Whole-genome CRISPR screening identifies molecular mechanisms of PD-L1 expression in adult T-cell leukemia/lymphoma.

ABSTRACT: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis and limited treatment options. Programmed cell death ligand 1(PD-L1) is recognized to be involved in the pathobiology of ATLL. However, what molecules control PD-L1 expression and whether genetic or pharmacological intervention might modify PD-L1 expression in ATLL cells are still unknown. To comprehend the regulatory mechanisms of PD-L1 expression in ATLL cells, we performed unbiased genome-wide clustered regularly interspaced short palindromic repeat (CRISPR) screening in this work. In ATLL cells, we discovered that the neddylation-associated genes NEDD8, NAE1, UBA3, and CUL3 negatively regulated PD-L1 expression, whereas STAT3 positively did so. We verified, in line with the genetic results, that treatment with the JAK1/2 inhibitor ruxolitinib or the neddylation pathway inhibitor pevonedistat resulted in a decrease in PD-L1 expression in ATLL cells or an increase in it, respectively. It is significant that these results held true regardless of whether ATLL cells had the PD-L1 3' structural variant, a known genetic anomaly that promotes PD-L1 overexpression in certain patients with primary ATLL. Pevonedistat alone showed cytotoxicity for ATLL cells, but compared with each single modality, pevonedistat improved the cytotoxic effects of the anti-PD-L1 monoclonal antibody avelumab and chimeric antigen receptor (CAR) T cells targeting PD-L1 in vitro. As a result, our work provided insight into a portion of the complex regulatory mechanisms governing PD-L1 expression in ATLL cells and demonstrated the in vitro preliminary preclinical efficacy of PD-L1-directed immunotherapies by using pevonedistat to upregulate PD-L1 in ATLL cells.

A retrospective observational study on disseminated herpes zoster in immunocompetent patients.

INTRODUCTION: Disseminated herpes zoster (DHZ) is a severe infection associated with high incidences and mortality rates in immunocompromised patients. Although studies have shown its occurrence in immunocompetent patients, its epidemiology, clinical presentation, and treatment outcomes in this cohort remain unknown. Thus, this study aimed to examine the clinical presentation, treatment, complications, and outcomes of DHZ in immunocompetent patients and compare these findings with previous studies. METHODS: We included 20 immunocompetent patients of DHZ at our institution and reviewed 42 previously published cases. We then investigated the clinical features, predisposing factors, laboratory findings, treatment, and outcomes of all cases including in-hospital mortality, neurological dysfunction at discharge, and postherpetic neuralgia. We compared DHZ-immunocompetent patients to DHZ-immunocompromised patients. RESULTS: Patients had a median age of 71.5 years and were predominantly male. The trigeminal area was the most common site of initial rash, with a mean dissemination time of 6.5 days. Pain was the most common symptom, followed by fever (approximately 40 % of cases); acyclovir was the most used treatment. Additionally, the in-hospital mortality was 0 %, neuropathy at discharge was observed in approximately 10 % of patients, and postherpetic neuralgia was present in approximately 40 % of patients. In the immunocompromised cases, the mortality rate was 12 %, which was higher than in our cases; however, the rates of neuropathy and postherpetic neuralgia were lower. CONCLUSIONS: This study provides new insights into the clinical presentation, treatment, and outcomes of DHZ cases in immunocompetent patients, highlighting its tendency for residual neurological damage despite having low mortality rates.

The Usefulness of Reduced Anion Gap and the Possibility of Pupillary Findings in the Treatment of Acute Bromvalerylurea Intoxication.

Bromvalerylurea is found as an over-the-counter analgesic and hypnotic drug in Japan and can be purchased at drugstores or over the Internet. Therefore, both acute poisoning due to large doses taken in suicide attempts and chronic poisoning due to continuous use for chronic pain have been observed. We report a case of acute BVU poisoning due to the use of an over-the-counter hypnotic sedative for a suicide attempt. A 34-year-old woman was referred to our ICU with unexplained disturbance of consciousness, respiratory failure, and shock. During ICU management, when her pupil diameter was measured with an automatic pupillometer to confirm her conscious state, the right pupil diameter was larger than the left, but one hour later, the left pupil diameter was larger than the right. The difference between right and left fluctuated with the time of day. After awakening, it was found that the patient had taken 108 tablets of Utt, an over-the-counter hypnotic sedative, and the possibility of acute poisoning by its component, BVU, was raised. Because a blood gas analysis at the time of admission showed metabolic acidosis with anion gap ≤1, a diagnosis of acute BVU poisoning was made. The patient's general condition stabilized, and she was transferred to the psychiatric ward. Symptoms of acute BVU poisoning include impaired consciousness and respiratory and circulatory depression, which may make it impossible to obtain a medical interview. When treating a patient with suspected drug intoxication who is unable to communicate, the clinician needs to include BVU poisoning in the differential when a reduced anion gap is observed. The clinician should also know that BVU poisoning can cause ocular manifestations such as anisocoria. This may lead to early diagnosis and therapeutic intervention.

Post-traumatic Delayed Bilateral Vocal Cord Paralysis Caused by Cervical Osteophytes: A Case Report.

Vocal fold paralysis occurs when the function of the vagus nerve or its distal branch, the recurrent laryngeal nerve, is diminished or absent. Bilateral vocal fold paralysis can present with varying degrees of severity and is sometimes fatal. Cervical osteophytes are a rare cause of bilateral vocal fold paralysis, with only a few cases reported. A 68-year-old man was brought to the emergency department because of a disturbance in consciousness following a fall. A CT scan of the head showed multiple cranium and brain injuries, and the patient was treated conservatively by neurosurgery. The day after the injury, dysphagia and dysarthria appeared. On the third day of admission, both vocal cords were fixed bilaterally in the paramedian position, and the patient was nearly choking on sputum. A CT scan showed that the intracranial lesions gradually improved, but the vocal cord paralysis remained. A cervical CT scan was performed to investigate the cause of the vocal cord paralysis, which revealed that cervical vertebral osteophytes were compressing the tracheoesophageal groove and the glottis. The patient was transferred to the hospital for rehabilitation, although bilateral vocal cord paralysis remained. Although rare, clinicians need to be aware that cervical osteophytes can cause vocal fold paralysis, which may be manifested when combined with further trauma. It is also important to note that traumatic vocal cord paralysis can be delayed.

Rapid Progression of Aortitis Caused by Methicillin-Sensitive Staphylococcus Aureus in a Patient With Pneumonia: A Case Report.

Infected aortic aneurysm is a rare but fatal disease that occurs through various mechanisms. In this report, we describe the case of a patient who was hospitalized for acute pneumonia and developed an infected aortic aneurysm in the descending aorta during the hospitalization. A 73-year-old Japanese man presented to the emergency department with a chief complaint of fever. He had a history of chronic renal failure due to nephrosclerosis and was on regular hemodialysis three times a week. The patient presented with an elevated inflammatory response, anemia, and low platelet counts after various tests. Computed tomography (CT) showed ground-glass opacity in the left lung with a small amount of pleural effusion, leading to a diagnosis of pneumonia. The patient was admitted to the hospital on the same day, and a course of antibiotics (ceftriaxone [CTRX]) was started. On the fourth day of hospitalization, methicillin-susceptible Staphylococcus aureus (MSSA) was detected in the blood sample, which was collected from the patient on the day of admission. The patient was treated for MSSA pneumonia and bacteremia, and the antibiotics were changed to cefazolin (CEZ). Treatment with antimicrobials resulted in a negative blood culture retest on day 5 and improvement of the inflammatory response. On the 12th day, improvements in pneumonia and pleurisy were observed on the CT scan; however, an abnormal bulge was seen on the dorsal side of the descending thoracic aorta with suspected partial vessel wall disruption, suggesting a ruptured infected aortic aneurysm. Despite treatment with antibiotics, the thoracic descending aortic aneurysm continued to dilate with progressing rupture, and the patient died on the 25th day of hospitalization. This is the first report of an infected aneurysm caused by Staphylococcus aureus, despite a negative blood culture. Patients at high risk might develop infected aneurysms, and the possibility of rapid dilation should always be considered.

Serotonin Syndrome Induced by Fentanyl Alone in an Adult Patient After Cardiac Surgery: A Case Report.

Serotonin syndrome is a rare but potentially fatal condition characterized by altered mental status, autonomic hyperactivity, and neuromuscular abnormalities. Although fentanyl is known to be a causative agent of serotonin syndrome, most reports have shown that fentanyl-related serotonin syndrome is caused by multiple drug interactions, and only one case of serotonin syndrome caused by fentanyl alone has been reported in a pediatric patient. In this report, we describe a case of postoperative serotonin syndrome caused by fentanyl alone in an adult patient after cardiac surgery. A 66-year-old male was diagnosed with unstable angina pectoris and underwent off-pump coronary artery bypass grafting. Two hours after the intensive care unit (ICU) admission, he exhibited symptoms of sweating, tremors, and muscle rigidity. Four hours later, the body temperature rose to 40.0 °C, suggesting malignant hyperthermia or a similar condition. Dantrolene was administered to the patient, and all symptoms improved within several minutes. However, the patient experienced a relapse of symptoms every four to six hours, requiring additional dantrolene treatment each time. Although no other serotonergic agents were used, we suspected serotonin syndrome induced by fentanyl alone and discontinued its use on postoperative day three. Following the discontinuation of fentanyl, no further episodes were observed. The patient was discharged from the hospital without any complications on postoperative day 29. During a subsequent check-up, the patient was found to have a sternal dehiscence and underwent one-stage sternal reconstruction. General anesthesia was induced and maintained without the use of fentanyl. The patient was discharged 10 days after surgery without symptoms of serotonin syndrome. In a patient with postoperative hyperthermia and neuromuscular abnormalities, serotonin syndrome should be considered when fentanyl is administered. Dantrolene may be beneficial in managing serotonin syndrome caused by fentanyl alone and/or benzodiazepine resistance.

Endogenous endophthalmitis caused by Streptococcus mitis: A case report.

RATIONALE: Endogenous endophthalmitis is a rare disease caused by hematogenous intraocular metastasis of bacteria from an infectious source. Diagnosing endogenous endophthalmitis is challenging for non-ophthalmologists. However, ophthalmic diseases can cause irreversible vision loss, making prompt diagnosis and treatment critical. Here we present a rare case of endogenous endophthalmitis initially misdiagnosed as a cataract. PATIENT CONCERNS: An 84-year-old Japanese man presented to the emergency department with fever and dysmotility. The patient was aware of a left subconjunctival hemorrhage and cloudy cornea upon arrival at the hospital, but he misunderstood it as a fall-induced subconjunctival hemorrhage and age-related cataracts. DIAGNOSES: On the day following admission, petechial hemorrhage on the eyelid conjunctiva and the detection of Streptococcus mitis in the blood culture results led us to suspect endophthalmitis rather than cataracts. A definitive diagnosis of endophthalmitis was made through ophthalmologic examinations, and endophthalmitis was considered secondary to endocarditis. INTERVENTIONS: Subsequently, antimicrobial treatment was continued. OUTCOMES: However, the patient developed myocardial infarction and died on the ninth day of hospitalization. LESSONS: Two important lessons were learned from the examination of this case of endogenous endophthalmitis caused by S mitis. First, endophthalmitis and cataracts can be misdiagnosed. Because the symptoms of endophthalmitis and cataracts, such as decreased vision, photophobia, and blurred vision, are similar, the eye must be cautiously examined. Second, endocarditis caused by S mitis may lead to endogenous endophthalmitis. Although S mitis is not pathogenic, endogenous endophthalmitis may occur in patients with certain risk factors, such as older age, cancer, and immunosuppression.

Specificity of DNA damage formation induced by femtosecond near-infrared laser filamentation in water.

We investigated the deoxyribonucleic acid (DNA) damage induced by laser filamentation, which was generated by focusing femtosecond near-infrared Ti:Sapphire laser light in water at several repetition rates ranging from 1000 Hz to 10 Hz. Using plasmid DNA (pUC19), the single-strand break, double-strand break, nucleobase lesions, and the fragmented DNA were analyzed and quantified by agarose gel electrophoresis. Additionally, the H2O2 concentration after irradiation was determined. We observed that (1) the DNA damage per laser shot and (2) the enzyme-sensitive base lesions per total DNA damage decreased as the laser repetition rate increased. Furthermore, (3) extraordinarily short DNA fragments were likely to be produced, compared with those produced using X-rays, and (4) most OH radicals could be eliminated by recombination to generate H2O2, preventing them from damaging the DNA. The Monte-Carlo simulation of the strand break formation implies that the observed dependency of strand break efficiency on the laser repetition rate is mainly due to diffusion of DNA molecules. These findings quantitatively and qualitatively revealed that an intense laser pulse induces a specific DNA damage profile that is not induced by X-rays, a sparsely ionizing radiation source.

Balloon pulmonary angioplasty under awake veno-arterial extracorporeal membrane oxygenation in a patient with class III obesity with chronic thromboembolic pulmonary hypertension complicated with multiple serious comorbidities.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a chronic disease that can rapidly deteriorate into circulatory collapse when complicated by comorbidities. We herein describe a case involving a 43-year-old woman with class III obesity (body mass index of 63 kg/m2) and severe CTEPH associated with total occlusion of the left main pulmonary artery who subsequently developed circulatory collapse along with multiple comorbidities, including acute kidney injury, pulmonary tuberculosis, and catastrophic antiphospholipid syndrome. The patient was successfully treated with two sessions of rescue balloon pulmonary angioplasty with veno-arterial extracorporeal membrane oxygenation (V-A ECMO) support under local anesthesia without sedation, at cannulation and during the V-A ECMO run, to avoid invasive mechanical ventilation. This case suggests the potential usefulness of rescue balloon pulmonary angioplasty under awake V-A ECMO support for rapidly deteriorating, inoperable CTEPH in a patient with class III obesity complicated with multiple comorbidities.

Safety and tolerability of OP-724 in patients with haemophilia and liver cirrhosis due to HIV/HCV coinfection: an investigator-initiated, open-label, non-randomised, single-centre, phase I study.

OBJECTIVE: Patients with haemophilia and HIV who acquire hepatitis C virus (HCV) after receiving contaminated blood products can experience accelerated progression of liver fibrosis and a poor prognosis, making liver disease a prominent cause of mortality among these patients. In the current study, we aimed to evaluate the safety and tolerability of the potential antifibrotic agent OP-724-a CREB-binding protein/ß-catenin inhibitor-in this patient subset. DESIGN: In this single-centre, open-label, non-randomised, phase I trial, we sequentially enrolled patients with cirrhosis following HIV/HCV coinfection classified as Child-Pugh (CP) class A or B. Five patients received an intravenous infusion of OP-724 at doses of 140 or 280 mg/m2 for 4 hours two times weekly over 12 weeks. The primary endpoint was the incidence of serious adverse events (SAEs). Secondary endpoints included the incidence of AEs and improved liver stiffness measure (LSM), as determined by vibration-controlled transient elastography. This study was registered at ClinicalTrials.gov (NCT04688034). RESULTS: Between 9 February 2021 and 5 July 2022, five patients (median age: 51 years) were enrolled. All five patients completed 12 cycles of treatment. SAEs were not observed. The most common AEs were fever (60%) and gastrointestinal symptoms (diarrhoea: 20%, enterocolitis: 20%). Improvements in LSM and serum albumin levels were also observed. CONCLUSION: In this preliminary assessment, intravenous administration of 140 or 280 mg/m2/4 hours OP-724 over 12 weeks was well tolerated by patients with haemophilia combined with cirrhosis due to HIV/HCV coinfection. Hence, the antifibrotic effects of OP-724 warrant further assessment in patients with cirrhosis. TRIAL REGISTRATION NUMBER: NCT04688034.

Characteristics and prognosis of patients with COVID-19 and hematological diseases in Japan: a cross-sectional study.

The Japanese Society of Hematology performed an observational cross-sectional study to clarify the morbidity, prognosis, and prognostic factors in patients with COVID-19 with hematological diseases (HDs) in Japan. The study included patients with HDs who enrolled in our epidemiological survey and had a COVID-19 diagnosis and a verified outcome of up to 2 months. The primary endpoints were characteristics and short-term prognosis of COVID-19 in patients with HDs. A total of 367 patients from 68 institutes were enrolled over 1 year, and the collected data were analyzed. The median follow-up among survivors was 73 days (range, 1-639 days). The 60-day overall survival (OS) rate was 86.6%. In the multivariate analysis, albumin ≤ 3.3 g/dL and a need for oxygen were independently associated with inferior 60-day OS rates (hazard ratio [HR] 4.026, 95% confidence interval (CI) 1.954-8.294 and HR 14.55, 95% CI 3.378-62.64, respectively), whereas 60-day survival was significantly greater in patients with benign rather than malignant disease (HR 0.095, 95% CI 0.012-0.750). Together, these data suggest that intensive treatment may be necessary for patients with COVID-19 with malignant HDs who have low albumin levels and require oxygen at the time of diagnosis.