WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma.

Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors driven by populations of cancer stem cells (CSCs). However, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy-resistant niche and identified WDR5 as indispensable for this population. WDR5 is a component of the WRAD complex, which promotes SET1 family-mediated Lys4 methylation of histone H3 (H3K4me), associated with positive regulation of transcription. In GBM CSCs, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, including the POU5F1(OCT4)::SOX2 motif. Use of a SOX2/OCT4 reporter demonstrated that WDR5 inhibitor treatment diminished cells with high reporter activity. Furthermore, WDR5 inhibitor treatment and WDR5 knockdown altered the stem cell state, disrupting CSC in vitro growth and self-renewal, as well as in vivo tumor growth. These findings highlight the role of WDR5 and the WRAD complex in maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers.

The Impact of Continuous Positive Airway Pressure upon Pleural Fluid Pressures during Thoracentesis.

BACKGROUND: Excessive drop of pleural pressure (Ppl) during therapeutic thoracentesis may be related to adverse events and/or to repeated procedures due to incomplete drainage. OBJECTIVE: This was a pilot study of the impact of the application of continuous positive airway pressure (CPAP) at +5 cm H2O upon the Ppl profile during thoracentesis. METHODS: This was a prospective, controlled study of 49 consecutive adults who underwent thoracentesis. Enrollment was via alternation on a one-to-one basis. Pleural manometry was used to compare serial Ppl in patients using CPAP at +5 cm H2O (CPAP group) with Ppl in patients without CPAP (control group). RESULTS: Mean volumes drained were comparable between CPAP and control groups (1,380 vs. 1,396 mL). Patients in the CPAP group had a significantly greater change in volume per centimeter water column pressure (p = 0.0231, 95% confidence interval 6.41-82.61). No patient in the CPAP group had a Ppl less than -20 cm H2O at termination of the procedure, while 8 (33%) control group patients developed a pressure lower than -20. No patient in either group developed re-expansion pulmonary edema. CONCLUSION: The application of CPAP at +5 cm H2O mitigates the decreases in Ppl caused by thoracentesis via an increase in pleural compliance. The clinical implications of this finding merit study.

Patient-Reported Dyspnea Correlates Poorly with Aerobic Exercise Capacity Measured During Cardiopulmonary Exercise Testing.

BACKGROUND: Patient-reported dyspnea plays a central role in assessing cardiopulmonary disease. There is little evidence, however, that dyspnea correlates with objective exercise capacity measurements. If the correlation is poor, dyspnea as a proxy for objective assessment may be misleading. OBJECTIVE: To compare patient's perception of dyspnea with maximum oxygen uptake (MaxVO2) during cardiopulmonary exercise testing (CPET). METHODS: Fifty patients undergoing CPET for dyspnea evaluation were studied prospectively. Dyspnea assessment was measured by a metabolic equivalent of task (METs) table, Mahler Dyspnea Index, Borg Index, number of blocks walked, and flights of stairs climbed before stopping due to dyspnea. These descriptors were compared to MaxVO2. RESULTS: MaxVO2 showed low correlation with METs table (r = 0.388, p = 0.005) and no correlation with Mahler Index (r = 0.24, p = 0.093), Borg Index (r = -0.017, p = 0.905), number of blocks walked (r = 0.266, p = 0.077) or flights of stairs climbed (r = 0.188, p = 0.217). When adjusted for weight (maxVO2/kg), there was significant correlation between MaxVO2 and METs table (r = 0.711, p < 0.001), moderate correlation with blocks walked (r = 0.614, p < 0.001), and low correlation with Mahler Index (r = 0.488 p = 0.001), Borg Index (r = -0.333 p = 0.036), and flights of stairs (r = 0.457 p = 0.004). Subgroup analysis showed worse correlation when patients with normal CPET were excluded (12/50 excluded). Patients with BMI < 30 had no correlation between Max VO2 and the assessment methods, while patients with BMI > 30 had moderate correlation between MaxVO2 and METs table (r = 0.568, p = 0.002). CONCLUSION: Patient-reported dyspnea correlates poorly with MaxVO2 and fails to predict exercise capacity. Reliance on reported dyspnea may result in suboptimal categorization of cardiopulmonary disease severity.

Subepidermal Calcified Nodules of the Eyelid Differ in Children and Adults.

PURPOSE: Subepidermal calcified nodule of the eyelid is considered as one of the types of calcinosis cutis. It generally occurs in children, and is not known to be associated with systemic disease. The authors report histopathological and clinical findings in 14 cases of subepidermal calcified nodule of the eyelid, including 3 older patients with unique microscopic features. METHODS: Clinical records and pathological materials were critically reviewed in each case, including von kossa, CD3, CD20, and CD68 stains. RESULTS: The 14 cases presented clinically as nodular eyelid lesions. All were treated with surgical excision. The authors found 2 distinct histopathological patterns which correlated with the patients' age. In young patients, the authors observed multiple, small calcified bodies within the dermis surrounded by chronic inflammation and granulomatous foreign body reaction. On the other hand, in elderly patients, lesions were characterized by a single, large, well-demarcated amorphous calcified deposit surrounded by fibrous tissue, without chronic inflammation or foreign body reaction. One of these patients, a 70-year-old man, also suffered from gout. The presence of subepidermal calcified nodule was not documented as a preoperative diagnostic possibility in any of the cases. CONCLUSIONS: Subepidermal calcified nodule of the eyelid is a rare condition, but should be considered in any patient presenting with a painless white to yellowish colored nodule of the ocular adnexa, particularly during the teenage years. Clinicians and pathologists should be aware that this entity has a distinct appearance and could be associated with systemic conditions in elderly patients.

Search and Rescue: A Case Report and Discussion of Iatrogenic Intravascular Foreign Bodies.

The following case report demonstrates an unusual case of a patient with multiple intravascular iatrogenic foreign bodies. An inferior vena cava filter was identified in the abdominal aorta, and multiple hydrophilic wire fragments were found in the pulmonary circulation. After describing the management of this patient, we discuss how radiologists can best distinguish between various intravascular iatrogenic foreign bodies. Determining the type of catheter or wire within the patient can not only establish the chronicity of the finding, but can determine whether or not endovascular retrieval is recommended, and by what method. It is of the utmost importance that providers be able to distinguish between various intravascular devices in order to prevent ongoing or further harm to the patient.

POEM Procedure: What the Radiologist Needs to Know for This New Surgical Intervention for Achalasia.

Achalasia is a debilitating condition resulting from the failure of appropriate lower esophageal sphincter relaxation. Traditionally, the treatment of choice for achalasia has been a Heller myotomy, performed either via laparotomy or laparoscopically. The latter method has gained wide popularity in its documented lower postoperative morbidity. Recently, however, a new technique has been developed that can be performed by both thoracic surgeons and endoscopists-Per-Oral Endoscopic Myotomy. This procedure offers an alternative to invasive surgery and provides excellent outcomes with minimal recovery time.1 This article would help familiarize radiologists with this new technique, as well as both normal and abnormal postoperative appearances.

Night and day proteinuria in patients with sleep apnea.

BACKGROUND: Previous studies have suggested an association between obstructive sleep apnea (OSA) and heavy proteinuria. Two recent studies cast doubt on the association between OSA and proteinuria, but neither studied the effect of disordered sleep per se on urinary protein excretion. METHODS: We prospectively studied 75 patients undergoing polysomnography for suspected OSA. We excluded patients with renal insufficiency, diabetes mellitus, and systemic lupus erythematosus and those administered angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Urine protein-creatinine (P/C) ratio was measured on the date of the polysomnography before sleep (awake P/C ratio) and on awakening (asleep P/C ratio). Severity of OSA was stratified by means of the apnea-hypopnea index (AHI). RESULTS: Twenty-six patients (35%) did not have OSA, 25 patients (33%) had mild OSA, 9 patients (12%) had moderate OSA, and 15 patients (20%) had severe OSA. Asleep P/C ratio was less than 0.2 in 96% of patients, and awake P/C ratio was less than 0.2 in 89% of patients. No patient had an asleep P/C ratio greater than 1.0. There was no correlation between log asleep P/C ratio and log AHI ( r = -0.042; P = 0.73) or log awake P/C ratio and log AHI (r = 0.004; P = 0.97). No significant differences could be shown between mean log P/C ratio for either the asleep or awake urine collection across any of the 4 OSA severity strata. CONCLUSION: We found clinically significant proteinuria to be absent in stable outpatients with OSA. Proteinuria in patients with OSA should not be attributed to sleep apnea and warrants further evaluation.

Fever of unknown origin and pancytopenia caused by culture-proven delayed onset disseminated bacillus Calmette-Guerin (BCG) infection after intravesical instillation.

A 78-year-old man was diagnosed with bladder carcinoma in situ and was successfully treated with intravesical bacillus Calmette-Guérin (BCG) instillations. At 6 months after the last dose, he developed fever, weight loss and malaise. He had an extensive negative workup at an outside hospital and was treated empirically with ciprofloxacin for 2 weeks. The fever resolved but returned months later and he was readmitted with pancytopenia, elevated alkaline phosphatase and ground glass opacities on the chest CT. Bone marrow and liver biopsies showed non-caseating granulomas and were negative for acid-fast bacillus (AFB) and fungal stains. Mycobacterium tuberculosis complex PCR of the bone marrow was negative. Owing to the high clinical suspicion of disseminated BCG infection, the patient was treated empirically. After 9 weeks of incubation, the bone marrow AFB culture grew Mycobacterium bovis. Within 2 months of treatment his symptoms resolved and his laboratory results normalised.

Endobronchial ultrasound with transbronchial needle aspiration in the diagnosis of bilateral hilar and mediastinal lymphadenopathy.

BACKGROUND: : Bilateral hilar and/or mediastinal lymphadenopathy (BHL±ML) is an important radiographic finding. Since it was examined 38 years ago by Winterbauer and colleagues, better diagnostic techniques have been developed. The purpose of this study was to reexamine the diagnosis of BHL±ML by Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA). METHODS: : We carried out a retrospective analysis of data from 78 consecutive patients with BHL±ML who underwent EBUS-TBNA. Patient's characteristics including age, sex, symptoms, radiographic abnormalities, lymph node size, procedural complications, and the final pathologic diagnosis were recorded. RESULTS: : There were 8 diagnostic categories. Sarcoidosis was the most common diagnosis (73%), followed by lymphoma (10%), and reactive lymphadenopathy (10%). Nonlymphoma malignancy was found in 1 case. Seventy-three percent of the patients with sarcoidosis had stage 1 and 27% had stage 2 disease. The diagnosis was made by EBUS-TBNA in 92.3% of the cases. The diagnostic accuracy for EBUS-TBNA was 95% for stage 1 and 93% for stage 2. Fifty one percent of the patients were asymptomatic. Fifty seven percent of sarcoidosis and 36% of the nonsarcoidosis patients were asymptomatic. There were no significant complications from EBUS-TBNA. CONCLUSIONS: : EBUS-TBNA is a safe and minimally invasive procedure with a high diagnostic yield for BHL±ML. Sarcoidosis is still the most common diagnosis but the incidence seems to have decreased over the years. The increase in nonsarcoidosis patients and the evidence that lymphoma does occur in some asymptomatic patients suggests that biopsy confirmation with EBUS-TBNA is warranted.

An algorithmic approach to chronic dyspnea.

QUESTION: The objective of the study was to prospectively evaluate an algorithmic approach to the cause(s) of chronic dyspnea. MATERIALS/PATIENTS/METHODS: Prospective observational study. The study group consisted of 123 patients with a chief complaint of dyspnea of unknown cause present for >8 weeks. Dyspnea severity scores were documented at entry and after therapy. Patients underwent an algorithmic approach to dyspnea. Therapy could be instituted at any time that data supported a treatable diagnosis. Whenever possible, accuracy of diagnosis was confirmed with an improvement in dyspnea after therapy. Tests required, spectrum and frequency of diagnoses, and the values of individual tests were determined. RESULTS: Cause(s) was(were) diagnosed in 122/123 patients (99%); 97 patients had one diagnosis and 25 two diagnoses. Fifty-three percent of diagnoses were respiratory and 47% were non-respiratory. Following therapy, dyspnea improved in 63% of patients. CONCLUSIONS: The prospective algorithmic approach led to diagnoses in 99% of cases. A third of patients were diagnosed with each tier of the algorithm, thus minimizing the need for invasive testing. Specific diagnoses led to improvement in dyspnea in the majority of cases. Based on the results of this study, the algorithm can be revised to further minimize unnecessary tests without loss of diagnostic accuracy.