Angiogenic inhibitor pre-administration improves the therapeutic effects of immunotherapy.

In lung cancer, immune checkpoint inhibitors (ICIs) are often inadequate for tumor growth inhibition. Angiogenic inhibitors (AIs) are required to normalize tumor vasculature for improved immune cell infiltration. However, in clinical practice, ICIs and cytotoxic antineoplastic agents are simultaneously administered with an AI when tumor vessels are abnormal. Therefore, we examined the effects of pre-administering an AI for lung cancer immunotherapy in a mouse lung cancer model. Using DC101, an anti-vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody, a murine subcutaneous Lewis lung cancer (LLC) model was used to determine the timing of vascular normalization. Microvessel density (MVD), pericyte coverage, tissue hypoxia, and CD8-positive cell infiltration were analyzed. The effects of an ICI and paclitaxel after DC101 pre-administration were investigated. On Day 3, increased pericyte coverage and alleviated tumor hypoxia represented the highest vascular normalization. CD8+ T-cell infiltration was also highest on Day 3. When combined with an ICI, DC101 pre-administration significantly reduced PD-L1 expression. When combined with an ICI and paclitaxel, only DC101 pre-administration significantly inhibited tumor growth, but simultaneous administration did not. AI pre-administration, and not simultaneous administration, may increase the therapeutic effects of ICIs due to improved immune cell infiltration.

A phase I/II study of osimertinib in EGFR exon 20 insertion mutation-positive non-small cell lung cancer.

OBJECTIVES: Several preclinical data proposed a potential efficacy of osimertinib, a third-generation EGFR tyrosine kinase inhibitor, for EGFR exon 20 insertion (EGFR ex20ins)-positive non-small cell lung cancer (NSCLC). However, reported case series and a retrospective study proposed controversial efficacy. The efficacy of osimertinib in EGFR ex20ins-positive NSCLC have not been well evaluated in prospective clinical trials. In this study, we performed a prospective, single-arm, multi-center, open-label, non-randomized phase I/II study to evaluate efficacy of osimertinib for EGFR ex20ins-positive NSCLC. MATERIALS AND METHODS: From August 2018 to January 2020, 14 NSCLC patients with EGFR ex20ins were enrolled, of whom 2 were excluded because they did not meet the inclusion criteria. Efficacy and safety of 80 mg osimertinib were evaluated. In addition, we performed a translational exploratory study to clarify the association of mutation type-specific drug sensitivity, osimertinib pharmacokinetic data, and clinical efficacy. RESULTS: Of the evaluated patients, none experienced objective response, 7 experienced stable disease (58.3%), and 5 experienced disease progression (41.7%). The median progression free survival (PFS) was 3.8 months, and the median overall survival was 15.8 months. Interestingly, the exploratory study demonstrated statistically significant positive correlation between plasma osimertinib concentration/in vitro IC50 ratio and PFS (R = 0.9912, P = 0.0001), highlighting the mutation type-specific concentration-dependent efficacy of osimertinib for EGFR ex20ins-positive NSCLC. CONCLUSIONS: Regular dose, 80 mg/day, of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins. The translational study proposed the potential efficacy of higher dose osimertinib in a subgroup of EGFR ex20ins-positive NSCLC.

Nivolumab-induced immune thrombocytopenia in a patient with malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive tumor. Nivolumab showed durable antitumor effect in patients with recurrent MPM and was approved for those patients in Japan in 2018. Immune related adverse event (irAE) is occurred in various organs and is suggestive to be related to better outcome of nivolumab. Frequency of hematological irAE is low and there are few reports about hematological irAE and association between irAE and outcome of nivolumab in patients with MPM. We present a case of recurrent MPM who responded to nivolumab treatment and experienced nivolumab-induced immune thrombocytopenia (ITP). Although high dose dexamethasone was administered and platelet count increased transiently, re-administration of dexamethasone was required to maintain normal count of platelet. The careful and intensive management of ITP treatment is necessary in cases who show no response or relapse to initial glucocorticoids treatment. This is the first report about nivolumab-induced ITP and association with response to nivolumab in MPM.

Large cell neuroendocrine carcinoma of the lung that responded to nivolumab: A case report.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare type of lung cancer, accounting for 3% of all lung cancers. The prognosis is poor and the standard therapy has not been well established. Herein, we report a case of advanced LCNEC of the lung that responded to nivolumab. The patient was a 62-year old man with stage IVB LCNEC of the lung. The disease progressed following the administration of second-line chemotherapy, and he was treated with nivolumab 3 mg/kg as the third-line treatment. Although treatment was ceased after two cycles due to interstitial pneumonia, the disease remained stable for approximately six months under observation. There was no other adverse event related to nivolumab. Following patient mortality from tumor progression, PD-L1 expression was observed to be negative (tumor proportion score <1%) by a re-examination of the primary biopsy specimen. The case herein suggests that nivolumab may be a possible treatment option for LCNEC.

Lung metastasis from gastric cancer presenting as diffuse ground-glass opacities.

Most metastatic lung tumors display well-defined, round, multiple nodular shadows, whereas the presence of diffuse ground-glass opacities on chest computed tomography generally suggests non-malignant conditions. Here, we report an unusual case of pulmonary metastasis from gastric cancer in which diffuse ground-glass opacities were observed in all lung segments. A 59-year-old man with a 3-month history of worsening chest pain and shortness of breath was referred to the pulmonary clinic. Chest computed tomography revealed low attenuation areas, suggesting emphysema, along with diffuse ground-glass opacities and interlobular septal thickening in both lungs. A transbronchial lung biopsy specimen revealed signet-ring cell carcinoma infiltrating the alveolar septa. Immunohistochemical staining of the cancer cells was positive for CDX-2, cytokeratin 7, and cytokeratin 20, and negative for surfactant apoprotein-A, TTF-1, and Napsin A. Gastrointestinal endoscopy revealed an ulcerative tumor in the stomach, and a biopsy from the tumor demonstrated malignant cells with similar morphology and immunophenotypes as those in the lungs. The final diagnosis was diffuse lung metastasis from gastric cancer. Our case shows that although multiple, well-defined nodules are typically considered to be the classic presentation of pulmonary metastasis, clinicians should also be aware of the possibility of pulmonary metastasis presenting as diffuse ground-glass opacities.

Postcontraction hyperemia after electrical stimulation: potential utility in rehabilitation of patients with upper extremity paralysis.

The purpose of this study was to compare postcontraction hyperemia after electrical stimulation between patients with upper extremity paralysis caused by upper motor neuron diseases and healthy controls. Thirteen healthy controls and eleven patients with upper extremity paralysis were enrolled. The blood flow in the basilic vein was measured by ultrasound before the electrical stimulation of the biceps brachii muscle and 30 s after the stimulation. The stimulation was performed at 10 mA and at a frequency of 70 Hz for 20 s. The mean blood flow in the healthy control group and in upper extremity paralysis group before the electrical stimulation was 60 ± 20 mL/min (mean ± SD) and 48 ± 25 mL/min, respectively. After the stimulation, blood flow in both groups increased to 117 ± 23 mL/min and 81 ± 41 mL/min, respectively. We show that it is possible to measure postcontraction hyperemia using an ultrasound system. In addition, blood flow in both groups increased after the electrical stimulation because of postcontraction hyperemia. These findings suggest that evaluating post contraction hyperemia in patients with upper extremity paralysis can assess rehabilitation effects.

The impact of high-frequency magnetic stimulation of peripheral nerves: muscle hardness, venous blood flow, and motor function of upper extremity in healthy subjects.

The purpose of this study was to investigate the impact of high-frequency peripheral nerve magnetic stimulation on the upper limb function. Twenty-five healthy adults (16 men and 9 women) participated in this study. The radial nerve of the non-dominant hand was stimulated by high-frequency magnetic stimulation device. A total of 600 impulses were applied at a frequency of 20 Hz and intensity of 1.2 resting motor threshold (rMT). At three time points (before, immediately after, and 15 min after stimulation), muscle hardness of the extensor digitorum muscle on the stimulated side was measured using a mechanical tissue hardness meter and a shear wave imaging device, cephalic venous blood flow on the stimulated side was measured using an ultrasound system, and the Box and Block test (BBT) was performed. Mechanical tissue hardness results did not show any significant differences between before, immediately after, and 15 min after stimulation. Measurements via shear wave imaging showed that muscle hardness significantly decreased both immediately and 15 min after stimulation compared to before stimulation (P < 0.05). Peripheral venous blood flow and BBT score significantly increased both immediately and 15 min after stimulation compared to before stimulation (P < 0.01). High-frequency peripheral nerve magnetic stimulation can achieve effects similar to electrical stimulation in a less invasive manner, and may therefore become an important element in next-generation rehabilitation.

Development of FES-rowing machine.

As per present social needs, assisting machines are very much needed for persons of advanced age. We analyzed and developed a fitness apparatus suitable for meeting the requirement of elderly people. The proposed apparatus consists of a rowing machine and Functional Electrical Stimulation (FES), that can be used to exercise every muscle of a person of advanced age. The rowing mechanism was actually developed to train rowers and can train the legs and upper body parts most effectively. Move over FES can assist the exercise of the legs by using surface electrical stimulation. An experiment was conducted and the results prove that the developed apparatus can train the muscles of the person of advanced age effectively and can compensate exercise shortage.

Clinical results of rehabilitation for accessory nerve palsy after radical neck dissection.

CONCLUSIONS: Occupational therapy significantly improves shoulder range of motion in patients with accessory nerve palsy after radical neck dissection, but it has limited effects on the associated pain. OBJECTIVE: To evaluate the outcome of occupational therapy rehabilitation for patients with accessory nerve palsy. PATIENTS AND METHODS: The occupational therapy group involved 35 shoulders of 29 patients with accessory nerve palsy after radical neck dissection; the control group included 10 shoulders of 9 patients who did not receive occupational therapy. All patients had a malignant tumor in the head or neck that necessitated radical neck dissection. We collected data pertaining to resting pain, motion pain, and the active and passive range of motion during shoulder flexion and abduction. RESULTS: Occupational therapy did not adequately relieve resting or motion pain, but all patients achieved independence in activities of daily living and housekeeping activities. Although occupational therapy significantly improved shoulder elevation for all movements, shoulder elevation was significantly better for flexion than for active and passive abduction.

Hybrid functional electrical stimulation with medial linkage knee-ankle-foot orthoses in complete paraplegics.

We have previously restored ambulation in paraplegics by performing hybrid functional electrical stimulation (FES) with medial linkage knee-ankle-foot orthosis (MLKAFO). The most common MLKAFO (hinge-type MLKAFO) has the hypothetical axis that is lower than the physiological hip joint position, resulting in slow velocity and short step length. A new MLKAFO (sliding-type MLKAFO), which uses sliding medial linkages, has been developed to correct the axial discrepancy of the hinge-type MLKAFO that causes limited hip joint excursion. There have been reports of instability associated with sliding medial linkages, but the mechanism of this instability is unclear. The purpose of the present study was to evaluate the effects of FES with MLKAFOs on ambulation in paraplegics. Two complete paraplegic patients (levels T8 and T12, respectively) participated in this study. Kinematics data during ambulation were obtained using a motion analysis system. We measured gait velocity and hip progression during the standing phase. The sliding-type MLKAFO produced faster gait velocity than did the hinge-type MLKAFO, but it caused pelvis instability without FES. Pelvis instability was controlled by hybrid FES using the sliding-type MLKAFO. With hybrid FES, the sliding-type MLKAFO provides better gait performance than the hinge-type MLKAFO, but the hinge-type MLKAFO provides greater pelvis stability during walking. Moreover, FES provides sufficient propulsion to allow the complete paraplegics to walk.

Grasping power by means of functional electrical stimulation in a case of C6 complete tetraplegia.

Grasping power (GP) by means of functional electrical stimulation (FES) was measured in a case of C6 complete tetraplegia. This was compared with GP by means of the dynamic tenodesis effect, the flexor hinge splint and the GP of normal female. Palmar grasp strength by means of FES was approximately 16% of the control group and 2.4 times greater than the flexor hinge splint. Lateral grasp strength by FES was approximately 13% of the control group. Our results suggest that FES is more effective than the flexor hinge splint in increasing the GP of tetraplegic patients, and that a stronger and stable GP, which is not affected by wrist position, makes FES practical for improving activities of daily living (ADL).

Occupational therapy for accessory nerve palsy after radical neck dissection.

The subjects in this study were ten patients with accessory nerve palsy after radical neck dissection. All the primary diseases that accounted for radical neck dissection were malignant tumors located at the head or neck. Every patient received occupational therapy and underwent evaluations before and after the therapy. The data we collected included the existence of resting pain and motion pain, and the active and passive range of motion during shoulder flexion and abduction. The occupational therapy programs were not adequately effective for resting and motion pain, however, every patient gained independence for activities of daily living and housekeeping activities. The occupational therapy significantly improved the patient's shoulder elevation in all movements; although, the active abduction was always significantly poor compared with flexion. In the meantime, there were no significant differences between passive shoulder flexion and abduction at all times. We can therefore understand that the accessory nerve palsy especially affects active shoulder abduction induced by the trapezius paralysis. Occupational therapy is an effective treatment for the improvement of shoulder function, however, the occupational therapy has limited effectiveness for coping with the pain.