Three-year prognosis after low-dose oral food challenge for children with wheat allergy.

BACKGROUND: Low-dose oral food challenge (LD-OFC) is an approach to avoid complete elimination in high-risk patients with wheat allergy (WA). We examined the 3-year prognosis after LD-OFC among patients who passed and failed LD-OFC. METHODS: Children with immediate-type WA aged ≤6 years with a history of reaction to ≤390 mg of wheat protein underwent their first LD-OFC with 52 mg (baseline LD-OFC). After passing the LD-OFC, children stepped up to 390, 1300, and 5200 mg step-by-step every 3-6 months. After failing LD-OFC, children repeated LD-OFC every 6-12 months. We assessed wheat tolerance defined as consuming 5200 mg without symptoms for 3 years after baseline LD-OFC. RESULTS: The median age of 124 children was 2.4 years, and the wheat- and ω-5-gliadin-specific immunoglobulin E (IgE) levels (kUA/L) were 23.6 and 2.1, respectively. Upon baseline LD-OFC, 57% passed (LD-tolerant), whereas 43% failed (LD-reactive). Within 3 years, 38% of the LD-reactive group passed re-administered LD-OFC, and 70% of all participants avoided complete elimination. The percentage of the participants who became capable of consuming 390 mg (87% vs. 18%), 1300 mg (78% vs. 13%), and acquired tolerance (70% vs. 13%) was significantly higher in the LD-tolerant group than in the LD-reactive group (p < 0.001). Predictors of persistent WA in the LD-tolerant group were older age (adjusted odds ratio, 1.63), ω-5-gliadin-specific IgE level (1.62 per 10-fold increase), and other food allergies (1.94). CONCLUSIONS: LD-tolerant patients frequently acquired wheat tolerance within 3 years. Even if once positive, one-third could pass the re-administered LD-OFC within 3 years.

[JAPANESE TRANSLATION AND LINGUISTIC VALIDATION OF THE RECAP OF ATOPIC ECZEMA (RECAP)].

BACKGROUND: The Recap of atopic eczema (RECAP), a new core outcome of the atopic dermatitis trial, was translated into Japanese and linguistically validated. METHODS: Translation into Japanese was accomplished according to the ISPOR (International Society for Pharmacoeconomics and Outcome Research) guidelines and the basic guidelines for scale translation. The translation process included two forward translations, reconciliation with native English speakers, third-party back translation, cognitive debriefing, review and harmonization by the original authors. Twenty-seven atopic dermatitis and pediatric specialists from 21 centers in Japan participated in the translation process. Cognitive debriefing was conducted through face-to-face interviews using a think-aloud method with the interview guide including questions about comprehensibility, relevance, comprehensiveness, recall period and suggested improvements, based on the COSMIN methodology. RESULTS: No linguistic or cultural problems were encountered in the translation into Japanese. Cognitive debriefings were conducted with 10 adult patients and 10 parents of pediatric patients. Some minor modifications were made following discussion and approval by the research team and the original authors. The Japanese version of RECAP was considered to be understandable, comprehensive and relevant for adult patients and families of pediatric patients. CONCLUSION: The Japanese version of the RECAP, which has been validated as linguistically equivalent to the original version, is now available. Further evaluation of the measurement properties is needed in the future.

Facial redness in Japanese adolescents with atopic dermatitis treated with dupilumab: A case series.

This case series study is the first report of Japanese adolescents who experienced dupilumab facial redness after starting dupilumab treatment for refractory atopic dermatitis. In every case, dupilumab facial redness subsided without discontinuation of dupilumab within 3 months after onset.

An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress.

Activation of the KRAS oncogene is a source of replication stress, but how this stress is generated and how it is tolerated by cancer cells remain poorly understood. Here we show that induction of KRASG12V expression in untransformed cells triggers H3K27me3 and HP1-associated chromatin compaction in an RNA transcription dependent manner, resulting in replication fork slowing and cell death. Furthermore, elevated ATR expression is necessary and sufficient for tolerance of KRASG12V-induced replication stress to expand replication stress-tolerant cells (RSTCs). PrimPol is phosphorylated at Ser255, a potential Chk1 substrate site, under KRASG12V-induced replication stress and promotes repriming to maintain fork progression and cell survival in an ATR/Chk1-dependent manner. However, ssDNA gaps are generated at heterochromatin by PrimPol-dependent repriming, leading to genomic instability. These results reveal a role of ATR-PrimPol in enabling precancerous cells to survive KRAS-induced replication stress and expand clonally with accumulation of genomic instability.

Phase Ib/II Study of a Liposomal Formulation of Eribulin (E7389-LF) plus Nivolumab in Patients with Advanced Solid Tumors: Results from Phase Ib.

Purpose: To determine a recommended dose of liposomal eribulin (E7389-LF) in combination with nivolumab in patients with advanced solid tumors, and to evaluate the safety, efficacy, pharmacokinetics, and biomarker impact of this regimen. Experimental Design: Japanese patients with advanced, nonresectable, or recurrent solid tumors and no existing alternative standard/effective therapy (except nivolumab monotherapy) were assigned to either E7389-LF 1.7 mg/m2 plus nivolumab 360 mg every 3 weeks, E7389-LF 2.1 mg/m2 plus nivolumab 360 mg every 3 weeks, E7389-LF 1.1 mg/m2 plus nivolumab 240 mg every 2 weeks, or E7389-LF 1.4 mg/m2 plus nivolumab 240 mg every 2 weeks. Primary objectives were to evaluate the safety/tolerability of each dose cohort and to determine the recommended phase II dose (RP2D). Secondary/exploratory objectives, including safety [dose-limiting toxicities (DLT) and adverse events (AE)], pharmacokinetics, efficacy [including objective response rate (ORR)], and biomarker results were used in determining the RP2D. Results: Twenty-five patients were enrolled to treatment [E7389-LF 1.7 mg/mg2 every 3 weeks (n = 6), E7389-LF 2.1 mg/m2 every 3 weeks (n = 6), E7389-LF 1.1 mg/m2 every 2 weeks (n = 7), E7389-LF 1.4 mg/m2 every 2 weeks (n = 6)]. Twenty-four patients were evaluated for DLTs, of whom 3 had DLTs (1 at E7389-LF 1.7 mg/m2 every 3 weeks, 1 at 1.1 mg/m2 every 2 weeks, and 1 at 1.4 mg/m2 every 2 weeks). All patients had ≥1 treatment-related treatment-emergent AE (TEAE); 68.0% had ≥1 grade 3-4 treatment-related TEAE. Changes in vasculature and IFN-related biomarkers were seen in each cohort. The overall ORR was 16%. Conclusions: E7389-LF plus nivolumab was tolerable overall; the recommended dose for future study was 2.1 mg/m2 plus nivolumab 360 mg every 3 weeks. Significance: This phase Ib part of a phase Ib/II study assessed the tolerability and activity of a liposomal formulation of eribulin (E7389-LF) plus nivolumab in 25 patients with advanced solid tumors. The combination was tolerable overall; 4 patients had a partial response. Vasculature and immune-related biomarker levels increased, suggesting vascular remodeling.

Prevalence of psychological distress, quality of life, and satisfaction among patients and family members following comprehensive genomic profiling testing: Protocol of the Quality of life for Cancer genomics and Advanced Therapeutics (Q-CAT) study.

Precision medicine is rapidly changing the diagnostic and treatment spectrum of oncology. In May 2019, comprehensive genomic profiling (CGP) (somatic and/or germline) was approved for reimbursement in Japan. While the promise of novel and targeted therapies has elevated hopes for the benefits of CGP, the lack of relevant genomic findings and/or limited access to relevant therapies remain important themes in this field. These challenges may also negatively influence the psychology of both cancer patients and their family members. However, few studies have reported longitudinal data on quality of life (QOL) with CGP. Here, we report the protocol of a prospective study, Q-CAT (QOL for Cancer genomics and Advanced Therapeutics among patients and their family members), which aims to explore the mental burden on patients and families arising from the implementation of CGP testing by collecting real-world longitudinal data using outcomes obtained with an electronic patient report, known as ePRO. This study has been registered with the Japan Registry of Clinical Trials (jRCT1030200039).

Subsequent treatment for locally advanced non-small-cell lung cancer that progressed after definitive chemoradiotherapy and consolidation therapy with durvalumab: a multicenter retrospective analysis (TOPGAN 2021-02).

PURPOSE: For patients with locally advanced non-small-cell lung cancer (LA-NSCLC) that progressed after definitive chemoradiotherapy (CRT) and durvalumab consolidation therapy, no subsequent standard treatment exists. The type of treatment selected for each timing of disease progression and its efficacy have not been investigated. METHODS: We retrospectively enrolled patients with LA-NSCLC or inoperable NSCLC that progressed after definitive CRT and durvalumab consolidation therapy at 15 Japanese institutions. Patients were classified into the following: Early Discontinuation group (disease progression within 6 months after durvalumab initiation), Late Discontinuation group (disease progression from 7 to 12 months after durvalumab initiation), and Accomplishment group (disease progression from 12 months after durvalumab initiation). RESULTS: Altogether, 127 patients were analyzed, including 50 (39.4%), 42 (33.1%) and 35 (27.5%) patients from the Early Discontinuation, Late Discontinuation, and Accomplishment groups, respectively. Subsequent treatments were Platinum plus immune checkpoint inhibitors (ICI) in 18 (14.2%), ICI in 7 (5.5%), Platinum in 59 (46.4%), Non-Platinum in 35 (27.6%), and tyrosine kinase inhibitor in 8 (6.3%) patients. In the Early Discontinuation, Late Discontinuation, and Accomplishment groups, 4 (8.0%), 7 (16.7%), and 7 (20.0%) patients were receiving Platinum plus ICI; 21 (42.0%), 22 (52.4%), and 16 (45.7%) were receiving Platinum, and 20 (40.0%), 8 (19.0%), and 7 (20.0%) were receiving Non-Platinum, respectively. No significant difference in progression-free survival was observed in the timing of disease progression. CONCLUSION: In patients with LA-NSCLC hat progressed after definitive CRT and durvalumab consolidation therapy, subsequent treatment may change depending on the timing of disease progression.

First-in-human study of ONO-4578, an antagonist of prostaglandin E2 receptor 4, alone and with nivolumab in solid tumors.

EP4, a prostaglandin E2 receptor, has shown an immunosuppressive activity on cancer cells. This first-in-human study evaluated ONO-4578, a highly selective EP4 antagonist, as monotherapy and in combination with nivolumab in patients with advanced or metastatic solid tumors. A daily dose ranging from 30 mg to 100 mg of ONO-4578 monotherapy and that ranging from 2 mg to 60 mg of ONO-4578 with biweekly nivolumab 240 mg were administered. A total of 31 patients were enrolled, 10 receiving monotherapy and 21 receiving combination therapy. Overall, 26 patients experienced treatment-related adverse events. Dose-limiting toxicities were observed in three patients; one of six patients receiving 100 mg monotherapy developed grade 3 duodenal ulcer and two of six patients receiving 60 mg combination therapy developed either grade 3 erythema multiforme or grade 3 increased amylase and grade 4 increased lipase. One patient with small-cell lung cancer who received 40 mg combination therapy had a partial response, and three patients with monotherapy and six patients with combination therapy had stable disease. Pharmacodynamics analyses showed that ONO-4578 had EP4 antagonistic activity at doses as low as 2 mg. In conclusion, the maximum tolerated dose of ONO-4578 alone or in combination with nivolumab was not reached. ONO-4578 was well tolerated at the tested doses and showed signs of antitumor activity. Considering safety, efficacy, and pharmacokinetics/pharmacodynamics results, ONO-4578 40 mg daily with nivolumab 240 mg biweekly was selected as the recommended dose for future clinical trials. (Registration: JapicCTI-173,496 and NCT03155061).

Risk factors for failing a repeat oral food challenge in preschool children with hen's egg allergy.

BACKGROUND: Children with hen's egg (HE) allergy and a positive initial oral food challenge (OFC) require rechallenge to assess for tolerance. However, the risk factors for a positive repeat OFC remain unclear. METHODS: We retrospectively analyzed data from 243 preschool children who failed an initial OFC with half a heated HE and repeated the same OFC after 6-24 months. Logistic regression models were used to determine risk factors for a positive repeat OFC, including factors that were ascertainable immediately after the initial OFC and at the repeat OFC as variables. RESULTS: The median age, egg white-, and ovomucoid-specific IgE (sIgE) were 3.5 years, 12.7, and 7.2 kUA /L, respectively. The median interval between OFCs was 12.4 months and repeat OFCs were positive in 132 (54%) patients. One multivariate analysis model indicated that risk factors for a positive repeat OFC included cumulative dose (adjusted odds ratio [aOR]:0.58), anaphylaxis (aOR: 3.09), total serum IgE (aOR: 0.41), ovomucoid-sIgE (aOR: 3.21), and age (aOR: 1.68) at the initial OFC. Another model indicated that the risk factors were cumulative dose (aOR: 0.59) and anaphylaxis (aOR: 3.41) at initial OFC and total serum IgE (aOR: 0.36), ovomucoid-sIgE (aOR: 4.93), and age (aOR: 1.30) at repeat OFC. CONCLUSION: Low threshold dose and severe symptoms at initial OFC, and low total serum IgE, high ovomucoid-sIgE and higher age at initial and repeat OFCs are risk factors for the persistence of HE allergy and they may be useful when deciding the rechallenge interval for heated HE in preschool children.

Phenotyping of immediate-type food allergies based on 10 years of research: A latent class analysis.

BACKGROUND: Food allergy is a disease with a diverse and variable natural history, and some patients may react to two or more food antigens. This study aimed to classify and characterize the long-term prognosis of infantile-onset, immediate-type food allergies, focusing on three major antigens in Japan: egg, milk, and wheat. METHODS: All children who visited our hospital with food allergies, including suspected cases, were prospectively registered in our medical database. Among the children in this database, subjects registered by the age of 1 year with immediate-type symptoms or sensitization to the above three antigens were included. The course of the subjects up to the age of 6 years was analyzed. Cox regression analysis and repeated-measures latent class analysis (LCA) were performed to reveal risk factors and tolerance patterns for food allergies. RESULTS: We included 915 patients with immediate-type food allergy symptoms and 276 sensitized asymptomatic patients in this study. The number of patients with immediate-type symptoms to egg, milk, and wheat was 609, 443, and 235, respectively. The number of patients with multiple food allergies was 302. The proportion of patients with tolerance to egg, milk, and wheat at 6 years of age was 74%, 69%, and 75%, respectively. LCA revealed 7 classes of prognosis for food allergies. The largest class was transient egg allergy alone (19.6%), and there were severe cases of multiple food allergies (6.5%). CONCLUSIONS: This study demonstrated the prognosis of food allergy classes in Japan, including multiple food allergies, with 7 classes with its own characteristics.

Practical consideration for successful sequential tumor biopsies in first-in-human trials.

In first-in-human (FIH) trials, sequential tumor biopsies, i.e., two consecutive tumor biopsies, the first performed at baseline (pretreatment) and the second during the early treatment period (on-treatment), provide proof of concept in investigational new drugs. We evaluated the success of sequential tumor biopsies in FIH trials, and explored approaches for improved success rates. We retrospectively reviewed the sequential tumor biopsies required in 17 of 52 FIH trials conducted from 2015 to 2020. One hundred and thirty-eight patients were identified. Success of either pretreatment or on-treatment biopsy alone, and of sequential tumor biopsies, was defined as the acquisition of viable tumor cells and as obtaining tumor cells from both biopsy specimens, respectively. The success rates of pretreatment and on-treatment biopsy were 98.6% and 94.2%, respectively, and of sequential tumor biopsies was 70.3%. Adverse events associated with the pretreatment biopsies (33.3% positive; 72.0% negative) and timing of the first imaging assessment (before on-treatment biopsy = 40.0%; after on-treatment biopsy = 82.7%) correlated with successful sequential tumor biopsies. The reasons for unsuccessful sequential tumor biopsies could be categorized into two groups: 1) patient refusal of the on-treatment biopsy (most frequently due to early disease progression); and 2) absence of tumor cells in the pretreatment or on-treatment biopsy specimen. We propose an approach to achieving greater success in sequential tumor biopsies in FIH trials; the first imaging assessment during the study should be scheduled after on-treatment biopsy. (Registration number UMIN000042487, Date of registration November 18, 2020).

Long-term outcomes of oral immunotherapy for anaphylactic egg allergy in children.

Background: Studies of long-term oral immunotherapy (OIT) in children with anaphylactic egg allergy are limited. Objective: Our aim was to investigate the long-term outcomes of OIT for anaphylactic egg allergy. Methods: The participants included children (aged ≥ 5 years) with a history of anaphylaxis in response to eggs and objective reactions to oral food challenge (OFC) with 250 mg of egg protein. In the OIT group, the home starting dose of egg protein set during 5 days of hospitalization was ingested once daily and gradually increased to 1000 mg. Over the next year, participants temporarily discontinued OIT for 2 weeks and underwent OFC with 3100 mg of egg protein annually until they passed. The historical control group comprised patients who did not receive OIT and repeated OFCs annually. Results: In the OIT group (n = 20), the baseline median egg white- and ovomucoid-specific IgE levels were 45.5 and 38.5 kUA/L, respectively. The rate of passing OFC with 3100 mg of egg protein gradually increased in the OIT group, with rates of 20% at 1 year, 35% at 2 years, and 55% at 3 years, which were significantly higher than the rates in the historical control group at 3 years (5% [P < .001]). In the OIT group, 5 anaphylaxis events (0.04%) occurred at home, and 1 participant required intramuscular adrenaline. Furthermore, egg white- and ovomucoid-specific IgE levels decreased significantly after 3 years in both groups, whereas in the OIT group, these specific IgG and IgG4 levels increased significantly after a year. Conclusion: Long-term OIT accelerated immunologic changes and enabled ingestion of 3100 mg of egg protein in half of the participants with anaphylactic egg allergy.

Real-world efficacy of atezolizumab in non-small cell lung cancer: A multicenter cohort study focused on performance status and retreatment after failure of anti-PD-1 antibody.

BACKGROUND: Atezolizumab is a programmed death-ligand 1 (PD-L1) targeted monoclonal antibody that inhibits PD-L1 interacting with its receptors PD-1 and B7-1, thereby enhancing anticancer immunity. Some real-world efficacy and safety studies of anti-PD-1 antibody have been previously reported. However, there have been no reports investigating the efficacy of atezolizumab monotherapy in clinical practice which have focused on performance status and previous anti-PD-1 antibody treatment. METHODS: We retrospectively reviewed consecutive advanced NSCLC patients who received atezolizumab monotherapy between April 2018 and February 2019 at eight institutions. A total of 152 patients with NSCLC were enrolled in this study. RESULTS: A total of 38 patients (25%) had already been treated with anti-PD-1 treatment (nivolumab or pembrolizumab) before atezolizumab. The median OS and TTF was 384 days (12.8 months) (95% confidence interval [CI]: 206-424), and 42 days (1.4 months) (95% CI: 27-56) in all patients, respectively. ECOG PS 0 had significantly longer OS (median OS; not reached, p < 0.0001) and TTF (median TTF; 63 days, p = 0.012) compared with PS 1 or 2-3. Most retreated patients were unable to continue atezolizumab for a longer period, but seven patients (18.4%) were able to continue atezolizumab over four months as an ICI retreatment. CONCLUSIONS: In previously treated advanced NSCLC patients, atezolizumab monotherapy demonstrated good efficacy and safety regardless of heavily treated patients in real-world clinical practice, and ECOG PS 0 was a favorable predictive factor. The efficacy of retreatment with atezolizumab was limited but was well tolerated in patients treated with prior anti-PD-1 antibody.

Long-term follow-up of fixed low-dose oral immunotherapy for children with severe cow's milk allergy.

BACKGROUND: The efficacy and safety of cow's milk (CM) low-dose oral immunotherapy (LOIT) at one-year follow-up have been previously reported. We investigated the outcome of fixed long-term LOIT in children with severe CM allergy. METHODS: Children with positive reactions to oral food challenge (OFC) with 3 mL CM were included. The LOIT group (n = 33) ingested up to 3 mL CM for 1 year. After a two-week CM avoidance, 3 and 25 mL OFCs were performed. Children with positive reactions continued with 3 mL ingestion, with OFCs repeated yearly. Regular home consumption of 25 mL CM after passing the OFCs was defined as 25 mL short-term unresponsiveness (25 mL STU). The historical control group (n = 16) with reactions to 3 mL OFC eliminated daily CM ingestion. RESULTS: The proportion of 25 mL STU in the LOIT group was 27%, 52%, and 61% after 1, 2, and 3 years, respectively, and the 3-year percentage was significantly higher than that in the historical control group (13%, P = .002). In the LOIT group, only one child developed severe symptoms. Furthermore, in this group, CM- and casein-specific immunoglobulin E (sIgE) levels decreased significantly and casein-specific IgG and IgG4 levels increased significantly after 3 years, whereas the historical control group presented no significant change in these parameters. Baseline sIgE levels were significantly low in children achieving 25 mL STU. CONCLUSION: Continued fixed LOIT yields immunologic improvement and may be effective and safe for severe CM allergy.

A randomized trial of oral immunotherapy for pediatric cow's milk-induced anaphylaxis: Heated vs unheated milk.

BACKGROUND: Severe reactions may develop during cow's milk (CM) oral immunotherapy (OIT). We investigated the safety and efficacy of low-dose OIT with heated milk (HM) or unheated milk (UM) in children with anaphylaxis. METHODS: Children with symptom onset after ingestion of 3-mL HM on a double-blind, placebo-controlled food challenge were randomly assigned to the HM (n = 17) or UM (n = 16) group. HM group ingested milk powder heated at 125°C for 30 seconds, whereas the UM group used UM. Patients were hospitalized for 5 days; the HM or UM was gradually increased to 3 mL/day; 3-mL/day ingestion was continued at home. One year later, the patients underwent 2-day consecutive 3- and 25-mL HM-oral food challenges (OFCs) after 2-week avoidance. RESULTS: At baseline, milk- and casein-specific immunoglobulin E (IgE) levels were 56.0 and 51.4 kUA/L in the HM group, and 55.2 and 65.6 kUA/L in the UM group, respectively. One year later, 35% and 18% in the HM group and 50% and 31% in UM group passed the 3 and 25 mL OFCs, respectively. Rates of moderate or severe symptoms and respiratory symptoms per home dose were significantly lower in the HM than in the UM group (0.7% and 1.2% vs 1.4% and 2.6%, respectively, P < .001). ß-lactoglobulin-specific IgG4 levels significantly increased from baseline only in the UM group, whereas casein-specific IgG4 levels significantly increased from baseline in both groups. CONCLUSIONS: HM-OIT induced immunological changes more safely than the UM-OIT. The possibility of lower treatment efficacy with HM-OIT needs to be evaluated in larger studies.