The significance of BAP1 and MTAP/CDKN2A expression in well-differentiated papillary mesothelial tumour: a series of 21 cases and a review of the literature.

The nomenclature and diagnostic criteria of well-differentiated papillary mesothelial tumour (WDPMT) have been changed in the 2021 World Health Organization (WHO) classification of thoracic tumours, and a new entity, mesothelioma in situ (MIS), introduced. Histologically these two entities may be similar. However, MIS is regarded as a precursor to invasive mesothelioma and requires demonstration of loss of BAP1 and/or MTAP/CDKN2A for diagnosis, whereas performance of these ancillary tests is desirable but not essential for a diagnosis of WDPMT, in which the significance of BAP1 and/or MTAP/CDKN2A loss is not well understood or well defined. Against this backdrop, we undertook an investigation of 21 cases of WDPMT, identified from our case files and diagnosed according to 2021 WHO criteria, to explore the relationship between histology and BAP1 and MTAP/CDKN2A expression with clinical features including asbestos exposure, focality of tumours and clinical outcome. There were 18 women and three men, with ages ranging from 23-77 years (median 62 years), in which six had a history of asbestos exposure, two had no exposure, and in 13 exposure history was unavailable. Of 20 peritoneal tumours and one pleural tumour, 13 were detected incidentally at the time of surgery for unrelated conditions and eight peritoneal tumours were multifocal at the time of diagnosis. BAP1 immunohistochemistry (IHC) was performed in all 21 tumours, with nine tumours showing BAP1 expression loss. MTAP/CDKN2A testing was performed in 14 tumours, comprising MTAP IHC in 12 and CDKN2A fluorescence in situ hybridisation (FISH) in two, with three tumours showing MTAP/CDKN2A expression loss. Two tumours with MTAP/CDKN2A loss also showed BAP1 expression loss. Four patients progressed to invasive mesothelioma, including one male with a pleural tumour and asbestos exposure, and three females with multifocal peritoneal tumours, two with asbestos exposure and one without exposure. BAP1 expression loss was seen in all tumours from the four patients who progressed to invasive mesothelioma, whilst two of these tumours showed retained MTAP IHC and two were not tested. There was one patient with a tumour with MTAP loss and retained BAP1 who died from unrelated causes 5 months after diagnosis. Eight patients received WDPMT-specific treatment in addition to the initial excision. Survival for all patients ranged from 4-218 months, with one patient dying of mesothelioma at 49 months. Based on our results in this series of 21 patients with WDPMT diagnosed according to 2021 WHO criteria, we propose that WDPMT with BAP1 expression loss may best be regarded as papillary MIS and that a history of asbestos exposure and the presence of multifocal tumours in patients diagnosed with WDPMT should prompt ancillary testing with BAP1 IHC. Further we propose that BAP1 IHC should be essential in the diagnosis of WDPMT, with the diagnosis restricted to those tumours which show retained BAP1 expression. However more studies in larger cohorts of patients are needed to explore the relationship between BAP1 expression and MTAP loss in WDPMT, which will help to define this entity and separate it more clearly from MIS and invasive mesothelioma.

A novel GSN variant outside the G2 calcium-binding domain associated with Amyloidosis of the Finnish type.

Gelsolin (GSN) variants have been implicated in amyloidosis of the Finnish type. This case series reports a novel GSN:c.1477T>C,p.(Trp493Arg) variant in a family with ocular and systemic features consistent with Finnish Amyloidosis. Exome sequencing performed on affected individuals from two families manifesting cutis laxa and polymorphic corneal stromal opacities demonstrated the classic GSN:c.654G>A,p.Asp214Asn variant in single affected individual from one family, and a previously undocumented GSN:c.1477T>C variant in three affected first-degree relatives from a separate family. Immunohistochemical studies on corneal tissue from a proband with the c.1477T>C variant identified gelsolin protein within histologically defined corneal amyloid deposits. This study reports a novel association between the predicted pathogenic GSN:c.1477T>C variant and amyloidosis of the Finnish type, and is the first to provide functional evidence of a pathological GSN variant at a locus distant to the critical G2 calcium-binding region, resulting in the phenotype of amyloidosis of the Finnish type.

The potential utility of GATA binding protein 3 for diagnosis of malignant pleural mesotheliomas.

Malignant pleural mesothelioma is associated with asbestos exposure and poor outcomes. The usefulness of immunohistochemistry for diagnosis of sarcomatoid mesothelioma, especially the desmoplastic type, is limited, and more effective markers are required. GATA binding protein 3 (GATA3) has been suggested as a diagnostic marker for sarcomatoid mesothelioma. The potential usefulness of GATA3 for prognostication and its clinical and pathological correlations in different subtypes of mesothelioma have not been evaluated. We investigated the immunohistochemical labeling and associations for GATA3, BRCA1-associated protein 1 (BAP1), and Ki67 labeling in three major histological types of pleural malignant mesotheliomas. We examined 149 clinically annotated malignant mesotheliomas and assessed associations of GATA3 expression with clinical variables and prognosis. In addition, we labeled 10 cases of fibrous pleuritis with GATA3, all of which were negative. GATA3 was positive in 75 of 149 (50%) mesotheliomas, with the highest incidence of labeling seen in the sarcomatoid subtype (73%), compared with the biphasic (50%) and epithelioid (40%), mesotheliomas. A total of eight desmoplastic mesotheliomas showed labeling with GATA3. Patients whose tumors had sarcomatoid histology showed poorer survival than those with the other subtypes (p < 0.001), but overall GATA3 labeling did not have a statistically significant association with survival (p = 0.602). There was no association of GATA3 labeling and BAP1 status or Ki67 index. Our study includes the largest cohort of mesotheliomas that has been labeled for GATA3 to date. GATA3 is a useful marker for sarcomatoid mesothelioma, including the desmoplastic subtype. Discordance in GATA3 and BAP1 labeling of epithelioid and sarcomatoid components in the biphasic subtype is not uncommon.

Subsymptomatic Aerobic Exercise for Patients With Postconcussion Syndrome: A Critically Appraised Topic.

Clinical Scenario: Patients who experience prolonged concussion symptoms can be diagnosed with postconcussion syndrome (PCS) when those symptoms persist longer than 4 weeks. Aerobic exercise protocols have been shown to be effective in improving physical and mental aspects of health. Emerging research suggests that aerobic exercise may be useful as a treatment for PCS, where exercise allows patients to feel less isolated and more active during the recovery process. Clinical Question: Is aerobic exercise more beneficial in reducing symptoms than current standard care in patients with prolonged symptoms or PCS lasting longer than 4 weeks? Summary of Key Findings: After a thorough literature search, 4 studies relevant to the clinical question were selected. Of the 4 studies, 1 study was a randomized control trial and 3 studies were case series. All 4 studies investigated aerobic exercise protocol as treatment for PCS. Three studies demonstrated a greater rate of symptom improvement from baseline assessment to follow-up after a controlled subsymptomatic aerobic exercise program. One study showed a decrease in symptoms in the aerobic exercise group compared with the full-body stretching group. Clinical Bottom Line: There is moderate evidence to support subsymptomatic aerobic exercise as a treatment of PCS; therefore, it should be considered as a clinical option for reducing PCS and prolonged concussion symptoms. A previously validated protocol, such as the Buffalo Concussion Treadmill test, Balke protocol, or rating of perceived exertion, as mentioned in this critically appraised topic, should be used to measure baseline values and treatment progression. Strength of Recommendation: Level C evidence exists that the aerobic exercise protocol is more effective than the current standard of care in treating PCS.

The Comparison of Instrument-Assisted Soft Tissue Mobilization and Self-Stretch Measures to Increase Shoulder Range of Motion in Overhead Athletes: A Critically Appraised Topic.

Clinical Scenario: Shoulder range of motion (ROM) in throwing athletes relies on a balance of mobility and stability to maintain proper function and health that, if disrupted, can lead to shoulder injury. There have been several studies that address the relationship between ROM deficits and overhead injuries; however, it may be unclear to clinicians which interventions are most effective for increasing ROM in the glenohumeral joints of overhead athletes. CLINICAL QUESTION: In overhead athletes who have deficient shoulder ROM, is instrument-assisted soft tissue mobilization (IASTM) more effective at acutely increasing ROM over the course of a patient's treatment when compared with self-stretching? Summary of Key Findings: A thorough literature review yielded 3 studies relevant to the clinical question, and all 3 studies were included. Two articles found a significant increase in acute ROM when compared with a self-stretch measure. All 3 articles showed increases in internal rotation and horizontal adduction, and 1 study reported an increase in total arc of shoulder ROM. Clinical Bottom Line: There is moderate evidence to support the use of IASTM to acutely increase ROM in the glenohumeral joint of overhead athletes. Clinicians should be aware of the variability with recommended treatment times; however, positive results have been seen with treatments lasting 5 to 6 minutes per treatment region. There is no consensus for treatment intensity, and certain IASTM tools require certification. Strength of Recommendation: Grade B evidence exists that IASTM is more effective at increasing shoulder ROM (ie, internal rotation, horizontal adduction, external rotation, total arc of motion) in overhead athletes than self-stretching measures.

Myocardial stiffness and the timing difference between tissue Doppler imaging Ea and peak mitral valve opening can distinguish physiological hypertrophy in athletes from hypertrophic cardiomyopathy.

AIM: To differentiate between physiological and pathological left ventricular hypertrophy in athletes using echocardiography. METHODS AND RESULTS: Eleven patients with mild hypertrophic cardiomyopathy were compared against 17 international rowers with mild left ventricular hypertrophy, and 30 age matched controls. The time difference between peak Ea (Doppler tissue imaging) and peak mitral valve opening (using M-mode) was measured simultaneously. A novel index (E/Ea)/LVEDD, as a measure of left ventricular stiffness was recorded. In athletes the peak Ea preceded peak mitral opening by: median (interquartile range) 20 ms (10,20), control group 15 ms (0,30), compared with HCM where Ea followed peak mitral opening by 10 ms (0,20), P<0.0001. In athletes the index of left ventricular stiffness was lower than controls 1.2 (0.93,1.4) versus 1.5 (1.3,1.6), and HCM 2.2 (2.0,2.3), P<0.0001. CONCLUSION: Physiological hypertrophy can be differentiated from hypertrophic cardiomyopathy in athletes using the Ea-peak mitral opening difference, and our index of ventricular stiffness.