A Phase 1b/2a Study of GC1118 with 5-Fluorouracil, Leucovorin and Irinotecan (FOLFIRI) in Patients with Recurrent or Metastatic Colorectal Cancer / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#GC1118 is a novel antibody targeting epidermal growth factor receptor (EGFR) with enhanced blocking activity against both low- and high-affinity EGFR ligands. A phase 1b/2a study was conducted to determine a recommended phase 2 dose (RP2D) of GC1118 in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (phase 1b) and to assess the safety and efficacy of GC1118 plus FOLFIRI as a second-line therapy for recurrent/metastatic colorectal cancer (CRC) (phase 2a). @*Materials and Methods@#Phase 1b was designed as a standard 3+3 dose-escalation study with a starting dose of GC1118 (3 mg/kg/week) in combination with biweekly FOLFIRI (irinotecan 180 mg/m2; leucovorin 400 mg/m2; 5-fluorouracil 400 mg/m2 bolus and 2,400 mg/m2 infusion over 46 hours) in patients with solid tumors refractory to standard treatments. The subsequent phase 2a part was conducted with objective response rate (ORR) as a primary endpoint. Patients with KRAS/NRAS/BRAF wild-type, EGFR-positive, recurrent/metastatic CRC resistant to the first-line treatment were enrolled in the phase 2a study. @*Results@#RP2D of GC1118 was determined to be 3 mg/kg/wk in the phase 1b study (n=7). Common adverse drug reactions (ADRs) observed in the phase 2a study (n=24) were acneiform rash (95.8%), dry skin (66.7%), paronychia (58.3%), and stomatitis (50.0%). The most common ADR of ≥ grade 3 was neutropenia (33.3%). ORR was 42.5% (95% confidence interval [CI], 23.5 to 62.0), and median progression-free survival was 6.7 months (95% CI, 4.0-8.0). @*Conclusion@#GC1118 administered weekly at 3 mg/kg in combination with FOLFIRI appears as an effective and safe treatment option in recurrent/metastatic CRC.

Background-penalty-free waveguide enhancement of CARS signal in air-filled anti-resonance hollow-core fiber.

We study coherent anti-Stokes Raman spectroscopy in air-filled anti-resonance hollow-core photonic crystal fiber, otherwise known as "revolver" fiber. We compare the vibrational coherent anti-Stokes Raman signal of N2, at ∼2331 cm-1, generated in ambient air (no fiber present), with the one generated in a 2.96 cm of a revolver fiber. We show a ∼170 times enhancement for the signal produced in the fiber, due to an increased interaction path. Remarkably, the N2 signal obtained in the revolver fiber shows near-zero non-resonant background, due to near-zero overlap between the laser field and the fiber cladding. Through our study, we find that the revolver fiber properties make it an ideal candidate for the coherent Raman spectroscopy signal enhancement.

Active optical metasurfaces: comprehensive review on physics, mechanisms, and prospective applications.

Optical metasurfaces with subwavelength thickness hold considerable promise for future advances in fundamental optics and novel optical applications due to their unprecedented ability to control the phase, amplitude, and polarization of transmitted, reflected, and diffracted light. Introducing active functionalities to optical metasurfaces is an essential step to the development of next-generation flat optical components and devices. During the last few years, many attempts have been made to develop tunable optical metasurfaces with dynamic control of optical properties (e.g., amplitude, phase, polarization, spatial/spectral/temporal responses) and early-stage device functions (e.g., beam steering, tunable focusing, tunable color filters/absorber, dynamic hologram, etc) based on a variety of novel active materials and tunable mechanisms. These recently-developed active metasurfaces show significant promise for practical applications, but significant challenges still remain. In this review, a comprehensive overview of recently-reported tunable metasurfaces is provided which focuses on the ten major tunable metasurface mechanisms. For each type of mechanism, the performance metrics on the reported tunable metasurface are outlined, and the capabilities/limitations of each mechanism and its potential for various photonic applications are compared and summarized. This review concludes with discussion of several prospective applications, emerging technologies, and research directions based on the use of tunable optical metasurfaces. We anticipate significant new advances when the tunable mechanisms are further developed in the coming years.

Short- vs Standard-Course Outpatient Antibiotic Therapy for Community-Acquired Pneumonia in Children: The SCOUT-CAP Randomized Clinical Trial.

IMPORTANCE: Childhood community-acquired pneumonia (CAP) is usually treated with 10 days of antibiotics. Shorter courses may be effective with fewer adverse effects and decreased potential for antibiotic resistance. OBJECTIVE: To compare a short (5-day) vs standard (10-day) antibiotic treatment strategy for CAP in young children. DESIGN, SETTING, AND PARTICIPANTS: Randomized double-blind placebo-controlled clinical trial in outpatient clinic, urgent care, or emergency settings in 8 US cities. A total of 380 healthy children aged 6 to 71 months with nonsevere CAP demonstrating early clinical improvement were enrolled from December 2, 2016, to December 16, 2019. Data were analyzed from January to September 2020. INTERVENTION: On day 6 of their originally prescribed therapy, participants were randomized 1:1 to receive 5 days of matching placebo or 5 additional days of the same antibiotic. MAIN OUTCOMES AND MEASURES: The primary end point was the end-of-treatment response adjusted for duration of antibiotic risk (RADAR), a composite end point that ranks each child's clinical response, resolution of symptoms, and antibiotic-associated adverse effects in an ordinal desirability of outcome ranking (DOOR). Within each DOOR rank, participants were further ranked by the number of antibiotic days, assuming that shorter antibiotic durations were more desirable. Using RADAR, the probability of a more desirable outcome was estimated for the short- vs standard-course strategy. In a subset of children, throat swabs were collected between study days 19 and 25 to quantify antibiotic resistance genes in oropharyngeal flora. RESULTS: A total of 380 children (189 randomized to short course and 191 randomized to standard course) made up the study population. The mean (SD) age was 35.7 (17.2) months, and 194 participants (51%) were male. Of the included children, 8 were Asian, 99 were Black or African American, 234 were White, 32 were multiracial, and 7 were of unknown or unreported race; 33 were Hispanic or Latino, 344 were not Hispanic or Latino, and 3 were of unknown or unreported ethnicity. There were no differences between strategies in the DOOR or its individual components. Fewer than 10% of children in either strategy had an inadequate clinical response. The short-course strategy had a 69% (95% CI, 63-75) probability of a more desirable RADAR outcome compared with the standard-course strategy. A total of 171 children were included in the resistome analysis. The median (range) number of antibiotic resistance genes per prokaryotic cell (RGPC) was significantly lower in the short-course strategy compared with the standard-course strategy for total RGPC (1.17 [0.35-2.43] vs 1.33 [0.46-11.08]; P = .01) and ß-lactamase RGPC (0.55 [0.18-1.24] vs 0.60 [0.21-2.45]; P = .03). CONCLUSIONS AND RELEVANCE: In this study, among children responding to initial treatment for outpatient CAP, a 5-day antibiotic strategy was superior to a 10-day strategy. The shortened approach resulted in similar clinical response and antibiotic-associated adverse effects, while reducing antibiotic exposure and resistance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02891915.

Policy Suggestions to Improve Patient Access to New Drugs in Korea

Objective@#This study aimed to overview and assess the effectiveness of the policies and regulations that have governed new drug access in Korea, and to propose policies to enhance patient access to drugs, particularly for new innovative medicines. @*Methods@#We approached drug access issues in two perspectives: approval lag (or availability) and reimbursement lag (or affordability). The issues were identified and evaluated through the review of literature, public documents, reports published by the government agencies and private organizations, and news articles. @*Results@#To shorten approval lag, it is recommended to hire and train more reviewers at the Ministry of Food and Drug Safety. Increasing user fees to a realistic level can facilitate this process. To reduce reimbursement lag, flexible incremental cost-effectiveness ratio threshold, alternative cost-effectiveness evaluation, and establishment of funding source other than the national health insurance are identified as the areas to be improved. @*Conclusion@#The current policies and regulations had to be supplemented by new systems to drastically promote patient accessibility to new drugs, consequently in order to promote national public health.

Policy Suggestions to Improve Patient Access to New Drugs in Korea

Objective@#This study aimed to overview and assess the effectiveness of the policies and regulations that have governed new drug access in Korea, and to propose policies to enhance patient access to drugs, particularly for new innovative medicines. @*Methods@#We approached drug access issues in two perspectives: approval lag (or availability) and reimbursement lag (or affordability). The issues were identified and evaluated through the review of literature, public documents, reports published by the government agencies and private organizations, and news articles. @*Results@#To shorten approval lag, it is recommended to hire and train more reviewers at the Ministry of Food and Drug Safety. Increasing user fees to a realistic level can facilitate this process. To reduce reimbursement lag, flexible incremental cost-effectiveness ratio threshold, alternative cost-effectiveness evaluation, and establishment of funding source other than the national health insurance are identified as the areas to be improved. @*Conclusion@#The current policies and regulations had to be supplemented by new systems to drastically promote patient accessibility to new drugs, consequently in order to promote national public health.

Enhanced subwavelength coupling and nano-focusing with optical fiber-plasmonic hybrid probe.

Metallic nanowires supporting surface plasmon polaritons can localize optical fields at nanoscale tapered ends for near-field imaging. Radially polarized light through the optical fiber or free space efficiently excites the converging radial plasmons at the apex of a sharp tip. However, such radial vector mode excitation through optical fiber requires precise polarization control and strongly polarization maintaining state in optical fiber, thus inducing a complexity for optical applications. In this paper, we propose a photonic-plasmonic probe that uses the linearly polarized source to excite the nanoscale plasmonic hotspot. The linearly polarized fiber mode is converted to radial surface plasmon polaritons (SPPs) through asymmetric coupling at the base of the metallic nano-tip. The radial SPP's then propagate along the half ellipsoid tip and are focused at the tip apex giving rise to the nanoscale concentration of optical energy. The probe can be implemented with near-field imaging techniques such as tip-enhanced Raman microscopy to obtain topographic and chemical spectroscopic information in atomic resolution for studying light-matter interaction at the nanoscale.

Use of Molecular Imaging in Clinical Drug Development: a Systematic Review / 대한핵의학회잡지

BACKGROUND@#Molecular imaging such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can provide the crucial pharmacokinetic-pharmacodynamic information of a drug non-invasively at an early stage of clinical drug development. Nevertheless, not much has been known how molecular imaging has been actually used in drug development studies.@*METHODS@#We searched PubMed using such keywords as molecular imaging, PET, SPECT, drug development, and new drug, or any combination of those to select papers in English, published from January 1, 1990, to December 31, 2015. The information about the publication year, therapeutic area of a drug candidate, drug development phase, and imaging modality and utility of imaging were extracted.@*RESULTS@#Of 10,264 papers initially screened, 208 papers met the eligibility criteria. The more recent the publication year, the bigger the number of papers, particularly since 2010. The two major therapeutic areas using molecular imaging to develop drugs were oncology (47.6%) and the central nervous system (CNS, 36.5%), in which efficacy (63.5%) and proof-of-concept through either receptor occupancy (RO) or other than RO (29.7%), respectively, were the primary utility of molecular imaging. PET was used 4.7 times more frequently than SPECT. Molecular imaging was most frequently used in phase I clinical trials (40.8%), whereas it was employed rarely in phase 0 or exploratory IND studies (1.4%).@*CONCLUSIONS@#The present study confirmed the trend that molecular imaging has been more actively employed in recent clinical drug development studies although its adoption was rather slow and rare in phase 0 studies.

Use of Molecular Imaging in Clinical Drug Development: a Systematic Review / 대한핵의학회잡지

BACKGROUND: Molecular imaging such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can provide the crucial pharmacokinetic-pharmacodynamic information of a drug non-invasively at an early stage of clinical drug development. Nevertheless, not much has been known how molecular imaging has been actually used in drug development studies.METHODS: We searched PubMed using such keywords as molecular imaging, PET, SPECT, drug development, and new drug, or any combination of those to select papers in English, published from January 1, 1990, to December 31, 2015. The information about the publication year, therapeutic area of a drug candidate, drug development phase, and imaging modality and utility of imaging were extracted.RESULTS: Of 10,264 papers initially screened, 208 papers met the eligibility criteria. The more recent the publication year, the bigger the number of papers, particularly since 2010. The two major therapeutic areas using molecular imaging to develop drugs were oncology (47.6%) and the central nervous system (CNS, 36.5%), in which efficacy (63.5%) and proof-of-concept through either receptor occupancy (RO) or other than RO (29.7%), respectively, were the primary utility of molecular imaging. PET was used 4.7 times more frequently than SPECT. Molecular imaging was most frequently used in phase I clinical trials (40.8%), whereas it was employed rarely in phase 0 or exploratory IND studies (1.4%).CONCLUSIONS: The present study confirmed the trend that molecular imaging has been more actively employed in recent clinical drug development studies although its adoption was rather slow and rare in phase 0 studies.

Data exclusivity through New Drug Reexamination in Korea: sibutramine hydrochloride (Reductil®) vs. sibutramine mesylate (Slimmer®) as an example

The ‘equivalent-or-more-but-not-the-same-data’ provision in the Regulation on the Safety and Efficacy Evaluation of New Drug in Korea has served as the de facto data exclusivity term for any drug identical to a product subject to new drug reexamination. The legal debate that occurred between Abbott Korea and Hanmi in association with the approval of their sibutramine products, i.e., Reductil® vs. Slimmer®, showed why data exclusivity plays an important role to protect intellectual property of the innovator drug when incrementally modified drugs had to rely on the safety and efficacy data of the innovator drug for approval. The regulatory science and legal issues regarding the case of Reductil® vs Slimmer® were discussed, and the importance of data exclusivity was emphasized as a useful tool to protect intellectual property besides patent.

Quantitative, three-dimensional imaging of aluminum drop combustion in solid propellant plumes via digital in-line holography.

Burning aluminized propellants eject reacting molten aluminum drops with a broad size distribution. Prior to this work, in situ measurement of the drop size statistics and other quantitative flow properties was complicated by the narrow depth-of-focus of microscopic videography. Here, digital in-line holography (DIH) is demonstrated for quantitative volumetric imaging of the propellant plume. For the first time, to the best of our knowledge, in-focus features, including burning surfaces, drop morphologies, and reaction zones, are automatically measured through a depth spanning many millimeters. By quantifying all drops within the line of sight, DIH provides an order of magnitude increase in the effective data rate compared to traditional imaging. This enables rapid quantification of the drop size distribution with limited experimental repetition.

A bioequivalence study of two levofloxacin tablets in healthy male subjects

Levofloxacin is a bactericidal broad spectrum antibiotic against Gram-positive and Gram-negative pathogens. A randomized, two-treatment, two-period, two-way crossover study was conducted to evaluate the bioequivalence of Lectacin 250 mg tablet, a generic levofloxacin, to its reference drug, Cravit 250 mg tablet. Each period was separated by a 7-day washout. Serial blood samples were collected until 24 h after dosing and plasma levofloxacin concentrations were determined using a high performance liquid chromatography. Pharmacokinetic parameters were analyzed using K-BE Test 2007 and BA calc 2007 (Ministry of Food and Drug Safety, Cheongju-si, South Korea). The peak concentration (Cmax) and the area under the plasma concentration versus time curve from 0 to the last measurable concentration (AUC(0-t)) for the generic and reference levofloxacin were 4.48+/-0.89 mg/L and 4.46+/- 0.95 mg/L, and 25.33+/-4.12 mg*h/L and 25.77+/-4.01 mg*h/L, respectively, leading to a geometric mean ratio (90% confidence interval) of the generic to the reference levofloxacin of 1.0060 (0.9339-1.0842) and 0.9810 (0.9476-1.0159), respectively, for Cmax and AUC(0-t). Lectacin 250 mg tablet is bioequivalent to Cravit 250 mg tablet.

Accurate measurement of out-of-plane particle displacement from the cross correlation of sequential digital in-line holograms.

A new method to quantify three-dimensional particle fields using digital in-line holography is presented. From sequentially recorded holograms, the maximum cross correlation of edge sharpness within local particle windows yields an accurate measurement of particle displacements. Experiments demonstrate out-of-plane displacement uncertainty of approximately 0.15 mean particle diameters, which is roughly an order-of-magnitude improvement compared with alternative methods. Application to shotgun pellets demonstrates robustness despite experimental noise.

Effect of placebo on ambulatory blood pressure monitoring in children.

BACKGROUND: Ambulatory blood pressure monitoring (ABPM) has been proposed as a useful tool for more accurately diagnosing hypertension (HTN) and evaluating blood pressure (BP) response in pediatric anti-hypertensive trials. ABPM captures multiple BP measurements during routine daily activities and is thus an excellent method for identifying white-coat HTN. Additionally, ABPM measurements in adults do not demonstrate the placebo effect commonly seen with casual BP measurements, although this has yet to be evaluated in children. Therefore,, the aim of this study was to assess the effect of placebo on ABPM measurements in children. METHODS: A total of 141 children aged 5-16 years with elevated BP were randomized into a multi-center, single-blind, cross-over trial. Subjects received a placebo pill prior to wearing a 24-h ABPM device at one of two visits separated by 1-2 weeks. Study procedures were otherwise identical at both visits. RESULTS: Mean systolic and diastolic BP for all measured time periods were similar between visits, as was the number of children diagnosed with HTN at each visit. CONCLUSION: Having confirmed HTN at baseline did not affect the impact of placebo on mean BP. If confirmed, this lack of placebo effect on ABPM measurements may allow for the design of direct comparison pediatric anti-hypertensive trials without a placebo arm.

Equivalence Margin of the Biosimilar Product

The equivalence margin is the largest difference that is clinically acceptable between the test (or experimental) drug and the active control (or reference) drug. This paper discusses the scientific principles, along with the regulatory issues, that need to be addressed when determining the equivalence margin for the biosimilar product. The concept of assay sensitivity is introduced, and the ways to ensure assay sensitivity in the equivalence trial are emphasized. A hypothetical example is presented to show how an equivalence margin is determined. The regulatory agency should carefully assess if the equivalence margin of the biosimilar product was determined using a scientifically valid and clinically relevant approach, not subject to selection bias. This is important because the consumer risk of erroneously declaring equivalence when in fact it is not must be controlled conservatively low in the approval of any biosimilar products.

Trends in hospital and surgeon volume and operative mortality for cancer surgery.

BACKGROUND: We measured 13-year trends in operative mortality for six cancer resections. We then examined whether these trends are driven by changes in hospital and surgeon volume or by changes that occurred among all providers, regardless of volume. METHODS: We analyzed administrative discharge data on patients who received one of six cancer resections in Florida, New Jersey, and New York for three time periods: 1988 to 1991, 1992 to 1996, and 1997 to 2000. Descriptive statistics and nested regression models were used to test for changes in the association between inpatient mortality and annual hospital and annual surgeon volume over time, adjusting for patient and hospital characteristics. RESULTS: Unadjusted inpatient mortality rates for the six cancer resections declined between .8 and 4.0 percentage points between the time periods 1988 to 1991 and 1997 to 2000. Over this time period, annual hospital and surgeon volumes for the six cancer operations increased an average of 24.3% and 24.2%, respectively. The logistic regressions indicated a relatively stable relationship over time between both increased hospital and surgeon volume and lower inpatient mortality. Simulations suggest that increases in hospital and surgeon procedure volume over time led to a reduction in inpatient mortality ranging from .1 percentage points for rectal cancer to 2.3 percentage points for pneumonectomy. CONCLUSIONS: Persistence of the volume-outcome relation and increasing hospital and surgeon volumes explain much of the decline over time in inpatient mortality for five of the six cancer operations studied. Concentrating cancer resections among high-volume providers should lead to further reduced inpatient mortality.

Fuentes internacionales de cooperación para el financiamiento de la salud en los países en desarrollo / International sources of financial cooperation for health in developing countries

Se ha realizado un estudio que evalúa el estado actual de la asistencia internacional de financiamiento para las actividades de salud con objeto de averiguar cuán eficaz podría ser la cooperación internacional de financiamiento en el esfuerzo de lograr la salud para todos y el ritmo a que la misma debería aumentar. Tal cooperación puede proporcionar una contribución importante, y tal vez suficiente, aun cuando sea necesario realizar cambios primordiales en los procedimientos para suministrar la asistencia relacionada con la salud (AU)

Fuentes internacionales de cooperacion para el financiamiento de la salud en los paises en desarrollo. / International sources of financial cooperation for health in developing countries

Se ha realizado un estudio que evalua el estado actual de la asistencia internacional de financiamiento para las actividades de salud con objeto de averiguar cuan eficaz podria ser la cooperacion internacional de financiamiento en el esfuerzo de lograr la salud para todos y el ritmo a que la misma deberia aumentar.Tal cooperacion puede proporcionar una contribucion importante, y tal vez suficiente aun cuando sea necesario realizar cambios primordiales en los procedimientos para suministrar la asistencia relacionada con la salud