Upper Respiratory Symptoms as Long COVID: Insight from a Multicenter Cohort Study.

Objective: This study aimed to investigate the clinical features of long COVID cases presenting with upper respiratory symptoms, a topic not yet fully elucidated. Study Design: Prospective cohort study. Setting: A multicenter study involving 26 medical facilities in Japan. Methods: Inclusion criteria were patients aged ≥18 years old with a confirmed COVID-19 diagnosis via severe acute respiratory syndrome coronavirus 2 polymerase chain reaction or antigen testing, who were hospitalized at the participating medical facilities. Analyzing clinical information and patient-reported outcomes from 1009 patients were analyzed. The outcome measured the degree of initial symptoms for taste or olfactory disorders and assessed the likelihood of these symptoms persisting as long COVID, as well as the impact on quality of life if the upper respiratory symptoms persisted as long COVID. Results: Patients with high albumin, low C-reactive protein, and low lactate dehydrogenase in laboratory tests tended to experience taste or olfactory disorders as part of long COVID. Those with severe initial symptoms had a higher risk of experiencing residual symptoms at 3 months, with an odds ratio of 2.933 (95% confidence interval [CI], 1.282-6.526) for taste disorders and 3.534 (95% CI, 1.382-9.009) for olfactory disorders. Presence of upper respiratory symptoms consistently resulted in lower quality of life scores. Conclusion: The findings from this cohort study suggest that severe taste or olfactory disorders as early COVID-19 symptoms correlate with an increased likelihood of persistent symptoms in those disorders as long COVID.

Clinical utility of the Oncomine Dx Target Test multi-CDx system and the possibility of utilizing those original sequence data.

BACKGROUND: Companion diagnostic tests play a crucial role in guiding treatment decisions for patients with non-small cell lung cancer (NSCLC). The Oncomine Dx Target Test (ODxTT) Multi-CDx System has emerged as a prominent companion diagnostic method. However, its efficacy in detecting driver gene mutations, particularly rare mutations, warrants investigation. AIMS: This study aimed to assess the performance of the ODxTT in detecting driver gene mutations in NSCLC patients. Specifically, we aimed to evaluate its sensitivity in detecting epidermal growth factor receptor (EGFR) mutations, a key determinant of treatment selection in NSCLC. MATERIALS AND METHODS: We conducted a retrospective analysis of NSCLC patients who underwent testing with the ODxTT at Keio University Hospital between May 2020 and March 2022. Patient samples were subjected to both DNA and RNA tests. Driver gene mutation status was assessed, and instances of missed mutations were meticulously examined. RESULTS: Of the 90 patients, five had nucleic acid quality problems, while 85 underwent both DNA and RNA tests. Driver gene mutations were detected in 56/90 (62.2%) patients. Of the 34 patient specimens, driver mutations were not detected using the ODxTT; however, epidermal growth factor receptor (EGFR) mutations were detected using polymerase chain reaction-based testing in two patients, and a KRAS mutation was detected by careful examination of the sequence data obtained using the ODxTT in one patient. For the above three cases, carefully examining the gene sequence information obtained using the ODxTT could identify driver mutations that were not mentioned in the returned test results. Additionally, we confirmed comparable instances of overlook results for EGFR mutations in the dataset from South Korea, implying that this type of oversight could occur in other countries using the ODxTT. EGFR mutation was missed in ODxTT in Japan (6.3%, 2/32), South Korea (2.0%, 1/49), and overall (3.7%, 3/81). CONCLUSION: Even if sufficient tumor samples are obtained, rare EGFR mutations (which are excluded from the ODxTT's genetic mutation list) might not be detected using the current ODxTT system due to the program used for sequence analysis. However, such rare EGFR mutations can still be accurately detected on ODxTT's sequence data using next-generation sequencing.

Comprehensive analysis of long COVID in a Japanese nationwide prospective cohort study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly since 2019, and the number of reports regarding long COVID has increased. Although the distribution of long COVID depends on patient characteristics, epidemiological data on Japanese patients are limited. Hence, this study aimed to investigate the distribution of long COVID in Japanese patients. This study is the first nationwide Japanese prospective cohort study on long COVID. METHODS: This multicenter, prospective cohort study enrolled hospitalized COVID-19 patients aged ≥18 years at 26 Japanese medical institutions. In total, 1200 patients were enrolled. Clinical information and patient-reported outcomes were collected from medical records, paper questionnaires, and smartphone applications. RESULTS: We collected data from 1066 cases with both medical records and patient-reported outcomes. The proportion of patients with at least one symptom decreased chronologically from 93.9% (947/1009) during hospitalization to 46.3% (433/935), 40.5% (350/865), and 33.0% (239/724) at 3, 6, and 12 months, respectively. Patients with at least one long COVID symptom showed lower quality of life and scored higher on assessments for depression, anxiety, and fear of COVID-19. Female sex, middle age (41-64 years), oxygen requirement, and critical condition during hospitalization were risk factors for long COVID. CONCLUSIONS: This study elucidated the symptom distribution and risks of long COVID in the Japanese population. This study provides reference data for future studies of long COVID in Japan.

Longitudinal long COVID symptoms in Japanese patients after COVID-19 vaccinations.

We conducted a subgroup analysis of a study on the long-term effects of COVID-19 (long COVID) in Japan to assess the effect of vaccination on long COVID symptoms. We assessed the clinical course of 111 patients with long COVID at the time of vaccination. The follow-up period was one year from the onset of COVID-19 or until the administration of the third vaccine dose. Of the 111 patients, 15 (13.5%) reported improvement, four (3.6%) reported deterioration, and 92 (82.9%) reported no change in their long COVID symptoms after vaccination. The most common long COVID symptoms before vaccination were alopecia, dyspnea, muscle weakness, fatigue, and headache among participants whose symptoms improved. Reduced dyspnea and alopecia were the most frequently reported improvements in symptoms after vaccination. Some symptoms persisted, including sleep disturbance, myalgia, and hypersensitivity. Vaccination did not appear to have a clinically important effect on patients with long COVID symptoms.

Long-Term Treatment-Free Survival After Multimodal Therapy in a Patient with Stage IV Lung Adenocarcinoma.

We report the first case of a patient with non-small cell lung cancer (NSCLC) with malignant pleural effusion (MPE) who achieved disease- and treatment-free survival for nearly 10 years. A 50-year-old man was diagnosed with NSCLC with MPE and underwent chemotherapy and salvage thoracic surgery. The patient received chemotherapy with cisplatin, pemetrexed, and bevacizumab, and a partial response was achieved. After informed consent was obtained from the patient, right middle lobectomy was performed to achieve local tumor control. Postoperative adjuvant chemotherapy with pemetrexed and bevacizumab was discontinued after almost 1 year of chemotherapy due to side effects such as diarrhea and muscle weakness. The patient has survived without recurrence of lung cancer for more than 11 years after being diagnosed and nearly 10 years after discontinuing chemotherapy.

Thymoma-associated T-cell immunodeficiency after radiotherapy: A case report.

Acquired immunodeficiency in thymoma (Good's syndrome) without hypogammaglobulinemia is a rare condition. Here we describe the case of a 29-year-old Japanese woman with thymoma-associated T cell immunodeficiency after radiation therapy. She was admitted to the hospital with refractory pneumonia, which resulted from as T cell immunodeficiency, as revealed through low peripheral lymphocytes and oral candidiasis triggered through radiotherapy and required long-term antimicrobial therapy. Although radiotherapy is commonly administered for thymoma, our findings suggest that physicians should consider carrying out lymphocyte counts during thymoma treatment.

A case of thrombomodulin mutation causing defective thrombin binding with absence of protein C and TAFI activation.

Thrombomodulin functions as an anticoagulant through thrombin binding and protein C activation. We herein report the first case of hereditary functional thrombomodulin deficiency presenting with recurrent subcutaneous hemorrhage and old cerebral infarction. The patient had a homozygous substitution of glycine by aspartate at amino acid residue 412 (Gly412Asp) in the thrombin-binding domain of the thrombomodulin gene (designated thrombomodulin-Nagasaki). In vitro assays using a recombinant thrombomodulin with the same mutation as the patient showed a total lack of thrombin binding and activation of protein C and thrombin-activatable fibrinolysis inhibitor (TAFI). Marked clinical and laboratory improvement was obtained with recombinant human soluble thrombomodulin therapy.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor: A retrospective multicenter study of its real-world efficacy and safety in advanced/recurrent non-small cell lung carcinoma.

BACKGROUND: Osimertinib is recommended for T790M mutation-positive advanced non-small cell lung cancer (NSCLC) resistant to first- and second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Recently, some reports exist on the real-world use of osimertinib; however, reports involving third/later-line use are few. Hence, this study was conducted to evaluate the efficacy and safety of osimertinib used in various treatment lines for T790M-positive NSCLC patients. METHODS: This retrospective, observational, multicenter study included T790M-positive advanced/recurrent NSCLC patients treated with osimertinib from May 2016 to March 2018. The clinical characteristics, efficacy, and adverse events were retrospectively investigated. The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). PFS-associated clinical characteristics were evaluated using the Cox proportional hazards model. RESULTS: The objective response rate (ORR) and disease control rate (DCR) were 60.7% and 91.1%, respectively; the median PFS was 11.0 months. There were no significant differences in the median PFS for patients treated with osimertinib as second-line and third-/later-line (14.5 vs. 11.0 months respectively, P = 0.327). Analysis using the Cox proportional hazards model for clinical features affecting PFS also revealed no significant factors. Adverse events of grade ≥ 3 were reported in 15 patients (26.8%); the most common were anemia (n = 3) and cutaneous toxicity (n = 3). Grade 4 neutropenia was observed in one patient; any-grade pneumonitis was observed in six patients (10.7%), including one with grade 3 pneumonitis. CONCLUSIONS: Osimertinib demonstrated efficacy even when administered as third-/later-line treatment to NSCLC patients. Osimertinib-related pneumonitis was observed more frequently than previously reported. KEY POINTS: Significant findings of the study Osimertinib shows efficacy even as later-line treatment in T790M mutation-positive NSCLC patients previously treated with EGFR-TKIs. However, the incidence of ≥ grade 3 adverse events, especially pneumonitis, was higher than that previously reported by other studies. What this study adds Osimertinib was approved for previously EGFR-TKI-treated EGFR T790M-positive NSCLC. With the increasing frequency of its use as first-line treatment, this study provides valuable evidence for the efficacy and safety of osimertinib for previously EGFR-TKI-treated NSCLC.

Sequential use of second-generation tyrosine kinase inhibitors following imatinib therapy in pediatric chronic myeloid leukemia: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group.

BACKGROUND: The details of the sequential use of imatinib for first-line treatment followed by second-generation tyrosine kinase inhibitors (2G-TKIs) for pediatric chronic myeloid leukemia (CML) are still unknown. This study analyzed clinical responses and adverse effects of the use of 2G-TKIs following imatinib in pediatric chronic phase (CP)-CML. PROCEDURES: The Japanese Pediatric Leukemia/Lymphoma Study Group conducted a retrospective study of patients with newly diagnosed CML from 1996 to 2011. A total of 152 cases that received imatinib as first-line therapy were analyzed. RESULTS: Excluding 46 cases treated with hematopoietic stem cell transplantation before nilotinib and dasatinib became available, 31 of 106 patients changed to 2G-TKIs. The primary reason for changing from imatinib was poor response, followed by intolerance, with the main reason for the latter being musculoskeletal events. Switches from imatinib to 2G-TKIs with intolerance occurred significantly earlier than switches with poor response. Sixteen and 15 patients were treated with nilotinib and dasatinib, respectively, following imatinib therapy. After switching to 2G-TKIs, the response status improved in 63% of evaluable patients. The adverse effect profiles of nilotinib and dasatinib tended to be different, with hyperbilirubinemia observed in 33% of nilotinib-treated patients, but in none of the cases with dasatinib. CONCLUSION: This retrospective study represents the first series of children and adolescents in whom sequential use of imatinib followed by 2G-TKIs was reported. These data provide useful insights into the selection of 2G-TKIs as first-line treatment for children and adolescents with CP-CML.

High Incidence of Deep Vein Thrombosis in the Perioperative Period of Neurosurgical Patients.

INTRODUCTION: A prospective study was designed to elucidate incidence and predictors of deep venous thrombosis (DVT) in patients undergoing craniotomies. MATERIALS AND METHODS: Ninety-two patients who underwent craniotomies received pre- and postoperative venous ultrasonography and/or contrast-enhanced spiral computed tomography for diagnosis of DVT. The primary endpoint was DVT occurrence. Serial levels of serum D-dimer, soluble fibrin, and thrombin-antithrombin complex (TAT) were analyzed. RESULTS: Twenty-four of 92 patients (26.1%) had DVT, of whom 10 (41.7%) were diagnosed preoperatively. In patients with preoperative DVT, age, incidence of decreased performance status and leg paresis, levels of D-dimer, soluble fibrin, and TAT were significantly greater. In patients with postoperative DVT, length of surgery, incidence of decreased postoperative performance status, levels of D-dimer on postoperative days (POD) 3, 7, and 14, and TAT on POD7 were significantly greater. Patients with postoperative DVT had elevated D-dimer levels on POD 7 compared with POD 3. The D-dimer cutoff of 2.65 µg/mL at POD 7 could be used to identify DVT with 85.7% sensitivity and 72.3% specificity. A cutoff of 5.25 µg/mL at POD 7 yielded a specificity of 96.9%. Decreased performance status and elevated D-dimer were independent predictors for preoperative DVT, prolonged operation time, and elevated D-dimer on POD 7 for postoperative DVT. CONCLUSIONS: DVT frequently was observed in patients before and after undergoing craniotomies. Patients with decreased performance status should be preoperatively screened for DVT by checking D-dimer levels. Elevated D-dimer levels on POD 7 compared with POD 3 and D-dimer levels greater than 2.65 µg/mL at POD7 suggest the presence of DVT.

CNS high-grade neuroepithelial tumor with BCOR internal tandem duplication: a comparison with its counterparts in the kidney and soft tissue.

Central nervous system high-grade neuroepithelial tumors with BCOR alteration (CNS HGNET-BCOR) are a recently reported rare entity, identified as a small fraction of tumors previously institutionally diagnosed as so-called CNS primitive neuroectodermal tumors. Their genetic characteristic is a somatic internal tandem duplication in the 3' end of BCOR (BCOR ITD), which has also been found in clear cell sarcomas of the kidney (CCSK) and soft tissue undifferentiated round cell sarcomas/primitive myxoid mesenchymal tumors of infancy (URCS/PMMTI), and these BCOR ITD-positive tumors have been reported to share similar pathological features. In this study, we performed a clinicopathological and molecular analysis of six cases of CNS HGNET-BCOR, and compared them with their counterparts in the kidney and soft tissue. Although these tumors had histologically similar structural patterns and characteristic monotonous nuclei with fine chromatin, CNS HGNET-BCOR exhibited glial cell morphology, ependymoma-like perivascular pseudorosettes and palisading necrosis, whereas these features were not evident in CCSK or URCS/PMMTI. Immunohistochemically, diffuse staining of Olig2 with a mixture of varying degrees of intensity, and only focal staining of GFAP, S-100 protein and synaptophysin were observed in CNS HGNET-BCOR, whereas these common neuroepithelial markers were negative in CCSK and URCS/PMMTI. Therefore, although CNS HGNET-BCOR, CCSK and URCS/PMMTI may constitute a group of BCOR ITD-positive tumors, only CNS HGNET-BCOR has histological features suggestive of glial differentiation. In conclusion, we think CNS HGNET-BCOR are a certain type of neuroepithelial tumor relatively close to glioma, not CCSK or URCS/PMMTI occurring in the CNS.

Siblings with congenital thrombotic thrombocytopenic purpura.

Congenital thrombotic thrombocytopenic purpura (TTP) is a rare hereditary deficiency of ADAMTS13 (von Willebrand factor-cleaving protease) characterized by thrombocytopenia and microangiopathic hemolytic anemia. The spectrum of the clinical phenotype is wide, ranging from asymptomatic episodes of thrombocytopenia to life-threatening multiorgan failure. Reportedly, some patients develop isolated thrombocytopenia during childhood. We herein report sibling cases of congenital TTP. An 11-year-old boy with thrombocytopenia accompanied by influenza virus infection was referred to our hospital. He had a history of severe neonatal jaundice. His 15-year-old brother also had recurrent thrombocytopenia with approximately 10 episodes of recurrence since 3 years of age. Their ADAMTS13 activities were low and ADAMTS13 inhibitors were negative, and a gene analysis confirmed the diagnosis of congenital TTP. Notably, congenital TTP should be included in the differential diagnosis, and it is essential to determine the ADAMTS13 activity for pediatric patients with thrombocytopenia of unknown etiology.

Fracture of the Tibial Baseplate 16 Years after Miller-Galante II Total Knee Arthroplasty.

We report a rare case of tibial baseplate fracture of Miller-Galante II (MG II) prosthesis. We examine the factors that may cause such late fracture and review the literature on radiographic analysis and retrieval studies. A 76-year-old woman, who had undergone bilateral MG II total knee arthroplasty due to rheumatoid arthritis 16 years earlier, presented to our department with a 3-month history of left knee pain. Plain radiographs revealed severe distortion of the medial tibial component. During revision knee arthroplasty, we observed severe metallosis in the knee joint, polyethylene insert deformation, and posteromedial coronal baseplate fracture. After removal of the fractured tray, a bone deficit due to osteolysis was noted. The revision prosthesis (LCCK, Zimmer-Biomet) was implanted uneventfully. Four months after revision surgery, the patient was ambulating and had no complications. The implants on the right side had survived without complications for 17 years. We speculate that the primary causative factor of the fatigue fracture of the base plate due to loss of bony support most likely secondary to osteolysis was varus malalignment at primary implantation. This case highlights the importance of paying close attention to the correct alignment of each component at primary implantation.

Flow cytometric analysis as an additional predictive tool of treatment response in children with chronic-phase chronic myeloid leukemia treated with imatinib.

Bone marrow samples of newly diagnosed children with chronic-phase chronic myeloid leukemia (CML) were obtained at diagnosis and after imatinib initiation and stained with anti-human CD34, CD38, CD123, CD45RA, cMpl, and lineage antibodies. Flow cytometric analysis revealed that granulocyte macrophage progenitor predominance in CML progenitors at diagnosis and elevated cMpl expression in bone marrow progenitors at 3 months may predict poor outcome in children with chronic-phase CML treated with imatinib. We recommend flow cytometric analysis of bone marrow in the early phase of treatment, as it is a convenient tool that may predict treatment response and guide CML management.

High-dose Cepharanthin for pediatric chronic immune thrombocytopenia in Japan.

BACKGROUND: A nationwide, multicenter and observational study was retrospectively conducted to evaluate the clinical utility of Cepharanthin (CEP) for pediatric patients with chronic immune thrombocytopenia (ITP). METHODS: Clinical and laboratory data for 46 Japanese patients aged <16 years who were diagnosed as having chronic ITP in 14 hospitals during 2001-2011, and were treated with CEP for >12 months, were analyzed. RESULTS: Median daily CEP dose was 1 mg/kg (range, 0.12-2 mg/kg). Median platelet count prior to CEP was 20.5 × 109 /L (IQR, 8.3-53.0 × 109 /L), and then significantly increased to 58.5 × 109 /L (IQR, 22.8-115.0 × 109 /L) and 69.0 × 109 /L (IQR, 23.0-134.0 × 109 /L) at 12 and 24 months of treatment, respectively. No life-threatening bleeds or moderate-severe adverse events were reported. Of 38 patients who received both corticosteroids (CS) and CEP, 17 patients (45%) were weaned from CS, and 15 patients (39%) attained the reduced dose of CS. The duration from the start of CEP to the stopping of CS was a median of 413 days (range, 49-1734 days) in patients who were weaned from CS. CONCLUSIONS: CEP alone or combined with CS was useful for the management of pediatric chronic ITPs.

The Rapid Induction of Carbapenem-Resistance in an Aeromonas dhakensis Blood Isolate.

Meropenem-susceptible and -resistant Aeromonas dhakensis isolates from blood cultures of a fatal case of septicemia were analyzed. The two isolates were homologous and gene expression of metallo-ß-lactamase in the resistant strain was upregulated. Physicians should be aware of the possibility of the induction of carbapenem-resistance, following the use of carbapenems in the treatment of Aeromonas infection.

Leukostasis in Children and Adolescents with Chronic Myeloid Leukemia: Japanese Pediatric Leukemia/Lymphoma Study Group.

BACKGROUND: The details of leukostasis in children and adolescents with chronic myeloid leukemia (CML) are unknown. This study determined the characteristics of leukostasis in children and adolescents with CML. PROCEDURE: A total of 256 cases from a retrospective study of patients with CML conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group from 1996 to 2011 were analyzed, and of these, 238 cases were evaluated in this study. RESULTS: Leukostasis was diagnosed in 23 patients (9.7%). The median leukocyte count and spleen size below the left costal margin in cases with leukostasis were significantly higher and larger when compared to those in cases without leukostasis (458.5 × 10(9) /l vs. 151.8 × 10(9) /l (P < 0.01), and 13 vs. 5 cm (P < 0.01), respectively). Leukostasis occurred with ocular symptoms in 14 cases, priapism in four cases, and dyspnea, syncope, headache, knee pain, difficulty hearing, and aseptic necrosis of the femoral head in one case each. One case had two leukostasis symptoms simultaneously. Three cases were diagnosed before imatinib became available. Five cases received special treatment, and in the remaining 15 cases, all of these symptoms resolved after treatment with imatinib. CONCLUSIONS: This retrospective study represents the largest series of children and adolescents in which leukostasis of CML has been reported. Our data provide useful insight into the characteristics of leukostasis in recent cases of children and adolescents with CML.