Integrated femtosecond pulse generator on thin-film lithium niobate.

Integrated femtosecond pulse and frequency comb sources are critical components for a wide range of applications, including optical atomic clocks1, microwave photonics2, spectroscopy3, optical wave synthesis4, frequency conversion5, communications6, lidar7, optical computing8 and astronomy9. The leading approaches for on-chip pulse generation rely on mode-locking inside microresonators with either third-order nonlinearity10 or with semiconductor gain11,12. These approaches, however, are limited in noise performance, wavelength and repetition rate tunability 10,13. Alternatively, subpicosecond pulses can be synthesized without mode-locking, by modulating a continuous-wave single-frequency laser using electro-optic modulators1,14-17. Here we demonstrate a chip-scale femtosecond pulse source implemented on an integrated lithium niobate photonic platform18, using cascaded low-loss electro-optic amplitude and phase modulators and chirped Bragg grating, forming a time-lens system19. The device is driven by a continuous-wave distributed feedback laser chip and controlled by a single continuous-wave microwave source without the need for any stabilization or locking. We measure femtosecond pulse trains (520-femtosecond duration) with a 30-gigahertz repetition rate, flat-top optical spectra with a 10-decibel optical bandwidth of 12.6 nanometres, individual comb-line powers above 0.1 milliwatts, and pulse energies of 0.54 picojoules. Our results represent a tunable, robust and low-cost integrated pulsed light source with continuous-wave-to-pulse conversion efficiencies an order of magnitude higher than those achieved with previous integrated sources. Our pulse generator may find applications in fields such as ultrafast optical measurement19,20 or networks of distributed quantum computers21,22.

Relaxation of the electro-optic response in thin-film lithium niobate modulators.

Thin-film lithium niobate (TFLN) is a promising electro-optic (EO) photonics platform with high modulation bandwidth, low drive voltage, and low optical loss. However, EO modulation in TFLN is known to relax on long timescales. Instead, thermo-optic heaters are often used for stable biasing, but heaters incur challenges with cross-talk, high power, and low bandwidth. Here, we characterize the low-frequency (1 mHz to 1 MHz) EO response of TFLN modulators, investigate the root cause of EO relaxation and demonstrate methods to improve bias stability. We show that relaxation-related effects can enhance EO modulation across a frequency band spanning 1kHz to 20kHz in our devices - a counter-intuitive result that can confound measurement of half-wave voltage (V π) in TFLN modulators. We also show that EO relaxation can be slowed by more than 104-fold through control of the LN-metal interface and annealing, offering progress toward lifetime-stable EO biasing. Such robust EO biasing would enable applications for TFLN devices where cross-talk, power, and bias bandwidth are critical, such as quantum devices, high-density integrated photonics, and communications.

Single-drive electro-optic frequency comb source on a photonic-wire-bonded thin-film lithium niobate platform.

Stable pulse and flat-top frequency comb generation are an indispensable component of many photonic applications, from ranging to communications. Lithium niobate on insulator is an excellent electro-optic (EO) platform, exhibiting high modulation efficiency and low optical loss, making it a fitting candidate for pulse generation through electro-optic modulation of continuous-wave (CW) light, a commonly utilized method for generating ultrashort pulses. Here, we demonstrate an on-chip electro-optic comb generation module on thin-film lithium niobate (TFLN) consisting of a Mach-Zehnder interferometer (MZI) amplitude modulator (AM) and a cascaded phase modulator (PM) system driven by a single-electrode drive. We show that when operated in the correct regime, the lithium niobate chips can generate frequency combs with excellent spectral power flatness. In addition, we optically package one of the pulse generator chips via photonic wire bonding. The pulses generated by the photonic-wire-bonded device are compressed to 840 fs pulse duration using an optical fiber and show extremely stable operation.

Safety and Preliminary Efficacy of Ramucirumab in Combination with FOLFOX4 in Patients with Advanced Hepatocellular Carcinoma: A Nonrandomized, Open-Label, Phase Ib Study.

LESSONS LEARNED: The combination of ramucirumab (8 mg/kg intravenous, day 1 every 2 weeks) and FOLFOX4 as first-line treatment in patients with advanced hepatocellular carcinoma (HCC) was not sufficiently tolerated. Preliminary efficacy data suggest that the combination may provide clinical benefit to patients with HCC. Dose modification and patient selection should be considered for the future development of ramucirumab plus FOLFOX chemotherapy for advanced HCC. BACKGROUND: The objective of this study was to investigate the safety, preliminary efficacy, pharmacokinetics, and immunogenicity of ramucirumab plus FOLFOX4 as first-line treatment in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients received ramucirumab (8 mg/kg) intravenously (IV) on day 1, followed by FOLFOX4 (oxaliplatin 85 mg/m2 IV on day 1, folinic acid 200 mg/m2 IV, bolus fluorouracil [5-FU] 400 mg/m2 , and a continuous infusion of 5-FU 600 mg/m2 over 22 hours, on days 1 and 2) every 2 weeks. The primary endpoint was to assess the safety and tolerability of the combination therapy. RESULTS: Eight patients (6 men, 2 women) were treated; all eight patients experienced at least one treatment-emergent adverse event (TEAE) of grade ≥3. Dose-limiting toxicities occurred in three patients (37.5%): hepatic hemorrhage (grade 4), blood bilirubin increased (grade 3), and febrile neutropenia (grade 3). Two patients discontinued study because of hepatic hemorrhage (grade 4) and blood bilirubin increase (grade 3). Six deaths occurred due to progressive disease, and no deaths due to TEAEs. CONCLUSION: There were no unexpected safety findings with ramucirumab plus FOLFOX4 based on the known safety and toxicity of this regimen. The combination was not sufficiently tolerated in patients with advanced HCC at the specified dose and schedule.

Development of the Autosomal Dominant Polycystic Kidney Disease Impact Scale: A New Health-Related Quality-of-Life Instrument.

BACKGROUND: The impact of autosomal dominant polycystic kidney disease (ADPKD) on health-related quality of life (HRQoL) is not well understood due to a lack of instruments specific to the condition. STUDY DESIGN: Content for a new self-administered patient-reported outcome (PRO) questionnaire to assess ADPKD-related HRQoL was developed through clinical expert and patient focus group discussions. The new PRO instrument was administered to study patients with ADPKD to evaluate its reliability and validity. SETTING & PARTICIPANTS: 1,674 adult patients with ADPKD participated in this research: 285 patients in focus groups to generate questionnaire content, 15 patients in debriefing interviews to refine the PRO questionnaire, and 1,374 patients to assess the performance and measurement properties of the PRO questionnaire. OUTCOME: A new PRO questionnaire. RESULTS: The ADPKD Impact Scale (ADPKD-IS), consisting of 14 items representing 3 conceptual domains (physical, emotional, and fatigue) plus 4 additional questions, was developed. The instrument's reliability (regarding internal consistency and test-retest consistency) and validity (content and construct) were supported. LIMITATIONS: Need for more responsiveness testing when more data from clinical use become available over time. Complex concepts such as ADPKD-related pain and impact on a patient's HRQoL need further evaluation. CONCLUSIONS: The ADPKD-IS is a new patient-centric tool that reliably and validly provides a standardized method for assessing HRQoL and overall disease burden in patients with ADPKD.

Exposure-response relationship of ramucirumab in East Asian patients from RAINBOW: a randomized clinical trial in second-line treatment of gastric cancer.

BACKGROUND: Ramucirumab is a recombinant human IgG1 neutralizing monoclonal antibody specific for vascular endothelial growth factor receptor-2. Second-line ramucirumab, in conjunction with paclitaxel (ramucirumab 8 mg/kg or placebo in combination with 80 mg/m2 paclitaxel), has been shown to be effective and safe in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma in RAINBOW, a global phase III randomized clinical trial. We conducted an exploratory exposure-response analysis of efficacy and safety of ramucirumab in East Asian patients from the RAINBOW trial. METHODS: Using sparse pharmacokinetic samples collected in the RAINBOW trial, a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady state (C min,ss) using a nonlinear mixed-effect modeling approach. Kaplan-Meier and Cox proportional hazards analyses were conducted to evaluate ramucirumab exposure (C min,ss) and efficacy relationship by overall survival and progression-free survival. Exposure-safety relationships were assessed descriptively. RESULTS: Two hundred and twenty-two East Asian patients were included in this exposure-response analysis. Higher ramucirumab C min,ss was associated with longer overall survival (p = 0.0115) and progression-free survival (p = 0.0179) in this patient cohort. Patients with higher ramucirumab C min,ss (≥56.87 ng/ml median) had higher incidences of grade ≥3 leukopenia and neutropenia, but not febrile neutropenia or hypertension. CONCLUSIONS: This exploratory analysis suggests a positive relationship between efficacy and ramucirumab exposure with manageable toxicities in East Asian patients from RAINBOW, consistent with the overall exposure-response analysis from this trial. A regimen with a higher dosage of ramucirumab warrants further consideration for East Asian patients with gastric/GEJ cancer.

Age does not influence efficacy of ramucirumab in advanced gastric cancer: Subgroup analyses of REGARD and RAINBOW.

BACKGROUND AND AIM: REGARD and RAINBOW were global, phase 3, randomized, double-blind trials of second-line ramucirumab for metastatic gastric or gastroesophageal junction adenocarcinoma. Exploratory subgroup analyses were described to assess the efficacy and safety of ramucirumab in REGARD and RAINBOW in young (≤ 45 and < 65 years) and elderly (≥ 65, ≥ 70, and ≥ 75 years) patients. METHODS: Patients were randomized 2:1 to receive ramucirumab plus best supportive care or placebo plus best supportive care (REGARD) or 1:1 to ramucirumab plus paclitaxel or placebo plus paclitaxel (RAINBOW). Subpopulation Treatment Effect Pattern Plots assessed efficacy and adverse events by age groups for ramucirumab versus placebo. RESULTS: The hazard ratios (HRs) for overall survival favored treatment with ramucirumab: REGARD ≤ 45 years (HR: 0.59, 95% confidence interval: 0.27-1.26), < 65 years (0.80, 0.59-1.10), ≥ 65 years (0.72, 0.48-1.08), ≥ 70 years (0.73, 0.44-1.23), and ≥ 75 years (0.59, 0.25-1.37); and RAINBOW ≤ 45 years (0.56, 0.33-0.93), < 65 years (0.78, 0.63-0.97), ≥ 65 years (0.88, 0.66-1.18), and ≥ 70 years (0.88, 0.60-1.28). The exception was elderly patients aged ≥ 75 years in RAINBOW (0.97, 0.47-2.01); however, patient numbers were low in this subgroup (n = 36). Similar findings were observed for progression-free survival, for which HRs numerically favored ramucirumab-treated patients. Adverse events (including grade ≥ 3) were not associated with age. CONCLUSIONS: In comparison with placebo, ramucirumab conferred improvements in efficacy across age groups with a tolerable safety profile. Despite some limitations, these exploratory analyses support the use of ramucirumab in advanced gastric cancer, irrespective of age.

The economic burden of advanced gastric cancer in Taiwan.

BACKGROUND: Gastric cancer is one of the leading causes of cancer-related deaths in both sexes worldwide, especially in Eastern Asia. This study aimed to estimate the economic burden of advanced gastric cancer (AGC) in Taiwan. METHODS: The costs of AGC in 2013 were estimated using resource use data from a chart review study (n = 122 with AGC) and national statistics. Annual per-patient costs, where patients' follow-up periods were adjusted for, were estimated with 82 patients who had complete resource use data. The costs were composed of direct medical costs, direct non-medical costs (healthcare travel and caregiver costs), morbidity costs, and mortality costs. Relevant unit costs were retrieved mainly from literature and national statistics, and applied to the resource use data. A broad definition of morbidity and mortality costs was employed to value the productivity loss in patients with unpaid employment, economically inactive and unemployed as well as the life years after the age of retirement. Their narrow definitions were also used in sensitivity analyses, using age- and/or sex-specific employment rates. Forgone future earnings/productivity loss were discounted at 3%. Annual per-patient costs were projected to estimate the total costs of AGC at the national level with an estimated number of patients with AGC (N = 2611) in Taiwan in 2013. RESULTS: The mean age of the 82 patients was 59.3 (SD: 11.9) years, and 67.1% were male. Per-patient costs were US$26,431 for direct medical costs, US$4669 for direct non-medical costs, US$5758 for morbidity costs, and US$145,990 for mortality costs (per death). These per-patient costs were projected to incur total AGC costs of US$423 million at the national-level. Mortality costs accounted for 77.3% of the total costs, followed by direct medical costs (16.3%), morbidity costs (3.6%), and direct non-medical costs (2.9%). CONCLUSION: AGC was found to exert a significant economic burden in Taiwan, incurring US$423 million in 2013. This represents about 0.08% of the Taiwanese economy. Mortality costs appeared to be the single greatest contributor to the burden, followed by direct medical costs. Early detection and providing effective treatments will help to reduce its burden on patients, caregivers and society as a whole. A poster of this study was presented at the 2016 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in San Francisco, CA, USA.

Subgroup analysis of East Asians in RAINBOW: A phase 3 trial of ramucirumab plus paclitaxel for advanced gastric cancer.

BACKGROUND AND AIM: East Asia has higher gastric cancer incidence and mortality rates than other regions. We present a subgroup analysis of East Asians in the positive study RAINBOW. METHODS: Patients with advanced gastric or gastroesophageal junction adenocarcinoma previously treated with platinum and fluoropyrimidine received ramucirumab 8 mg/kg or placebo on days 1 and 15 plus paclitaxel 80 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. RESULTS: Of 665 intention-to-treat patients, 223 were East Asian. Median overall survival was 12.1 months for ramucirumab plus paclitaxel and 10.5 months for placebo plus paclitaxel (hazard ratio: 0.986, 95% confidence interval: 0.727-1.337, P = 0.929). Median progression-free survival was 5.5 months for ramucirumab plus paclitaxel and 2.8 months for placebo plus paclitaxel (hazard ratio: 0.628, 95% confidence interval: 0.473-0.834, P = 0.001). Objective response rates were 34% for ramucirumab plus paclitaxel and 20% for placebo plus paclitaxel. Grade ≥ 3 neutropenia (60% vs 28%) and leukopenia (34% vs 13%) were higher for ramucirumab plus paclitaxel. The rate of febrile neutropenia was low (4% vs 4%). Special interest adverse events included any grade bleeding/hemorrhage (55% vs 25%), proteinuria (27% vs 7%), and hypertension (22% vs 2%). CONCLUSIONS: Ramucirumab plus paclitaxel significantly improves progression-free survival and response rate, with prolonged median overall survival and an acceptable safety profile in East Asians with advanced gastric cancer.

Health care resource use, productivity, and costs among patients with moderate to severe plaque psoriasis in the United States.

BACKGROUND: Comprehensive studies on costs of moderate to severe plaque psoriasis (MSPP) have not been conducted in the United States. OBJECTIVE: We sought to evaluate current health care resource use, productivity, and costs among patients with MSPP in routine practice. METHODS: A total of 200 adults seeking MSPP treatment enrolled in 9 US sites. Consented patients reported symptoms, treatment, lost productivity, and costs; 6-month retrospective chart review captured health care resource use and clinical characteristics. Costs were assigned to health care resource use and lost productivity using standard algorithms. Differences by Psoriasis Area and Severity Index (PASI) group, based on PASI score (≤10, >10-≤20, >20) at enrollment, were evaluated. Analyses included descriptive statistics and analysis of variance or Kruskal-Wallis tests. RESULTS: Most patients (79.5%) were prescribed 1 or more MSPP medications (mean: 1.5); 36.0% and 9.0% received self-administered biologics and systemic therapies, respectively. Mean number of nonprescription treatments was 12.3. Differences by PASI group were observed for overall work and activity impairment (P < .02). Six-month total MSPP direct costs per patient were $11,291; indirect costs were $2101 and differed across PASI groups (P = .0008). LIMITATIONS: This study enrolled patients with MSPP actively seeking care. CONCLUSION: Despite treatment, a number of patients with MSPP continue to experience moderate to severe PASI scores, impaired functioning, and high costs suggesting a need for new treatment options.

Impact of Alzheimer's Disease on Caregiver Questionnaire: internal consistency, convergent validity, and test-retest reliability of a new measure for assessing caregiver burden.

BACKGROUND: There is a lack of validated instruments to measure the level of burden of Alzheimer's disease (AD) on caregivers. The Impact of Alzheimer's Disease on Caregiver Questionnaire (IADCQ) is a 12-item instrument with a seven-day recall period that measures AD caregiver's burden across emotional, physical, social, financial, sleep, and time aspects. Primary objectives of this study were to evaluate psychometric properties of IADCQ administered on the Web and to determine most appropriate scoring algorithm. METHODS: A national sample of 200 unpaid AD caregivers participated in this study by completing the Web-based version of IADCQ and Short Form-12 Health Survey Version 2 (SF-12v2™). The SF-12v2 was used to measure convergent validity of IADCQ scores and to provide an understanding of the overall health-related quality of life of sampled AD caregivers. The IADCQ survey was also completed four weeks later by a randomly selected subgroup of 50 participants to assess test-retest reliability. Confirmatory factor analysis (CFA) was implemented to test the dimensionality of the IADCQ items. Classical item-level and scale-level psychometric analyses were conducted to estimate psychometric characteristics of the instrument. Test-retest reliability was performed to evaluate the instrument's stability and consistency over time. RESULTS: Virtually none (2%) of the respondents had either floor or ceiling effects, indicating the IADCQ covers an ideal range of burden. A single-factor model obtained appropriate goodness of fit and provided evidence that a simple sum score of the 12 items of IADCQ can be used to measure AD caregiver's burden. Scales-level reliability was supported with a coefficient alpha of 0.93 and an intra-class correlation coefficient (for test-retest reliability) of 0.68 (95% CI: 0.50-0.80). Low-moderate negative correlations were observed between the IADCQ and scales of the SF-12v2. CONCLUSIONS: The study findings suggest the IADCQ has appropriate psychometric characteristics as a unidimensional, Web-based measure of AD caregiver burden and is supported by strong model fit statistics from CFA, high degree of item-level reliability, good internal consistency, moderate test-retest reliability, and moderate convergent validity. Additional validation of the IADCQ is warranted to ensure invariance between the paper-based and Web-based administration and to determine an appropriate responder definition.

Frequency comb generation via synchronous pumped χ(3) resonator on thin-film lithium niobate.

Resonator-based optical frequency comb generation is an enabling technology for a myriad of applications ranging from communications to precision spectroscopy. These frequency combs can be generated in nonlinear resonators driven using either continuous-wave (CW) light, which requires alignment of the pump frequency with the cavity resonance, or pulsed light, which also mandates that the pulse repetition rate and cavity free spectral range (FSR) are carefully matched. Advancements in nanophotonics have ignited interest in chip-scale optical frequency combs. However, realizing pulse-driven on-chip Kerr combs remains challenging, as microresonator cavities have limited tuning range in their FSR and resonance frequency. Here, we take steps to overcome this limitation and demonstrate broadband frequency comb generation using a χ(3) resonator synchronously pumped by a tunable femtosecond pulse generator with on-chip amplitude and phase modulators. Notably, employing pulsed pumping overcomes limitations in Kerr comb generation typically seen in crystalline resonators from stimulated Raman scattering.

Betel-nut chewing does not influence PD-L1 expression rates in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC): A prospective biomarker prevalence study.

This study explored the relationship between betel-nut chewing and programmed death-ligand 1 (PD-L1) expression in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients in Taiwan. A total 280 R/M HNSCC patients, predominantly male, were evaluated; 75.4 % of whom chewed betel-nut. The prevalence of PD-L1 expression (combined positive score ≥1) was 94.3 % with similar PD-L1 expression rates between betel-nut-exposed and non-exposed groups. PD-L1 prevalence did not differ in those who received prior first-or second-line systemic therapy. In summary, betel-nut exposure did not notably affect PD-L1 expression rates in R/M HNSCC patients in Taiwan.

Contextual factors influencing the association between the Affordable Care Act's Medicaid expansion and Veteran VA-Medicaid dual enrollment.

OBJECTIVE: To evaluate changes in dual enrollment after Affordable Care Act Medicaid expansion by VA priority group, (e.g., service connection), sex, and type of state expansion. STUDY SETTING: Our cohort was all Veterans ages 18-64 enrolled in VA and eligible for benefits due to military service-connection or low income from 2011 to 2016; the unit of analysis was person-year. STUDY DESIGN: Difference-in-difference and event-study analysis. The outcome was dual VA-Medicaid enrollment for at least 1 month annually. Medicaid expansion, VA priority status, whether a state expanded by a Section 1115 waiver, and sex were independent variables. We controlled for race, ethnicity, age, disease burden, distance to VA facilities, state, and year. DATA EXTRACTION METHODS: We used data from the VA Corporate Data Warehouse (CDW) regarding age and VA Priority Group to select our cohort of VA-enrolled individuals. We then took the cohort and crossed checked it with Medicaid Analytic Extract (MAX) and T-MSIS Analytic Files (TAF) to determine Medicaid enrollment status. PRINCIPAL FINDINGS: Service-connected Veterans experienced lower dual-enrollment increases across all sex and state-waiver groups (3.44 percentage points (95% CI: 1.83, 5.05 pp) for women, 3.93 pp (2.98, 4.98) for men, 4.06 pp (2.85, 5.27) for non-waiver states, and 3.00 pp (1.58 to 4.41) for waiver states) than Veterans who enrolled in the VA due to low income (8.19 pp (5.43, 10.95) for women, 9.80 pp (7.06, 12.54) for men, 10.21 pp (7.17, 13.25) for non-waiver states, and 7.39 pp (5.28, 9.50) for waiver states). CONCLUSIONS: Medicaid expansion is associated with dual enrollment. Dual-enrollment changes are greatest in those enrolled in the VA due to low income, but do not differ by sex or expansion type. Results can help VA identify groups disproportionately likely to have potential care-coordination issues due to usage of multiple health care systems.

Foodborne pathogen inactivation in fruit juices utilizing commercial scale high-pressure processing: Effects of acidulants and pH.

The effects of juice pH, type of acidulant, and post-treatment refrigeration on the high-pressure processing (HPP) inactivation of Escherichia coli O157:H7, Salmonella enterica, and Listeria monocytogenes in acid beverages were evaluated. Inoculated apple, orange, and grape juices (at their original pH and adjusted to pH 4.00, 4.50, and 5.00) were treated at 550 MPa for 1 min at 5 °C. In addition, inoculated model solutions acidified to a pH of 5.00 with acetic, citric, malic, and tartaric acids were treated at 400 MPa for 1 min at 5 °C. The effect of refrigerated storage for 24 h after treatment on pathogen inactivation in both experiments was also assessed. A greater than 5-log reduction of the three pathogens inoculated was achieved in all juices immediately after HPP at the juices' original pH, and of L. monocytogenes under all experimental conditions. Refrigerated storage for 24 h after HPP treatment improved the inactivation of E. coli O157:H7, to >5-log reduction, at pH 4.00 in apple juice and of Salmonella in the three juices at pH 4.00. The type of acidulant did not significantly (p > 0.01) affect E. coli or Salmonella inactivation in acidified model solutions but a greater than 5-log reduction after HPP was only achieved for L. monocytogenes when acetic acid was used. The effectiveness of HPP for pathogen inactivation depended largely on product pH and the target pathogen of concern.

Treatment Patterns and Health Resource Utilization in Patients With HR+/ HER2- Locally Advanced or Metastatic Breast Cancer in a Real-World Setting in Taiwan.

OBJECTIVES: This study aimed to understand current treatment patterns and healthcare resource utilization (HRU) of women with locally advanced or metastatic breast cancer (advanced breast cancer [ABC]) in Taiwan overall and within the subgroup of patients who were postmenopausal women with no previous systemic therapy in the ABC setting. METHODS: A chart review of anonymized data on patient characteristics, treatment patterns, and HRU was conducted via an online physician survey including 118 patient charts from women ≥ 18 years old with hormone receptor positive/human epidermal growth receptor negative ABC, diagnosed between 2015 and 2017. RESULTS: The mean age of all patients was 56.6 years (range 29-83). Among the 118 patients, the most common first-line systemic therapy group after diagnosis of ABC was endocrine-based therapy (39.0%) or endocrine therapy (ET) plus chemotherapy (ChT) combinations (38.1%). In the postmenopausal subgroup (n = 56), ET-based therapy was the most common (44.6%). Oncologist visits, at annual rate of 9.20 (95% confidence interval 8.81-9.60), and hospitalizations, at annual rate of 1.08 (95% confidence interval 0.96-1.22), were key drivers of HRU. Of the 118 patients, the 72 with at least one ChT agent in their first-line regimen had an annual hospitalization rate of 1.4 versus 0.45 admissions compared with the 46 patients on first-line ET-based therapy. CONCLUSIONS: Current treatment patterns suggest an unmet need for new medications that lead to reduction in high rate of ChT use. Results can inform future evaluations of new ABC treatments that estimate the health economic impact of their adoption in Taiwan.

Treatment Patterns and Health Resource Utilization in Patients With Hepatocellular Carcinoma After Failure of Sorafenib in Real-World Setting in Taiwan.

OBJECTIVES: This study aimed to characterize current treatment patterns and healthcare resource utilization (HRU) observed among patients with hepatocellular carcinoma (HCC) after the failure of sorafenib in real-world setting in Taiwan. METHODS: A chart review was conducted in 130 patients; the inclusion criteria were patients with HCC who were aged 20 years or older and had received systemic therapy or best supportive care after failure of first-line systemic treatment with sorafenib between 2016 and 2018. Anonymized data on patient characteristics, treatment pathways, and survival were abstracted. RESULTS: The mean age of patients was 61.7 years (range 27-84); of these 130 patients, 103 (79%) were male, 81 (62%) had high alpha-fetoprotein (AFP) levels (≥400 ng/mL), and 96 (78.0%) were deceased at the time of data abstraction. After sorafenib therapy, 60 patients (46%) received systemic therapy, including nivolumab monotherapy (42%) and chemotherapy (25%). Oncologist visits at a semiannual per-patient rate of 3.7 (95% confidence interval [CI] 3.4-4.0) and hospitalizations at rate of 1.1 (95% CI 1.0-1.3) were the key contributors to HRU. Semiannual per-patient hospitalization rate was 1.3 (95% CI 1.1-1.5) in the high-AFP group. Median survival from discontinuation of sorafenib was 6.9 months (95% CI 5.9-9.0). CONCLUSIONS: This real-world evidence research on treatment patterns reflected substantial HRU consistent with the severity of HCC, particularly in the high-AFP group. Findings highlighted continuing high mortality in HCC, underlying a need for new treatments that can lengthen survival. Results can inform future evaluations of new HCC treatments that estimate the health economic impact of their adoption in Taiwan.

Mirror-induced reflection in the frequency domain.

Mirrors are ubiquitous in optics and are used to control the propagation of optical signals in space. Here we propose and demonstrate frequency domain mirrors that provide reflections of the optical energy in a frequency synthetic dimension, using electro-optic modulation. First, we theoretically explore the concept of frequency mirrors with the investigation of propagation loss, and reflectivity in the frequency domain. Next, we explore the mirror formed through polarization mode-splitting in a thin-film lithium niobate micro-resonator. By exciting the Bloch waves of the synthetic frequency crystal with different wave vectors, we show various states formed by the interference between forward propagating and reflected waves. Finally, we expand on this idea, and generate tunable frequency mirrors as well as demonstrate trapped states formed by these mirrors using coupled lithium niobate micro-resonators. The ability to control the flow of light in the frequency domain could enable a wide range of applications, including the study of random walks, boson sampling, frequency comb sources, optical computation, and topological photonics. Furthermore, demonstration of optical elements such as cavities, lasers, and photonic crystals in the frequency domain, may be possible.

Patient Perspectives on Health-Related Quality of Life in Diffuse Large B-Cell Lymphoma Treated with Car T-Cell Therapy: A Qualitative Study.

INTRODUCTION: Chimeric antigen receptor T-cell (CAR T) therapy offers a potentially curative option for patients with relapsed and refractory hematologic malignancies, including diffuse large B-cell lymphoma (DLBCL). Patient-reported experiences with CAR T therapy are limited and have not been well characterized. The purpose of this qualitative study was to explore patient descriptions of key domains of health-related quality of life (HRQoL) in DLBCL patients treated with CAR T therapy. METHODS: A targeted literature review was initially conducted to inform the development of the interview guide comprising predetermined open-ended questions. Two focus groups were conducted with a total of 18 patients with DLBCL identified from patient advisory boards. Focus group sessions were recorded and transcribed verbatim. MAXQDA 18.2.0 qualitative data analysis software was utilized to facilitate a constant-comparative coding process to identify key concepts. RESULTS: Eight domain impairments (social functioning, emotional functioning, fatigue, physical functioning, cognitive functioning, role functioning, sleep, and pain/discomfort) were identified from the qualitative analysis and endorsed by DLBCL patients treated with CAR T. Compared with before CAR T therapy, patients reported increased impairment in every domain during or immediately after CAR T therapy. This impairment improved for each domain 6 months after CAR T therapy except for pain/discomfort. Compared with before CAR T therapy, improvement in impairment for each domain was observed 6 months after CAR T therapy except for fatigue, sleep, and pain/discomfort. CONCLUSION: This study provides meaningful information regarding the impact of CAR T therapy on HRQoL in patients with DLBCL throughout their treatment journey. Health care professionals and investigators can utilize these data in examining existing patient-reported outcome (PRO) measures that are used in DLBCL clinical trials and to better understand the needs of DLBCL survivors.

Second-line treatment of advanced hepatocellular carcinoma: Time for more individualized treatment options?

Hepatocellular carcinoma (HCC) is the most frequently diagnosed primary tumor of the liver and is usually detected as advanced disease. It is an aggressive disease that often progresses rapidly when it fails to respond to treatment. As such, patients have limited opportunities to try different subsequent-line treatment regimens. In the last 5 years, the number of agents and/or regimens available for the treatment of advanced HCC has significantly increased, which has made treatment choices for this patient population increasingly complex. In the second-line setting, several phase III trials of regorafenib (RESORCE), ramucirumab (REACH/REACH-2), and cabozantinib (CELESTIAL) have demonstrated clinically meaningful survival benefits in patients with the disease. However, the median overall survival of patients with advanced HCC remains unchanged at approximately 12 mo from the start of systemic second-line therapy, with a limited duration of response. Evidence from the REACH/REACH-2 trials demonstrated for the first time that baseline alpha-fetoprotein (AFP) levels can be used as an identification factor to select those who are likely to benefit the most from ramucirumab treatment. Ramucirumab is both well tolerated and efficacious and has a clinically acceptable safety profile. Therefore, it should be considered an option for patients with AFP levels ≥ 400 ng/mL.