Background and clinical significance of biomarker-based patient enrichment in non-small-cell lung cancer drug development.

Pharmaceutical companies have adopted biomarker-based enrichment (personalized) strategies to improve research and development productivity. We explored the background in which personalized strategies are adopted and examined whether their adoption is linked to improved efficacy of new drugs approved for non-small cell lung cancer (NSCLC) by US Food and Drug Administration (FDA). We extracted data from the first labels of drugs approved for NSCLC between May 2003 and February 2021, and performed a qualitative comparative analysis and meta-analysis. Personalized strategies were adopted in more than half of the trials (16/27) and were often used in trials aimed at obtaining first-line indications and in drugs that were not first-in-class. The meta-analysis showed that personalized trials had significantly improved progression-free survival (PFS) hazard ratio (HR) than trials without personalization but not for relative response rate ratio (RRR) or overall survival (OS) HR. Trials in which PFS HR was the primary endpoint tended to have improved PFS HR, and trials in which OS HR was the primary endpoint had worse PFS HR. The efficacy endpoints that are substantially affected by personalized strategies appear to differ, especially for new drugs with novel mechanism of action (MOA), because trial designs are employed to validate drug-specific advantages.

Linkage-Editing Pseudo-Glycans: A Reductive α-Fluorovinyl-C-Glycosylation Strategy to Create Glycan Analogs with Altered Biological Activities.

The acetal (O-glycoside) bonds of glycans and glycoconjugates are chemically and biologically vulnerable, and therefore C-glycosides are of interest as more stable analogs. We hypothesized that, if the O-glycoside linkage plays a vital role in glycan function, the biological activities of C-glycoside analogs would vary depending on their substituents. Based on this idea, we adopted a "linkage-editing strategy" for the creation of glycan analogs (pseudo-glycans). We designed three types of pseudo-glycans with CH2 and CHF linkages, which resemble the O-glycoside linkage in terms of bond lengths, angles, and bulkiness, and synthesized them efficiently by means of fluorovinyl C-glycosylation and selective hydrogenation reactions. Application of this strategy to isomaltose (IM), an inducer of amylase expression, and α-GalCer, which activates iNKT cells, resulted in the discovery of CH2-IM, which shows increased amylase production ability, and CHF-α-GalCer, which shows activity opposite that of native α-GalCer, serving as an antagonist of iNKT cells.

Comparison of factors associated with drooling between intractable neuromuscular disease and cerebral palsy.

Drooling represents a common and noteworthy symptom in patients with intractable neuromuscular disease (IND) and cerebral palsy (CP) and can lead to poor quality of life (QOL) and higher incidence of death due to aspiration of saliva. Identifying the factors affecting drooling is crucial to improving QOL and improving the poor prognosis of patients with IND and CP. This study sought to assess the prevalence of drooling and to elucidate the associated factors, drugs, and differences between patients with IND and CP. We included hospitalized patients with IND and CP. Among the 269 patients, 69 of 162 patients with IND (42.6%) and 75 of 107 patients with CP (70.1%) exhibited drooling. Drooling in IND was significantly higher in patients with tube feeding and those who had a previous stroke than in patients with potential oral intake and those having no history of stroke. In individuals with CP, drooling was significantly negatively associated with age. Taltirelin in patients with IND had a significant positive association with drooling, and antipsychotics and centrally acting muscle relaxants in those with CP had a significant negative association with drooling. Our results suggest that the factors associated with frequent drooling differ between IND and CP cases, and patients who should be screened for drooling are those with decreased swallowing function, those with IND who have had a previous stroke, and young patients with CP. Moreover, clinicians should consider the impact of drugs on drooling in IND and CP cases.

Dosimetric Comparison of Helical Tomotherapy and HyperArc Treatment Plans for Angiosarcoma of the Scalp.

BACKGROUND/AIM: Angiosarcoma of the scalp (AS) is a rare tumor that has often been treated by total scalp irradiation (TSI). TSI has technical and dosimetric challenges. This study aimed to compare the dosimetric performance of helical tomotherapy (HT) plans with that of HyperArc (HA) plans for TSI in AS. PATIENTS AND METHODS: A planning study was conducted for 11 patients with AS (70 Gy/35 fr). HT and HA planning was performed using TomoHDA and TrueBeam Edge systems, respectively. The performance of three different plans were compared: HT, HA, and HA with half-field beams (HF-HA). The dose distribution and dosimetric parameters for each plan were evaluated. RESULTS: All constraint parameters for the target and organs at risk (OARs) met the goals within acceptable limits for the three techniques. The HA and HF-HA plans provided significantly lower mean brain dose (12.46±2.48 Gy and 8.02±1.48 Gy) than did the HT plan (17.59±3.47 Gy). The doses receiving 0.1 cc of the volume for brainstem and chiasm were significantly lower in the HA and HF-HA plans than those in the HT plan. The HA and HF-HA plans provided a shorter beam-on time (155±3 s and 181±14 s) than did the HT plan (962±221 s). CONCLUSION: The HA plan provided significantly better OARs sparing than the HT plan for TSI in AS and had an advantage to using half-field beams.

Regulatory Environment and Approvals in Cell and Gene Therapy Products Between Japan, the USA, and the EU.

BACKGROUND: This study aimed to demonstrate the differences in the way cell and gene therapy (CGT) products have been developed and reviewed for approval in Japan, the USA, and the EU by comparing regulations and successfully launched products in each region, and to examine the background to such differences. METHODS: Information on relevant regulations and approved CGT products were collected from the public source and compared by region. RESULTS: While regulations on CGT products are largely consistent among these regions, some differences could have a substantial impact on the practices defining CGT products, the timing of responses required to comply with the regulations for handling gene-modified organisms, and the acceptable validation processes under good manufacturing practice regulations. Although CGT products are given some preferential status in all regions, the preferential treatment given to CGT products varies across regions. The CGT products launched in each region also differ significantly in type, indications, the nature of the developers, and the clinical evidence submitted. While all the cellular products launched in Japan were approved based on small uncontrolled trials, most cellular products in the USA and EU were approved based on controlled studies. A trend was observed for companies to enter their home markets. CONCLUSION: Our study showed differences of regulations on CGT products and of features in approved products as well as the trend of their home market entries, which may have been driven by a different context than that of traditional pharmaceuticals.

Revisiting the Term "Compassionate Use" and Leadership of the World Health Organization in Resolving Confusion in the Age of COVID-19 and Beyond.

We discuss the term "compassionate use" (CU) as an example of terminology having a huge impact on drug regulation. CU is used in many confusing situations, and its meaning varies significantly. We ethically affirm the necessity of CU. We insist that CU should be properly placed in exceptional status. The regulation of CUs is much more lenient than that of clinical trials because of the difference in the purpose. Whether consciously or unconsciously, abuse results in confusion and is never acceptable. The World Health Organization (WHO) proposed not to use the previous term CU but to replace it with another one. WHO also proposed the term MEURI (monitored emergency use of unregistered and experimental interventions). However, this was extremely incomplete, and WHO used the term CU subsequently. The main purpose of the proposal needs to be thoroughly implemented. In the context of the COVID-19 pandemic and beyond, expectations regarding WHO's role and leadership in global health issues are rising. We hope that WHO will play a major role in promoting research ethics preparedness while discontinuing the use of confusing terms such as CU and will develop alternative terms and their content. We discuss the evaluation of MEURI, the Japanese version of CU, and appropriate and inappropriate terminology related to the therapeutic use of unapproved drugs. We also discuss the expected appearance of CU including its name. It is appropriate to target group/cohort patients and unapproved drugs in the late stage of development. It is also important to solve the problem of incentives for CUs of pharmaceutical companies that are rushing to obtain marketing approval. The UK's Early Access to Medicine Scheme has provided many suggestions. We believe that our opinion can contribute to WHO's efforts to resolve the confusion and promote research ethics preparedness in health emergencies.

Spatial Distribution of the Network Structure in Epoxy Resin via the MAXS-CT Method.

We have succeeded in visualizing the spatial heterogeneity of the reaction ratio in epoxy resins by combining medium-angle X-ray scattering (MAXS) and computed tomography (CT). The reaction ratio is proportional to the degree of cross-linking between epoxy and amine in epoxy resins. The reaction ratio and its spatial inhomogeneity affect the toughness of epoxy resins. However, there has been no non-destructive method to measure the spatial inhomogeneity of the reaction ratio, although we can measure only the spatially averaged reaction ratio by Fourier-transform infrared spectroscopy (FT-IR). We found that the scattering peak reflected the cross-linking structures in the q region of MAXS and that the peak intensity is proportional to the reaction ratio. By reconstructing CT images from this peak intensity, we visualized the spatial heterogeneity of the reaction ratio. The application of this method may not be limited to epoxy resins but may extend to studying the heterogeneity of cross-linked structures in other materials.

Evaluation of Stopping Power Ratio Calculation Using Dual-energy Computed Tomography With Fast Kilovoltage Switching for Treatment Planning of Particle Therapy.

BACKGROUND/AIM: This study evaluated the calculation accuracy of the stopping power ratio (SPR) using dual-energy computed tomography with fast kilovoltage switching (FKSCT) for particle therapy. MATERIALS AND METHODS: A tissue characterization phantom with various reference materials was scanned to obtain single-energy computed tomography (SECT) images and generate virtual monochromatic images at 77 keV (VMI77keV) and 140 keV (VMI140keV), water density (WD) images, and effective Z (Zeff) images. For SECT, VMI77keV and VMI140keV lookup tables were generated to convert the measured Hounsfield value into the theoretical SPR for a normal phantom size. Subsequently, the reference materials were scanned in small and large phantoms. The SPR was calculated using the lookup tables of SECT (SPRSECT) images, VMI77keV (SPR77keV), and VMI140keV (SPR140keV), and it was derived from the WD and Zeff (SPRWD). RESULTS: In the normal-sized phantom, the overall mean difference between SPRWD and theoretical SPR was -0.3%, and remained below 2% for most reference materials. For the large phantom, the overall mean absolute difference for SPR140keV (3.0%, p=0.006) and SPRWD (3.2%, p=0.002) for the reference materials was significantly lower than that for SPRSECT (5.9%). For the small phantom, a significant reduction in the mean difference in the SPR calculation was observed in SPR77keV (1.0%, p=0.001) and SPR140keV (1.1%, p=0.013) compared with SPRSECT (2.2%). CONCLUSION: VMI140keV generated using FKSCT significantly improves the estimation accuracy of SPR compared with SECT. Thus, FKSCT may be used to improve the dose calculation accuracy for treatment planning of particle therapy.

Financial Literacy and Gambling Behavior in the United States.

Problem gambling is becoming a growing concern in the United States because of the proliferation of, and state support for, gambling opportunities. The economic cost along with the physical and mental health problems associated with problem gambling make it necessary to study how problem gambling can be reduced. Our study examines whether financial literacy could be a means to reducing gambling frequency in the United States. We use data from the Preference Parameter Study of Osaka University, Japan, and apply instrumental variable probit regression models. The results show that, generally, financial literacy does not have a relationship with gambling frequency, but the relationship is significant in the states where electronic gambling machines (EGMs) are available. The results imply that gamblers are irrational and fail to assess the risks of gambling as well as the probabilities that maximize expected payoffs. It appears that gamblers' psychological gain from gambling outweighs the negative expected utility when there is easy access to gambling. Thus, rationality with regard to gambling decisions does not work unless the easy access to EGMs is controlled. Our results further show that males, older people, people with higher household income, and people who have easy access to gambling are likely to be frequent gamblers.

Artifact removal in the contour areas of SAXS-CT images by Tikhonov-L1 minimization.

Small-angle X-ray scattering (SAXS) coupled with computed tomography (CT), denoted SAXS-CT, has enabled the spatial distribution of the characteristic parameters (e.g. size, shape, surface, length) of nanoscale structures inside samples to be visualized. In this work, a new scheme with Tikhonov regularization was developed to remove the effects of artifacts caused by streak scattering originating from the reflection of the incident beam in the contour regions of the sample. The noise due to streak scattering was successfully removed from the sinogram image and hence the CT image could be reconstructed free from artifacts in the contour regions.

Machine log file-based dose verification using novel iterative CBCT reconstruction algorithm in commercial software during volumetric modulated arc therapy for prostate cancer patients.

PURPOSE: To evaluate the utility of the use of iterative cone-beam computed tomography (CBCT) for machine log file-based dose verification during volumetric modulated arc therapy (VMAT) for prostate cancer patients. METHODS: All CBCT acquisition data were used to reconstruct images with the Feldkamp-Davis-Kress algorithm (FDK-CBCT) and the novel iterative algorithm (iCBCT). The Hounsfield unit (HU)-electron density curves for CBCT images were created using the Advanced Electron Density Phantom. The I'mRT and anthropomorphic phantoms were irradiated with VMAT after CBCT registration. Subsequently, fourteen prostate cancer patients received VMAT after CBCT registration. Machine log files and both CBCT images were exported to the PerFRACTION software, and a 3D patient dose was reconstructed. Mean dose for planning target volume (PTV), the bladder, and rectum and the 3D gamma analysis were evaluated. RESULTS: For the phantom studies, the variation of HU values was observed at the central position surrounding the bones in FDK-CBCT. There were almost no changes in the difference of doses at the isocenter between measurement and reconstructed dose for planning CT (pCT), FDK-CBCT, and iCBCT. Mean dose differences of PTV, rectum, and bladder between iCBCT and pCT were approximately 2% lower than those between FDK-CBCT and pCT. For the clinical study, average gamma analysis for 2%/2 mm was 98.22% ± 1.07 and 98.81% ± 1.25% in FDK-CBCT and iCBCT, respectively. CONCLUSIONS: A similar machine log file-based dose verification accuracy is obtained for FDK-CBCT and iCBCT during VMAT for prostate cancer patients.

Focal surface occlusion.

This paper proposes focal surface occlusion to provide focal cues of occlusion masks for multiple virtual objects at continuous depths in an occlusion-capable optical see-through head-mounted display. A phase-only spatial light modulator (PSLM) that acts as a dynamic free-form lens is used to conform the focal surface of an occlusion mask to the geometry of the virtual scene. To reproduce multiple and continuous focal blurs while reducing the distortion of the see-through view, an optical design based on afocal optics and edge-based optimization to exploit a property of the occlusion mask is established. The prototype with the PSLM and transmissive liquid crystal display can reproduce the focus blur of occluded objects at multiple and continuous depths with a field of view of 14.6°.

Patient Preferences for Attributes of Chemotherapy for Lung Cancer: Discrete Choice Experiment Study in Japan.

Our study objective was to determine lung cancer chemotherapy attributes that are important to patients in Japan. A discrete choice experiment survey in an anonymous web-based questionnaire format with a reward was completed by 200 lung cancer patients in Japan from November 25, 2019, to November 27, 2019. The relative importance of patient preferences for each attribute was estimated using a conditional logit model. A hierarchical Bayesian logit model was also used to estimate the impact of each demographic characteristic on the relative importance of each attribute. Of the 200 respondents, 191 with consistent responses were included in the analysis. In their preference, overall survival was the most important, followed by diarrhea, nausea, rash, bone marrow suppression (BMS), progression-free survival, fatigue, interstitial lung disease, frequency of administration, and duration of administration. The preferences were influenced by demographic characteristics (e.g., gender and age) and disease background (e.g., cancer type and stage). Interestingly, the experience of cancer drug therapies and adverse events had a substantial impact on the hypothetical drug preferences. For the Japanese lung cancer patients, improved survival was the most important attribute that influenced their preference for chemotherapy, followed by adverse events, including diarrhea, nausea, rash, and BMS. The preferences varied depending on the patient's demographic and experience. As drug attributes can affect patient preferences, pharmaceutical companies should be aware of the patient preferences and develop drugs that respond to segmented market needs.

Evaluation of two-dimensional electronic portal imaging device using integrated images during volumetric modulated arc therapy for prostate cancer.

BACKGROUND: The aim of the study was to evaluate analysis criteria for the identification of the presence of rectal gas during volumetric modulated arc therapy (VMAT) for prostate cancer patients by using electronic portal imaging device (EPID)-based in vivo dosimetry (IVD). MATERIALS AND METHODS: All measurements were performed by determining the cumulative EPID images in an integrated acquisition mode and analyzed using PerFRACTION commercial software. Systematic setup errors were simulated by moving the anthropomorphic phantom in each translational and rotational direction. The inhomogeneity regions were also simulated by the I'mRT phantom attached to the Quasar phantom. The presence of small and large air cavities (12 and 48 cm3) was controlled by moving the Quasar phantom in several timings during VMAT. Sixteen prostate cancer patients received EPID-based IVD during VMAT. RESULTS: In the phantom study, no systematic setup error was detected in the range that can happen in clinical (< 5-mm and < 3 degree). The pass rate of 2% dose difference (DD2%) in small and large air cavities was 98.74% and 79.05%, respectively, in the appearance of the air cavity after irradiation three quarter times. In the clinical study, some fractions caused a sharp decline in the DD2% pass rate. The proportion for DD2% < 90% was 13.4% of all fractions. Rectal gas was confirmed in 11.0% of fractions by acquiring kilo-voltage X-ray images after the treatment. CONCLUSIONS: Our results suggest that analysis criteria of 2% dose difference in EPID-based IVD was a suitable method for identification of rectal gas during VMAT for prostate cancer patients.

Exploratory Analysis of the Factors Associated With Success Rates of Confirmatory Randomized Controlled Trials in Cancer Drug Development.

This study examined the outcomes of recent confirmatory randomized controlled trials (RCTs) in phase III that were initiated between 2005 and 2017 for oncologic drugs in the United States and identified several factors that were associated with the success of RCTs. Our regression analysis showed that studies with progression-free survival or response rate as primary end point were more likely to succeed than studies with overall survival (odds ratio (OR) = 2.94 and 6.23, respectively). The status of development was also linked with success rates. Studies for non-lead indication tended to have lower success rates than studies for lead indication (OR = 0.68). Studies for first-line therapy were observed to have low success rates compared with studies for post second-line therapies (OR = 0.37). Studies for which strong prior evidence was not listed in their publication tended to be more successful than studies that followed rigorous RCTs or single arm studies for the indication. These results suggest that historical success rates may reflect not only the important features of trials, which can be observed directly from study design and results, but also the background status of trials in clinical development pathways.

Detectability of fiducials' positions for real-time target tracking system equipping with a standard linac for multiple fiducial markers.

PURPOSE: To investigate the detectability of fiducial markers' positions for real-time target tracking system equipping with a standard linac. The hypothesis is that the detectability depends on the type of fiducial marker and the gantry angle of acquired triggered images. METHODS: Three types of ball fiducials and four slim fiducials with lengths of 3 and 5 mm were prepared for this study. Triggered images with three similar fiducials were acquired at every 10° during the conformal arc irradiation to detect the target position. Although only one type of arrangement was prepared for the ball fiducials, a three-type arrangement was prepared for the slim fiducials, such as parallel, orthogonal, and oblique with 45° to the gantry-couch direction. To measure the detectability of the real-time target tracking system for each fiducial and arrangement, detected marker positions were compared with expected marker positions at every angle of acquired triggered images. RESULTS: For the ball-type fiducial, the maximum difference between the detected marker positions and expected marker positions was 0.3 mm in all directions. For the slim fiducial arranged parallel and oblique with 45°, the maximum difference was 0.4 mm in all directions. When each slim fiducial was arranged orthogonal to the gantry-couch direction, the maximum difference was 1.5 mm for the length of 3 mm, and 3.2 mm for the length of 5 mm. CONCLUSIONS: The detectability of fiducial markers' positions for the real-time target tracking system equipping with a standard linac depends on the form and insertion angles of the fiducials.

Dosimetric impact of baseline drift in volumetric modulated arc therapy with breath holding.

BACKGROUND: We investigated the change of dose distributions in volumetric modulated arc therapy (VMAT) under baseline drift (BD) during breath holding. MATERIALS AND METHODS: Ten VMAT plans recalculated to a static field at a gantry angle of 0° were prepared for measurement with a 2D array device and five original VMAT plans were prepared for measurement with gafchromic films. These measurement approaches were driven by a waveform reproducing breath holding with BD. We considered breath holding times of 15 and 10 s, and BD at four speeds; specifically, BD0 (0 mm/s), BD0.2 (0.2 mm/s), BD0.3 (0.3 mm/s), and BD0.4 (0.4 mm/s). The BD was periodically reproduced from the isocenter along the craniocaudal direction and the shift during breath holding (ShiftBH) ranged 0-6 mm.The dose distribution of BD0.2, BD0.3 and BD0.4 were compared to that of BD0 using gamma analysis with the criterion of 2%/2 mm. RESULTS: The mean pass rates of each ShiftBH were 99.8% and 98.9% at 0 mm, 96.8% and 99.4% at 2 mm, 94.9% and 98.6% at 3 mm, 91.5% and 98.4% at 4 mm, 70.8% and 94.1% at 4.5 mm, and 55.0% and 83.6% at 6 mm for the array and film measurements, respectively. CONCLUSION: We found significant differences in ShiftBH above 4 mm (ρ < 0.05). Hence, it is recommended that breath holding time should be shortened for patients to preserve the reproducibility of dose distributions.

Quantitative Preferences for Lung Cancer Treatment from the Patients' Perspective: A Systematic Review.

BACKGROUND: Regulatory agencies as well as private organizations pursue programs that advocate patient centricity and emphasize the importance of dialog with patients. Various methods are applied to elicit the preferences of patients regarding the aspects of treatment they lend more importance to. Decisions on treatment choices are critical to patients with lung cancer because of their poor prognosis and the serious trade-off between safety and efficacy in traditional cytotoxic chemotherapy. METHODS: We conducted a systematic literature review of quantitative patient preference studies of patients with lung cancer. Our exhaustive search of MEDLINE, CINAHL, EMBASE, PLOS, and SpringerLink identified 15 relevant studies published from January 2000 to April 2020 that enabled us to assess the relative importance of treatment attributes according to lung cancer patients' perspective. RESULTS: The literature review revealed that patients with lung cancer tend to place a higher weight on efficacy and quality of life (QoL) attributes than on other attributes. Overall survival was found to be the most important among the efficacy attributes. The consequences of adverse events seemed less important than the possible efficacy from therapies. The clinical utility of treatment, such as the route of administration, was generally not considered important. It remains inconclusive whether sociodemographic factors and/or medical history affect the relative importance of a patient's preference. CONCLUSION: Our systematic review clarified that patients generally prefer a better efficacy profile to a better safety profile, which underscores the importance of improved benefits in anti-lung cancer drug development.

Amino-acid selective isotope labeling enables simultaneous overlapping signal decomposition and information extraction from NMR spectra.

Signal overlapping is a major bottleneck for protein NMR analysis. We propose a new method, stable-isotope-assisted parameter extraction (SiPex), to resolve overlapping signals by a combination of amino-acid selective isotope labeling (AASIL) and tensor decomposition. The basic idea of Sipex is that overlapping signals can be decomposed with the help of intensity patterns derived from quantitative fractional AASIL, which also provides amino-acid information. In SiPex, spectra for protein characterization, such as 15N relaxation measurements, are assembled with those for amino-acid information to form a four-order tensor, where the intensity patterns from AASIL contribute to high decomposition performance even if the signals share similar chemical shift values or characterization profiles, such as relaxation curves. The loading vectors of each decomposed component, corresponding to an amide group, represent both the amino-acid and relaxation information. This information link provides an alternative protein analysis method that does not require "assignments" in a general sense; i.e., chemical shift determinations, since the amino-acid information for some of the residues allows unambiguous assignment according to the dual selective labeling. SiPex can also decompose signals in time-domain raw data without Fourier transform, even in non-uniformly sampled data without spectral reconstruction. These features of SiPex should expand biological NMR applications by overcoming their overlapping and assignment problems.