Whole-genome and transcriptome analysis enhances precision cancer treatment options.

BACKGROUND: Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data provided by whole-genome and transcriptome sequencing and analysis (WGTA) present an opportunity to align a much larger proportion of patients to therapies. PATIENTS AND METHODS: Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected. RESULTS: Clinically actionable targets were identified for 83% of patients, of which 37% of patients received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, poly-ADP ribose polymerase inhibitors and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%) and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies. CONCLUSIONS: Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.

Methylprednisolone in severe COVID-19 with acute respiratory distress syndrome - less is more?

INTRODUCTION: Corticosteroids, particularly methylprednisolone, are part of the treatment for severe COVID-19 with acute respiratory distress syndrome (ARDS). In this study, we aimed to compare the mortalities of patients treated with higher versus lower doses of methylprednisolone. Secondary outcomes included oxygenation, need for mechanical ventilation, length of stay in intensive care unit (ICU), secondary infection, improvement of PaO2/FiO2 (PF) ratio, and inflammatory response as expressed by C-reactive protein (CRP). MATERIALS AND METHODS: A retrospective cohort study conducted at Sarawak General Hospital from 1st June to 30th September 2021. Patients who received intravenous methylprednisolone for severe COVID-19 in the ICU were identified and divided into two groups: higher dose (cumulative dose more than 10 mg per kg) and lower dose (cumulative dose less than 10 mg per kg). RESULTS: Out of a total of 165 patients, 40 (24.2%) patients received higher dose methylprednisolone. There was no significant difference in socio-demographic characteristics (age, gender, body mass index), COVID-19 vaccination status, laboratory parameters (lymphocyte count, CRP, lactate dehydrogenase, D-dimer), or usage of immunomodulator therapy between the groups. Overall mortality was 23.6%. Mortality in the higher dose group was twice as high compared to lower dose group (37.5% versus 19.2%) (OR 3.79, 95% CI 1.24-11.59, p<0.05). In addition, the higher dose cohort developed more secondary infections (87.5%) and had longer stays in ICU (median 11 days, IQR 8- 15). No significant difference was found between both cohorts in terms of CRP reduction, improvement of PF ratio, or the need for mechanical ventilation post methylprednisolone. CONCLUSION: In this study, the use of higher dose methylprednisolone in COVID-19 with ARDS was not associated with better clinical outcomes. A lower dose of methylprednisolone might be sufficient in treating severe COVID-19 with ARDS.

Inter-relationships among psychopathology, premorbid adjustment, cognition and psychosocial functioning in first-episode psychosis: a network analysis approach.

BACKGROUND: Better understanding of interplay among symptoms, cognition and functioning in first-episode psychosis (FEP) is crucial to promoting functional recovery. Network analysis is a promising data-driven approach to elucidating complex interactions among psychopathological variables in psychosis, but has not been applied in FEP. METHOD: This study employed network analysis to examine inter-relationships among a wide array of variables encompassing psychopathology, premorbid and onset characteristics, cognition, subjective quality-of-life and psychosocial functioning in 323 adult FEP patients in Hong Kong. Graphical Least Absolute Shrinkage and Selection Operator (LASSO) combined with extended Bayesian information criterion (BIC) model selection was used for network construction. Importance of individual nodes in a generated network was quantified by centrality analyses. RESULTS: Our results showed that amotivation played the most central role and had the strongest associations with other variables in the network, as indexed by node strength. Amotivation and diminished expression displayed differential relationships with other nodes, supporting the validity of two-factor negative symptom structure. Psychosocial functioning was most strongly connected with amotivation and was weakly linked to several other variables. Within cognitive domain, digit span demonstrated the highest centrality and was connected with most of the other cognitive variables. Exploratory analysis revealed no significant gender differences in network structure and global strength. CONCLUSION: Our results suggest the pivotal role of amotivation in psychopathology network of FEP and indicate its critical association with psychosocial functioning. Further research is required to verify the clinical significance of diminished motivation on functional outcome in the early course of psychotic illness.

Abnormal cognitive effort allocation and its association with amotivation in first-episode psychosis.

BACKGROUND: Abnormal effort-based decision-making represents a potential mechanism underlying motivational deficits (amotivation) in psychotic disorders. Previous research identified effort allocation impairment in chronic schizophrenia and focused mostly on physical effort modality. No study has investigated cognitive effort allocation in first-episode psychosis (FEP). METHOD: Cognitive effort allocation was examined in 40 FEP patients and 44 demographically-matched healthy controls, using Cognitive Effort-Discounting (COGED) paradigm which quantified participants' willingness to expend cognitive effort in terms of explicit, continuous discounting of monetary rewards based on parametrically-varied cognitive demands (levels N of N-back task). Relationship between reward-discounting and amotivation was investigated. Group differences in reward-magnitude and effort-cost sensitivity, and differential associations of these sensitivity indices with amotivation were explored. RESULTS: Patients displayed significantly greater reward-discounting than controls. In particular, such discounting was most pronounced in patients with high levels of amotivation even when N-back performance and reward base amount were taken into consideration. Moreover, patients exhibited reduced reward-benefit sensitivity and effort-cost sensitivity relative to controls, and that decreased sensitivity to reward-benefit but not effort-cost was correlated with diminished motivation. Reward-discounting and sensitivity indices were generally unrelated to other symptom dimensions, antipsychotic dose and cognitive deficits. CONCLUSION: This study provides the first evidence of cognitive effort-based decision-making impairment in FEP, and indicates that decreased effort expenditure is associated with amotivation. Our findings further suggest that abnormal effort allocation and amotivation might primarily be related to blunted reward valuation. Prospective research is required to clarify the utility of effort-based measures in predicting amotivation and functional outcome in FEP.

Febrile neutropenia and its associated hospitalization in breast cancer patients on docetaxel-containing regimen: A retrospective cohort study on duration of prophylactic GCSF administration.

PURPOSE: To compare febrile neutropenia (FN) incidence and hospitalization among breast cancer patients on docetaxel with no granulocyte colony-stimulating factors (GCSF) primary prophylaxis (PP), 4/5-day PP, or 7-day PP. METHODS: We identified 3916 breast cancer patients using docetaxel-cyclophosphamide (TC), doxorubicin-cyclophosphamide then docetaxel (AC-T), fluorouracil-epirubicin-cyclophosphamide then docetaxel (FEC-T), docetaxel-carboplatin-trastuzumab (TJH), or docetaxel-doxorubicin-cyclophosphamide (TAC) from a hospital pharmacy dispensing database in Hong Kong between 2014 and 2016. Patients were offered GCSF within 5 days since administering docetaxel. Outcomes included FN incidence, time to first hospitalization, hospitalization rate, and duration. RESULTS: In TC regimen, FN incidence (with odds ratio, OR) of patients with no PP, 4/5-day PP, and 7-day PP was 21.69%, 7.95% (OR 0.31, p < 0.001), and 5.33% (OR 0.20, p < 0.001), respectively. In TJH regimen, FN incidence of patients with no PP, 4/5-day PP, and 7-day PP was 38.26%, 8.33% (OR 0.15, p < 0.001), and 8.57% (OR 0.15, p < 0.001), respectively. FN incidence of patients on AC-T regimen with no PP and 4/5-day PP was 20.93% and 6.84%, respectively (OR 0.28, p = 0.005); with FEC-T regimen, the incidence was 9.91% and 4.77%, respectively (OR 0.46, p = 0.035). Only 3.27% FN cases were not hospitalized. Mean (±standard deviation, SD) time to first hospitalization was 8.21 ± 2.44 days. Mean (±SD) duration of hospitalization for patients with no PP, 4/5-day PP, and 7-day PP was 4.66 ± 2.60, 4.37 ± 2.85, and 5.12 ± 2.97 days, respectively. CONCLUSION: GCSF prophylaxis in breast cancer patients on docetaxel could reduce FN incidence and hospitalization. 4/5-day PP demonstrated similar efficacy to 7-day PP with superior saving benefits on healthcare expenditure.

Diagnostic yield of medical thoracoscopy in exudative pleural effusions in a region with high tuberculosis burden.

INTRODUCTION: Pleural effusion is frequently encountered in respiratory medicine. However, despite thorough assessment including closed pleural biopsy, the cause of around 20% of pleural effusions remains undetermined. Medical thoracoscopy (MT) is the investigation of choice in these circumstances especially if malignancy is suspected. The aim of this study is to evaluate the diagnostic yield of MT in exudative pleural effusions in a single center from East Malaysia. METHODS: Retrospective chart review of all adult patients who underwent MT for undiagnosed exudative pleural effusion in a 24-month duration. RESULTS: Our cohort comprised of 209 patients with a median age of 61 years old (IQR 48.5-69.5). There were 92 (44%) patients with malignant pleural effusion (MPE) and 117 (56%) benign effusions; which included 85 tuberculous pleural effusion (TBE) and 32 cases of non-tuberculous exudative pleural effusion. Conclusive pathological diagnosis was made in 79.4% of the cases. For diagnosis of MPE, MT had a sensitivity of 89.1% (95% CI 80.4-94.3), specificity of 100% (95% CI 96.0-100.0), and positive predictive value (PPV) of 100% (95% CI 94.4-100) and negative predictive value (NPV) of 92.1% (95% CI 85.6-95.9). For TBE, MT had a sensitivity of 90.5% (95% CI 81.8-95.6), specificity of 100% (95% CI 96.3- 100.0) PPV of 100% (95% CI 94.1-100) and NPV of 93.9% (95% CI 88.0-97.2). Overall complication rate was 3.3%. CONCLUSIONS: MT showed excellent sensitivity and specificity in the diagnosis of exudative pleural effusion in this region. It reduces empirical therapy by providing histological evidence of disease when initial non-invasive investigations were inconclusive.

Enhanced recovery after surgery for liver resection.

INTRODUCTION: Enhanced recovery after surgery (ERAS) reduces postoperative length of hospital stay and patient stress response to liver surgery. The aim of the present study was to evaluate the efficacy and feasibility of an ERAS programme for liver resection. METHODS: A multidisciplinary ERAS protocol was implemented for both open and laparoscopic liver resection in a tertiary hospital in Hong Kong. The clinical outcomes of patients who underwent liver resection and underwent the ERAS perioperative programme were compared with those who received a conventional perioperative programme between September 2015 and July 2016. Propensity score matching analysis was used to minimise background differences. RESULTS: A total of 20 patients who underwent liver resection were recruited to the ERAS programme. Their clinical outcomes were compared with another 20 patients who received hepatectomy under a conventional perioperative programme after propensity score matching. The ERAS programme was associated with a significantly shorter length of hospital stay (P=0.033) without an increase in complication rates in patients who underwent open liver resection. There was no such significant association in patients who underwent laparoscopic liver resection. No patients required readmission in this cohort. CONCLUSIONS: The ERAS perioperative programme for liver resection is safe and feasible. It significantly shortened the hospital stay after open liver resection but not after laparoscopic liver resection.

Drainage of multiloculated tuberculous pleural effusion by medical thoracoscopy: When and why should it be considered?

Tuberculous pleural effusion (TBE) is a common encounter in our region. Up to 50% of patients with TBE will develop residual pleural thickening (RPT) which can lead to functional impairment. However, the need of drainage remains controversial. We report a case of end-stage renal failure patient who presented with right multiloculated tuberculous pleural effusion which was drained via a medical thoracoscope. Patient reports immediate relief of breathlessness post procedure and one month follow up shown significant improvement of RPT. We also discussed the current perspective on the rationale of TBE drainage and the role of medical thoracoscope in TBE management.

Colon carcinoma with endobronchial metastasis masquerading as bronchial asthma causing ball valve effect.

Malignant central airway obstruction (CAO) with ball valve effect (BVE) in the lung is rare. We discuss a case of metastatic colon cancer who presented with asthma like symptoms which thoracic computed tomography and bronchoscopy revealed an intraluminal tumour obstructing the left main bronchus in a ball valve manner. Airway patency was restored urgently with immediate alleviation of symptoms. This illustrates the importance of recognizing subtle features of central airway obstruction to allow expedition of appropriate investigations and therapy.

Relationship of amotivation to neurocognition, self-efficacy and functioning in first-episode psychosis: a structural equation modeling approach.

BACKGROUND: Better understanding of the complex interplay among key determinants of functional outcome is crucial to promoting recovery in psychotic disorders. However, this is understudied in the early course of illness. We aimed to examine the relationships among negative symptoms, neurocognition, general self-efficacy and global functioning in first-episode psychosis (FEP) patients using structural equation modeling (SEM). METHOD: Three hundred and twenty-one Chinese patients aged 26-55 years presenting with FEP to an early intervention program in Hong Kong were recruited. Assessments encompassing symptom profiles, functioning, perceived general self-efficacy and a battery of neurocognitive tests were conducted. Negative symptom measurement was subdivided into amotivation and diminished expression (DE) domain scores based on the ratings in the Scale for the Assessment of Negative Symptoms. RESULTS: An initial SEM model showed no significant association between functioning and DE which was removed from further analysis. A final trimmed model yielded very good model fit (χ2 = 15.48, p = 0.63; comparative fit index = 1.00; root mean square error of approximation <0.001) and demonstrated that amotivation, neurocognition and general self-efficacy had a direct effect on global functioning. Amotivation was also found to mediate a significant indirect effect of neurocognition and general self-efficacy on functioning. Neurocognition was not significantly related to general self-efficacy. CONCLUSION: Our results indicate a critical intermediary role of amotivation in linking neurocognitive impairment to functioning in FEP. General self-efficacy may represent a promising treatment target for improvement of motivational deficits and functional outcome in the early illness stage.

Gender effect on public stigma changes towards psychosis in the Hong Kong Chinese population: a comparison between population surveys of 2009 and 2014.

PURPOSE: Public stigma is an important barrier to the recovery of patients with psychosis. The current study aimed to investigate the change in stigma towards psychosis and knowledge about psychosis between 2009 and 2014 among the Chinese population in Hong Kong, with a specific focus on gender role. METHODS: Random telephone survey of general population in Hong Kong was conducted in 2009 and 2014. Stigma was measured with the revised Link's Perceived Discrimination-Devaluation Scale (LPDDS). Logistic regression was used to explore the effect of time on the change of knowledge of psychosis, and linear regression was used to explore the effect of time on the change of stigma. Change of knowledge and stigma based on gender was specifically explored. RESULTS: In total, 1016 and 1018 subjects completed the survey in 2009 and 2014, respectively. Significantly, more people agreed with medication treatment for psychosis and fewer people had misunderstanding about psychosis. However, there was no significant change in stigma levels. Males were found to have a significant deterioration of stigma (B = 0.099, SE = 0.033, ß = 0.100, p = 0.003) but not females. Significantly, more males endorsed medication treatment for psychosis (χ 2 = 5.850, df = 1, p = 0.016) but no change for females (χ 2 = 1.401, df = 1, p = 0.238). CONCLUSIONS: Results of this study suggested that there was an improvement in the biological understanding of psychosis but no change of public stigma within the Hong Kong Chinese population. The specific role of gender in relation to stigma and level of knowledge about psychosis indicates that this should be a consideration in designing future anti-stigma campaigns.

Visual working memory deterioration preceding relapse in psychosis.

BACKGROUND: Relapse is distressingly common after the first episode of psychosis, yet it is poorly understood and difficult to predict. Investigating changes in cognitive function preceding relapse may provide new insights into the underlying mechanism of relapse in psychosis. We hypothesized that relapse in fully remitted first-episode psychosis patients was preceded by working memory deterioration. METHOD: Visual memory and verbal working memory were monitored prospectively in a 1-year randomized controlled trial of remitted first-episode psychosis patients assigned to medication continuation (quetiapine 400 mg/day) or discontinuation (placebo). Relapse (recurrence of positive symptoms of psychosis), visual (Visual Patterns Test) and verbal (Letter-Number span test) working memory and stressful life events were assessed monthly. RESULTS: Remitted first-episode patients (n = 102) participated in the study. Relapsers (n = 53) and non-relapsers (n = 49) had similar baseline demographic and clinical profiles. Logistic regression analyses indicated relapse was associated with visual working memory deterioration 2 months before relapse [odds ratio (OR) 3.07, 95% confidence interval (CI) 1.19-7.92, P = 0.02], more stressful life events 1 month before relapse (OR 2.11, 95% CI 1.20-3.72, P = 0.01) and medication discontinuation (OR 5.52, 95% CI 2.08-14.62, P = 0.001). CONCLUSIONS: Visual working memory deterioration beginning 2 months before relapse in remitted first-episode psychosis patients (not baseline predictor) may reflect early brain dysfunction that heralds a psychotic relapse. The deterioration was found to be unrelated to a worsening of psychotic symptoms preceding relapse. Testable predictors offer insight into the brain processes underlying relapse in psychosis.

Delusional disorder and schizophrenia: a comparison of the neurocognitive and clinical characteristics in first-episode patients.

BACKGROUND: Delusional disorder (DD) is thought to be distinct from schizophrenia (SZ). However, few systematic investigations have been conducted on DD because of the difficulty in ascertaining a representative sample size. Existing knowledge has been mostly generated from inpatient cohorts, which may be biased towards a more severe sample. METHOD: We compared the demographic, clinical and cognitive differences between 71 patients with first-episode DD and 71 age-matched patients with first-episode SZ. Participants were consecutively recruited from a population-based territory-wide study of early psychosis in Hong Kong targeting first-episode psychosis. Basic demographic information, premorbid functioning, duration of untreated psychosis, pathways to care, symptomatology, social, occupational, and cognitive functioning were comprehensively assessed using standardized measurements. RESULTS: Patients with DD had less premorbid schizoid and schizotypal traits compared to patients with SZ. More patients with DD were married compared to patients with SZ. However, at first episode, there were no significant differences between the two groups in regards to the duration of untreated psychosis, pathways to care, symptom severity, neurocognitive performance, treatment, and functioning. CONCLUSIONS: Our findings challenge previous thinking that patients with DD had better functioning than patients with SZ. This study not only provides an updated perspective into conceptualizing the clinical differences between DD and SZ, but also expands the descriptive account of the two disorders to include the neurocognitive dimension.

10-year outcome study of an early intervention program for psychosis compared with standard care service.

BACKGROUND: Despite evidence on the short-term benefits of early intervention (EI) service for psychosis, long-term outcome studies are limited by inconsistent results. This study examined the 10-year outcomes of patients with first-episode psychosis who received 2-year territory-wide EI service compared to those who received standard care (SC) in Hong Kong using an historical control design. METHOD: Consecutive patients who received the EI service between 1 July 2001 and 30 June 2002, and with diagnosis of schizophrenia-spectrum disorders, were identified and matched with patients who received SC first presented to the public psychiatric service from 1 July 2000 to 30 June 2001. In total, 148 matched pairs of patients were identified. Cross-sectional information on symptomatology and functioning was obtained through semi-structured interview; longitudinal information on hospitalization, functioning, suicide attempts, mortality and relapse over 10 years was obtained from clinical database. There were 70.3% (N = 104) of SC and 74.3% (N = 110) of EI patients interviewed. RESULTS: Results suggested that EI patients had reduced suicide rate (χ2 (1) = 4.35, p = 0.037), fewer number [odds ratio (OR) 1.56, χ2 = 15.64, p < 0.0001] and shorter duration of hospitalization (OR 1.29, χ2 = 4.06, p = 0.04), longer employment periods (OR -0.28, χ2 = 14.64, p < 0.0001) and fewer suicide attempts (χ2 = 11.47, df = 1, p = 0.001) over 10 years. At 10 years, no difference was found in psychotic symptoms, symptomatic remission and functional recovery. CONCLUSIONS: The short-term benefits of the EI service on number of hospitalizations and employment was sustained after service termination, but the differences narrowed down. This suggests the need to evaluate the optimal duration of the EI service.

Transnasal penetrating intracranial injury with a chopstick.

We report the first case of a transnasal penetrating intracranial injury in Hong Kong by a chopstick. A 49-year-old man attempted suicide by inserting a wooden chopstick into his left nose and then pulled it out. The chopstick caused a transnasal penetrating brain injury, confirmed by contrast magnetic resonance imaging of the brain. He was managed conservatively. Later he developed meningitis without a brain abscess and was prescribed antibiotics for 6 weeks. He enjoyed a good neurological recovery. This case illustrates that clinician should have a high index of suspicion for penetrating intracranial injury due to a nasally inserted foreign body, even though it had already been removed. In such cases moreover, brain magnetic resonance imaging is the imaging modality of choice, as it can delineate the path of penetration far better than plain computed tomography.