Treatment patterns and clinical outcomes in patients with metastatic triple-negative breast cancer: a large-scale data analysis using the Japanese claims database.

PURPOSE: This study evaluated treatment patterns and clinical outcomes among patients with metastatic triple-negative breast cancer (mTNBC) in real-world clinical settings in Japan. METHODS: The treatment patterns, time to next treatment or death (TTNTD), time to treatment discontinuation, adverse events of interest, and medical costs of treating patients with mTNBC in first-, second-, and third-line settings were investigated using data of patients meeting the inclusion criteria between January 2017 and March 2022 in a Japanese medical claims database. The treatment regimens for mTNBC were defined according to the Japanese Breast Cancer Society Clinical Practice Guidelines. RESULTS: In this study, 2236 patients with mTNBC (median age 66.0 years; 99.8% female) were included in the first-line cohort. Of these, 46.6% and 20.8% were included in the second- and third-line cohorts, respectively. The two most frequently used treatments were capecitabine (19.1%) and S-1 (tegafur-gimeracil-oteracil) (14.5%) in the first-line cohort, eribulin (18.3%) and bevacizumab/paclitaxel (14.4%) in the second-line cohort, and eribulin (19.4%) and bevacizumab/paclitaxel (17.5%) in the third-line cohort. The TTNTD shortened as the line of therapy progressed (median 8.0, 6.5, and 5.2 months for the first-, second-, and third-line treatments, respectively). Nausea/vomiting and neutropenia/leukopenia occurred in 62.8% and 18.3% of all patients, respectively. The medical total costs per day were 6.7, 10.2, and 12.9 thousand yen during the first-/second-/third-line treatments, respectively. CONCLUSION: This study provides insight into current treatment patterns for mTNBC in Japan. The cost-benefit balance worsens with later-line treatment and a high unmet need for mTNBC drug treatment remains.

Pterygoid Muscle Necrosis Caused by Radiation and Intra-Arterial Cisplatin Infusion Chemotherapy (RADPLAT): A Case Report.

Introduction: Radiation and intra-arterial cisplatin infusion chemotherapy (RADPLAT) for advanced maxillary sinus cancer has accumulated evidence as a treatment with fewer complications and better 5-year survival rates. In this study, we report a case in which pterygoid muscle necrosis occurred 6 months following RADPLAT treatment for maxillary sinus cancer. Case Presentation: The 45-year-old woman had a long history of taking immunosuppressants against rheumatoid arthritis (RA) prior to treatment. Although achieving complete response (CR) to RADPLAT, the patient developed trismus (1 fingerbreadth or less) 6 months following treatment. Abscess formation and recurrence were suspected from the imaging findings; however, the biopsy with endoscopy indicated necrotic tissue. Currently, 18 months have passed without cancer recurrence. Although trismus temporarily improved with rehabilitation, the width of the mouth opening is currently a few millimeters, so the patient can only take liquid food. Conclusion: Pterygoid muscle necrosis should be recognized as a new major complication.

[Foot drop and cyclic sensory disturbance of the right lower limb due to endometriosis].

We report the case of a 40-year-old woman, with endometriosis, who presented with a history of foot drop and cyclic sensory disturbance of the right lower limb. She was initially diagnosed with lumbar disc herniation. Neurological examination revealed muscle weakness and sensory disturbance associated with the right sciatic nerve. Nerve conduction studies revealed a low amplitude sensory nerve action potential in the right superficial fibular and sural nerves. Pelvic magnetic resonance imaging revealed an endometriotic cyst in the right ovary, and an endometriotic lesion extending from the right ovary, pelvis, and the right sciatic nerve. Though her symptoms moderately improved with hormonal therapy, the foot drop remained. Our case and previous reports suggest that endometriosis with sciatic neuropathy shows cyclic neurological symptoms during menstruation, with a higher incidence on the right extremity. This case highlights that endometriosis should be considered as a potential differential diagnosis in women of reproductive age with sciatic nerve dysfunction. Its cyclic neurological manifestations should be investigated.

Prognostic significance of the harmonized maximum standardized uptake value of 18F-FDG-PET/CT in patients with resectable oral tongue squamous cell carcinoma: a multicenter study.

OBJECTIVES: To investigate the usefulness of harmonized 18F-FDG-PET/CT parameters for predicting the postoperative recurrence and prognosis of oral tongue squamous cell carcinoma (OTSCC). METHODS: We retrospectively analyzed the cases of 107 OTSCC patients who underwent surgical resection at four institutions in Japan in 2010-2016 and evaluated the harmonized PET parameters of the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) for the primary tumor as the pSUVmax, pMTV, and pTLG. For lymph node metastasis, we used harmonized PET parameters of nodal-SUVmax, nodal-total MTV (tMTV), and nodal-total TLG (tTLG). The associations between the harmonized PET parameters and the patients' relapse-free survival (RFS) and overall survival (OS) were evaluated by the Kaplan-Meier method and Cox proportional hazard regression analysis for model 1 (preoperative stage) and model 2 (preoperative + postoperative stages). RESULTS: The harmonized SUVmax values were significantly lower than those before harmonization (p=0.012). The pSUVmax was revealed as a significant preoperative risk factor for RFS and OS. Nodal-SUVmax, nodal-tMTV, and nodal-tTLG were significant preoperative risk factors for OS. The combination of pSUVmax + nodal-SUVmax significantly stratified the patients into a low-risk group (pSUVmax <3.97 + nodal-SUVmax <2.85 or ≥2.85) and a high-risk group (pSUVmax ≥3.97 + nodal-SUVmax <2.85 or pSUVmax ≥3.97 + nodal-SUVmax ≥2.85) for recurrence and prognosis (RFS: p=0.001; OS: p<0.001). CONCLUSIONS: The harmonized pSUVmax is a significant prognostic factor for the survival of OTSCC patients. The combination of pSUVmax and nodal-SUVmax identified OTSCC patients at high risk for recurrence and poor prognosis at the preoperative stage.

The Usefulness of Total Laryngectomy in Sarcopenic Patients With Hypopharyngeal and Laryngeal Cancer.

BACKGROUND/AIM: Sarcopenia has an adverse effect on postoperative complications and prognoses in head and neck cancer. This study focused on hypopharyngeal and laryngeal cancer patients with sarcopenia and analyzed the body composition following treatment when the larynx was preserved and when total laryngectomy was performed to examine the usefulness of laryngectomy. PATIENTS AND METHODS: We retrospectively reviewed 88 primary hypopharyngeal and laryngeal cancer patients aged 65 years or older with cT2N0M0 or higher who visited our department. RESULTS: There were no significant differences in the 3-year overall survival rate and the 1-year local control rate between the laryngeal preservation group and laryngectomy group. The average change one year following treatment in the laryngeal preservation group, when compared to prior to treatment, was a significant decrease in the body weight (BW) of -0.035, skeletal muscle mass (SMM) of -0.030, skeletal muscle mass index (SMI) of -0.026, body mass index (BMI) of -0.034, and grip strength (GS) of -0.066. The average change one year following treatment in the laryngectomy group, compared with prior to treatment, was an increase in BW of +0.028, SMM of +0.026, SMI of +0.008, BMI of +0.032, and GS of +0.026. Although no changes in serum biochemical testing after treatment were observed in the laryngeal preservation group, albumin, transferrin, and transthyretin all exhibited significant improvement or a tendency toward improvement in the laryngectomy group. The patients with sarcopenia before treatment in the laryngeal preservation group had a significantly higher incidence of aspiration pneumonia. CONCLUSION: The presence or absence of sarcopenia before starting treatment is considered to be an index for selecting total laryngectomy.

A routing method with adaptively adjusting memory information based on local routing history.

Finding the shortest paths for packets from sources to destinations in packet-switched communication networks is an inevitable problem in building a future high-speed information society. A routing method with memory information has already been proposed to alleviate the congestion of large volumes of packet flow. This routing method shows a high transmission completion rate even for large volumes of packet flows in communication networks with scale-free properties. However, the method exhibits poor performance for networks with local triangular connections and long distances between nodes. To overcome these problems, in this study, we first enhanced the routing performance of the conventional communication network models by using the betweenness centrality of nodes, which is one of the network centralities that measures the number of shortest paths that pass through each node in the networks. Subsequently, we adaptively changed the transmitting paths of packets by using only local information. Numerical simulations indicated that our routing method performs successfully for various topologies of communication networks by avoiding the congested node, and effectively using the memory information.

Final analysis of a post-marketing surveillance study of dabrafenib and trametinib combination therapy in Japanese patients with unresectable malignant melanoma with BRAF V600 mutation.

Targeted therapy with a combination of dabrafenib and trametinib has been developed and widely used for treatment of melanoma. However, data regarding its safety and efficacy in Japanese patients with malignant melanoma are limited. A post-marketing surveillance (PMS) study was conducted to investigate the safety and efficacy of combination therapy in a Japanese clinical setting with a surveillance period of June 2016 to March 2022; 326 patients with unresectable malignant melanoma with BRAF mutation were enrolled. The interim results were published in July 2020. Herein, we report the results of the final analysis based on the data collected until the completion of the PMS study. The safety analysis population included 326 patients, the majority of whom had stage IV disease (79.14%) and Eastern Cooperative Oncology Group performance status 0 or 1 (85.28%). All patients were treated with the approved dose of dabrafenib, while 99.08% were treated with the approved dose of trametinib. Adverse events (AEs) occurred in 282 patients (86.50%) and the major AEs (incidence ≥5%) were pyrexia (47.85%), malignant melanoma (33.44%), hepatic function abnormal (9.82%), rash and blood creatine phosphokinase increased (8.59% each), malaise (6.44%), nausea (5.52%), and diarrhea and rhabdomyolysis (5.21% each). The incidences rates of adverse drug reactions of safety specifications were 45.71% for pyrexia, 15.95% for hepatic impairment, 12.58% for rhabdomyolysis, 4.60% for cardiac disorders, and 3.07% for eye disorders. In the efficacy analysis population of 318 patients, the objective response rate was 58.18% (95% confidence interval [CI] 52.54%-63.66%). The progression-free survival rates at 90, 180, and 360 days were 88.14% (95% CI 84.00%-91.26%), 69.53% (63.85%-74.50%), and 52.07% (45.71%-58.03%), respectively. Consistent with previous interim results, no new safety or efficacy concerns were observed in this final analysis of a PMS study conducted in a Japanese real-world clinical setting.

Neurogenic pulmonary edema caused by right insular cortex infarction.

We report a case of neurogenic pulmonary edema (NPE) caused by middle cerebral artery infarction involving the right insular cortex. Hyperactivity of the insular cortex, which regulates sympathetic function, can cause NPE. The NPE should be considered in the differential diagnosis of dyspneic patients with insular cortex infarction.

Identification of a novel ALDH1A3-selective inhibitor by a chemical probe with unrelated bioactivity: An approach to affinity-based drug target discovery.

The identification of biologically active target compounds and their binding proteins is important in mechanism-of-action studies for drug development. Additionally, the newly discovered binding proteins provide unforeseen ideas for novel drug discovery and for subsequent structural transformation to improve target specificity. Based on the lead and final candidate compounds related to the type 5 phosphodiesterase (PDE5) inhibitor E4021, we designed chemical probes and identified their target proteins by the affinity chromatography approach. Aldehyde dehydrogenase family 1 member A3 (ALDH1A3), currently reported as a cancer stem cell target, was clearly isolated as a binding protein of the lead 'immature' inhibitor probe against PDE5. In the early derivatization to the closely related structure, Compound 5 (ER-001135935) was found to significantly inhibit ALDH1A3 activity. The discovery process of a novel ALDH1A3-selective inhibitor with affinity-based binder identification is described, and the impact of this identification method on novel drug discovery is discussed.

[A case of methotrexate-associated diffuse large B-cell lymphoma with splenial lesions of the corpus callosum on brain MRI after complete remission with chemotherapy].

An 86-year-old woman in a wheelchair was accompanied by her husband and son as she visited our outpatient clinic due to disturbed consciousness and fever. Twenty-seven years earlier, she had been diagnosed with rheumatoid arthritis and had been treated with methotrexate (MTX) and low-dose prednisolone (PSL). She stopped taking MTX four years previously when she was diagnosed with diffuse large B cell lymphoma of the paranasal sinus. Her lymphoma went into remission after six cycles of systemic immunochemotherapy. MRI after hospitalization revealed a lesion in the splenium of the corpus callosum that was hyperintense on diffusion-weighted imaging and which had low apparent diffusion coefficient values. An analysis of the cerebrospinal fluid revealed no atypical cells. The MRI findings were atypical, but her consciousness disturbance improved, leading to the diagnosis of mild encephalitis/encephalopathy with a reversible splenial lesion, which would be associated with a transient consciousness disturbance with a good course. However, her consciousness worsened over the next 3 weeks. One month later, a contrast-enhanced MRI showed an enlarged lesion in the callosum as well as new lesions, and the diagnosis of secondary CNS lymphoma was made. Brain biopsy is often not feasible. Less invasive and highly accurate diagnostic methods are needed, such as the identification of a spinal fluid tumor marker.

Predictive factors for malignant neoplasms veiled in deep neck infections.

Background: Malignant neoplasms (MNs) in the head and neck are occasionally hidden in deep neck infections (DNIs) that require emergency treatment, which potentially leads to delayed diagnosis of MNs.Objectives: This study aimed to identify predictive factors that can prevent delays in diagnosing MNs in patients with DNIs.Methods: We retrospectively analysed data from 83 patients admitted to our hospital who were diagnosed with DNIs.Results: Four patients (4.8%) had DNIs veiling MNs in the head and neck. Statistical analyses revealed a significant association (p = .0481) of platelet to albumin ratio (PAR; ≥ 98.9 × 103) with hidden MNs in DNIs. Furthermore, concomitant cervical lymphadenopathy, especially multiple lymphadenopathies and excluding abscesses, was higher in patients with DNIs veiling MNs (p = .0142 and p = .0023, respectively).Conclusions and Significance: The PAR, which can be easily measured and readily detected, was a potential predictive factor. Moreover, performing fine-needle aspiration for lymphadenopathies could help diagnose hidden MNs in DNIs.

Statistical potentials for RNA-protein interactions optimized by CMA-ES.

Characterizing RNA-protein interactions remains an important endeavor, complicated by the difficulty in obtaining the relevant structures. Evaluating model structures via statistical potentials is in principle straight-forward and effective. However, given the relatively small size of the existing learning set of RNA-protein complexes optimization of such potentials continues to be problematic. Notably, interaction-based statistical potentials have problems in addressing large RNA-protein complexes. In this study, we adopted a novel strategy with covariance matrix adaptation (CMA-ES) to calculate statistical potentials, successfully identifying native docking poses.

Lymphatic Dysfunction Exacerbates Cutaneous Tumorigenesis and Psoriasis-Like Skin Inflammation through Accumulation of Inflammatory Cytokines.

Lymphatic transport plays an important role in coordinating local immune responses. However, the biologic effects of impaired lymphatic flow in vivo are not fully understood. In this study, we investigated the roles of the lymphatic system in skin carcinogenesis and psoriasis-like inflammation using k-cyclin transgenic (kCYC+/-) mice, which demonstrate severe lymphatic dysfunction. kCYC+/- mice showed augmented tumor growth in the two-stage skin carcinogenesis model and severe clinical scores in imiquimod-induced psoriasis-like skin inflammation compared with wild-type mice. Although mRNA levels of inflammatory cytokines in skin after topical application of 12-O-tetradecanoylphorbol-13-acetate or imiquimod were comparable between kCYC+/- and wild-type mice, protein levels of inflammatory cytokines, such as IL-17A, IL-22, and IL-23, were significantly upregulated in kCYC+/- mice in both models. Consistently, signal transducer and activator of transcription 3 pathway and NF-κB signaling were augmented in epidermal keratinocytes in kCYC+/- mice. These results suggest that lymphatic dysfunction in kCYC+/- mice caused accumulation of inflammatory cytokines, leading to the exacerbation of two-stage skin carcinogenesis and imiquimod-induced psoriasis-like skin inflammation. These findings add insight into the clinical problems of secondary malignancies and inflammatory dermatoses that may occur with extremity lymphedema.

Inhibition of FGFR Reactivates IFNγ Signaling in Tumor Cells to Enhance the Combined Antitumor Activity of Lenvatinib with Anti-PD-1 Antibodies.

Combination therapies consisting of immune checkpoint inhibitors plus anti-VEGF therapy show enhanced antitumor activity and are approved treatments for patients with renal cell carcinoma (RCC). The immunosuppressive roles of VEGF in the tumor microenvironment are well studied, but those of FGF/FGFR signaling remain largely unknown. Lenvatinib is a receptor tyrosine kinase inhibitor that targets both VEGFR and FGFR. Here, we examine the antitumor activity of anti-PD-1 mAb combined with either lenvatinib or axitinib, a VEGFR-selective inhibitor, in RCC. Both combination treatments showed greater antitumor activity and longer survival in mouse models versus either single agent treatment, whereas anti-PD-1 mAb plus lenvatinib had enhanced antitumor activity compared with anti-PD-1 mAb plus axitinib. Flow cytometry analysis showed that lenvatinib decreased the population of tumor-associated macrophages and increased that of IFNγ-positive CD8+ T cells. Activation of FGFR signaling inhibited the IFNγ-stimulated JAK/STAT signaling pathway and decreased expression of its target genes, including B2M, CXCL10, and PD-L1. Furthermore, inhibition of FGFR signaling by lenvatinib restored the tumor response to IFNγ stimulation in mouse and human RCC cell lines. These preclinical results reveal novel roles of tumor FGFR signaling in the regulation of cancer immunity through inhibition of the IFNγ pathway, and the inhibitory activity of lenvatinib against FGFRs likely contributes to the enhanced antitumor activity of combination treatment comprising lenvatinib plus anti-PD-1 mAb. SIGNIFICANCE: FGFR pathway activation inhibits IFNγ signaling in tumor cells, and FGFR inhibition with lenvatinib enhances antitumor immunity and the activity of anti-PD-1 antibodies.

Up-front neck dissection followed by chemoradiotherapy for T1-T3 hypopharyngeal cancer with advanced nodal involvement.

BACKGROUND: The advantage of up-front neck dissection (UFND) followed by chemoradiotherapy (CRT) for hypopharyngeal cancer (HPC) with advanced neck involvement remains controversial. We aimed to determine the indications. METHODS: The data of 41 and 14 patients with stage IVA/B (T1-T3 and ≥N2a) HPC who underwent UFND followed by CRT and received CRT, respectively, were retrospectively analyzed and compared. RESULTS: The 5-year overall survival (OS) and disease-specific survival rates for the UFND and CRT groups were 61% and 52% (p = 0.1019), and 89% and 74% (p = 0.2333), respectively. Moreover, patients aged ≥70 years or those with a pulmonary disease history had a significantly poorer prognosis due to aspiration pneumonia in the UFND group. The 5-year regional control (RC) for the UFND and CRT groups were 92% and 57%, respectively (p = 0.0001). CONCLUSIONS: UFND followed by CRT was feasible with satisfactory RC. To further improve OS, aspiration pneumonia prevention is essential.

E7386, a Selective Inhibitor of the Interaction between ß-Catenin and CBP, Exerts Antitumor Activity in Tumor Models with Activated Canonical Wnt Signaling.

The Wnt/ß-catenin signaling pathway plays crucial roles in embryonic development and the development of multiple types of cancer, and its aberrant activation provides cancer cells with escape mechanisms from immune checkpoint inhibitors. E7386, an orally active selective inhibitor of the interaction between ß-catenin and CREB binding protein, which is part of the Wnt/ß-catenin signaling pathway, disrupts the Wnt/ß-catenin signaling pathway in HEK293 and adenomatous polyposis coli (APC)-mutated human gastric cancer ECC10 cells. It also inhibited tumor growth in an ECC10 xenograft model and suppressed polyp formation in the intestinal tract of ApcMin /+ mice, in which mutation of Apc activates the Wnt/ß-catenin signaling pathway. E7386 demonstrated antitumor activity against mouse mammary tumors developed in mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice. Gene expression profiling using RNA sequencing data of MMTV-Wnt1 tumor tissue from mice treated with E7386 showed that E7386 downregulated genes in the hypoxia signaling pathway and immune responses related to the CCL2, and IHC analysis showed that E7386 induced infiltration of CD8+ cells into tumor tissues. Furthermore, E7386 showed synergistic antitumor activity against MMTV-Wnt1 tumor in combination with anti-PD-1 antibody. In conclusion, E7386 demonstrates clear antitumor activity via modulation of the Wnt/ß-catenin signaling pathway and alteration of the tumor and immune microenvironments, and its antitumor activity can be enhanced in combination with anti-PD-1 antibody. SIGNIFICANCE: These findings demonstrate that the novel anticancer agent, E7386, modulates Wnt/ß-catenin signaling, altering the tumor immune microenvironment and exhibiting synergistic antitumor activity in combination with anti-PD-1 antibody.

Pathogenic Autoimmunity in Atherosclerosis Evolves From Initially Protective Apolipoprotein B100-Reactive CD4+ T-Regulatory Cells.

BACKGROUND: Throughout the inflammatory response that accompanies atherosclerosis, autoreactive CD4+ T-helper cells accumulate in the atherosclerotic plaque. Apolipoprotein B100 (apoB), the core protein of low-density lipoprotein, is an autoantigen that drives the generation of pathogenic T-helper type 1 (TH1) cells with proinflammatory cytokine secretion. Clinical data suggest the existence of apoB-specific CD4+ T cells with an atheroprotective, regulatory T cell (Treg) phenotype in healthy individuals. Yet, the function of apoB-reactive Tregs and their relationship with pathogenic TH1 cells remain unknown. METHODS: To interrogate the function of autoreactive CD4+ T cells in atherosclerosis, we used a novel tetramer of major histocompatibility complex II to track T cells reactive to the mouse self-peptide apo B978-993 (apoB+) at the single-cell level. RESULTS: We found that apoB+ T cells build an oligoclonal population in lymph nodes of healthy mice that exhibit a Treg-like transcriptome, although only 21% of all apoB+ T cells expressed the Treg transcription factor FoxP3 (Forkhead Box P3) protein as detected by flow cytometry. In single-cell RNA sequencing, apoB+ T cells formed several clusters with mixed TH signatures that suggested overlapping multilineage phenotypes with pro- and anti-inflammatory transcripts of TH1, T helper cell type 2 (TH2), and T helper cell type 17 (TH17), and of follicular-helper T cells. ApoB+ T cells were increased in mice and humans with atherosclerosis and progressively converted into pathogenic TH1/TH17-like cells with proinflammatory properties and only a residual Treg transcriptome. Plaque T cells that expanded during progression of atherosclerosis consistently showed a mixed TH1/TH17 phenotype in single-cell RNA sequencing. In addition, we observed a loss of FoxP3 in a fraction of apoB+ Tregs in lineage tracing of hyperlipidemic Apoe-/- mice. In adoptive transfer experiments, converting apoB+ Tregs failed to protect from atherosclerosis. CONCLUSIONS: Our results demonstrate an unexpected mixed phenotype of apoB-reactive autoimmune T cells in atherosclerosis and suggest an initially protective autoimmune response against apoB with a progressive derangement in clinical disease. These findings identify apoB autoreactive Tregs as a novel cellular target in atherosclerosis.

In operando visualization of electrolyte stratification dynamics in lead-acid battery using phase-contrast X-ray imaging.

An understanding of electrolyte stratification behaviours in lead-acid battery electrolytes during battery operation is important for optimal operation and design of lead-acid batteries for vehicle applications. In this paper, we present an in operando phase-contrast X-ray imaging technique for quantitatively visualizing electrolyte stratification dynamics that arise in electrolytes during battery operation.

Toward Atomistic Modeling of Irreversible Covalent Inhibitor Binding Kinetics.

Covalent inhibitors have emerged as an important drug class in recent years, largely due to their many unique advantages as compared to noncovalent inhibitors, including longer duration of action, lower prolonged systemic exposure, higher potency, and selectivity. However, the potential off-target toxicity of covalent inhibitors, particularly of irreversible covalent inhibitors, represents a great challenge in covalent drug development. Therefore, accurate calculation of protein covalent inhibitor reaction kinetics to guide the design of selective inhibitors would greatly benefit covalent drug discovery efforts. In the present paper, we present a computational method to calculate the relative reaction kinetics between congeneric irreversible covalent inhibitors and their protein receptors. The method combines density functional theory calculations of the transition state barrier height of the rate-limiting step for reaction between the warhead of the inhibitor and a single protein residue, and molecular-mechanics-based free energy calculations to account for the interactions between the ligand in the transition state and the protein environment. The method was tested on four pharmaceutically interesting irreversible covalent binding systems involving 28 ligands; the mean unsigned error (MUE) of the relative reaction rate for all pairs of ligands between the predictions and experimental results for these tested systems is 0.79 log unit. This is to our knowledge the first time where the reaction kinetics of protein irreversible covalent inhibition have been directly calculated with physics-based free energy calculation methods and transition state theory. We anticipate the outstanding accuracy demonstrated here across a broad range of target classes will have a strong impact on the design of selective covalent inhibitors.

Efficacy and Safety of Guselkumab in Japanese Patients With Palmoplantar Pustulosis: A Phase 3 Randomized Clinical Trial.

IMPORTANCE: Palmoplantar pustulosis (PPP) causes erythematous, scaly plaques with recurrent sterile pustules refractory to treatment and with few randomized clinical trials conducted. Evidence points to involvement of interleukin 23 in the pathogenesis of PPP. OBJECTIVE: To determine the efficacy and safety of guselkumab, an anti-IL-23 monoclonal antibody, in Japanese patients with PPP. DESIGN, SETTING, AND PARTICIPANTS: A phase 3 randomized clinical trial was conducted from December 15, 2015, to December 12, 2017. A total of 159 enrolled patients (aged ≥20 years) had an inadequate response to conventional therapies, with a diagnosis of PPP for 24 or more weeks before screening. Intention-to-treat analysis was performed. INTERVENTIONS: Subcutaneous injections of guselkumab, 100 or 200 mg, at weeks 0, 4, and 12, and every 8 weeks thereafter were administered; placebo was given at weeks 0, 4, and 12. MAIN OUTCOMES AND MEASURES: Changes from baseline in PPP Area and Severity Index (PPPASI) score (possible score range, 0-72, with higher scores indicating greater area and severity), PPP severity index (PPSI) score (possible score range, 0-12, with higher scores indicating greater severity), and proportion of PPPASI-50 (≥50% reduction) responders at weeks 16 and 52 were assessed. Safety was monitored through week 52. RESULTS: A total of 159 patients (mean [SD] age at diagnosis, 46.8 [11.9] years; 126 women [79.2%]) were enrolled. Treatment groups comprised guselkumab, 100 mg (n = 54), guselkumab, 200 mg (n = 52), or placebo (n = 53). Both guselkumab groups demonstrated significant improvement in least-squares mean changes in PPPASI score compared with placebo: -15.3 and -11.7 in the guselkumab 100-mg and 200-mg groups, respectively, and -7.6 in the placebo group (difference [SE] vs placebo: -7.7 [1.7] in the 100-mg group, P < .001; 95% CI, -11.00 to -4.38; and -4.1 [1.7] in the 200-mg group, P < .017; 95% CI, -7.47 to -0.75]). Least-squares mean changes in PPSI score showed significant improvement in both guselkumab groups (100 mg: -2.0 [0.5]; P < .001; 95% CI, -2.96 to -0.95; 200 mg: -1.0 [0.5; P = .04; 95% CI, -2.06 to -0.03). A significantly higher proportion of patients in the guselkumab 100-mg group (31 [57.4%]) achieved a PPPASI-50 response at week 16 vs placebo (18 [34.0%]; P = .02); however, the result was not significant for the guselkumab 200-mg group (19 [36.5%]) vs placebo; P = .78). Each efficacy end point improved consistently through week 52. Health-related quality of life improved significantly as indicated by a reduction in the Dermatology Life Quality Index score (100 mg: -2.6; 95% CI, -4.0 to -1.2; P < .001; 200 mg: -1.6; 95% CI, -3.1 to -0.2; P = .03). Serious treatment-emergent adverse events were observed in 8 patients (placebo group, 2 of 53 [3.8%]; combined guselkumab group, 6/157≠10.5%). No serious infections were reported. CONCLUSIONS AND RELEVANCE: Targeting interleukin 23 with guselkumab may be an effective and safe treatment option for a recalcitrant disease such as PPP. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02641730.