Clinical factors associated with shorter durable response, and patterns of acquired resistance to first-line pembrolizumab monotherapy in PD-L1-positive non-small-cell lung cancer patients: a retrospective multicenter study.

BACKGROUND: Despite the wide-spread use of immune checkpoint inhibitors (ICIs) in cancer chemotherapy, reports on patients developing acquired resistance (AR) to ICI therapy are scarce. Therefore, we first investigated the characteristics associated with shorter durable responses of ICI treatment and revealed the clinical patterns of AR and prognosis of the patients involved. METHODS: We conducted a retrospective multi-center cohort study that included NSCLC patients with PD-L1 tumor proportion scores of ≥50% who received first-line pembrolizumab and showed response to the therapy. Among patients showing response, progression-free survival (PFS) was investigated based on different clinically relevant factors. AR was defined as disease progression after partial or complete response based on Response Evaluation Criteria in Solid Tumors. Among patients with AR, patterns of AR and post-progression survival (PPS) were investigated. Oligoprogression was defined as disease progression in up to 5 individual progressive lesions. RESULTS: Among 174 patients who received first-line pembrolizumab, 88 showed response and were included in the study. Among these patients, 46 (52%) developed AR. Patients with old age, poor performance status (PS), at least 3 metastatic organs, or bone metastasis showed significantly shorter PFS. Among 46 patients with AR, 32 (70%) developed AR as oligoprogression and showed significantly longer PPS than those with non-oligoprogressive AR. CONCLUSIONS: Patients with old age, poor PS, at least 3 metastatic organs, or bone metastasis showed shorter durable responses to pembrolizumab monotherapy. Oligoprogressive AR was relatively common and associated with better prognosis. Further research is required to develop optimal approaches for the treatment of these patients.

[Treatment with ramelteon for sleep disturbance in severely disabled children and young adults].

OBJECTIVE: The aim of this study was to determine the efficacy and safety of ramelteon for severely disabled children and young adults who had already been treated for sleep disturbance with melatonin at a dose of 3 mg. METHODS: Eleven patients, who were aged between 3-25 years and included 4 patients with cerebral palsy, -took 3-8 mg of ramelteon at bedtime, after a one-week of washout period. Sleep states were evaluated using sleep diaries recorded by caregivers or using actigraphs. RESULTS: Ramelteon was effective in 8 out of the 11 patients. Ramelteon was tolerated well except for mild daytime sleepiness in three patients. CONCLUSIONS: This preliminary study showed the efficacy and safety of ramelteon for sleep disturbance in severely disabled children and young adults. Further trials are necessary to determine optimal dosage and safety of ramelteon in children.

Questionnaire survey on sleep habits of 3-year-old children in Asahikawa City: Comparison between 2005 and 2020.

BACKGROUND: Good sleep is essential for children's healthy growth. In 2005, we conducted a questionnaire survey on children's sleep habits and their background, targeting parents who attended health checkups for their 3-year-old children in Asahikawa City, Hokkaido. In 2020, we performed a secondary survey, including additional questions regarding media usage. We analyzed changes in children's sleep environment by comparing the results of both surveys. METHODS: Children from 500 families (n = 420; 219 males, 201 females; mean age, 3.6 years) who underwent 3.5-year-old health checkups (per the changed schedule in 2015) in Asahikawa City from July 2020 to November 2020 and their parents who had completely answered the questionnaire were included. RESULTS: The proportion of children who used childcare support system such as nursery schools or kindergarten increased from 30% in the previous survey to 95% in the present survey. The mean nocturnal sleep duration of children was 9.33 h in the present survey, 0.77 h shorter than that in the previous survey; similar to the previous survey results, it was significantly short (8.71 h) in children who went to bed after 10 PM. Moreover, it was significantly short in children who watched television for more than two hours or used media within two hours before going to bed or if parents used smartphones or watched motion pictures for >30 min/day. The rate of consulting pediatricians regarding sleep problems decreased from 3% to 2.4%. CONCLUSION: Parents' lifestyles greatly influenced children's sleep habits in 2020. Pediatricians should actively participate in managing children's sleep problems.

GRIA3 p.Met661Thr variant in a female with developmental epileptic encephalopathy.

The X-linked human glutamate receptor subunit 3 (GRIA3) gene (MIM *305915, Xq25) encodes ionotropic α amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-type glutamate receptor subunit 3, which mediates postsynaptic neurotransmission. Variants in this gene can cause a variety of neurological disorders, primarily reported in male patients. Here, we report a female patient with developmental and epileptic encephalopathy who carries the novel de novo GRIA3 variant NM_007325.5: c.1982T > C: p.Met661Thr.

Wisconsin syndrome with brain volume laterality: a case report and review of the literature.

BACKGROUND: Wisconsin syndrome is a congenital anomaly caused by a 3q interstitial deletion. It is associated with characteristic facies and developmental delays. Only 33 cases with a deletion estimated to be in the associated region 3q25 have been reported. CASE REPORT: We present the case of a 5-year-old Japanese girl with a 3q24q25.2 deletion. Her facial features corresponded to the Wisconsin syndrome phenotype, and she exhibited brain volume laterality, which has not been reported previously. CONCLUSION: The clinical features of our case may contribute to narrowing down the list of candidate genes of Wisconsin syndrome.

Comprehensive assessment of PD-L1 expression, tumor mutational burden and oncogenic driver alterations in non-small cell lung cancer patients treated with immune checkpoint inhibitors.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) have proven to be effective treatment for lung cancer. However, a precise predictive immuno-oncology biomarker is still under development. We investigated the associations among PD-L1 expression, tumor mutational burden (TMB), and oncogenic driver alterations in advanced non-small cell lung cancer (NSCLC) patients treated with ICIs. MATERIALS AND METHODS: This multicenter cohort study included 1017 lung cancer patients. PD-L1 expression using four IHC assays (22C3, 28-8, SP263, SP142), TMB by whole-exome sequencing and oncogenic driver alterations were analyzed comprehensively. Clinical characteristics, treatment and survival data were collected. RESULTS: The results of 22C3 and 28-8 for PD-L1 expression showed acceptable concordance (k = 0.89; 95% confidence interval [CI], 0.87-0.92), and the clinical outcomes of ICIs classified according to PD-L1 expression by both assays were also approximately the same. There was slight concordance (k = 0.16; 95% CI, 0.11-0.22) between 22C3 and SP142, and high PD-L1 expression by SP142 was correspond to very high PD-L1 expressions by other assays. Patients with both high PD-L1 expression and high TMB showed a good response to ICIs with the response rate of 64% and median progression-free survival of 9.0 months despite of small population. Common EGFR or STK11 mutations showed a lower rate of high PD-L1 expression and a worse efficacy of ICIs and KRAS mutations had no negative impact on response to ICIs. CONCLUSION: Comprehensive assessment of PD-L1 expression, TMB, and oncogenic driver alterations would help to better predict the clinical outcomes of ICIs in NSCLC patients.

Severe gastrointestinal symptoms caused by a novel DDX3X variant.

Mutations in DDX3X have recently been identified as a common cause of intellectual disability and congenital anomalies. DDX3X (Xp11.4) encodes the DEAD box RNA helicase that plays an important role in gene regulation, apoptosis, and oncogenesis. Here, we report a case of 6-year-old Japanese girl with a novel variant (NM_001193416.3: c.1574A > G; p.(Tyr525Cys), who exhibited psychomotor retardation, severe constipation, and a recurrent paralytic ileus. This is the second report of severe gastrointestinal symptoms being associated with this disease. This report expands the phenotype caused by DDX3X variants and reveals an important clinical aspect for patients and medical staff.

[Surgical management for intractable aspiration in handicapped children].

Intractable aspiration is a life-threatening medical problem. Sixteen patients with intractable aspiration underwent surgical management. Their underlying diseases were cerebral palsy (n = 6), degenerative diseases (n = 5), acquired hypoxic ischemic encephalopathy (n = 4), and congenital myopathy (n = 1). Laryngotracheal separation was performed in nine patients with median age of 2 years 6 months (range: 7 mo - 13 y 5 mo), and laryngectomy was performed in seven with median age of 7 years 4 month (range: 1 y 6 mo - 17 y 1 mo). Surgical interventions were effective in all patients with respiratory distress. The most common complication was increased drawling in six patients, who recovered within 6 months of clinical follow-up. Other complications were tracheal granulations (n = 4), bleeding (n = 2), narrowing of the tracheal hole (n = 2), tracheomalacia (n = 2), ruptured suture (n = 1), and tracheal abscess (n = 1). Considering the underlying diseases and age, surgical management for intractable aspiration should be performed at appropriate timing.

Genitopatellar syndrome: the first reported case in Japan.

Genitopatellar syndrome (GPS) is mainly characterized by an absence of patellae, congenital flexion contractures of the lower limbs, psychomotor retardation, and anomalies of the external genitalia and kidneys. We report an 18-year-old female with a novel heterozygous truncating mutation in exon 17 of the KAT6B gene [MC_000010.11:c.3603_3606 del, p.Arg1201fs]. This is the first report of typical GPS in a Japanese individual. The details of our findings may contribute to elucidating the mechanism underlying GPS-specific clinical features.

Induction of claudin-4 by nonsteroidal anti-inflammatory drugs and its contribution to their chemopreventive effect.

Nonsteroidal anti-inflammatory drugs (NSAID) have shown chemopreventive effects in both preclinical and clinical studies; however, the precise molecular mechanism governing this response remains unclear. We used DNA microarray techniques to search for genes whose expression is induced by the NSAID indomethacin in human gastric carcinoma (AGS) cells. Among identified genes, we focused on those related to tight junction function (claudin-4, claudin-1, and occludin), particularly claudin-4. Induction of claudin-4 by indomethacin was confirmed at both mRNA and protein levels. NSAIDs, other than indomethacin (diclofenac and celecoxib), also induced claudin-4. All of the tested NSAIDs increased the intracellular Ca2+ concentration. Other drugs that increased the intracellular Ca2+ concentration (thapsigargin and ionomycin) also induced claudin-4. Furthermore, an intracellular Ca2+ chelator [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid] inhibited the indomethacin-dependent induction of claudin-4. These results strongly suggest that induction of claudin-4 by indomethacin is mediated through an increase in the intracellular Ca2+ concentration. Overexpression of claudin-4 in AGS cells did not affect cell growth or the induction of apoptosis by indomethacin. On the other hand, addition of indomethacin or overexpression of claudin-4 inhibited cell migration. Colony formation in soft agar was also inhibited. Suppression of claudin-4 expression by small interfering RNA restored the migration activity of AGS cells in the presence of indomethacin. Based on these results, we consider that the induction of claudin-4 and other tight junction-related genes by NSAIDs may be involved in the chemopreventive effect of NSAIDs through the suppression of anchorage-independent growth and cell migration.

[Evaluation of social functioning ability of disabled children].

Since 1999, we have been trying to establish a reliable method for evaluating social functioning ability (SFA) of physically handicapped children, in cooperation with the Project of Comprehensive Study of Disability, Social Health, and Welfare supported by the Ministry of Health, Labor and Welfare, Japan. In this study, we investigated the reliability and accuracy of the 4th edition of "The Evaluation of SFA". This evaluation consists of 40 items in 15 areas. We examined 45 disabled patients (26 males and 19 females) aged 12-27 years (mean age, 16 years). The reliability was checked by agreement of evaluations of the same patient carried out by two examiners. The results showed good reliability (kappa value of 0.42). According to the results of questionnaires, 97% of the examiners regarded this evaluation to be useful. Although the score of SFA correlated with intelligent quotient/development quotient, the score did not correlate with motor disability level. We hope that this evaluation will be widely used to upgrade SFA of disabled children.

[Effects of tizanidine for refractory sleep disturbance in disabled children with spastic quadriplegia].

Tizanidine is a centrally acting alpha-2 adrenoreceptor agonist widely used in the treatment of spasticity in patients with cerebral or spinal injury, and it is causing drawsiness in some of them. Based on these drug actions, we administered tizanidine to 21 spastic quadriplegic children with severe sleep disturbance not improved by conventional therapies. All these patients were showing abnormalities of both the induction and maintenance of sleep. The dosage of tizanidine was 0.1 to 0.2 mg/kg/day, divided into two or three doses. If daytime drowsiness was severe, tizanidine admistration was restricted to just prior to bedtime. In 13 patients (61.9%), we found improvement in sleep induction and/or maintenance. Moreover, patients' families were satisfied with the treatment. There were no detectable side effects except facial pallor in two patients (9.5%) whose treatment was discontinued. Severe muscle hypertonia causes severe pain, which generates strong sympathetic nerve activity and subsequent sleep disturbance. We consider that tizanidine has direct effects on the induction of sleep, and promotes muscular relaxation bringing about good sleep. We conclude that tizanidine is useful for the treatment of refractory sleep disturbance in spastic quadriplegic patients.

[Combined use of melatonin and low-dose flunitrazepam for treatment of sleep disturbance in a child with spastic quadriplegia: evaluation using polysomnography].

A 14-year-old boy born at 39 gestational weeks with the birth weight of 3,250 g, had severe mental retardation and spastic quadriplegia of unknown etiology from early childhood. At 7 years of age, disturbance of night sleep appeared with several awakenings. Combined treatment with melatonin (MLT; 0.04 mg/kg) and flunitrazepam (FNZ; 0.025 mg/kg) was more effective than monotherapy with FNZ for the sleep disturbance. Difference of the effects of the combined therapy and the monotherapy for the sleep disturbance were assessed by polysomnographies (PSGs), consisted of EEG (C3, C4), bipolar EOG and surface EMG on the mentalis muscle. The PSGs were performed twice at 13 years 6 months old, and at 14 years 1 month old. In both trials, the number of awakening was fewer, total sleep time was longer, percent (%) stage I and II were lower and %REM sleep was larger in combined MLT and FNZ therapy than in FNZ monotherapy. The present study suggests that the combined MLT and FNZ therapy not only reduces awakening during sleep but also normalizes sleep architecture. This therapy is valuable because normalization of sleep is important for the developing brain as it reflects the normal functioning of the aminergic neurons of the midbrain and the brainstem which have important roles for morphological and functional development of the brain in immature brain.