Global Epidemiology and Genetics of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading cancers worldwide. Classically, HCC develops in genetically susceptible individuals who are exposed to risk factors, especially in the presence of liver cirrhosis. Significant temporal and geographic variations exist for HCC and its etiologies. Over time, the burden of HCC has shifted from the low-moderate to the high sociodemographic index regions, reflecting the transition from viral to nonviral causes. Geographically, the hepatitis viruses predominate as the causes of HCC in Asia and Africa. Although there are genetic conditions that confer increased risk for HCC, these diagnoses are rarely recognized outside North America and Europe. In this review, we will evaluate the epidemiologic trends and risk factors of HCC, and discuss the genetics of HCC, including monogenic diseases, single-nucleotide polymorphisms, gut microbiome, and somatic mutations.

Computed tomography venography versus intravascular ultrasound in the diagnosis of iliofemoral vein stenosis.

Background: Iliofemoral vein stenosis can cause debilitating chronic venous disease. Diagnostic tools include both computed tomography venography (CTV) and intravascular ultrasonography (IVUS). We aim to compare the diagnostic performance of CTV and IVUS. Patients and methods: We performed a retrospective study of patients with chronic venous disease presenting with iliac vein compression or post-thrombotic limb symptoms, excluding those with acute deep vein thrombosis, high anaesthesia risk, or who had contrast allergy. All patients received CTV before IVUS, as part of the diagnostic work-up and intervention. The cross-sectional area (CSA) of iliofemoral vein segments obtained from both studies were compared against reference CSAs to derive percentage stenosis. A 50% reduction in CSA was considered significant. Results: We studied 50 patients between May 2018 and April 2019. 58% of patients had severe disease CEAP C5-6. 48% of patients had at least one vein segment with significant stenosis. The left proximal common iliac vein was the most commonly stenosed vein segment (n = 12, 24% on IVUS). CSA measurements from CTV were greater than those of IVUS, with a correlation coefficient of 0.57 (p < 0.005). Conversely, percentage stenosis measured on CTV was lower than on IVUS, with approximately one-third of significant stenosis missed on CTV (58 veins from CTV vs. 78 from IVUS, p < 0.005). With IVUS as the gold standard, CTV has low sensitivity (37.2%, 95% CI 26.5-48.9) and high specificity (92.5%, 95% CI 89.3-94.9) in detecting significant stenosis. Conclusions: CTV has limited diagnostic performance in identifying iliofemoral vein stenosis. Patients with normal CTV findings should proceed with IVUS imaging if the clinical features are supportive of iliofemoral vein stenosis.

Turning waste medicines to cost savings: A pilot study on the feasibility of medication recycling as a solution to drug wastage.

BACKGROUND: Unused medicines represent a major source of wastage in healthcare systems around the world. Previous studies have suggested the potential cost savings from recycling the waste medicines. However, issues of product safety and integrity often deter healthcare institutions from recycling donated medications. AIM: To evaluate the feasibility of medication recycling and to assess the actual cost savings from recycling waste medicines and whether reusability of waste medicines differed among various drug classes and donor sources. DESIGN AND SETTING: Donated medications from hospitals, private medical clinics and patients were collected and assessed using a medication recycling protocol in a hospice care setting from November 2013 through January 2014. Costs were calculated using a reference pricing list from a public hospital. RESULTS: A total of 244 donations, amounting to 20,759 dosage units, were collected during the study period. Most donations (90.8%) were reusable, providing a total of S$5266 in cost savings. Less than 2 h daily was spent by a single pharmacy technician on the sorting and distributing processes. Medications donated by health facilities were thrice more likely to be reusable than those by patients (odds ratio = 3.614, 95% confidence interval = 3.127, 4.176). Medications belonging to Anatomical Therapeutic Chemical class G (0.0%), H (8.2%) and L (30.0%) were the least reusable. CONCLUSION: Most donated medications were reusable. The current protocol can be further streamlined to focus on the more reusable donor sources and drug classes and validated in other settings. Overall, we opine that it is feasible to practise medication recycling on a larger scale to reduce medication wastage.

Follow-up care practices and barriers to breast cancer survivorship: perspectives from Asian oncology practitioners.

PURPOSE: The aim of this study is to evaluate the perspectives of Asian oncology practitioners on the physical and psychosocial issues experienced by breast cancer survivors (BCS), current survivorship care practices, and the barriers to follow-up care. METHODS: This was a cross-sectional survey study. Oncology practitioners were recruited from a major cancer center in Singapore and through two regional cancer meetings that took place in Singapore and Malaysia in 2013. RESULTS: A total of 126 oncology practitioners from various Southeast Asian countries, mostly nurses (58.7 %) and physicians (37.3 %), were recruited. The majority of the respondents agreed that fatigue (78.4 %) and anxiety (69.1 %) were the most common physical and psychosocial problems experienced by BCS. Monitoring for physical and treatment-related adverse effects (80.7 %) and reviewing patients' noncancer medical history (65.3 %) were the most practiced aspects of follow-up care. Compared with the other practitioners, the physicians were more likely to communicate with other healthcare professionals (adjusted OR = 4.24, 95 % CI 1.54 to 11.72; p = 0.005). Most of the respondents also agreed that patient-specific barriers were the main impediments to follow-up care. CONCLUSION: This study provides insights into the various aspects of breast cancer survivorship care from the perspectives of oncology practitioners and shows that survivorship care is relatively inadequate in Asia. There is a need for new survivorship care models to meet the needs of Asian BCS and to complement the unique healthcare systems of Asia.

Association between Total Daily Doses with duration of hospitalization among readmitted patients in a multi-ethnic Asian population.

Increased length of stay (LOS) in the hospital incurs substantial financial costs on the healthcare system. Multiple factors are associated with LOS. However, few studies have been done to associate the impact of Total Daily Doses (TDD) and LOS. Hence, the aim of this study is to examine the association between patients' LOS upon readmission and their TDD before readmission. A retrospective cross-sectional study of readmission cases occurring from 1st January to 31st March 2013 was conducted at a regional hospital. Demographics and clinical variables were collected using electronic medical databases. Univariable and multiple linear regressions were used. Confounders such as comorbidities and drug related problems (DRP) were controlled for in this study. There were 432 patients and 649 readmissions examined. The average TDD and LOS were 18.04 ± 8.16 and 7.63 days ± 7.08 respectively. In the univariable analysis, variables that were significantly associated with the LOS included age above 75 year-old, race, comorbidity, number of comorbidities, number of medications, TDD and thrombocytopenia as DRPs. In the multiple linear regression, there was a statistically significant association between TDD (ß = 0.0733, p = 0.030) and LOS. Variables that were found significant were age above 75 year-old (ß = 1.5477, p = 0.008), Malay (ß = -1.5123, p = 0.033), other races (ß = -2.6174, p = 0.007), depression (ß = 2.1551, p = 0.031) and thrombocytopenia as a type of DRP (ß = 7.5548, p = 0.027). When TDD was replaced with number of medications, number of medications (ß = 0.1487, p = 0.021), age of 75 year-old (ß = 1.5303, p = 0.009), Malay (ß = -1.4687, p = 0.038), race of others (ß = -2.6499, p = 0.007), depression (ß = 2.1951, p = 0.028) and thrombocytopenia as a type of DRP (ß = 7.5260, p = 0.028) were significant. In conclusion, a significant relationship between TDD and number of medications before readmission and the LOS upon readmission was established. This finding highlights the importance of optimizing patients' TDD in the attempt of reducing their LOS.

Impact of COVID infection on lung function test and quality of life.

Post-COVID-19 pulmonary sequalae are well-recognized early in the pandemic. Survivorship clinics are crucial for managing at-risk patients. However, it is unclear who requires pulmonary function test (PFT) and when PFTs should be performed. We aim to investigate for whom and how these interval PFTs should be performed. We performed a single-centre, prospective cohort study on COVID-19 survivors between 1st May 2020 and 31st April 2022. These patients were followed up at 6, 9 and 12 months with interval PFT and Short Form-36 (SF-36) Health Survey. Those with PFT defects were offered a computed tomography scan of the thorax. Of the 46 patients recruited, 17 (37%) had severe/critical illness. Compared to those with mild/moderate disease, these patients were more likely to experience DLCO defects (59% versus 17%, p = 0.005) and had lower SF-36 scores (mean physical component summary score of 45 ± 12 versus 52 ± 8, p = 0.046). These differences were most notable at 6 months, compared to the 9- and 12-months intervals. DLCO defects were also associated with older age, raised inflammatory markers and extensive CXR infiltrates. Besides interstitial-like abnormalities, obesity and undiagnosed lung conditions accounted for 39% of the PFT abnormalities. Interval PFTs can be performed earliest 6 months post-COVID-19. Patients with normal tests were unlikely to develop new abnormalities and would not require repeat PFTs. Abnormal PFTs can be followed-up with repeat PFTs 6 monthly until resolution. Non-COVID-19 differentials should be considered for persistent PFT abnormalities.

A Rare Case of Dengue Encephalitis with Raised Procalcitonin.

BACKGROUND Dengue virus is a common arbovirus with uncertain neurotropism. Dengue encephalitis is a rare but fatal manifestation of severe dengue. Diagnosis requires high clinical suspicion. It should be routinely considered in patients with encephalopathy, especially in countries where dengue virus is endemic. Unlike other forms of severe dengue, the typical warning signs and biochemical derangements are not reliable markers for dengue encephalitis. Alternative biochemical markers of dengue encephalitis are needed. CASE REPORT We present a case of dengue encephalitis with distinctly raised procalcitonin (13.2 µg/L), in the absence of the typical warning signs and biochemical derangements of severe dengue. The patient was a 65-year-old man with fever and sudden loss of consciousness in the absence of other localizing signs/symptoms. Inflammatory markers were raised, with findings of leptomeningeal enhancement on brain computed tomography suggestive of meningoencephalitis. Septic workup was unremarkable (normal renal and liver functions, negative blood and urine cultures). The typical neurotropic microorganisms were not detected in the cerebrospinal fluid. On day 4 of admission, the patient reported abdominal pain and hematuria with a new onset of bicytopenia. Subsequent investigations for dengue infection were positive for serum dengue NS1 antigen and dengue RNA (type 2 strain) in cerebrospinal fluid, confirming the diagnosis of dengue encephalitis. The patient was managed supportively and experienced full clinical recovery. CONCLUSIONS Dengue encephalitis is a rare condition with nonspecific biochemical and imaging abnormalities. We demonstrated that a raised procalcitonin level can occur in the setting of dengue encephalitis. In endemic countries, this finding may prompt further investigations for dengue encephalitis in patients with meningoencephalitis.

Review of imaging and endovascular intervention of iliocaval venous compression syndrome.

Iliocaval venous compression syndrome (ICS) is the extrinsic compression of the common iliac vein by the overlying iliac artery against the vertebra. Chronic compression can lead to venous stenosis and stasis, which manifests as chronic venous disease and treatment resistance. Therefore, early recognition of ICS and prompt treatment are essential. Clinical presentations of ICS can be ambiguous and diagnosis requires a high index of suspicion with the relevant imaging studies. The initial imaging test is typically a Duplex ultrasound for vessel assessment and pelvic ultrasound to exclude a compressive mass, which is followed by computed tomography (CT) or magnetic resonance (MR) venography. CT and MRI can identify the anatomical causes for venous compression. In patients with high clinical suspicion for ICS, negative findings on CT and MR venography would still warrant further investigations. Definitive diagnosis can be established using catheter-based venography complemented with intravascular ultrasonography but the nature of their invasiveness limits its utility as a routine imaging modality. In this review paper, we will discuss the evidence, utility and limitations of the existing imaging modalities and endovascular intervention used in the management of ICS.

Multiple neoplasia in a patient with Gitelman syndrome harboring germline monoallelic MUTYH mutation.

Gitelman syndrome is a rare, recessively inherited disease characterized by chronic hypokalemia and hypomagnesemia as a result of defective electrolyte co-transport at the level of the distal convoluted tubule of the kidney. Here, we present the first report of a patient with Gitelman syndrome who developed multiple neoplasia including colorectal polyposis, synchronous colorectal cancers, recurrent breast fibroadenomata and a desmoid tumor. Whole-exome sequencing confirmed germline compound heterozygous mutations of c.179C > T and c.1326C > G in SLC12A3, and in addition, identified a monoallelic germline c.934-2A > G splice site mutation in MUTYH. In vitro, magnesium deficiency potentiated oxidative DNA damage in lymphoblastoid cell lines derived from the same patient. We postulate that monoallelic MUTYH mutations may manifest in the presence of cooperative non-genetic mechanisms, in this case possibly magnesium deficiency from Gitelman syndrome.

Endovascular Deep Vein Stenting of Symptomatic Post-Thrombotic and Non-Thrombotic Iliac Vein Stenotic Lesions: A Multicentre Cohort Experience from Singapore.

INTRODUCTION: This paper presents our experience with deep venous stenting in a multi-ethnic Asian cohort of patients with symptomatic Non-Thrombotic Iliac Vein Lesions (NIVL) and Post-Thrombotic Syndrome (PTS). MATERIALS AND METHODS: This was a multicentre retrospective cohort study of patients who had symptomatic deep venous disease. Stent patency rate was evaluated using Duplex ultrasonography immediately post-intervention and at 3, 6 and 12 months. Clinical outcomes were evaluated using the revised Venous Clinical Severity Score (rVCSS) and Visual Analogue Scale (VAS) pain score at baseline and 3 months post-procedure. RESULTS: 87 patients (males = 47/87 (54.0%)); median age = 62 years (IQR 55 - 70)) and 115 limbs were analysed (left = 76/115 (66.1%)). Median follow-up time was 175 (IQR 57 - 257) days. 97/115 (84.3%) had NIVLs and 55/115 (47.8%) had May-Thurner-Syndrome. 43/115 (37.4%) had Clinical, Etiology, Anatomy and Pathophysiology (CEAP) 6 disease. Primary stent patency rates were 98.2% (112/114), 97.9% (93/95), 95.7% (89/93) and 92.8% (64/69) immediately post-intervention, 3, 6 and 12 months, respectively. The 6-month secondary patency rate was 99.1% (114/115). Mean rVCSS and VAS improved from 11.52 (±3.54) to 5.77 (±2.36) (P < 0.01) and 6.62 (±1.93) to 2.92 (±1.50) (P < 0.01) respectively, at 3 months. 41/43 (95.3%) venous ulcers healed over a median time of 169 days (IQR 120 - 253). CONCLUSIONS: Short term primary patency rates following deep venous stenting are excellent, with few re-interventions. Patients presented with NIVLs rather than PTS. There was excellent clinical improvement at 3 months, with a high and expedient venous ulcer healing rate.

Missense PALB2 germline variant disrupts nuclear localization of PALB2 in a patient with breast cancer.

The PALB2 protein is essential to RAD51-mediated homologous recombination (HR) repair. Germline monoallelic PALB2 pathogenic variants confer significant risks for breast cancer. However, the majority of PALB2 variants remain classified as variants of unknown significance (VUS). We aim to functionally and mechanistically evaluate three novel PALB2 VUS. Patient-derived lymphoblastoid cell lines containing the VUS were analyzed for nuclear localization and foci formation of RAD51 as a measure of HR efficiency. To understand the mechanism underlying the HR deficiency, PALB2 nuclear localization was assessed using immunofluorescence studies. Among these VUS, c.3251C>T (p.Ser1084Leu) occurred in a patient with metastatic breast cancer while c.1054G>C (p.Glu352Gln) and c.1057A>G (p.Lys353Glu) were seen in patients with squamous cell carcinoma of skin and renal cell carcinoma respectively. Variant c.3251C>T was located within the WD40 domain which normally masked the nuclear export signal sequence responsible for nuclear delocalization of PALB2. Correspondingly, c.3251C>T displayed aberrant cytoplasmic localization of PALB2 which led to an impaired RAD51 nuclear localization and foci formation. On the other hand, both c.1054G>C and c.1057A>G showed intact HR functions and nuclear localization of PALB2, consistent with their locations within domains of no known function. Additionally, the prevalence of c.1054G>C was similar among healthy controls and patients with breast cancer (as seen in other studies), suggestive of its non-pathogenicity. In conclusion, our studies provided the functional evidence showing the deleterious effect of c.3251C>T, and non-deleterious effects of c.1054G>C and c.1057A>G. Using the ClinGen Pathogenicity calculator, c.3251C>T remains a VUS while c.1054G>C and c.1057A>G may be classified as likely benign variants.

Case Report: An Unusual Presentation of Bilateral Subclavian Stenosis in a Patient with Asymptomatic Hypotension.

BACKGROUND Subclavian stenosis is an uncommon clinical condition associated with severe cardiovascular complications, usually presenting with claudication and subclavian steal syndrome. Here we describe the rare case of bilateral subclavian artery stenosis in an asymptomatic patient. CASE REPORT Our patient was a 63-year-old chronic smoker with no prior medical history whose chief complaint was dyspnea from an exacerbation of his chronic obstructive pulmonary disease (COPD). He was hypotensive with blood pressure 74/56 mmHg at admission, which raised suspicion for sepsis, adrenal insufficiency but the workup (renal panel, full blood count and synacthen tests) were normal. He quickly recovered after we treated his COPD exacerbation, but his hypotension persisted despite repeated fluid challenges. To evaluate for structural causes of his hypotension, we performed a full cardiovascular examination with 4 limb blood pressure measurements and found upper limb hypotension and lower limb hypertension. Subsequent imaging with ultrasound and computed tomography confirmed the presence of bilateral subclavian artery stenosis. Our diagnosis was thus bilateral subclavian artery stenosis secondary to atherosclerosis from chronic smoking. The patient was subsequently referred to vascular surgery for consideration of surgical revascularization. CONCLUSIONS Bilateral subclavian stenosis is extremely rare and requires a high index of clinical suspicion. Early diagnosis is important in the primary prevention of associated cardiovascular diseases.

Functional analysis of clinical BARD1 germline variants.

Germline pathogenic variants in BRCA1/2 account for one-third of familial breast cancers. The majority of BRCA1 function requires heterodimerization with BARD1. In contrast to BRCA1, BARD1 is a low-penetrance gene with an unclear clinical relevance, partly because of limited functional evidence. Using patient-derived lymphoblastoid cells, we functionally characterized two pathogenic variants (c.1833dupT, c.2099delG) and three variants of uncertain significance (VUSs) (c.73G>C, c.1217G>A, c.1918C>A). Three of these patients had breast cancers, whereas the remaining had colorectal cancers (n = 3). Both patients with pathogenic variants (c.1833dupT, c.2099delG) developed breast cancers with aggressive disease phenotypes such as triple-negative breast cancer and high cancer grades. As BARD1 encompasses multiple functional domains, including those of apoptosis and homologous recombination repair, we hypothesized that the function being impaired would correspond with the domain where the variant was located. Variants c.1918C>A, c.1833dupT, c.1217G>A, and c.2099delG, located within and proximal to apoptotic domains of ankyrin and BRCT, were associated with impaired apoptosis. Conversely, apoptosis function was preserved in c.73G>C, which was distant from the ankyrin domain. All variants displayed normal BRCA1 heterodimerization and RAD51 colocalization, consistent with their location being distal to BRCA1-and RAD51-binding domains. In view of deficient apoptosis, VUSs (c.1217G>A and c.1918C>A) may be pathogenic or likely pathogenic variants. In summary, functional analysis of BARD1 VUSs requires a combination of assays and, more importantly, the use of appropriate functional assays with consideration to the variant's location.

Germline Pathogenic Variants in Homologous Recombination and DNA Repair Genes in an Asian Cohort of Young-Onset Colorectal Cancer.

BACKGROUND: Growing evidence suggests a role for cancer susceptibility genes such as BRCA2 and PALB2 in young-onset colorectal cancers. Using a cohort of young colorectal cancer patients, we sought to identify and provide functional evidence for germline pathogenic variants of DNA repair genes not typically associated with colorectal cancer. METHODS: We recruited 88 patients with young-onset colorectal cancers seen at a general oncology center. Whole-exome sequencing was performed to identify variants in DNA repair and colorectal cancer predisposition genes. Pathogenic BRCA2 and PALB2 variants were analyzed using immunoblot and immunofluorescence on patient-derived lymphoblastoid cells. RESULTS: In general, our cohort displayed characteristic features of young-onset colorectal cancers. Most patients had left-sided tumors and were diagnosed at late stages. Four patients had familial adenomatous polyposis, as well as pathogenic APC variants. We identified 12 pathogenic variants evenly distributed between DNA repair and colorectal cancer predisposition genes. Six patients had pathogenic variants in colorectal cancer genes: APC (n = 4) and MUTYH monoallelic (n = 2). Another six had pathogenic variants in DNA repair genes: ATM (n = 1), BRCA2 (n = 1), PALB2 (n = 1), NTHL1 (n = 1), and WRN (n = 2). Pathogenic variants BRCA2 c.9154C>T and PALB2 c.1059delA showed deficient homologous recombination repair, evident from the impaired RAD51 nuclear localization and foci formation. CONCLUSION: A substantial portion of pathogenic variants in young-onset colorectal cancer was found in DNA repair genes not previously associated with colorectal cancer. This may have implications for the management of patients. Further studies are needed to ascertain the enrichment of pathogenic DNA repair gene variants in colorectal cancers.

Association between number of doses per day, number of medications and patient's non-compliance, and frequency of readmissions in a multi-ethnic Asian population.

OBJECTIVE: To investigate whether number of doses per day and number of medications are significantly associated with the number of readmissions and to study the association of readmission frequency with other medical and socio-demographic variables. METHODS: Retrospective cross-sectional study involving 432 patients who were readmitted within 15 days of previous hospital discharge between January 1, 2013 and March 31, 2013. Relevant medical records were collected from the national electronic databases of every public tertiary hospital in Singapore. Significant variables (p < 0.05) were identified using forward selection and modeled using generalized linear mixed models. RESULTS: A total of 649 unplanned readmissions were reviewed. At a multivariable level, number of readmission was significantly associated with the number of medications (p = 0.002) and number of doses per day (p = 0.003) after adjusting for race, liver disease, schizophrenia and non-compliance. CONCLUSION: Complex medication regimen (i.e. multiple medications and multiple doses per day) is a statistically significant predictor of number of readmissions. Simplifying therapeutic regimens with alternatives such as longer-acting or fixed-dose combination drugs may facilitate better patient adherence and reduce costly readmissions.