Neprilysin inhibition promotes skeletal growth via the CNP/NPR-B pathway.

C-type natriuretic peptide (CNP) plays a crucial role in enhancing endochondral bone growth and holds promise as a therapeutic agent for impaired skeletal growth. To overcome CNP's short half-life, we explored the potential of dampening its clearance system. Neprilysin (NEP) is an endopeptidase responsible for catalyzing the degradation of CNP. Thus, we investigated the effects of NEP inhibition on skeletal growth by administering sacubitril, a NEP inhibitor, to C57BL/6 mice. Remarkably, we observed a dose-dependent skeletal overgrowth phenotype in mice treated with sacubitril. Histological analysis of the growth plate revealed a thickening of the hypertrophic and proliferative zones, mirroring the changes induced by CNP administration. The promotion of skeletal growth observed in wild-type mice treated with sacubitril was nullified by the knockout of cartilage-specific NPR-B. Notably, sacubitril promoted skeletal growth in mice only at 3-4 weeks of age, a period when endogenous CNP and NEP expression was higher in the lumbar vertebrae. Additionally, sacubitril facilitated endochondral bone growth in organ culture experiments using tibial explants from fetal mice. These findings suggest that NEP inhibition significantly promotes skeletal growth via the CNP/NPR-B pathway, warranting further investigations for potential applications in people with short stature.

Case Report: The leopard sign as a potential characteristic of chronic granulomatous disease-associated colitis, unrelated to colitis severity.

Background: Chronic granulomatous disease (CGD) is an inborn immune disorder in which the phagocytic system cannot eradicate pathogens, and autoinflammation occurs. Approximately half of the patients have associated gastrointestinal symptoms. Although most cases with CGD-associated colitis present nonspecific histology, colonoscopy in some cases shows brownish dots over a yellowish oedematous mucosa, which is termed a "leopard sign". However, the significance of these signs remains unclear. Methods: We collected data from patients with CGD whose colonoscopic findings showed the leopard sign. Results: Three patients with CGD and leopard signs were enrolled in this study. One patient underwent colonoscopy for frequent diarrhoea and weight gain failure, and another for anal fistula. The third patient was without gastrointestinal symptoms and underwent colonoscopy as a screening test before allogeneic haematopoietic cell transplantation (HCT). Endoscopic findings showed a mild leopard sign in the first case; however, non-contiguous and diffuse aphthae were observed throughout the colon. The other two cases were unremarkable except for the leopard sign. All the patients achieved remission with oral prednisolone or HCT. One patient underwent colonoscopy after HCT; results revealed improvements in endoscopy (including the leopard sign) and histological findings. However, another patient underwent colonoscopy after prednisolone treatment; this revealed no change in the leopard sign. Conclusion: The leopard sign in the colon may be a characteristic endoscopic finding of CGD, even in patients who do not develop severe gastrointestinal symptoms; however, it does not reflect the severity of CGD-associated colitis.

Clinical significance of Bacteroides fragilis as a potential prognostic factor in colorectal cancer.

INTRODUCTION: Bacteroides fragilis (B. fragilis) is considered to act in an anti-inflammatory manner on the intestinal tract. On the contrary, enterotoxigenic B. fragilis (ETBF), a subtype of B. fragilis, produces an enterotoxin (BFT; B. fragilis toxin), leading to asymptomatic chronic infections and colonic tumor formation. However, the impact of B. fragilis and ETBF on the clinical outcome of colorectal cancer (CRC) remains unclear. We aim to assess whether their presence affects the outcome in patients with CRC after curative resection. METHODS: We obtained 197 pairs of matched formalin-fixed paraffin-embedded samples from cancerous and adjacent non-cancerous tissues of patients with pathological stage (pstage) II and III CRC after curative resection. The presence of B. fragilis and ETBF were estimated using real-time polymerase chain reaction, and recurrence-free survival (RFS) and overall survival (OS) of the patients were analyzed. RESULTS: 16S rRNA for B. fragilis and bft DNA were detected in 120 (60.9%) and 12 (6.1%) of the 197 patients, respectively. B. fragilis-positive patients had better RFS than B. fragilis-negative patients, although that was not statistically significant. In subgroup analysis, better outcomes on RFS were observed in the presence of B. fragilis in pstage II and left-sided CRC. The association of B. fragilis positivity on OS was accentuated in the depth of T4 subgroup. No significant differences were observed in RFS and OS between ETBF and non-toxigenic B. fragilis. CONCLUSIONS: Our findings suggest that the presence of B. fragilis is associated with better outcomes in patients with pstage II and III CRC after curative resection.

Utility of an endoscopic image processing system for framing laparoscopic images using surgeon's gaze point and voice commands during laparoscopic percutaneous extraperitoneal closure of inguinal hernia in children.

Introduction: In laparoscopic surgery, it is the assistant who manipulates the laparoscope and manages the field of view. Aim: To develop an endoscopic image processing system that can adjust laparoscopic images as intended by the surgeon without interrupting the surgical procedure. Material and methods: We developed a touchless user interface that displays a magnified image of the endoscope using information of the surgeon's gaze point acquired by an eye-tracking device and the surgeon's voice commands, and evaluated its usefulness during laparoscopic percutaneous extraperitoneal closure (LPEC) of pediatric inguinal hernia. Results: LPEC was performed in 15 clinical cases of pediatric inguinal hernia using this system. In all cases, the internal inguinal ring could be ligated by digitally zooming and moving the endoscopic image by eye tracking and voice command while the scope was fixed. Conclusions: This new touchless user interface with eye tracking shows promise as a support system for laparoscopic surgery.

Peripherally inserted central catheters can be an alternative to tunneled central venous catheters in chemotherapy for hematological and oncological pediatric patients.

PURPOSE: Tunneled central venous catheters (TCVs) are commonly used for pediatric chemotherapy. Recently, peripherally inserted central catheters (PICCs) have been used instead. Although PICC has the advantages of simpler insertion and fewer severe complications, there is little information on the efficacy of PICC compared to TCV in pediatric chemotherapy. METHODS: Patients, aged younger than 18 years, with primary malignancy who received chemotherapy with PICC or TCV at our institution from December 2007 to August 2022 were included in the study. We retrospectively compared PICC and TCV using medical records. RESULTS: Within the observation period, 133 catheters (73 PICCs and 60 TCVs) were inserted. The median indwelling time was 99 days for PICCs and 182 days for TCVs, with TCVs being significantly longer (p < 0.001). There were no significant differences in the incidence of complications, such as infections, thrombosis, obstruction, or mechanical accidents. Comparing patients treated with PICC (PICC group) versus those with TCV (TCV group), the time from diagnosis to insertion was significantly shorter in the PICC group (p < 0.001). In the PICC group, none of the patients required general anesthesia, and chemotherapy was completed with PICC only. CONCLUSION: PICC can be an alternative to TCV in pediatric chemotherapy.

Spinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment.

Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance. The first cases of SMA were reported by Werdnig in 1891. Although the phenotypic variation of SMA led to controversy regarding the clinical entity of the disease, the genetic homogeneity of SMA was proved in 1990. Five years later, in 1995, the gene responsible for SMA, SMN1, was identified. Genetic testing of SMN1 has enabled precise epidemiological studies, revealing that SMA occurs in 1 of 10,000 to 20,000 live births and that more than 95% of affected patients are homozygous for SMN1 deletion. In 2016, nusinersen was the first drug approved for treatment of SMA in the United States. Two other drugs were subsequently approved: onasemnogene abeparvovec and risdiplam. Clinical trials with these drugs targeting patients with pre-symptomatic SMA (those who were diagnosed by genetic testing but showed no symptoms) revealed that such patients could achieve the milestones of independent sitting and/or walking. Following the great success of these trials, population-based newborn screening programs for SMA (more precisely, SMN1-deleted SMA) have been increasingly implemented worldwide. Early detection by newborn screening and early treatment with new drugs are expected to soon become the standards in the field of SMA.

Prediction-based prompt levothyroxine replacement to prevent a hypothyroid state after immune-related adverse events involving the thyroid gland.

Immune checkpoint inhibitors (ICIs) are used for various malignancies, although they frequently cause immune-related adverse events involving the thyroid gland (thyroid irAEs). We conducted a retrospective cohort study to elucidate thyroid function outcomes. Fifty of 639 patients who received PD-1 blockade therapy met criteria and were divided into the following groups: thyrotoxicosis with subsequent hypothyroidism (Toxic-Hypo, n = 21); thyrotoxicosis without subsequent hypothyroidism (Toxic, n = 9); and hypothyroidism without prior thyrotoxicosis (Hypo, n = 20). The Toxic-Hypo group developed thyroid irAEs earlier than the Toxic group (26 vs. 91 days; p < 0.001), and had higher serum free T4 levels (3.210 vs. 1.880 ng/dL; p = 0.011). In addition, positive anti-thyroglobulin antibodies (TgAbs) at thyroid irAE onset were more common in the Toxic-Hypo group (93.3%) than in the Toxic group (0.0%; p = 0.005) and Hypo group (44.4%; p = 0.007). The Toxic-Hypo group developed severe hypothyroidism and required larger levothyroxine (LT4) doses than the Hypo group (75 vs. 25 µg/day; p = 0.007). We predicted that patients with positive TgAbs who developed severe thyrotoxicosis within 4 weeks after the first ICI administration would develop subsequent hypothyroidism. We treated 4 such patients with prompt LT4 replacement, characterized by LT4 initiation after thyrotoxicosis improvement and quick dose titration. Their euthyroid state was successfully maintained, in contrast with patients receiving conventional replacement. In conclusion, rapid-onset severe thyrotoxicosis in patients with TgAbs correlated with a high likelihood of subsequent hypothyroidism. Accordingly, prompt LT4 replacement is suggested to prevent a severely hypothyroid state.

Nicotine Reduces Reactive Oxygen Species and Enhances Cell Proliferation via the α4 Nicotinic Acetylcholine Receptor Subunit in Human Induced Pluripotent Stem Cells.

The effects of smoking on fetal development and stem cell differentiation are not fully understood. Although nicotinic acetylcholine receptors (nAChRs) are expressed in many organs of the human body, their significance in human induced pluripotent stem cells (hiPSCs) remains unclear. After expression levels of nAChR subunits in hiPSCs were determined, the effects of the nAChR agonist, nicotine, on undifferentiated hiPSCs were evaluated using a Clariom S Array. We also determined the effect of nicotine alone and with a nAChR subunit antagonist on hiPSCs. nAChR α4, α7, and ß4 subunits were strongly expressed in hiPSCs. cDNA microarray, gene ontology, and enrichment analyses showed that exposing hiPSCs to nicotine altered expression of genes associated with immune responses, neurological system, carcinogenesis, cell differentiation, and cell proliferation. Particularly affected was metallothionein, which acts to decrease reactive oxygen species (ROS). The nicotine-induced reduction of ROS in hiPSCs was canceled by an α4 subunit or nonselective nAChR antagonist. HiPSC proliferation was increased by nicotine, and this effect, too, was canceled by an α4 antagonist. In conclusion, nicotine reduces ROS and enhances cell proliferation through the α4 nAChR subunit in hiPSCs. These findings provide new insight into the significance of nAChRs on human stem cells and fertilized human ova.

Magnesium Hydroxide Nanoparticles Inhibit the Biofilm Formation of Cariogenic Microorganisms.

Although various caries-preventive agents have been developed, dental caries is still a leading global disease, mostly caused by biological factors such as mutans streptococci. Magnesium hydroxide nanoparticles have been reported to exhibit antibacterial effects; however, they are rarely used in oral care practical applications. In this study, we examined the inhibitory effect of magnesium hydroxide nanoparticles on biofilm formation by Streptococcus mutans and Streptococcus sobrinus-two typical caries-causing bacteria. Three different sizes of magnesium hydroxide nanoparticles (NM80, NM300, and NM700) were studied, all of which inhibited biofilm formation. The results showed that the nanoparticles were important for the inhibitory effect, which was not influenced by pH or the presence of magnesium ions. We also determined that the inhibition process was mainly contact inhibition and that medium (NM300) and large (NM700) sizes were particularly effective in this regard. The findings of our study demonstrate the potential applications of magnesium hydroxide nanoparticles as caries-preventive agents.

Correction: Noguchi et al. PCR-Based Screening of Spinal Muscular Atrophy for Newborn Infants in Hyogo Prefecture, Japan. Genes 2022, 13, 2110.

The authors wish to make the following correction to this paper [...].

Phenotypic Variation in 46,XX Disorders of Sex Development due to the Fourth Zinc Finger Domain Variant of WT1: A Familial Case Report.

INTRODUCTION: The variants in the zinc finger (ZF) domains 1-3 in WT1 are one of the major causes of 46,XY disorders of sex development (DSD). Recently, variants in the fourth ZF (ZF4 variants) were reported to cause 46,XX DSD. However, all the 9 patients reported were de novo, and no familial cases were identified. CASE PRESENTATION AND RESULTS: The proband (16-year-old social female) had a 46,XX karyotype with dysplastic testes and moderate virilization in genitalia. A ZF4 variant, p.Arg495Gln, in WT1 was identified in the proband, her brother, and mother. The mother did not show any virilization with normal fertility, and the 46,XY brother developed normal puberty. CONCLUSION: The phenotypic variations due to the ZF4 variant are extremely broad in 46,XX cases.

An infant with A20 haploinsufficiency presenting with periodic fever syndrome: A case report.

A20 haploinsufficiency (HA20) is an early-onset autoinflammatory disease caused by loss-of-function variants of the TNFAIP3 gene, which encodes the protein A20. HA20 is typically characterized by Behçet's disease-like clinical symptoms, and patients usually present with a family history. Herein, we report a case of HA20 in a pediatric patient, presenting with periodic fever, abdominal pain, and vomiting, with no family history. This patient also harbored a novel heterozygous frameshift variant c.677del (p.Pro226LeufsTer2) of TNFAIP3. We initiated treatment with an anti-tumor necrosis factor-α agent that did not induce symptom resolution; we thus administered combination therapy, including prednisolone. Remission was then successfully achieved. We suggest that HA20 should be considered when an autoinflammatory disease is suspected and periodic fever syndrome is present, even in the absence of a family history of HA20 or Behçet's disease-like symptoms.

Delayed-onset immune-related adverse events involving the thyroid gland by immune checkpoint inhibitors in combination with chemotherapy: a case report and retrospective cohort study.

Immune checkpoint inhibitors (ICIs) frequently cause immune-related adverse events (irAEs) that often involve endocrine organs. Pembrolizumab and atezolizumab are currently administered in combination with chemotherapy for several malignancies. Although transient thyrotoxicosis within 6 weeks after the first ICI dose is the typical course of thyroid irAEs with ICI monotherapy, we encountered a unique course of a thyroid irAE in a patient who received combination therapy consisting of pembrolizumab plus pemetrexed and carboplatin. Delayed onset of thyrotoxicosis occurred at 22 weeks after the first dose of pembrolizumab. To understand more about this curious event, we conducted a retrospective cohort study of the following groups: pembrolizumab monotherapy (Pem-mono), pembrolizumab plus chemotherapy (Pem-combi), atezolizumab monotherapy (Atezo-mono), and atezolizumab plus chemotherapy (Atezo-combi). There were no differences in the incidence of overt thyroid irAEs: Pem-mono, 12 of 151 patients (7.9%) versus Pem-combi, 4 of 56 patients (7.1%) (p = 0.85) and Atezo-mono, 5 of 27 patients (18.5%) versus Atezo-combi, 5 of 57 patients (8.8%) (p = 0.20). Through detailed analyses of patients with thyrotoxicosis, we found some patients with delayed-onset thyroid irAE, defined as development at 16 weeks or more after the first ICI dose. Delayed-onset thyroid irAEs were only observed in the combination therapy groups: Pem-combi or Atezo-combi, 3 of 8 patients versus Pem-mono or Atezo-mono, 0 of 10 patients. Our observation that thyroid irAE development can be delayed with ICIs when used in combination with chemotherapy suggests longer monitoring of thyroid function is needed to avoid missing irAEs.

PCR-Based Screening of Spinal Muscular Atrophy for Newborn Infants in Hyogo Prefecture, Japan.

Spinal muscular atrophy (SMA) is a common devastating neuromuscular disorder, usually involving homozygous deletion of the SMN1 gene. Newly developed drugs can improve the motor functions of infants with SMA when treated in the early stage. To ensure early diagnosis, newborn screening for SMA (SMA-NBS) via PCR-based genetic testing with dried blood spots (DBSs) has been spreading throughout Japan. In Hyogo Prefecture, we performed a pilot study of SMA-NBS to assess newborn infants who underwent routine newborn metabolic screening between February 2021 and August 2022. Hyogo Prefecture has ~40,000 live births per year and the estimated incidence of SMA is 1 in 20,000-25,000 based on genetic testing of symptomatic patients with SMA. Here, we screened 8336 newborns and 12 screen-positive cases were detected by real-time PCR assay. Multiplex ligation-dependent probe amplification assay excluded ten false positives and identified two patients. These false positives might be related to the use of heparinized and/or diluted blood in the DBS sample. Both patients carried two copies of SMN2, one was asymptomatic and the other was symptomatic at the time of diagnosis. SMA-NBS enables us to prevent delayed diagnosis of SMA, even if it does not always allow treatment in the pre-symptomatic stage.

Case report: HLA-haploidentical hematopoietic cell transplant with posttransplant cyclophosphamide in a patient with leukocyte adhesion deficiency type I.

Leukocyte adhesion deficiency type I (LAD-I) is a rare autosomal recessive inborn error of immunity (IEI) caused by the defects in CD18, encoded by the ITGB2 gene. LAD-I is characterized by defective leukocyte adhesion to the vascular endothelium and impaired migration of leukocytes. Allogeneic hematopoietic cell transplant (HCT) is the only curative treatment for LAD-I. In an absence of ideal donor for HCT, human leukocyte antigen (HLA)-haploidentical HCT is performed. Posttransplant cyclophosphamide (PT-CY) is a relatively new graft-versus-host disease (GVHD) prophylactic measure and has been increasingly used in HLA-haploidentical HCT for malignant and nonmalignant diseases. However, experience in using PT-CY for rare IEIs, such as LAD-I, is very limited. We report a case of LAD-I successfully treated with HLA-haploidentical HCT with PT-CY. Complete chimerism was achieved, and the patient was cured. Her transplant course was complicated by mild GVHD, cytomegalovirus reactivation and veno-occlusive disease/sinusoidal obstruction syndrome, which were successfully treated. HLA-haploidentical HCT with PT-CY is a safe and effective option for patients with LAD-I when HLA-matched donors are unavailable.

Changes in the Incidence of Infantile Spinal Muscular Atrophy in Shikoku, Japan between 2011 and 2020.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder. Al-though there was no cure for SMA, newly developed therapeutic drugs (nusinersen, onasemnogene abeparvovec, and risdiplam) have been proven effective for the improvement of motor function and prevention of respiratory insufficiency of infants with SMA. Nusinersen was introduced in Japan in 2017 and onasemnogene abeparvovec in 2020. We hypothesized that the introduction of these drugs might influence the incidence of SMA (more precisely, increase the diagnosis rate of SMA) in Japan. To test this hypothesis, we conducted a second epidemiological study of infantile SMA using questionnaires in Shikoku, Japan between October 2021 and February 2022. The incidence of infantile SMA during the period 2016-2020 was 7.08 (95% confidence interval [CI] 2.45-11.71) per 100,000 live births. According to our previous epidemiological study, the incidence of infantile SMA during 2011-2015 was 2.70 (95% CI 0.05-5.35) per 100,000 live births. The increased incidence of infantile SMA suggests that the widespread news in Japan regarding the introduction of therapeutic agents, nusinersen and onasemnogene abeparvovec, raised clinicians' awareness about SMA, leading to increased and earlier diagnosis of SMA in Shikoku.

Factors predicting upstaging from clinical N0 to pN2a/N3a in breast cancer patients.

BACKGROUND: With sentinel node metastasis in breast cancer (BC) patients, axillary lymph node (ALN) dissection is often omitted from cases with breast-conserving surgery. Omission of lymph node dissection reduces the invasiveness of surgery to the patient, but it also obscures the number of metastases to non-sentinel nodes. The possibility of finding ≥ 4 lymph nodes (pN2a/pN3a) preoperatively is important given the ramifications for postoperative treatment. AIM: To search for clinicopathological factors that predicts upstaging from N0 to pN2a/pN3a. METHODS: Patients who were sentinel lymph node (SLN)-positive and underwent ALN dissection between September 2007 and August 2018 were selected by retrospective chart review. All patients had BC diagnosed preoperatively as N0 with axillary evaluation by fluorodeoxyglucose (FDG) positron emission tomography/computed tomography and ultrasound (US) examination. When suspicious FDG accumulation was found in ALN, the presence of metastasis was reevaluated by second US. We examined predictors of upstaging from N0 to pN2a/pN3a. RESULTS: Among 135 patients, we identified 1-3 ALNs (pN1) in 113 patients and ³4 ALNs (pN2a/pN3a) in 22 patients. Multivariate analysis identified the total number of SLN metastasis, the maximal diameter of metastasis in the SLN (SLNDmax), and FDG accumulation of ALN as predictors of upstaging to pN2a/pN3a. CONCLUSION: We identified factors involved in upstaging from N0 to pN2a/pN3a. The SLNDmax and number of SLN metastasis are predictors of ≥ 4 ALNs (pN2a/pN3a) and predictors of metastasis to non-sentinel nodes, which have been reported in the past. Attention should be given to axillary accumulations of FDG, even when faint.

Treatment resistance of rheumatoid arthritis relates to infection of periodontal pathogenic bacteria: a case-control cross-sectional study.

Recent studies have shown that periodontitis is associated with rheumatoid arthritis (RA) and periodontal bacteria, such as Aggregatibacter actinomycetemcomitans (Aa) and Porphyromonas gingivalis (Pg) are involved in the pathogenesis of RA via citrullinated proteins. Smoking has also been shown to be involved in the pathogenesis of RA; however, the extent of this involvement is still poorly understood. In addition, RA and polymyalgia rheumatica (PMR) are sometimes difficult to differentiate; however, the relationship between PMR and the factors from smoking and periodontal bacteria is unclear. The aim of this study was to clarify the relationship between periodontal pathogenic bacterial infections and smoking in patients with RA or PMR. This case-control study included 142 patients with untreated RA or PMR. This study evaluated the serum antibody titers against periodontal pathogenic bacterial antigens and an anti-citrullinated peptide antibody (ACPA). In patients with RA, the relationship between antibody titers and disease activity of RA and response after 3 months of treatment was also investigated. Additionally, the effects of smoking were evaluated. Although there was no significant difference in serum antibody titer against periodontal pathogenic bacteria between the ACPA-positive RA group and the ACPA-negative PMR group, we found an association between the elevated antibody titer against Pg and the degree of ACPA value, especially between negative group and high-value positive group (≥ 100 U/mL). The antibody titers against Aa and Pg did not differ depending on disease activity score 28 (DAS28) at baseline; however, patients with high antibody titers had poor RA therapeutic response as judged by DAS28 after 3 months. We could not find any association between smoking and any of these parameters. Periodontal pathogenic bacteria, especially Pg, are associated with elevated ACPA levels. Our findings suggest that Pg and Aa infections interfere with the therapeutic response of RA.

High-throughput Screening in Combination With a Cohort Study for Iodothyronine Deiodinases.

Regulatory mechanisms of iodothyronine deiodinases (DIOs) require further elucidation, and conventional methods for evaluating DIOs are unsuitable for high-throughput screening (HTS). Here we explored factors of transcriptional regulation of 3 types of DIOs (DIO1, DIO2, and DIO3) from a chemical library using our designed HTS. We constructed HTS based on a promoter assay and performed a screen of 2480 bioactive compounds. For compounds that were clinically approved, we validated hit compounds through a retrospective cohort study in our department that evaluated changes in thyroid function in patients using the compounds as drug therapy. Furthermore, we verified the involvement of DIOs using mice treated with the compounds. Of the hit compounds, 6 and 7 compounds transcriptionally up- and downregulated DIO1, respectively; 34 transcriptionally upregulated DIO2; and 5 and 2 compounds transcriptionally up- and downregulated DIO3, respectively. The cohort study clarified the clinical effects of some hit compounds: ritodrine increased free triiodothyronine (fT3)/free thyroxine (fT4) ratio and decreased serum thyroid-stimulating hormone (TSH) levels, tadalafil increased serum fT3 levels, and tyrosine kinase inhibitors (TKIs) decreased serum fT3 and fT4 levels and increased serum TSH levels. Following in vivo experiments using treated mice, consistent results were observed in ritodrine, which upregulated DIO2 in the thyroid gland. In conclusion, we completed HTS for DIOs and obtained attractive hit compounds. Our cohort study revealed the clinical significance of ritodrine, sildenafil, and TKIs. We hope our unique method will contribute to analyzing various targets and lists of hit compounds will promote understanding of DIOs.

Bone Marrow Carcinomatosis in a Stage IV Breast Cancer Patient Treated by Letrozole as First-Line Endocrine Therapy.

Bone marrow carcinomatosis (BMC) associated with breast cancer is a rare but often difficult-to-treat condition; we report a case of a female stage IV breast cancer patient in her seventies with BMC that improved with endocrine monotherapy. The patient had hemoglobinopenia and thrombocytopenia at the time of diagnosis. The diagnosis of BMC due to estrogen receptor-positive invasive lobular carcinoma was confirmed. After transfusion of 4 units of concentrated red blood cells, endocrine treatment with letrozole improved the hematopenia. Ten months after the treatment started, bone metastases worsened, so the patient was changed to combination therapy with palbociclib and fulvestrant, after which there was no worsening of the disease.