P = 0·909). The number of patients with a clinically relevant pancreatic fistula (grade B or C) was similar in the two groups (10 and 11 patients respectively; P = 0·789), as were complication rates (42 versus 40 per cent; P = 0·793) and mortality (none in either group; P = 0·999). Soft pancreas was the only independent risk factor for pancreatic fistula (odds ratio 4·42, 95 per cent confidence interval 1·85 to 10·53; P <0·001). CONCLUSION: This study showed that IsoRY reconstruction does not reduce the incidence of pancreatic fistula compared with CR. REGISTRATION NUMBER: NCT00915863 (http://www.clinicaltrials.gov/) and UMIN000001967 (http://www.umin.ac.jp/).

Observation of the spatial distribution of gravitationally bound quantum states of ultracold neutrons and its derivation using the Wigner function.

Ultracold neutrons (UCNs) can be bound by the potential of terrestrial gravity and a reflecting mirror. The wave function of the bound state has characteristic modulations. We carried out an experiment to observe the vertical distribution of the UCNs above such a mirror at the Institut Laue-Langevin in 2011. The observed modulation is in good agreement with that prediction by quantum mechanics using the Wigner function. The spatial resolution of the detector system is estimated to be 0.7 µm. This is the first observation of gravitationally bound states of UCNs with submicron spatial resolution.

One-year follow-up of zoster-associated pain in 764 immunocompetent patients with acute herpes zoster treated with famciclovir (FAMILIAR study).

BACKGROUND: Herpes zoster (HZ), a reactivation of varicella zoster virus manifested by skin blisters and neuralgia, can lead to postherpetic neuralgia in 10-20% of affected subjects. METHOD: In this study, a cohort of 764 patients with HZ was treated with 1500 mg/day of famciclovir for 7 days, and zoster-associated pain (ZAP) was monitored monthly thereafter for up to 12 months until pain resolution was achieved. Patients were questioned monthly by telephone, and pain was recorded using a numerical rating scale (NRS, 0-10). KEY RESULTS: A total of 751 of 764 (98.3%) patients completed follow-up. The percentage of patients with ZAP was 12.4% at day 90, 7.1% at 6 months and 4.0% at 1 year. After the third month, the NRS were 3 or less in most of the remaining patients with ZAP. Stratified analysis revealed significant persistence of ZAP in patients aged ≥50 years and in those aged ≥65 years, and in patients with either moderate-to-severe skin symptoms or severe pain at the initial consultation.Stratified analyses unexpectedly showed patients who commenced famciclovir at 0-2 days after onset of the eruption had a higher prevalence of ZAP at day 90 than those treated at 3-5 days or ≥6 days after rash onset (P = 0.0164, log-rank test). On further analysis, a higher proportion of patients (45.4%) treated at 0-2 days had moderate to severe symptoms compared with those treated at 3-5 days (40.5%) or ≥6 days (37.0%) (P = 0.0987, Cochran-Armitage test). CONCLUSION & INFERENCE: This study, with an exceptionally high follow-up rate, revealed several new findings, including the influence of disease severity on the delay between the onset of symptoms and seeking medical attention. Six adverse drug reactions were reported in five of 721 patients in the safety analysis, including two severe cases of vomiting and convulsions.

Increased frequency of skin-infiltrating FoxP3+ regulatory T cells as a diagnostic indicator of severe atopic dermatitis from cutaneous T cell lymphoma.

Differential diagnosis of cutaneous T cell lymphoma (CTCL) and severe atopic dermatitis (AD) is often difficult because of the similarity in their skin manifestations. However, such differentiation is extremely important because of the differences in remedy and prognosis. The aim of this study was to investigate new, helpful diagnostic aids for distinguishing CTCL from AD. The frequency of forkhead box protein 3(+) (FoxP3(+)) regulatory T cells (T(regs)) in cutaneous lesions was evaluated among the three populations. Serum-soluble interleukin-2 receptor (sIL-2R), immunoglobulin (Ig)E-radioimmunosorbent test, lactate dehydrogenase (LDH) and blood eosinophil count were measured in 11 CTCL patients (including three CTCL patients misdiagnosed previously with intractable AD), 10 adult AD patients and nine psoriasis patients. The frequency of T(regs) was increased significantly in cutaneous lesions of AD compared with those of CTCL. Serum IgE and LDH levels were also elevated significantly in AD compared with CTCL, whereas there were no significant differences in serum sIL-2R levels between CTCL and AD. In the three CTCL patients who were misdiagnosed with intractable AD, IgE and LDH levels were lower than in AD patients, whereas serum sIL-2R levels were as high as in AD patients and higher than in the other eight CTCL patients. The higher frequency of T(regs) in the cutaneous lesions of patients with AD than in those with CTCL and higher serum IgE and LDH levels in patients with AD than in those with CTCL might be helpful reference values for the differential diagnosis of these two diseases.

Megahertz repetition rate-based lock-in detection scheme for rapid data acquisition in terahertz time domain spectroscopy.

We report a fast pump modulation scheme in a terahertz time domain spectroscopy (THz-TDS) system by utilizing the intensity modulation from the megahertz repetition rate of the pump pulse for lock-in detection. In conventional THz-TDS, the modulation required for the high signal-to-noise ratio lock-in detection is achieved through the use of an optical chopper or an AC bias. Here, we propose the use of an electro-optic modulator (EOM), operated as a pulse picker, to vary the repetition rate of the pump pulse, relative to the probe pulse, allowing us to directly use the megahertz laser repetition rate as the reference modulation frequency for lock-in detection. Our proposed scheme is applicable to all types of pulsed THz emitters, including those that cannot be electronically biased. Since the maximum allowable modulation frequency is limited only by the laser repetition rate and/or by the bandwidth of the EOM, megahertz modulation rates, and, consequently, rapid data acquisition times, become possible. Using our technique, we were able to detect an oscillating signal with frequencies up to 10 kHz, using ∼1 µs integration time per point, ∼100× faster than previously reported values for THz-TDS systems.

Associations between Dietary Variety and Frailty in Community-Dwelling Older People Who Live Alone: Gender Differences.

OBJECTIVES: This study aimed to investigate the influences of living arrangements on the association between dietary variety and frailty by gender in community-dwelling older people. DESIGN: A cross-sectional study. SETTING: Nishinomiya city, Hyogo prefecture, Japan. PARTICIPANTS: A total of 4,996 randomly selected community-dwelling older people aged 65 years and older and living in Nishinomiya City. MEASUREMENTS: Survey questionnaires were distributed via mail. The frailty score was evaluated by the 5-item frailty screening index. Dietary variety was assessed using the dietary variety score developed for the general older Japanese population. RESULTS: A total of 2,764 community-dwelling participants aged ≥ 65 years responded to the questionnaires. After excluding missing data, 1,780 participants were included in the study analysis. The frailty scores in older men living alone were significantly higher than those in older men living with someone (P < 0.001). The dietary variety scores in older men living alone were significantly lower than those in older men living with someone (P < 0.001). However, differences in the frailty and dietary variety scores between living alone and living with someone were not were observed in older women (P = 0.360 and P = 0.265, respectively). In the multivariable regression analysis, the associations between dietary variety score and frailty score in living alone (ß= -0. 271, P = 0.011) were stronger than those in living with someone in the case of older men (ß= -0.131, P = 0.045). Similar associations between dietary variety and frailty were presented in older women living alone than in those living with someone (ß -0.114, P = 0.002; ß -0.088, P = 0.012, respectively). CONCLUSIONS: Older men who live alone had higher frailty score and lower dietary variety. The associations between dietary variety and frailty were different according to living arrangements in both older men and older women.

A phase II trial of short course fludarabine, mitoxantrone, rituximab followed by 9°Y-ibritumomab tiuxetan in untreated intermediate/high-risk follicular lymphoma.

BACKGROUND: A prospective, single-arm, open-label, multicenter, nonrandomised phase II trial to evaluate efficacy and safety of short fludarabine, mitoxantrone, and rituximab (FMR) induction followed by radioimmunotherapy, in untreated, intermediate/high-risk follicular non-Hodgkin's lymphoma (NHL) patients. PATIENTS AND METHODS: Fifty-five patients were treated using a sequential treatment schedule of four induction cycles of FMR chemoimmunotherapy, and a subsequent consolidating single administration of (90)Y-ibritumomab tiuxetan ((90)Y-IT), 8-14 weeks later. Patients were eligible for radioimmunotherapy if at least in partial response (PR) after induction, with normal platelet and granulocyte counts and a bone marrow infiltration ≤ 25%. Primary study end points were response rate and hematologic toxic effects; secondary end points were overall survival (OS) and progression-free survival (PFS). RESULTS: All the 55 patients received four induction cycles with an overall response rate of 96% (38 complete responses [CR] and 15 PR). Fifty-one patients (38 in CR and 13 in PR) received (90)Y-IT. By the end of the treatment, 49/55 patients achieved a CR. With a median follow-up of 21 months, the estimated 3-year PFS was 81% and the 3-year OS 100%. CONCLUSIONS: This study has established feasibility, tolerability, and efficacy of a regimen composed by short FMR induction with (90)Y-IT consolidation in untreated intermediate/high-risk follicular NHL patients.

Viscosupplementation in haemophilic arthropathy: a long-term follow-up study.

Haemophilic arthropathy is the most common clinical manifestation of haemophilia, secondary to recurrent haemarthroses and chronic synovitis. Modern bleeding-preventing drugs have limited significantly the incidence of severe arthropathy, and primary approach is usually conservative. Use of intra-articular injections of hyaluronan acid is considered one of the most efficient treatments for early stages of articular degenerative diseases. Assessment of long-term effectiveness of intra-articular administration of hyaluronic acid (HA) in knees, ankles and elbows of patients affected by haemophilic arthropathy was done for 46 patients (10 elbows, 24 knees and 25 ankles) affected by haemophilic arthropathy. They received injections of HA and were evaluated with Visual Analogue Scale, Short Form-36, World Federation of Haemophilia score and Petterson score with a 6-year mean follow-up. Most of the patients showed improvement in pain relief and functional recovery without any complications: only a limited number of patients (8.6%) found poor results, undergoing surgery or other further treatments in the follow-up period for persistent pain or limitation. Viscosupplementation is an effective therapeutic strategy in early stages of haemophilic arthropathy, with no complications and long-term good clinical results.