Stereotactic radiotherapy combined with immunotherapy or targeted therapy for metastatic renal cell carcinoma.

OBJECTIVES: To evaluate the safety and efficacy of stereotactic radiotherapy (SRT) in patients with metastatic renal cell carcinoma (mRCC) concurrently receiving targeted therapy (TT) or immunotherapy. PATIENTS AND METHODS: Data on patients with mRCC were extracted from a retrospective international multicentre register study (TOaSTT), investigating SRT concurrent (≤30 days) with TT/immune checkpoint inhibitor (ICI) therapy. Overall survival (OS), progression-free survival (PFS), local metastasis control (LC) and time to systemic therapy switch were analysed using Kaplan-Meier curves and log-rank testing. Clinical and treatment factors influencing survival were analysed using multivariate Cox regression. Acute and late SRT-induced toxicity were defined according to the Common Terminology Criteria for Adverse Events v.4.03. RESULTS: Fifty-three patients who underwent 128 sessions of SRT were included, of whom 58% presented with oligometastatic disease (OMD). ICIs and TT were received by 32% and 68% of patients, respectively. Twenty patients (37%) paused TT for a median (range) of 14 (2-21) days. ICI therapy was not paused in any patient. A median (range) of 1 (1-5) metastatic tumour was treated per patient, with a median (range) SRT dose of 65 (40-129.4) Gy (biologically effective dose). The OS, LC and PFS rates at 1 year were 71%, 75% and 25%, respectively. The median OS and PFS were not significantly different among patients receiving TT vs those receiving ICIs (P = 0.329). New lesions were treated with a repeat radiotherapy course in 46% of patients. After 1 year, 62% of patients remained on the same systemic therapy as at the time of SRT; this was more frequent for ICI therapy compared to TT (83% vs 36%; P = 0.035). OMD was an independent prognostic factor for OS (P = 0.004, 95% confidence interval [CI] 0.035-0.528) and PFS (P = 0.004; 95% CI 0.165-0.717) in multivariate analysis. Eastern Cooperative Oncology Group performance status (ECOG-PS) was the other independent prognostic factor for OS (P = 0.001, 95% CI 0.001-0.351). Acute grade 3 toxicity was observed in two patients, and late grade 3 toxicity in one patient. No grade 4 or 5 toxicity was observed. CONCLUSION: Combined treatment with TT or immunotherapy and concurrent SRT was safe, without signals of increased severe toxicity. As we observed no signal of excess toxicity, full-dose SRT should be considered to achieve optimal metastasis control in patients receiving TT or immunotherapy. Favourable PFS and OS were observed for patients with oligometastatic RCC with a good ECOG-PS, which should form the basis for prospective testing of this treatment strategy in properly designed clinical trials.

Definitive, intensity modulated tomotherapy with a simultaneous integrated boost for prostate cancer patients - Long term data on toxicity and biochemical control.

AIM: To report long-term data regarding biochemical control and late toxicity of simultaneous integrated boost intensity modulated radiotherapy (SIB-IMRT) with tomotherapy in patients with localized prostate cancer. BACKGROUND: Dose escalation improves cancer control after curative intended radiation therapy (RT) to patients with localized prostate cancer, without increasing toxicity, if IMRT is used. MATERIALS AND METHODS: In this retrospective analysis, we evaluated long-term toxicity and biochemical control of the first 40 patients with intermediate risk prostate cancer receiving SIB-IMRT. Primary target volume (PTV) 1 including the prostate and proximal third of the seminal vesicles with safety margins was treated with 70 Gy in 35 fractions. PTV 2 containing the prostate with smaller safety margins was treated as SIB to a total dose of 76 Gy with 2.17 Gy per fraction. Toxicity was evaluated using an adapted CTCAE-Score (Version 3). RESULTS: Median follow-up of living patients was 66 (20-78) months. No late genitourinary toxicity higher than grade 2 has been reported. Grade 2 genitourinary toxicity rates decreased from 58% at the end of the treatment to 10% at 60 months. Late gastrointestinal (GI) toxicity was also moderate, though the prescribed PTV Dose of 76 Gy was accepted at the anterior rectal wall. 74% of patients reported any GI toxicity during follow up and no toxicity rates higher than grade 2 were observed. Grade 2 side effects were reported by 13% of the patients at 60 months. 5-year freedom from biochemical failure was 95% at our last follow up. CONCLUSION: SIB-IMRT using daily MV-CT guidance showed excellent long-term biochemical control and low toxicity rates.

Clinical outcome of concomitant vs interrupted BRAF inhibitor therapy during radiotherapy in melanoma patients.

This corrects the article DOI: 10.1038/bjc.2017.85.

Solution-Processed Carbon Nanotube True Random Number Generator.

With the growing adoption of interconnected electronic devices in consumer and industrial applications, there is an increasing demand for robust security protocols when transmitting and receiving sensitive data. Toward this end, hardware true random number generators (TRNGs), commonly used to create encryption keys, offer significant advantages over software pseudorandom number generators. However, the vast network of devices and sensors envisioned for the "Internet of Things" will require small, low-cost, and mechanically flexible TRNGs with low computational complexity. These rigorous constraints position solution-processed semiconducting single-walled carbon nanotubes (SWCNTs) as leading candidates for next-generation security devices. Here, we demonstrate the first TRNG using static random access memory (SRAM) cells based on solution-processed SWCNTs that digitize thermal noise to generate random bits. This bit generation strategy can be readily implemented in hardware with minimal transistor and computational overhead, resulting in an output stream that passes standardized statistical tests for randomness. By using solution-processed semiconducting SWCNTs in a low-power, complementary architecture to achieve TRNG, we demonstrate a promising approach for improving the security of printable and flexible electronics.

Biomimetic Platinum-Promoted Polyene Polycyclizations: Influence of Alkene Substitution and Pre-cyclization Conformations.

Results of kinetic experiments and quantum chemical computations on a series of platinum-promoted polycyclization reactions are described. Analyses of these results reveal a reactivity model that reaches beyond the energetics of the cascade itself, incorporating an ensemble of pre-cyclization conformations of the platinum-alkene reactant complex, only a subset of which are productive for bi- (or larger) cyclization and lead to products. Similarities and differences between this scenario, including reaction coordinates for polycyclization, for platinum- and enzyme-promoted polycyclization reactions are highlighted.

Controlled n-Type Doping of Carbon Nanotube Transistors by an Organorhodium Dimer.

Single-walled carbon nanotube (SWCNT) transistors are among the most developed nanoelectronic devices for high-performance computing applications. While p-type SWCNT transistors are easily achieved through adventitious adsorption of atmospheric oxygen, n-type SWCNT transistors require extrinsic doping schemes. Existing n-type doping strategies for SWCNT transistors suffer from one or more issues including environmental instability, limited carrier concentration modulation, undesirable threshold voltage control, and/or poor morphology. In particular, commonly employed benzyl viologen n-type doping layers possess large thicknesses, which preclude top-gate transistor designs that underlie high-density integrated circuit layouts. To overcome these limitations, we report here the controlled n-type doping of SWCNT thin-film transistors with a solution-processed pentamethylrhodocene dimer. The charge transport properties of organorhodium-treated SWCNT thin films show consistent n-type behavior when characterized in both Hall effect and thin-film transistor geometries. Due to the molecular-scale thickness of the organorhodium adlayer, large-area arrays of top-gated, n-type SWCNT transistors are fabricated with high yield. This work will thus facilitate ongoing efforts to realize high-density SWCNT integrated circuits.

Gate-tunable carbon nanotube-MoS2 heterojunction p-n diode.

The p-n junction diode and field-effect transistor are the two most ubiquitous building blocks of modern electronics and optoelectronics. In recent years, the emergence of reduced dimensionality materials has suggested that these components can be scaled down to atomic thicknesses. Although high-performance field-effect devices have been achieved from monolayered materials and their heterostructures, a p-n heterojunction diode derived from ultrathin materials is notably absent and constrains the fabrication of complex electronic and optoelectronic circuits. Here we demonstrate a gate-tunable p-n heterojunction diode using semiconducting single-walled carbon nanotubes (SWCNTs) and single-layer molybdenum disulfide as p-type and n-type semiconductors, respectively. The vertical stacking of these two direct band gap semiconductors forms a heterojunction with electrical characteristics that can be tuned with an applied gate bias to achieve a wide range of charge transport behavior ranging from insulating to rectifying with forward-to-reverse bias current ratios exceeding 10(4). This heterojunction diode also responds strongly to optical irradiation with an external quantum efficiency of 25% and fast photoresponse <15 µs. Because SWCNTs have a diverse range of electrical properties as a function of chirality and an increasing number of atomically thin 2D nanomaterials are being isolated, the gate-tunable p-n heterojunction concept presented here should be widely generalizable to realize diverse ultrathin, high-performance electronics and optoelectronics.

Short Channel Field-Effect-Transistors with Inkjet-Printed Semiconducting Carbon Nanotubes.

Short channel field-effect-transistors with inkjet-printed semiconducting carbon nanotubes are fabricated using a novel strategy to minimize material consumption, confining the inkjet droplet into the active channel area. This fabrication approach is compatible with roll-to-roll processing and enables the formation of high-performance short channel device arrays based on inkjet printing.

High-speed, inkjet-printed carbon nanotube/zinc tin oxide hybrid complementary ring oscillators.

The materials combination of inkjet-printed single-walled carbon nanotubes (SWCNTs) and zinc tin oxide (ZTO) is very promising for large-area thin-film electronics. We compare the characteristics of conventional complementary inverters and ring oscillators measured in air (with SWCNT p-channel field effect transistors (FETs) and ZTO n-channel FETs) with those of ambipolar inverters and ring oscillators comprised of bilayer SWCNT/ZTO FETs. This is the first such comparison between the performance characteristics of ambipolar and conventional inverters and ring oscillators. The measured signal delay per stage of 140 ns for complementary ring oscillators is the fastest for any ring oscillator circuit with printed semiconductors to date.

Diastereoselective Pt catalyzed cycloisomerization of polyenes to polycycles.

Application of a tridentate NHC containing pincer ligand to Pt catalyzed cascade cyclization reactions has allowed for the catalytic, diastereoselective cycloisomerization of biogenic alkene terminated substrates to the their polycyclic counterparts.

Aerosol jet printed, low voltage, electrolyte gated carbon nanotube ring oscillators with sub-5 µs stage delays.

A central challenge for printed electronics is to achieve high operating frequencies (short transistor switching times) at low supply biases compatible with thin film batteries. In this report, we demonstrate partially printed five-stage ring oscillators with >20 kHz operating frequencies and stage delays <5 µs at supply voltages below 3 V. The fastest ring oscillator achieved 1.2 µs delay time at 2 V supply. The inverter stages in these ring oscillators were based on ambipolar thin film transistors (TFTs) employing semiconducting, single-walled carbon nanotube (CNT) networks and a high capacitance (∼1 µF/cm(2)) ion gel electrolyte as the gate dielectric. All materials except the source and drain electrodes were aerosol jet printed. The TFTs exhibited high electron and hole mobilities (∼20 cm(2)/(V s)) and ON/OFF current ratios (up to 10(5)). Inverter switching times t were systematically characterized as a function of transistor channel length and ionic conductivity of the gel dielectric, demonstrating that both the semiconductor and the ion gel play a role in switching speed. Quantitative scaling analysis suggests that with suitable optimization low voltage, printed ion gel gated CNT inverters could operate at frequencies on the order of 1 MHz.

Subnanowatt carbon nanotube complementary logic enabled by threshold voltage control.

In this Letter, we demonstrate thin-film single-walled carbon nanotube (SWCNT) complementary metal-oxide-semiconductor (CMOS) logic devices with subnanowatt static power consumption and full rail-to-rail voltage transfer characteristics as is required for logic gate cascading. These results are enabled by a local metal gate structure that achieves enhancement-mode p-type and n-type SWCNT thin-film transistors (TFTs) with widely separated and symmetric threshold voltages. These complementary SWCNT TFTs are integrated to demonstrate CMOS inverter, NAND, and NOR logic gates at supply voltages as low as 0.8 V with ideal rail-to-rail operation, subnanowatt static power consumption, high gain, and excellent noise immunity. This work provides a direct pathway for solution processable, large area, power efficient SWCNT advanced logic circuits and systems.

Ambient-processable high capacitance hafnia-organic self-assembled nanodielectrics.

Ambient and solution-processable, low-leakage, high capacitance gate dielectrics are of great interest for advances in low-cost, flexible, thin-film transistor circuitry. Here we report a new hafnium oxide-organic self-assembled nanodielectric (Hf-SAND) material consisting of regular, alternating π-electron layers of 4-[[4-[bis(2-hydroxyethyl)amino]phenyl]diazenyl]-1-[4-(diethoxyphosphoryl) benzyl]pyridinium bromide) (PAE) and HfO2 nanolayers. These Hf-SAND multilayers are grown from solution in ambient with processing temperatures ≤150 °C and are characterized by AFM, XPS, X-ray reflectivity (2.3 nm repeat spacing), X-ray fluorescence, cross-sectional TEM, and capacitance measurements. The latter yield the largest capacitance to date (1.1 µF/cm(2)) for a solid-state solution-processed hybrid inorganic-organic gate dielectric, with effective oxide thickness values as low as 3.1 nm and have gate leakage <10(-7) A/cm(2) at ±2 MV/cm using photolithographically patterned contacts (0.04 mm(2)). The sizable Hf-SAND capacitances are attributed to relatively large PAE coverages on the HfO2 layers, confirmed by X-ray reflectivity and X-ray fluorescence. Random network semiconductor-enriched single-walled carbon nanotube transistors were used to test Hf-SAND utility in electronics and afforded record on-state transconductances (5.5 mS) at large on:off current ratios (I(ON):I(OFF)) of ~10(5) with steep 150 mV/dec subthreshold swings and intrinsic field-effect mobilities up to 137 cm(2)/(V s). Large-area devices (>0.2 mm(2)) on Hf-SAND (6.5 nm thick) achieve mA on currents at ultralow gate voltages (<1 V) with low gate leakage (<2 nA), highlighting the defect-free and conformal nature of this nanodielectric. High-temperature annealing in ambient (400 °C) has limited impact on Hf-SAND leakage densities (<10(-6) A/cm(2) at ±2 V) and enhances Hf-SAND multilayer capacitance densities to nearly 1 µF/cm(2), demonstrating excellent compatibility with device postprocessing methodologies. These results represent a significant advance in hybrid organic-inorganic dielectric materials and suggest synthetic routes to even higher capacitance materials useful for unconventional electronics.

The impact of a gratitude intervention on mental well-being during COVID-19: A quasi-experimental study of university students.

Previous research suggest that gratitude interventions are effective in improving mental well-being, which might be beneficial to university students during the COVID-19 pandemic. This quasi-experimental study sought to investigate if a gratitude intervention will lead to higher mental well-being of university students during the COVID-19 pandemic. Participants (N = 47) mental well-being was assessed before and after 10 weekly gratitude reflection journals and statistically compared with a control group (N = 40). An analysis of covariance (ANCOVA) was used to analyze the data. The treatment group showed significantly higher well-being after the gratitude intervention compared with the control group (Cohen's d = 0.74). The treatment group significantly increased (Cohen's d = 0.35) and the control group significantly decreased (Cohen's d = -0.41). Gratitude interventions may be effective in improving the mental well-being of university students even during a crisis such as the COVID-19 pandemic. Gratitude interventions seem suitable for improving mental well-being for temporary mental challenges of university students such as a pandemic or other forms of crisis.

Metastasis directed stereotactic radiotherapy in NSCLC patients progressing under targeted- or immunotherapy: efficacy and safety reporting from the 'TOaSTT' database.

BACKGROUND: Metastasis directed treatment (MDT) is increasingly performed with the attempt to improve outcome in non-small cell lung cancer (NSCLC) patients receiving targeted- or immunotherapy (TT/IT). This study aimed to assess the safety and efficacy of metastasis directed stereotactic radiotherapy (SRT) concurrent to TT/IT in NSCLC patients. METHODS: A retrospective multicenter cohort of stage IV NSCLC patients treated with TT/IT and concurrent (≤ 30 days) MDT was established. 56% and 44% of patients were treated for oligoprogressive disease (OPD) or polyprogressive disease (PPD) under TT/IT, polyprogressive respectively. Survival was analyzed using Kaplan-Meier and log rank testing. Toxicity was scored using CTCAE v4.03 criteria. Predictive factors for overall survival (OS), progression free survival (PFS) and time to therapy switch (TTS) were analyzed with uni- and multivariate analysis. RESULTS: MDT of 192 lesions in 108 patients was performed between 07/2009 and 05/2018. Concurrent TT/IT consisted of EGFR/ALK-inhibitors (60%), immune checkpoint inhibitors (31%), VEGF-antibodies (8%) and PARP-inhibitors (1%). 2y-OS was 51% for OPD and 25% for PPD. After 1 year, 58% of OPD and 39% of PPD patients remained on the same TT/IT. Second progression after MDT was oligometastatic (≤ 5 lesions) in 59% of patients. Severe acute and late toxicity was observed in 5.5% and 1.9% of patients. In multivariate analysis, OS was influenced by the clinical metastatic status (p = 0.002, HR 2.03, 95% CI 1.30-3.17). PFS was better in patients receiving their first line of systemic treatment (p = 0.033, HR 1.7, 95% CI 1.05-2.77) and with only one metastases-affected organ (p = 0.023, HR 2.04, 95% CI 1.10-3.79). TTS was 6 months longer in patients with one metastases-affected organ (p = 0.031, HR 2.53, 95% CI 1.09-5.89). Death was never therapy-related. CONCLUSIONS: Metastases-directed SRT in NSCLC patients can be safely performed concurrent to TT/IT with a low risk of severe toxicity. To find the ideal sequence of the available multidisciplinary treatment options for NSCLC and determine what patients will benefit most, a further evaluated in a broader context within prospective clinical trials is needed continuation of TT/IT beyond progression combined with MDT for progressive lesions appears promising but requires prospective evaluation. TRIAL REGISTRATION: retrospectively registered.

Continued versus Interrupted Targeted Therapy during Metastasis-Directed Stereotactic Radiotherapy: A Retrospective Multi-Center Safety and Efficacy Analysis.

The increasing use of targeted therapy (TT) has resulted in prolonged disease control and survival in many metastatic cancers. In parallel, stereotactic radiotherapy (SRT) is increasingly performed in patients receiving TT to obtain a durable control of resistant metastases, and thereby to prolong the time to disseminated disease progression and switch of systemic therapy. The aims of this study were to analyze the safety and efficacy of SRT combined with TT in metastatic cancer patients and to assess the influence of continuous vs. interrupted TT during metastasis-directed SRT. The data of 454 SRTs in 158 patients from the international multicenter database (TOaSTT) on metastatic cancer patients treated with SRT and concurrent TT (within 30 days) were analyzed using Kaplan-Meier and log rank testing. Toxicity was defined by the CTCAE v4.03 criteria. The median FU was 19.9 mo (range 1-102 mo); 1y OS, PFS and LC were 59%, 24% and 84%, respectively. Median TTS was 25.5 mo (95% CI 11-40). TT was started before SRT in 77% of patients. TT was interrupted during SRT in 44% of patients, with a median interruption of 7 (range 1-42) days. There was no significant difference in OS or PFS whether TT was temporarily interrupted during SRT or not. Any-grade acute and late SRT-related toxicity occurred in 63 (40%) and 52 (33%) patients, respectively. The highest toxicity rates were observed for the combination of SRT and EGFRi or BRAF/MEKi, and any-grade toxicity was significantly increased when EGFRi (p = 0.016) or BRAF/MEKi (p = 0.009) were continued during SRT. Severe (≥grade 3) acute and late SRT-related toxicity were observed in 5 (3%) and 7 (4%) patients, respectively, most frequently in patients treated with EGFRi or BRAF/MEKi and in the intracranial cohort. There was no significant difference in severe toxicity whether TT was interrupted before and after SRT or not. In conclusion, SRT and continuous vs. interrupted TT in metastatic cancer patients did not influence OS or PFS. Overall, severe toxicity of combined treatment was rare; a potentially increased toxicity after SRT and continuous treatment with EGFR inhibitors or BRAF(±MEK) inhibitors requires further evaluation.

Predicting survival in melanoma patients treated with concurrent targeted- or immunotherapy and stereotactic radiotherapy : Melanoma brain metastases prognostic score.

BACKGROUND: Melanoma patients frequently develop brain metastases. The most widely used score to predict survival is the molGPA based on a mixed treatment of stereotactic radiotherapy (SRT) and whole brain radiotherapy (WBRT). In addition, systemic therapy was not considered. We therefore aimed to evaluate the performance of the molGPA score in patients homogeneously treated with SRT and concurrent targeted therapy or immunotherapy (TT/IT). METHODS: This retrospective analysis is based on an international multicenter database (TOaSTT) of melanoma patients treated with TT/IT and concurrent (≤30 days) SRT for brain metastases between May 2011 and May 2018. Overall survival (OS) was studied using Kaplan-Meier survival curves and log-rank testing. Uni- and multivariate analysis was performed to analyze prognostic factors for OS. RESULTS: One hundred ten patients were analyzed. 61, 31 and 8% were treated with IT, TT and with a simultaneous combination, respectively. A median of two brain metastases were treated per patient. After a median follow-up of 8 months, median OS was 8.4 months (0-40 months). The molGPA score was not associated with OS. Instead, cumulative brain metastases volume, timing of metastases (syn- vs. metachronous) and systemic therapy with concurrent IT vs. TT influenced OS significantly. Based on these parameters, the VTS score (volume-timing-systemic therapy) was established that stratified patients into three groups with a median OS of 5.1, 18.9 and 34.5 months, respectively (p = 0.001 and 0.03). CONCLUSION: The molGPA score was not useful for this cohort of melanoma patients undergoing local therapy for brain metastases taking into account systemic TT/IT. For these patients, we propose a prognostic VTS score, which needs to be validated prospectively.

Ni and Pd mediate asymmetric organoboron synthesis with ester functionality at the beta-position.

Catalytic systems based on Ni and Pd complexes modified with chiral P-P ligands can be used in a convenient strategy for enantioselectively adding a boron unit to the beta-position of alpha,beta-unsaturated esters.

Inkjet printed circuits based on ambipolar and p-type carbon nanotube thin-film transistors.

Ambipolar and p-type single-walled carbon nanotube (SWCNT) thin-film transistors (TFTs) are reliably integrated into various complementary-like circuits on the same substrate by inkjet printing. We describe the fabrication and characteristics of inverters, ring oscillators, and NAND gates based on complementary-like circuits fabricated with such TFTs as building blocks. We also show that complementary-like circuits have potential use as chemical sensors in ambient conditions since changes to the TFT characteristics of the p-channel TFTs in the circuit alter the overall operating characteristics of the circuit. The use of circuits rather than individual devices as sensors integrates sensing and signal processing functions, thereby simplifying overall system design.

Radiation-Hard Complementary Integrated Circuits Based on Semiconducting Single-Walled Carbon Nanotubes.

Increasingly complex demonstrations of integrated circuit elements based on semiconducting single-walled carbon nanotubes (SWCNTs) mark the maturation of this technology for use in next-generation electronics. In particular, organic materials have recently been leveraged as dopant and encapsulation layers to enable stable SWCNT-based rail-to-rail, low-power complementary metal-oxide-semiconductor (CMOS) logic circuits. To explore the limits of this technology in extreme environments, here we study total ionizing dose (TID) effects in enhancement-mode SWCNT-CMOS inverters that employ organic doping and encapsulation layers. Details of the evolution of the device transport properties are revealed by in situ and in operando measurements, identifying n-type transistors as the more TID-sensitive component of the CMOS system with over an order of magnitude larger degradation of the static power dissipation. To further improve device stability, radiation-hardening approaches are explored, resulting in the observation that SWNCT-CMOS circuits are TID-hard under dynamic bias operation. Overall, this work reveals conditions under which SWCNTs can be employed for radiation-hard integrated circuits, thus presenting significant potential for next-generation satellite and space applications.