Real-World Efficacy of Nintedanib Plus Docetaxel After Progression on Immune Checkpoint Inhibitors: Results From the Ongoing, Non-interventional VARGADO Study.

AIMS: To evaluate the efficacy and safety of nintedanib plus docetaxel in patients with advanced adenocarcinoma non-small cell lung cancer (NSCLC) who progressed after chemotherapy and immune checkpoint inhibitor (ICI) therapy. MATERIALS AND METHODS: VARGADO (NCT02392455) is an ongoing, prospective, non-interventional, real-world study of nintedanib plus docetaxel after first-line chemotherapy in the routine clinical treatment of patients with locally advanced, metastatic or locally recurrent adenocarcinoma NSCLC. Data were collected during routine visits. We report the results from cohort B (n = 80), who received third-line nintedanib plus docetaxel after first-line chemotherapy and second-line ICI therapy. RESULTS: The median duration of follow-up was 12.4 months. Median progression-free survival from initiation of third-line nintedanib plus docetaxel was 6.4 months (95% confidence interval 4.8, 7.3); median overall survival was 12.1 months (95% confidence interval 9.4, 13.5). The 1-year overall survival rate after initiation of third-line nintedanib plus docetaxel treatment (primary end point) was 52% (95% confidence interval 38.0%, 64.4%). Among 64 patients with a documented response, the objective response rate was 50% (n = 32; one complete response and 31 partial responses) and the disease control rate was 86% (n = 55). There were no new safety signals or unexpected toxicities. Among all treated patients, 74% (n = 59) experienced drug-related adverse events, most commonly (nintedanib-related/docetaxel-related) diarrhoea (34%/24%), a decreased white blood cell count (11%/19%) and nausea (13%/16%). CONCLUSIONS: Nintedanib plus docetaxel demonstrated a high response rate and disease stabilisation in the third-line setting after failure of prior chemotherapy and ICI treatment, with a manageable safety profile. These results suggest that nintedanib plus docetaxel represents an efficient treatment option after failure of prior ICIs. The ongoing VARGADO study provides valuable real-world data to inform clinical decision-making regarding treatment sequencing after chemotherapy and ICI failure in patients with adenocarcinoma NSCLC.

Mechanism of large optical nonlinearity in gold nanoparticle films.

The Z-scan technique, using femtosecond (fs) laser pulses at 1480 nm laser pulses, was used to measure the nonlinear optical properties of gold (Au) nanoparticle (NP) films made by both nanosecond (ns) and fs pulsed laser deposition (PLD) in vacuum. At irradiance levels of 1×1012 Wm-2, the ns-PLD films displayed induced absorption with ß=4×10-5 mW-1, and a negative lensing effect with n2=-4.7×10-11 m2 W-1 with somewhat smaller values for the fs-PLD films. These values of n2 imply an unphysically large change in the real part of the refractive index, demonstrating the need to take account of nonlinear changes of the Fresnel coefficients and multiple beam interference in Z-scan measurements on nanoscale films. Following this approach, the Z-scan observations were analyzed to determine the effective complex refractive index of the NP film at high irradiance. It appears that at high irradiance the NP film behaves as a metal, while at low irradiance it behaves as a low-loss dielectric. Thus, it is conjectured that, for high irradiance near the waist of the Z-scan laser beam, laser driven electron tunneling between NPs gives rise to metal-like optical behavior.

Ferromagnetic behaviour of nickel contacted multiwalled carbon nanotubes.

A novel method for the contact of ferromagnetic nano-nickel onto multiwalled carbon nanotubes (MWCNTs) is proposed in this work. The process involves the decomposition of the precursor: nickel carbonyl-Ni(CO)4 into nickel and CO by laser chemical vapour deposition at 150-200 degrees C and the deposition of nano-nickel onto MWCNTs. Field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), HR (High resolution) TEM, and Raman spectroscopy were employed for the detailed analysis of the nickel contacted MWCNTs. The ferro-magnetic nature of the sample was confirmed by Super-conducting Quantum Interference Device (SQUID) analysis.

Hydrogen in chemical vapour deposited carbon nanotubes: an active site for functionalization.

The presence of hydrogen in as-grown carbon nanotubes (CNTs) synthesized by microwave plasma (MP) chemical vapour deposition (CVD) technique is demonstrated. Our results showed that the MPCVD, as-grown CNTs were hydrogenated consisting of C-H bonds; whereas, the tubes synthesized by arc discharge consisted of non-hydrogenated multi-walled CNTs. Fourier transform infrared spectroscopy (FTIR) and micro-Raman spectroscopy techniques were used to detect C-H bonding in the as-grown CNTs. The effective functionalization of as-grown hydrogenated CNTs grown using a microwave CVD process is first time demonstrated by laser assisted CVD process. It was found that the laser-assisted CVD process resulted in the termination of hydrogen and the oxidation of as-grown CNT structure leading to the carboxylic group attachment. The FTIR results show the presence of -OH and C=O bonds in the functionalized samples. However, the non-hydrogenated CNTs could not be effectively functionalized by the same process, probably due to the fact that it did not contain active sites pre-requisite for functionalization, as did the CVD grown samples. The functionalization of CVD grown tubes is believed to take place at the 'active' hydrogen-terminated sites on the CNT surfaces.

Mesoporous silicas impregnated with cobalt and nickel oxide nanoparticles and the growth of carbon nanotubes there from.

Metal oxide-based nanoparticles of cobalt or nickel were deposited inside the pores and on the surface of hexagonal mesoporous silicas by a direct synthesis technique using Pluronic P85 and P123 surfactants as structure directing agents with the appropriate metal phthalocyanine as a metal precursor. Metal loadings were between 0.4-3.2 wt.%. XPS studies showed that the initial form of the metal oxide nanoparticles were [CoO] and [NiO] respectively. Samples of these materials formed from the P85 surfactant and 3.0 wt.% were used to grow carbon nanotubes (CNTs) from acetylene feedstock in a catalytic chemical vapour deposition (CCVD) reactor at 800 degrees C. CNT growth appeared to be random and the CNTs had diameters ranging from < 10 to > 90 nm. Treatment of the metal impregnated silicas with nitric acid produced materials which, under the same CNT growth conditions, afforded more uniform CNTs with diameters between 5-15 nm. No significant loss in mesophase ordering was seen in the TEM, PXRD or nitrogen physisorption analysis of the acid washed samples. CNTs grown with cobalt impregnated silicas formed with the P123 surfactant had diameters in the range 15-25 nm. Raman spectroscopy of the CNT products showed the nanotubes were highly graphitised and of good quality.

Growth of carbon nanotubes on Si substrate using Fe catalyst produced by pulsed laser deposition.

We report the growth of carbon nanotubes on the size controlled iron catalytic nanoparticles. The nanotubes were grown by thermal chemical vapour deposition (CVD) in the temperature range 600-850 degrees C. The Fe films were deposited on silicon by pulsed laser deposition in vacuum. Atomic force microscopy measurements were performed on the catalytic nanoparticles. The topography of the catalytic nanoparticles shows the homogenous distribution of Fe catalyst. We observe the nanotubes are produced only at temperatures between 650 and 800 degrees C, and within this narrow temperature regime the yield of nanotubes reaches a maximum around 750 degrees C and then declines. Raman measurements illustrate a high G/D peak ratio indicating good nanotube quality. By further defining the size of the catalyst the diameter of these carbon nanotubes can be controlled.

The effect of Nd:YAG radiation at nanosecond pulse duration on dentine crater depth.

The effect of laser parameters on laser-dentine interaction is little known. The aim of this in vitro study was to determine the effect on dentine crater depth of Nd:YAG laser radiation in relation to pulse repetition rate, total delivered energy, dentine site and the presence or absence of a dye. One hundred and forty-four sound third molars were extracted and sectioned transversely to provide 288 upper and lower cut surfaces. The upper surfaces were painted with a layer of dye (IR5) suitable for absorption at 1064 nm. The specimens were divided into 12 sub-groups each containing 12 upper and 12 lower specimens. These were exposed to a Nd:YAG laser with a 30 nanosecond (ns) pulse duration. This laser operated in a non-contact mode (spot diameter 165 microm) with pulse repetition rates of 2.5, 5.4 and 10.5 Hz. Four total energies were delivered at each repetition rate; 2.3, 3.63, 3.96, 4.29 joule (J) at 2.5 Hz repetition rate; 2.3, 2.64, 3.63, 4.29 J at 5.4 and 10.5 Hz repetition rates. Five outer and three inner sites were irradiated on each specimen. Each dentine crater depth was measured five times using a Reflex Microscope and a three-dimensional centre of gravity derived. An upper and lower specimen were taken from each sub-group and viewed under a scanning electron microscope (SEM). ANOVA was applied: total delivered energy and dyed/undyed were found to have a statistically significant effect on crater depth (p<0.0001). In general increasing energy and the presence of dye produced deeper craters. Inner/outer dentine location and repetition rate were not found to be statistically significant. All craters were carbonised.

Documentation of pain assessment and treatment: how are we doing?

The purpose of this analysis was to evaluate documentation of practice provided by a multidisciplinary team of nurses, physicians, and pharmacists who participated in an educational program on postoperative pain management. Chart audit of 787 patient charts at 6 sites revealed documentation of pain histories in approximately 75% of the charts, most often in the surgeon's history and physical examination. Examination of multiple assessment items indicated that the experimental group, relative to the control group, experienced an increase of more than 10% in the documentation of pain intensity, pain quality, pain duration, numeric rating scale used, pain behavior, factors that increase pain, vital signs, sedation level, cognitive status, social interaction, and mood from before the program to 6 months after the program. Across all sites, documentation of assessment, treatment, and treatment outcome data was infrequent and inconsistent. Calculation of documentation of 4 items that constituted a focused assessment of postoperative pain on the surgical floor revealed a significant program effect for assessment of pain quality and pain intensity. A postprogram survey of participants in the educational program revealed an increase in discussion of postoperative pain management with other practitioners and an increase in use of a 0 to 10 scale to rate pain. More documentation of patient pain history, clinical problems, treatment, and follow-up action is needed to improve practice and research.

The effect of Nd:YAG pulse duration on dentine crater depth.

OBJECTIVES: The effect of alteration of laser parameters on laser-dentine interaction, in particular the effect of pulse duration, has not been well documented. The aim of this in vitro study was to determine the effect on dentine crater depth of Nd:YAG laser pulse duration, and total delivered energy, dentine site and the presence or absence of dye. METHODS: Ninety-six sound third molars were extracted and sectioned transversely to provide 192 upper and lower cut surfaces. The upper surfaces were painted with a layer of dye (IR5) suitable for absorption at 1064 nm. The specimens were divided into 16 sub-groups and exposed to two Nd:YAG lasers; one of pulse duration 7 ms and the second of pulse duration 35 ps. Both lasers operated in a non-contact mode (spot diameter 165 microm) with repetition rates of 10.5 and 10 Hz, respectively. Four total energies (2.28, 2.64, 3.6, 4.2 J) were delivered to eight dyed and eight undyed sub-groups. Eight outer and five inner sites were irradiated on each specimen. Dentine crater depth was measured five times using a Reflex Microscope and a three-dimensional centre of gravity derived. An upper and lower specimen were taken from each sub-group and viewed under a SEM. RESULTS: ANOVA and multiple regression analysis were applied and the following factors were found to have a statistically significant effect on crater depth (p<0.0001): total delivered energy, pulse duration and inner/outer location. CONCLUSIONS: Increasing energy and pulse duration produced deeper craters. Similarly inner dentine sites produced deeper crater depths. Only craters produced at the ms pulse duration were carbonised. It would appear that laser-dentine interaction has a non-thermal component at picosecond pulse duration.

Blue amplified spontaneous emission from a stilbenoid-compound-doped polymer optical fiber.

We report on the fabrication and characteristics of a step-index glass-clad polymer optical fiber that uses a novel fluorescent stilbenoid compound for lasing and amplification applications. The compound, 1, 4-bis(4-diphenyl-amino-styryl)-benzene, is specifically designed for the blue region of the spectrum and has a very high quantum yield of 0.85 in a solid-state polymer host and a large Stokes shift. Significant spectral narrowing and superlinear increase of output intensity are observed under photoexcitation at 355 nm, which are indicative of the occurrence of amplified spontaneous emission. By means of gain spectroscopy, a large optical gain of up to 36 cm(-1) at 494 nm has been obtained for the fiber when it is transversely photoexcited at 12 mJ/cm(2) . The waveguide loss has been measured to be 0.7 cm(-1) at 494 nm. The demonstration of high gain and low waveguide loss has favorable implications for the construction of a very compact, tunable coherent light source.

Effect of Nd:YAG radiation at millisecond pulse duration on dentine crater depth.

BACKGROUND AND OBJECTIVE: The effect of laser parameters on laser-dentine interaction has not been explored fully. This in vitro study investigated the effect on dentine crater depth of Nd:YAG laser radiation with varying repetition rates, total delivered energy, and dentine site either dyed or undyed. STUDY DESIGN/MATERIALS AND METHODS: One hundred forty-four caries-free third molars were sectioned transversely to provide 288 upper and lower cut surfaces. The upper surfaces were dyed (IR5). These upper and lower cut surfaces were exposed to an Nd:YAG laser with a 7 millisecond (msec) pulse duration, pulse repetition rates (RR) of 2. 5, 5.4, and 10.5 Hz, and four total energies (2.28, 2.64, 3.6, 4.2 joules). Dentine crater depth was measured by using a Reflex microscope. Results were statistically analysed with analysis of variance. RESULTS: Crater depth increased with increase in total delivered energy and in dyed and inner dentine sites (P<0.0001) but decreased with increasing repetition rate (P< 0.0001). CONCLUSIONS: Increasing energy, dyed, and inner dentine sites produced deeper craters.

Fatal thrombotic thrombocytopenic purpura as a rare complication following allogeneic stem cell transplantation.

Thrombotic thrombocytopenic purpura (TTP) is a rare disease which, together with hemolytic uremic syndrome, is subsumed under thrombotic microangiopathy. After stem cell transplantation (SCT), this syndrome represents a possibly fatal complication with a higher incidence in allogeneic SCT than in autologous SCT. Although plasmapheresis offers an encouraging treatment modality in classic TTP, this seems less effective in bone marrow transplant-associated microangiopathy. This is probably due to a different etiology. We present a case of transplant-associated TTP with a fatal outcome despite multiple courses of plasmapheresis.

New strategies in GVHD prophylaxis.

Despite immunosuppressive therapy using cyclosporine (CsA) and prednisolone and methotrexate (MTX), the incidence for aGVHD grade II to IV after transplantation from HLA matched unrelated donors (MUD) is 78%, the incidence for grade III and IV 36%. Since GVHD contributes to morbidity and mortality after MUD-BMT, a more effective prophylactic regimen is needed in order to prevent these transplant-associated complications. Recently, we described that mycophenolate mofetil (MMF, CellCept), an immunosuppressive agent successfully used for the prevention of acute rejection in renal allograft recipients, can safely and effectively be used for the treatment of aGVHD in hematopoietic stem cell transplantation. Information on the i.v. formulation of mycophenolic acid (MPA) is not yet available. Here we report on the i.v. formulation of MMF in hematopoietic stem cell recipients. MMF is effective in the prophylaxis of acute GVHD after stem cell transplantation; the optimal dosage needs further investigation. At the present time the relevance of measurement of plasma MPA concentrations on MMF dosage is not yet understood and further evaluation is required.

Allogeneic transplantation of G-CSF mobilized peripheral blood stem cells from unrelated donors: a retrospective analysis.

BACKGROUND AND OBJECTIVES: Allogeneic peripheral blood stem cell transplantation (PBSCT) from matched siblings has lead to clinical results comparable to those of standard bone marrow transplantation (BMT). We report the outcome of 79 patients transplanted with PBSC from unrelated donors. DESIGN AND METHODS: In 61 cases PBSC were used for primary transplantation whereas 18 patients were treated for relapse or graft-failure. In 35 patients receiving primary transplants, T-cell depletion (TCD) using CD34 positive selection of PBSC with or without additional T-cell depletion had been performed to reduce the risk of graft-versus-host-disease (GvHD). RESULTS: The rate of primary graft-failure was higher (20%) in the TCD group than in that receiving unmanipulated grafts (UM) (5%, p=0.007). Patients with standard risk (n=34) receiving first transplants had a significantly better overall (60.4% vs. 24%, p=0.02) and disease-free survival (57.2% vs. 22.3%, p=0.006) compared to a high risk group of patients (n=21). There were no differences in the speed of neutrophil and platelet engraftment between TCD and UM transplants. As expected, the cumulative risk for acute GvHD grade II.-IV was significantly higher in the patients who had received UM grafts (71.8% vs. 38.1%, p=0.005). Although a trend towards a better survival rate was observed after TCD transplantation (52.2%) compared to the UM group (38.1%), this difference was not statistically significant. The probability of relapse was significantly higher in patients after UM transplants (38.8% vs. 8. 4%). This apparent paradox is explained by the higher number of high-risk patients in this group (p=0.03). Multivariable analysis of disease-free survival revealed risk category (p=0.02) and use of ATG (p=0.03) to be of significant impact. All patients (n=6) with non-malignant diseases are alive with full donor chimerism. INTERPRETATION AND CONCLUSIONS: These data show that PBSC from unrelated donors can be transplanted either unmanipulated or CD34 selected. Prospective studies comparing BMT with PBSCT from unrelated donors are needed in defined disease categories.

Clinical economics: calculating the cost of acute postoperative pain medication.

Few data are available that address the cost of postoperative pain management, although such knowledge would enhance our understanding of caregiver choices related to direct medical costs, such as type, frequency, and route of medication. This article describes the cost of postoperative pain medications before and after an educational program provided to nurses, pharmacists, and physicians in six community hospitals. Medication costs were calculated by averaging across all brands the average wholesale price of the most common dose administered in the sample for each medication. The median cost of postoperative pain medication across all days, all surgeries, was $9.46. Calculating the cost of acute postoperative pain medication suggested that cost over stay is highly influenced by the use of a few expensive medications. The relationship of medication cost to length of stay (LOS), function, and pain intensity is discussed.

Mycophenolate mofetil for the prophylaxis of acute GVHD in HLA-mismatched bone marrow transplant patients.

Mycophenolate mofetil (MMF), a new immunosuppressive drug successfully used in renal and heart transplant recipients, was used in combination with cyclosporin A (CsA), methotrexate (MTX) and prednisolone for the prophylaxis of acute graft-versus-host disease (aGVHD) after bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) from human leukocyte antigen (HLA)-mismatched, unrelated (n = 9) and related donors (n = 4) in an open single-centre phase II study. Thirteen patients, transplanted from HLA-mismatched donors of 18-57 yr of age, received 1 g MMF daily, starting at day 10, in addition to CsA and prednisolone for aGVHD prophylaxis. All patients were engrafted between days 13 and 15. Four of the 13 patients experienced aGVHD grade I/II (n = 2) and grade III (n = 2). All patients except 3 were alive on day 100 post-transplantation. No severe adverse effects of MMF were recorded. In our pilot study, we demonstrated that MMF can be used safely for the prophylaxis of aGVHD.

Organization of hospital-based acute pain management programs.

BACKGROUND: The management of acute pain is an aspect of hospital-based practice that has been neglected. Control of pain is important for ethical reasons, for compliance with new guidelines and standards, and for optimizing patient satisfaction and outcomes. METHODS: Be review the rationale for establishing priority to the control of acute pain, the importance of an institutional approach to improve pain management, and specific steps in the establishment and conduct of an acute pain program. RESULTS: Improvement in pain control depends on an institutional approach to facilitate changes in attitude and prioritization. Pain management programs should provide for patient and staff education, adequate documentation of care, institutional standards for pain control, quality assurance/continuous quality improvement (CQI) activities, and periodic review of practice and policy. CONCLUSIONS: Effective pain management can set the stage for a rehabilitational approach to postoperative care, which should lead to earlier recovery and improved outcomes.