Trajectory for the Regulatory Approval of a Combination of Pertuzumab Plus Trastuzumab for Pre-treated HER2-positive Metastatic Colorectal Cancer Using Real-world Data.

Utilizing real-world data (RWD) for effective clinical implementation is becoming more and more appealing as the cost of drug development rises, especially for patients with rare diseases and rare molecular subtypes for whom conducting randomized controlled trials is challenging. If a regulatory approval methodology based on RWD as an external control group can be established, drug development for rarer fractions can be accelerated by lowering costs and time, as well as reducing physical and emotional burdens on both patients and healthcare professionals. Since 2017, we have been prospectively collecting the clinical data of standard therapies in patients with rare molecular fractions under the SCRUM-Japan Registry platform, which is a qualified registry utilized as external control data for regulatory submission. Based on the results of the phase II TRIUMPH study (UMIN000027887) and the extracted data from the SCRUM-Japan Registry, the pharmaceutical company submitted an application for pertuzumab and trastuzumab in patients with HER2-positive metastatic colorectal cancer in April 2021. Pertuzumab and trastuzumab were approved as expanded indications on March 28, 2022, as 6 cases out of 14 extracted from the SCRUM-Japan Registry were classified and utilized as "evaluation material" under the review process of the Pharmaceuticals and Medical Devices Agency (PMDA). Through the TRIUMPH study and the SCRUM-Japan Registry, we have paved the way for regulatory approval of RWD in Japan. In future, we must define the steps for constructing regulatory-grade registries and the method/process for utilizing RWD by accumulating case experiences.

Stabilometric analysis of neck orientations during mealtime by a wearable device for dysphagia patients.

Postural changes are commonly used treatment to prevent the elderly from the risk of aspiration pneumonia. However, the evidence-based studies regarding effectiveness of this treatment remains unclear since no systematic method exists to measure constantly changing postures without disturbing usual eating behaviors. In this paper, using IMU system attached to a smart-phone based wearable technology, we analyzed data of the neck orientation angles obtained from the dysphagia patients and healthy adults during their mealtime and attempted to see if the obtained data can show differences regarding the dynamics of the angles.The result shows the possibilities to use the device to monitor neck orientations while the dysphagia patients eating their meals in daily lives.

Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial.

The applicability of circulating tumor DNA (ctDNA) genotyping to inform enrollment of patients with cancer in clinical trials has not been established. We conducted a phase 2 trial to evaluate the efficacy of pertuzumab plus trastuzumab for metastatic colorectal cancer (mCRC), with human epidermal growth factor receptor 2 (HER2) amplification prospectively confirmed by tumor tissue or ctDNA analysis ( UMIN000027887 ). HER2 amplification was confirmed in tissue and/or ctDNA in 30 patients with mCRC. The study met the primary endpoint with a confirmed objective response rate of 30% in 27 tissue-positive patients and 28% in 25 ctDNA-positive patients, as compared to an objective response rate of 0% in a matched real-world reference population treated with standard-of-care salvage therapy. Post hoc exploratory analyses revealed that baseline ctDNA genotyping of HER2 copy number and concurrent oncogenic alterations adjusted for tumor fraction stratified patients according to efficacy with similar accuracy to tissue genotyping. Decreased ctDNA fraction 3 weeks after treatment initiation associated with therapeutic response. Pertuzumab plus trastuzumab showed similar efficacy in patients with mCRC with HER2 amplification in tissue or ctDNA, showing that ctDNA genotyping can identify patients who benefit from dual-HER2 blockade as well as monitor treatment response. These findings warrant further use of ctDNA genotyping in clinical trials for HER2-amplified mCRC, which might especially benefit patients in first-line treatment.

Deep Learning-Based Swallowing Monitor for Realtime Detection of Swallow Duration.

Aspiration pneumonia is a life-threatening disease for the elderly. To prevent its risk, regular swallowing assessment is necessary; however, current screening tools for swallow assessment are not widely available and medical experts are insufficient. As a portable assessment tool, we have been developing a smartphone-based realtime monitoring device (GOKURI) which can evaluate swallowing ability based on swallow sounds. For better detection accuracy of the system, we integrated a deep learning model which was developed based on the swallowing anatomy. In this paper, we provide a detailed analysis to see how the swallow sounds detected by the deep learning-based monitor correspond to the actual swallow activities. Also, as an example of practical application of the system, we analyzed the changes of the swallow abilities over time by recording swallow sounds twice for the same participants at a nursing home. To minimize the risk of aspiration pneumonia, caregivers need to understand the disability levels of the patient's swallows so that safe feeding assistance can be provided. The result of this paper implies the possibility of using GOKURI as a daily swallowing monitor with minimum interventions.

Automatic Measurements of Neck Angles toward the Bedside Treatment for the Dysphagia Patients at the Community-Based Health Care.

For the elderly with dysphagiais, postural changes are a popular method to reduce the risk of aspiration pneumonia. Among them, the reclining position, a postural change set by the bed angles, has been widely used in practical settings. However, setting the reclining positions is difficult since all beds do not have a system to measure angles especially at the nursing facilities and patient's homes. Moreover, a anatomically critical angle is the one created by the larynx and the pharynx against the horizontal line, but we cannot check them without a medical equipment, such as X-ray or Videofluoroscopy (VF).We have been developing a smart-phone based wearable technology which can measure the neck angles automatically in realtime. In this research, we conducted a study to compare the IMU measured angles with the larynx and pharynx angles from the VF images, and analyzed if IMU can measure these angles properly. Additionally, we compared three angles with: 1) bed angles, 2) neck angles measured by IMU, and 3) bed angles set by a dysphagia treatment specialist, to show how different neck angles were set in the bedside practice. We will also discuss the IMU's future applications to keep the elderly eat safely in the community.

Robot-assisted voluntary initiation reduces control-related difficulties of initiating joint movement: A phenomenal questionnaire study on shaping and compensation of forward gait.

Humans employ various control strategies to initiate and maintain bodily movement. In case that the normal gait function is impaired, exoskeleton robots provide motor assistance during therapy. While the robotic control system builds on kinematic gait functions, the patient's voluntary efforts to initiate motion also contribute to the effectiveness of the therapy process. However, it is currently not well understood how voluntary initiation as a subjective capacity affects the physiological level of motor control. In order to understand the functional nexus between voluntary initiation and motor control, we interviewed patients undergoing robotic gait rehabilitation with the HAL exoskeleton robot about their experience and command of voluntarily initiating forward gait while using the HAL system. Their reports provide phenomenal evidence for voluntary initiation as a distinct cognitive act that comes as phenomenal performance. Furthermore, phenomenal evidence about the functional relation of intention and initiation correlates with FIM-M gait scores. Based on the assumption that HAL reduces control-related difficulties of voluntarily initiating joint movement, we identified two cognitive control strategies, shaping and compensation of gait, that imply a heterarchic organization of the human system of action control.

Smartphone-based swallowing monitoring and feedback device for mealtime assistance in nursing homes.

As many of the elderly are prone to dysphagia, preventing aspirations during mealtime assistance is a huge concern, especially for institutions operated with limited staff. Two of the main course of actions that are taken usually to prevent aspiration are the altering of bolus consistency and altering of the swallowing posture. To assist prevention of pneumonia, we have been developing a smartphone-based wearable technology that can evaluate swallowing ability in real-time. In this paper we will introduce modified version of Swallwoscope adding a posture detection system and a remote swallowing activity visualisation system to our previous work. We will evaluate the accuracy of the proposed posture detection system and also evaluate the feasibility of our device to determine bolus consistency. We plan to integrate these components in a network-based framework to share the relevant medical information within the community to enhance safety and pleasure of eating.