Impact of individualized treatment on recovery from fatigue and return to work in survivors of advanced-stage Hodgkin's lymphoma: results from the randomized international GHSG HD18 trial.

BACKGROUND: Persisting cancer-related fatigue impairs health-related quality of life (HRQoL) and social reintegration in patients with Hodgkin's lymphoma (HL). The GHSG HD18 trial established treatment de-escalation for advanced-stage HL guided by positron emission tomography after two cycles (PET-2) as new standard. Here, we investigate the impact of treatment de-escalation on long-term HRQoL, time to recovery from fatigue (TTR-F), and time to return to work (TTR-W). PATIENTS AND METHODS: Patients received European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and life situation questionnaires at baseline, interim, end of treatment, and yearly follow-up. TTR-F was defined as time from the end of chemotherapy until the first fatigue score <30. TTR-W was analyzed in previously working or studying patients and measured from the end of treatment until the first documented work or education. We compared duration of treatment on TTR-F and TTR-W using Cox proportional hazards regression adjusted for confounding variables. RESULTS: HRQoL questionnaires at baseline were available in 1632 (83.9%) of all randomized patients. Overall, higher baseline fatigue and age were significantly associated with longer TTR-F and TTR-W and male sex with shorter TTR-W. Treatment reduction from eight to four chemotherapy cycles led to a significantly shorter TTR-F [hazard ratio (HR) 1.41, P = 0.008] and descriptively shorter TTR-W (HR 1.24, P = 0.084) in PET-2-negative patients. Reduction from six to four cycles led to non-significant but plausible intermediate accelerations. The addition of rituximab caused significantly slower TTR-F (HR 0.70, P = 0.0163) and TTR-W (HR 0.64, P = 0.0017) in PET-2-positive patients. HRQoL at baseline and age were the main determinants of 2-year HRQoL. CONCLUSIONS: Individualized first-line treatment in patients with advanced-stage HL considerably shortens TTR-F and TTR-W in PET-2-negative patients. Our results support the use of response-adapted shortened treatment duration for patients with HL.

SAKK57/16 Nab-paclitaxel and Gemcitabine in Soft Tissue Sarcoma (NAPAGE): a phase I/II trial.

BACKGROUND: To determine whether the combination of nab-paclitaxel with gemcitabine has activity in patients with pretreated soft tissue sarcoma (STS). PATIENTS AND METHODS: NAPAGE is a phase Ib/II clinical trial investigating the combination of nab-paclitaxel (nab-pc) with gemcitabine employing two cohorts. One of a dose-de-escalation phase and one of expansion. In phase I, nab-pc was given at 150 mg/m2 in combination with gemcitabine 1000 mg/m2 every two weeks, until disease progression or unacceptable toxicity. This dose was recommended for phase II (RP2D), as there was no dose limiting toxicity (DLT) or discontinuations due to adverse events (AEs). The primary endpoint of the phase II was progression-free rate (PFR) at 3 months (H0: 20%, H1:40%). The secondary endpoints included progression free survival (PFS), overall survival (OS), AEs, objective response and patient-reported outcomes (PRO). Efficacy analysis was by intention to treat. RESULTS: The 3-month PFR was 56.4% (95% confidence interval CI: 39.6-72.2%). The 3-month and 6-month PFS were 58.4% (95% CI: 41.3-72.1%) and 44.6% (95% CI: 28.4-59.5%), respectively. Median PFS was 5.3 months (95% CI: 1.4-8.2) and median OS was 12.8 months (95% CI: 10.5-39.2). The most common treatment-related grade ≥ 3 AE were neutropenia (18%), followed by anemia (2.6%), hypertension (2.6%) and alanine aminotransferase increase (2.6%). Grade 1 and grade 2 peripheral sensory neuropathy (PNP) occurred in 15.4% and 20.5%, respectively. No grade 3-4 PNP was reported. CONCLUSIONS: Combining nab-pc and gemcitabine is safe. Promising activity is observed in pretreated STS patients with manageable toxicity. This regimen should be considered for further exploration.

Clinical characteristics and outcome of patients over 60 years with Hodgkin lymphoma treated in Switzerland.

Hodgkin lymphoma (HL) in older patients appears to be a different disease compared with younger patients with historically lower survival rates. This is related to a variety of factors, including increased treatment-related toxicity, the presence of comorbidities, and biologic differences. In order to better assess the clinical characteristics, treatment strategies, and outcome of this particular population, we conducted a population-based, retrospective analysis including 269 patients with HL older than 60 years (median age 71 years, range 60-94), treated between 2000 and 2017 in 15 referral centers across Switzerland. Primary endpoints were overall survival (OS), progression-free survival (PFS), and cause-specific survival (CSS). The vast majority of patients were treated with curative intent, either with a combined modality approach (chemotherapy followed by radiation therapy) or with systemic therapy. At a median follow-up of 6.6 years (95% confidence interval [CI], 6.0-7.6), 5-year PFS was 52.2% (95% CI, 46.0-59.2), 5-year OS was 62.5% (95% CI, 56.4-69.2), and 5-year CSS was 85.1.8% (95% CI, 80.3-90.1) for the entire cohort. A significant difference in terms of CSS was observed for patients older than 71 years in comparison to patients aged 60-70 years (hazard ratio 2.6, 1.3-5.0, p = 0.005). Bleomycin-induced lung toxicity (BLT) was documented in 26 patients (17.7%) out of the 147 patients exposed to this compound and was more frequent in patients older than 71 years (15/60, 25%). Outcome of HL pts older than 71 years appeared to decrease substantially in comparison to the younger counterpart. Treatment-related toxicities appeared to be relevant, in particular, BLT. New, potentially less toxic strategies need to be investigated in prospective clinical trials in this particular frail population.

Spatial Distortion of Vibration Modes via Magnetic Correlation of Impurities.

Long wavelength vibrational modes in the ferromagnetic semiconductor Ga_{0.91}Mn_{0.09}As are investigated using time resolved x-ray diffraction. At room temperature, we measure oscillations in the x-ray diffraction intensity corresponding to coherent vibrational modes with well-defined wavelengths. When the correlation of magnetic impurities sets in, we observe the transition of the lattice into a disordered state that does not support coherent modes at large wavelengths. Our measurements point toward a magnetically induced broadening of long wavelength vibrational modes in momentum space and their quasilocalization in the real space. More specifically, long wavelength vibrational modes cannot be assigned to a single wavelength but rather should be represented as a superposition of plane waves with different wavelengths. Our findings have strong implications for the phonon-related processes, especially carrier-phonon and phonon-phonon scattering, which govern the electrical conductivity and thermal management of semiconductor-based devices.

Hot carrier relaxation in CdTe via phonon-plasmon modes.

Carrier and lattice dynamics of laser excited CdTe was studied by time-resolved reflectivity for excitation fluences spanning about three orders of magnitude, from 0.064 to 6.14 mJ cm-2. At fluences below 1 mJ cm-2 the transient reflectivity is dominated by the dynamics of hybrid phonon-plasmon modes. At fluences above 1 mJ cm-2 the time-dependent reflectivity curves show a complex interplay between band-gap renormalization, band filling, carrier dynamics and recombination. A framework that accounts for such complex dynamics is presented and used to model the time-dependent reflectivity data. This model suggests that the excess energy of the laser-excited hot carriers is reduced much more efficiently by emitting hybrid phonon-plasmon modes rather than bare longitudinal optical phonons.

Nanoplasma dynamics of single large xenon clusters irradiated with superintense x-ray pulses from the linac coherent light source free-electron laser.

The plasma dynamics of single mesoscopic Xe particles irradiated with intense femtosecond x-ray pulses exceeding 10(16) W/cm2 from the Linac Coherent Light Source free-electron laser are investigated. Simultaneous recording of diffraction patterns and ion spectra allows eliminating the influence of the laser focal volume intensity and particle size distribution. The data show that for clusters illuminated with intense x-ray pulses, highly charged ionization fragments in a narrow distribution are created and that the nanoplasma recombination is efficiently suppressed.

Diffraction properties of periodic lattices under free electron laser radiation.

In this Letter, we report the pioneering use of free electron laser radiation for the investigation of periodic crystalline structures. The diffraction properties of silver behenate single nanocrystals (5.8 nm periodicity) with the dimensions of 20 nm x 20 nm x 20 microm and as powder with grain sizes smaller than 200 nm were investigated with 8 nm free electron laser radiation in single-shot modus with 30 fs long free electron laser pulses. This work emphasizes the possibility of using soft x-ray free electron laser radiation for these crystallographic studies on a nanometer scale.

Nanoscale depth-resolved coherent femtosecond motion in laser-excited bismuth.

We employ grazing-incidence femtosecond x-ray diffraction to characterize the coherent, femtosecond laser-induced lattice motion of a bismuth crystal as a function of depth from the surface with a temporal resolution of 193+/-8 fs. The data show direct consequences on the lattice motion from carrier diffusion and electron-hole interaction, allowing us to estimate an effective diffusion rate of D=2.3+/-0.3 cm(2)/s for the highly excited carriers and an electron-hole interaction time of 260+/-20 fs.

Spatiotemporal stability of a femtosecond hard-x-ray undulator source studied by control of coherent optical phonons.

We report on the temporal and spatial stability of the first tunable femtosecond undulator hard-x-ray source for ultrafast diffraction and absorption experiments. The 2.5-1 Angstrom output radiation is driven by an initial 50 fs laser pulse employing the laser-electron slicing technique. By using x-ray diffraction to probe laser-induced coherent optical phonons in bulk bismuth, we estimate an x-ray pulse duration of 140+/-30 fs FWHM with timing drifts below 30 fs rms measured over 5 days. Optical control of coherent lattice motion is demonstrated.

Gangrene of the toes in a patient with chronic myelogenous leukemia after long-term hydroxyurea therapy.

Gangrene of the toes and digits appears to be a rare but very severe complication of long-term hydroxyurea therapy. Nothing is known regarding the pathophysiology and the type of vascular damage leading to this syndrome. Here we report a case of a 49-year-old male presenting with gangrene of the toes of both feet 4.5 years after initiation of hydroxyurea therapy for chronic myelogenous leukemia. Blisters on the toes occurred for the first time 9 months prior to hospitalization. Successively, all ten toes showed signs of beginning gangrene with one toe removed surgically 8 months before admission. Presence of diabetes mellitus or peripheral angiopathy was ruled out and platelet counts were within the physiologic range during the last years, excluding thrombocythemia as another rare cause for gangrene in patients with myeloproliferative diseases. Whereas perimalleolar ulcerations of the legs are a more common complication of hydroxyurea, gangrene of the toes as a consequence of hydroxyurea treatment has been described previously only once in the literature. At this point in time cessation of hydroxyurea treatment appears to be the only therapeutic option, thereby avoiding further progress of gangrene in patients with chronic myelogenous leukemia treated with hydroxyurea.

Salvage therapy for multiple myeloma with thalidomide and CED chemotherapy.

The feasibility and efficacy of a combination of thalidomide, cyclophosphamide, etoposide, and dexamethasone were studied in 56 patients with poor-prognosis multiple myeloma. Of 50 patients evaluable for response, 4% achieved complete response (CR), 64% partial response (PR), 18% minimal response (MR), 6% stable disease (SD), and 8% progressive disease (PD), resulting in an objective response rate (> or = MR) of 86.0% (76.7% overall objective response rate in intent-to-treat analysis; n = 56). Subsequent to successful remission induction, 18 patients received autologous or allogeneic stem cell transplantation. The median progression-free survival in all patients was 16 months. The median overall survival time could not be calculated, since the last observed death occurred after 16 months of follow-up (median follow-up of 14 months) with a corresponding estimated survival probability of 55%. Severe adverse effects (World Health Organization III/IV) included infectious complications (35.7%) and cardiovascular events (7.1%). The data suggest that Thal improves antitumor activity of salvage chemotherapy regimens in poor-prognosis multiple myeloma.