[Retracted] Predictors of efficacy of anamorelin in patients with non­small cell lung cancer and cachexia: A retrospective study.

[This retracts the article DOI: 10.3892/ol.2023.14154.].

Assessing the Safety of Mechanically Fibrillated Cellulose Nanofibers (fib-CNF) via Toxicity Tests on Mice: Single Intratracheal Administration and 28 Days' Oral Intake.

Mechanically fibrillated cellulose nanofibers, known as fib-CNF (fiber length: 500 nm; diameter: 45 nm), are used in composites and as a natural thickener in foods. To evaluate their safety, we conducted a 28-day study in mice with inhalation exposure at 0.2 mg/body and oral administration of 400 mg/kg/day. Inhalation exposure to fib-CNF caused transient weight loss, changes in blood cell counts, and increased lung weights. These changes were attributed to adaptive responses. The oral administration of fib-CNF for 28 days resulted in no apparent toxic effects except for a slight decrease in platelet counts. The fib-CNF administration using the protocols studied appears to be safe in mice.

Selective miR-21 detection technology based on photocrosslinkable artificial nucleic acid-modified magnetic particles and hybridization chain reaction.

Recently, microRNA (miRNA) detection in blood has attracted attention as a new early detection technology for cancer. The extraction of target miRNA is a necessary preliminary step for detection; however, currently, most extraction methods extract all RNA from the blood, which limits the detection selectivity. Therefore, a method for the selective extraction and detection of target miRNA from blood is very important. In this study, we utilized photocrosslinkable artificial nucleic acids and the hybridization chain reaction (HCR) in an attempt to improve upon the current standard method RT-qPCR, which is hampered by problems with primer design and enzymatic amplification. By introducing photocrosslinkable artificial nucleic acids to oligonucleotide probes modified with magnetic particles with a sequence complementary to that of the target miRNA and irradiating them with light, covalent bonds were formed between the target miRNA and the oligonucleotide probes. These tight covalent bonds enabled the capture of miRNA in blood, and intensive washing ensured that only the target miRNA were extracted. After extraction, two types of DNA (H1 and H2) modified with fluorescent dyes were added and the fluorescence signals were amplified by the HCR in the presence of the target miRNA bound to the photocrosslinkable artificial nucleic acids, allowing for isothermal and enzyme-free miRNA detection. The novel method is suitable for selective miRNA detection in real blood samples. Because the reaction proceeds isothermally and no specialized equipment is used for washing, this detection technology is simple and selective and suitable for application to point-of-care technology using microfluidic devices.

Twisting of HeartMate II outflow graft 2.5 years after implantation-HM2 is still ongoing.

A 47-year-old woman with dilated cardiomyopathy underwent HeartMate II (HM2) implantation as a bridge-to-transplantation. Her postoperative course was good. However, 2.5 years after surgery, the outflow graft was found to be twisted and the graft and pump was exchanged. While HeartMate 3(HM3) twisting of the outflow graft is well documented, such malfunctions in HM2 are almost unknown. Although HM2 has since been discontinued, there are a significant number of patients using HM2 who are awaiting heart transplants or destination therapy. We caution that, even with HM2, the possibility of late-phase twisting requires vigilance.

Predictors of efficacy of anamorelin in patients with non­small cell lung cancer and cachexia: A retrospective study.

Anamorelin, a ghrelin receptor agonist, is approved in Japan for the treatment of cachexia in patients with lung and gastrointestinal cancer. However, there is limited research on the usefulness of anamorelin in clinical settings, therefore, the present study evaluated its efficacy using patient characteristics. A total of 40 patients with non-small cell lung cancer and cachexia who were prescribed anamorelin in the Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine (Aomori, Japan) between July 2021 and November 2022, were retrospectively assessed. Anamorelin was prescribed at a dose of 100 mg once daily to patients who had lost >5% of their body weight within 6 months. All patients were weighed before treatment and those who continued anamorelin treatment for 12 weeks were also weighed at 12 weeks. A logistic regression analysis was used to analyze the association between background characteristics and early discontinuation of treatment with anamorelin (within 4 weeks). The median age was 67 years (range, 36-88), and 65% of the patients were male. There were 24 patients (60.0%) with an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score 1, 11 patients (27.5%) with an ECOG-PS score 2 and five patients (12.5%) with an ECOG-PS score 3. The early discontinuation group included 11 patients (27.5%). An ECOG-PS score ≥2 (odds ratio, 7.85; 95% confidence interval, 1.43-43.21; P=0.018) was associated with early discontinuation. A total of 18/40 patients (45.0%) were able to continue anamorelin treatment for 12 weeks, and the mean change in body weight was +2.31 kg, which was a significant change from the weight recorded at baseline (P=0.027). The mean changes in lean body mass and soft lean mass between baseline and 12 weeks were +1.97 kg (P=0.14) and +1.26 kg (P=0.15), respectively. The results from the present study indicate that anamorelin is unlikely to be useful for patients with a poor general condition (ECOG-PS score ≥2).

A Biochemical Corrosion Monitoring Sensor with a Silver/Carbon Comb Structure for the Detection of Living Escherichia coli.

For the detection and monitoring of live bacteria, we propose a biochemical corrosion monitoring (BCM) sensor that measures galvanic current by using a Ag/C sensor comprising silver and carbon comb electrodes. The deposition of an Escherichia coli suspension containing an LB liquid medium on the Ag/C sensor increased the galvanic current. The time required for the current to reach 20 nA is defined as T20. T20 tends to decrease as the initial number of E. coli in the E. coli solution increases. A linear relationship was obtained between the logarithm of the E. coli count and T20 in a bacterial count range of 1-108 cfu/mL under culture conditions in which the growth rate of the bacteria was constant. Hence, the number of live E. coli could be determined from T20. Ag2S precipitation was observed on the surface of the Ag electrode of the Ag/C sensor, where an increase in the current was observed. This generation of galvanic current was attributed to the reaction between a small amount of free H2S metabolized by E. coli in the bacterial solution during its growth process and Ag-the sensor anode. The Ag/C sensor can detect a free H2S concentration of 0.041 µM in the E. coli solution. This novel biochemical sensor can monitor the growth behavior of living organisms without damaging them.

Second-line immunosuppressant administration for steroid-refractory immune-related adverse events in patients with lung cancer.

BACKGROUND: Evidence for use of second-line immunosuppressants for immune-related adverse events (irAEs) is inadequate. Therefore, a multicenter analysis should assess the efficacy of second-line immunosuppressants for severe irAEs associated with different malignant diseases. METHODS: This descriptive study aims to investigate the effects of second-line immunosuppressants on corticosteroid-refractory irAEs in patients with lung cancer. We analyzed the effects of second-line immunosuppressants on underlying lung cancer and associated adverse effects. RESULTS: Our study included 4589 patients who had received immune checkpoint inhibitor treatment, with 73 patients (1.6%) developing irAEs requiring second-line immunosuppressants. The most commonly observed irAE was pneumonitis (26 patients), followed by hepatobiliary disorders (15 patients) and enteritis (14 patients). We found a confirmed response rate of 42.3% for pneumonitis, which was lower than the response rates of 86.7% for hepatobiliary disorders and 92.9% for enteritis. The time from the start of corticosteroid therapy to the addition of a second-line immunosuppressant correlated significantly with the resolution of irAE to Grade 1 (correlation coefficients of r = 0.701, p < 0.005). The median progression-free survival and duration of response of underlying lung cancer from second-line immunosuppressant administration were 2.1 and 3.0 months, respectively. Of the patients with irAE, 27.4% developed infections and 5.5% might die due to infection. CONCLUSION: Second-line immunosuppressant response was confirmed in 72.2% of irAEs in patients with lung cancer, with lower response rates observed in irAE pneumonitis compared to other irAEs.

Surgery for spina bifida occulta: spinal lipoma and tethered spinal cord.

The technical evolution of the surgery for spina bifida occulta (SBO) over the course of a half-century was reviewed with special foci placed on the spinal lipoma and tethered spinal cord. Looking back through history, SBO had been included in spina bifida (SB). Since the first surgery for spinal lipoma in the mid-nineteenth century, SBO has come to be recognized as an independent pathology in the early twentieth century. A half-century ago, the only option available for SB diagnosis was the plain X-ray, and pioneers of the time persevered in the field of surgery. The classification of spinal lipoma was first described in the early 1970s, and the concept of tethered spinal cord (TSC) was proposed in 1976. Surgical management of spinal lipoma with partial resection was the most widely practiced approach and was indicated only for symptomatic patients. After understanding TSC and tethered cord syndrome (TCS), more aggressive approaches became preferred. A PubMed search suggested that there was a dramatic increase of publications on the topic beginning around 1980. There have been immense academic achievements and technical evolutions since then. From the authors' viewpoint, landmark achievements in this field are listed as follows: (1) establishment of the concept of TSC and the understanding of TCS; (2) unraveling the process of secondary and junctional neurulation; (3) introduction of modern intraoperative neurophysiological mapping and monitoring (IONM) for surgery of spinal lipomas, especially the introduction of bulbocavernosus reflex (BCR) monitoring; (4) introduction of radical resection as a surgical technique; and (5) proposal of a new classification system of spinal lipomas based on embryonic stage. Understanding the embryonic background seems critical because different embryonic stages bring different clinical features and of course different spinal lipomas. Surgical indications and selection of surgical technique should be judged based on the background embryonic stage of the spinal lipoma. As time flows forward, technology continues to advance. Further accumulation of clinical experience and research will open the new horizon in the management of spinal lipomas and other SBO in the next half-century.

Limited dorsal myeloschisis associated with intramedullary infantile hemangioma in the conus medullaris: illustrative case.

BACKGROUND: Limited dorsal myeloschisis (LDM) and intramedullary infantile hemangioma rarely coexist in the spinal cord. OBSERVATIONS: The authors describe the case of a 3-month-old girl who, despite lacking neurological symptoms or signs, had a cigarette burn-like mark at the lumbosacral area and skin dimpling in the gluteal area. Magnetic resonance imaging showed a low-set conus due to a thickened filum and an abnormal subcutaneous stalk connected to the conus medullaris. In combination with the skin lesions, these findings strongly implied nonsaccular-type LDM. An intramedullary mass in the conus medullaris was also shown on magnetic resonance imaging and was homogenously enhanced with isointensity on T1- and T2-weighted images. We prophylactically untethered the spinal cord and partially removed the intramedullary mass, which had no clear borders, for a safe surgical dissection. Histologically, the intramedullary mass was an infantile hemangioma, and the subcutaneous stalk was a lesion associated with LDM. The patient remained neurologically intact after surgery, and then 2 years later, there was spontaneous regression of the residual tumor. LESSONS: Although rare, nonsaccular type LDM may appear concurrently with intramedullary infantile hemangioma at the conus medullaris. The authors present a possible mechanism behind this concurrent presentation in the same area.

Soluble interleukin-2 receptor as a predictive biomarker for poor efficacy of combination treatment with anti-PD-1/PD-L1 antibodies and chemotherapy in non-small cell lung cancer patients.

Soluble interleukin-2 receptor (sIL-2R) suppresses effector T-cells. Few studies have assessed serum sIL-2R in patients receiving immunotherapy. We evaluated the association between serum sIL-2R levels and the efficacy of anti-programmed cell death 1/ programmed death-ligand 1 (anti-PD-1/PD-L1) antibody combined with chemotherapy in non-small cell lung cancer (NSCLC) patients. We prospectively enrolled NSCLC patients who received anti-PD-1/PD-L1 antibody combined with platinum-based chemotherapy between 8/2019 and 8/2020 and measured their serum sIL-2R. The patients were divided into high and low sIL-2R groups based on the median of sIL-2R levels at pretreatment. Progression-free survival (PFS) and overall survival (OS) of patients in the high and low sIL-2R groups were compared. The Kaplan-Meier curves of PFS and OS were evaluated using the log-rank test. The multivariate analysis of PFS and OS was performed using the Cox proportional hazard models. Among 54 patients (median age 65, range 34-84), 39 were male and 43 had non-squamous cell carcinoma. The sIL-2R cut-off value was 533 U/mL. Median PFS was 5.1 months (95% CI, 1.8-7.5 months) and 10.1 months (95% CI, 8.3-not reached [NR] months) in the high and low sIL-2R groups (P = 0.007), respectively. Median OS was 10.3 months (95% CI, 4.0-NR months) and NR (95% CI, 10.3-NR months) in the high and low sIL-2R groups (P = 0.005), respectively. Multivariate Cox regression analysis showed that high sIL-2R was significantly associated with shorter PFS and OS. SIL-2R may be a biomarker for the poor efficacy of anti-PD-1/PD-L1 antibody combined with chemotherapy.

Granulomatosis with Polyangiitis following COVID-19 in an Adolescent.

Granulomatosis with polyangiitis (GPA) is a systemic disease that causes vasculitis in various organs. Although the mechanism of pathogenesis remains unclear, infection has been reported to be a causative factor. We herein report a case of GPA that developed following coronavirus disease 2019 (COVID-19) in an adolescent girl. One month after contracting mild COVID-19, the patient had facial allodynia, a fever, and weight loss and was admitted for multiple nodular shadows on a chest roentgenogram. GPA was diagnosed based on pathological findings of the lung and nasal mucosal biopsies. She received methylprednisolone and rituximab, and her symptoms and radiological findings improved.

Surgical Management of Chiari Malformation Type I Associated with Syringomyelia: Outcome of Surgeries Based on the New Classification and Study of Cerebrospinal Fluid Dynamics.

Introduction: The mainstay of treatment of syringomyelia associated with Chiari malformation type I (CM-I) is the management of CM-I to normalize the cerebrospinal fluid (CSF) flow at the foramen magnum. CM-I is classified into three independent types. Surgical treatment was selected based on the mechanism of hindbrain ptosis in each CM-I type. Materials and Methods: Foramen magnum decompression (FMD: 213 cases), expansive suboccipital cranioplasty (ESCP: 87 cases), and craniocervical fixation (CCF: 30 cases) were performed. CSF flow dynamics were assessed pre- and post-surgery using cine phase contrast magnetic resonance imaging. During surgery, CSF flow dynamics were examined using color Doppler ultrasonography (CDU). Results: ESCP and FMD demonstrated high rates of improvement in neurological symptoms and signs (82.7%), whereas CCF demonstrated a high rate of improvement in neurological symptoms (89%). The pre-operative maximum flow velocity (cm/s) was significantly lower in patients than in controls and increased post-operatively. During surgery, CDU indicated that the volume of the major cistern was 8 mL, and the maximum flow velocity was >3 mL/s. Conclusions: An appropriate surgical treatment should be selected for CM-I to correct hindbrain ptosis. In addition, it is necessary to confirm the normalization of CSF flow at the foramen of Magendie.

Surgical Management of Chiari Malformation Type I and Instability of the Craniocervical Junction Based on Its Pathogenesis and Classification.

We investigated the mechanism underlying Chiari malformation type I (CM-I) and classified it according to the morphometric analyses of posterior cranial fossa (PCF) and craniocervical junction (CCJ). Three independent subtypes of CM-I were confirmed (CM-I types A, B, and C) for 484 cases and 150 normal volunteers by multiple analyses. CM-I type A had normal volume of PCF (VPCF) and occipital bone size. Type B had normal VPCF and small volume of the area surrounding the foramen magnum (VAFM) and occipital bone size. Type C had small VPCF, VAFM, and occipital bone size. Morphometric analyses during craniocervical traction test demonstrated instability of CCJ. Foramen magnum decompression (FMD) was performed in 302 cases. Expansive suboccipital cranioplasty (ESCP) was performed in 102 cases. Craniocervical posterolateral fixation (CCF) was performed for CCJ instability in 70 cases. Both ESCP and FMD showed a high improvement rate of neurological symptoms and signs (84.4%) and a high recovery rate of the Japanese Orthopaedic Association (JOA) score (58.5%). CCF also showed a high recovery rate of the JOA score (69.7%), with successful joint stabilization (84.3%). CM-I type A was associated with other mechanisms that caused ptosis of the brainstem and cerebellum (CCJ instability and traction and pressure dissociation between the intracranial cavity and spinal canal cavity), whereas CM-I types B and C demonstrated underdevelopment of the occipital bone. For CM-I types B and C, PCF decompression should be performed, whereas for small VPCF, ESCP should be performed. CCF for CCJ instability (including CM-I type A) was safe and effective.

Right Ventricular Outflow Tract Myxoma with Absent Pulmonary Valve.

Myxoma is the most common benign cardiac tumor. Absent pulmonary valves, often treated surgically in childhood, are associated with 3-6% of tetralogy of Fallot. It is unusual for absent pulmonary valves without other congenital heart diseases to be asymptomatic until adulthood. Here, we report the unique case of an 80-year-old female with right ventricular outflow tract myxoma and absent pulmonary valve that has, to our knowledge, never been reported. We successfully performed a simple mass resection and pulmonary valve implantation.

Clinical efficacy of dacomitinib in rechallenge setting for patients with epidermal growth factor receptor mutant non-small cell lung cancer: A multicenter retrospective analysis (TOPGAN2020-02).

BACKGROUND: Dacomitinib is the second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) for mutant non-small cell lung cancer (NSCLC). EGFR-TKIs are often re-administered in Japan after the disease progression prior EGFR-TKI. There is little evidence of dacomitinib in rechallenge setting. This study evaluated clinical outcomes of dacomitinib in rechallenge setting. METHODS: Patients who received dacomitinib for advanced EGFR-mutant NSCLC who had progressed after EGFR-TKI in nine institutions in Japan were included in the analyses. RESULTS: In total, 43 patients were analyzed. The median progression-free survival (PFS) was 4.3 months (95% confidence interval [CI], 2.5-5.6). The overall survival (OS) was 10.5 months (95% CI, 7.4-not reached). The overall response rate was 25.5% (95% CI, 13.1-33.7). Subset analysis indicated that patients with EGFR exon 21 L858R showed longer PFS than those with EGFR exon 19 deletion (5.8 vs. 4.1 months) (p = 0.018). The most common adverse events leading to dose modification were diarrhea, paronychia, rash, and oral mucositis. CONCLUSION: In the real practice in Japan, dacomitinib showed a worthwhile treatment option for NSCLC patients with EGFR mutation after failure of previous EGFR-TKI. The benefit was especially pronounced in patients with the exon 21 mutation.

Photo-Cross-Linked Probe-Modified Magnetic Particles for the Selective and Reliable Recovery of Nucleic Acids.

Polymerase chain reaction (PCR) assays are used to diagnose various infectious diseases such as Coronavirus disease 2019 by detecting the nucleic acids of the pathogen. However, in practice, the yield of the extraction process and the inhibition of the reverse transcription reaction and PCR by foreign substances reduce the sensitivity and may yield false negative results. The sensitivity of the PCR test can be improved by using technologies that can reliably capture the target nucleic acid and remove foreign substances. In this study, we developed photo-cross-linkable probe-modified magnetic particles (PPMPs) for the sequence-specific recovery of target nucleic acids using photo-cross-linkable artificial nucleic acid probes and magnetic particles. Nucleic acid probes modified with photo-cross-linkable artificial nucleic acids can hybridize with the target nucleic acids in a sequence-specific manner and then securely capture the target nucleic acids by UV irradiation-mediated covalent bonding. Then the target nucleic acid is detected by trapping the target-bound probe on the surface of the magnetic particles and subjecting these collected magnetic particles to PCR. Recovery of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) N gene pseudo-DNA (120 bp) was performed using PPMPs. We confirmed that the PPMPs captured the target consistently even after washes were done with denaturing agents and surfactants. Even in the presence of foreign DNA fragments, PPMPs were able to specifically recover the target DNA. This method allows for a more accurate detection by recovering only the target DNA for PCR. Hence, PPMPs can be successfully used for PCR-mediated detection of SARS-CoV-2 and other pathogens whose nucleic acid sequences are known.

[Pediatric Hemispheric Glioma].

About one-third of pediatric low-grade glioma and a half of pediatric high-grade glioma occur in the cerebrum. Pediatric hemispheric glioma may harbor diagnostic and therapeutically targetable genetic abnormalities, including BRAF V600E, H3.3 G34R/V, FGFR1 alternation, MYB or MYBL1 alternation, and NTRK/ALK/ROS1/MET fusion. In addition, the efficacy of molecular-targeted agents, such as BRAF inhibitors, MEK inhibitors, and NTRK inhibitors, against pediatric glioma with the relevant mutations has been demonstrated in several clinical trials. Furthermore, checkpoint inhibitors are considered a choice of treatment for hypermutated glioma, which is typically observed in patients with constitutional mismatch repair deficiency syndrome. Cancer gene panel testing, approved for insurance coverage in Japan in 2019, has been beneficial to pediatric cancer patients. However, to promote the clinical application of the recent molecular understanding of pediatric neuro-oncology, some issues have to be addressed. Herein, we review the genetic profiles of pediatric hemispheric glioma and introduce the current medical situation of precision medicine for pediatric patients with glioma in Japan.

Two cases of catastrophic deterioration and multiple leaflet detachment in Trifecta valves.

Reports of early and catastrophic acute structural valve deterioration (SVD) in Trifecta valve (Abbott, St Paul, MN, USA) with multiple leaflet detachment are rare. We encountered two cases of early SVD in Trifecta valve with tears on two leaflets. Both cases presented with acute heart failure because of aortic insufficiency, and underwent redo aortic valve replacement; one patient died due to multiple organ failure caused by cardiogenic shock. Durability issues with the Trifecta valves; thus, necessitates long-term vigilance in aortic replacement patients.

Total arch replacement with both frozen elephant trunk and transthoracic aorto-axillary extra-anatomical bypass through partial sternotomy for acute aortic dissection in a tracheostomy patient.

Median sternotomy near an existing tracheostoma risks deep sternal wound infection after cardiac surgery. We present herein a case of acute type A aortic dissection in a patient with a permanent tracheostoma after laryngectomy. Total arch replacement with both frozen elephant trunk and extra-anatomical bypass for supra-aortic trunks was performed through T-shaped partial sternotomy, resulting in recovery without deep sternal wound infection.