Prediction of hospital mortality among critically ill patients in a single centre in Asia: comparison of artificial neural networks and logistic regression-based model.

INTRODUCTION: This study compared the performance of the artificial neural network (ANN) model with the Acute Physiologic and Chronic Health Evaluation (APACHE) II and IV models for predicting hospital mortality among critically ill patients in Hong Kong. METHODS: This retrospective analysis included all patients admitted to the intensive care unit of Pamela Youde Nethersole Eastern Hospital from January 2010 to December 2019. The ANN model was constructed using parameters identical to the APACHE IV model. Discrimination performance was assessed using area under the receiver operating characteristic curve (AUROC); calibration performance was evaluated using the Brier score and Hosmer-Lemeshow statistic. RESULTS: In total, 14 503 patients were included, with 10% in the validation set and 90% in the ANN model development set. The ANN model (AUROC=0.88, 95% confidence interval [CI]=0.86-0.90, Brier score=0.10; P in Hosmer-Lemeshow test=0.37) outperformed the APACHE II model (AUROC=0.85, 95% CI=0.80-0.85, Brier score=0.14; P<0.001 for both comparisons of AUROCs and Brier scores) but showed performance similar to the APACHE IV model (AUROC=0.87, 95% CI=0.85-0.89, Brier score=0.11; P=0.34 for comparison of AUROCs, and P=0.05 for comparison of Brier scores). The ANN model demonstrated better calibration than the APACHE II and APACHE IV models. CONCLUSION: Our ANN model outperformed the APACHE II model but was similar to the APACHE IV model in terms of predicting hospital mortality in Hong Kong. Artificial neural networks are valuable tools that can enhance real-time prognostic prediction.

Docetaxel, Cisplatin, and 5-FU Triplet Therapy as Conversion Therapy for Locoregionally Advanced Unresectable Esophageal Squamous Cell Carcinoma.

BACKGROUND: The standard treatment for locoregionally advanced unresectable esophageal squamous cell carcinoma was radical chemoradiotherapy. However, the prognosis was modest. Emerging evidence showed the concept of induction chemotherapy with a goal of conversion surgery. METHODS: We reviewed the long-term, clinical outcomes and safety data of induction chemotherapy using docetaxel-cisplatin-5FU (DCF) and subsequent definitive treatment, either surgery or radical chemoradiotherapy (CRT), in locally advanced unresectable esophageal cancer in Queen Mary Hospital, Hong Kong. A total of 47 patients (median age 62 years, male: 41 (87.2%)) with locoregionally advanced unresectable esophageal cancer received induction DCF. The response rate was 65.9% (complete/partial response: n = 31). After induction DCF, 24 patients (41.4%) had radical surgery and 7 (14.9%) had definitive CRT. RESULTS: The median overall survival (mOS) was significantly longer in patients received subsequent surgery compared with those with definitive CRT (mOS: 40.2 vs. 9.1 months, hazard ratio 3.33, 95% confidence interval 1.22-9.07, p = 0.02) and no definitive treatment (mOS: 40.2 vs. 6.3 months, hazard ratio 8.51, 95% confidence interval 3.7-19.73, p < 0.001). Patients who received surgery, female, and those with supraclavicular lymph node involvement had a better OS. Twenty-one patients (44.7%) developed grade 3/4 adverse events during induction DCF, and two died after chemotherapy because of trachea-esophageal fistula complicated with sepsis. Eleven patients who had surgery had postoperative complications and none had postoperative mortality. CONCLUSIONS: Induction DCF and subsequent conversion surgery offered a chance of cure with long-term survival benefit and manageable toxicities in patients with locoregionally advanced unresectable esophageal cancer.

Ten-year territory-wide trends in the utilisation and clinical outcomes of extracorporeal membrane oxygenation in Hong Kong.

INTRODUCTION: The utilisation of extracorporeal membrane oxygenation (ECMO) has been rapidly increasing in Hong Kong. This study examined 10-year trends in the utilisation and clinical outcomes of ECMO in Hong Kong. METHODS: We retrospectively reviewed the records of all adult patients receiving ECMO who were admitted to the intensive care units (ICUs) of public hospitals in Hong Kong between 2010 and 2019. Temporal trends across years were assessed using the Mann-Kendall test. Observed hospital mortality was compared with the Acute Physiology and Chronic Health Evaluation (APACHE) IV-predicted mortality. RESULTS: The annual number of patients receiving ECMO increased from 18 to 171 over 10 years. In total, 911 patients received ECMO during the study period: 297 (32.6%) received veno-arterial ECMO, 450 (49.4%) received veno-venous ECMO, and 164 (18.0%) received extracorporeal cardiopulmonary resuscitation. The annual number of patients aged ≥65 years increased from 0 to 47 (27.5%) [P for trend=0.001]. The median (interquartile range) Charlson Comorbidity Index increased from 1 (0-1) to 2 (1-3) [P for trend<0.001] while the median (interquartile range) APACHE IV score increased from 90 (57-112) to 105 (77-137) [P for trend=0.003]. The overall standardised mortality ratio comparing hospital mortality with APACHE IV-predicted mortality was 1.11 (95% confidence interval=1.01-1.22). Hospital and ICU length of stay both significantly decreased (P for trend=0.011 and <0.001, respectively). CONCLUSION: As ECMO utilisation increased in Hong Kong, patients put on ECMO were older, more critically ill, and had more co-morbidities. It is important to combine service expansion with adequate resource allocation and training to maintain quality of care.

Update on the Recommendations on Breast Cancer Screening by the Cancer Expert Working Group on Cancer Prevention and Screening.

Breast cancer (BC) is the most common cancer among women in Hong Kong. The Food and Health Bureau commissioned The University of Hong Kong (HKU) to conduct the Hong Kong Breast Cancer Study (HKBCS) with the aim of identifying relevant risk factors for BC in Hong Kong and developing a locally validated BC risk assessment tool for Hong Kong Chinese women. After consideration of the most recent international and local scientific evidence including findings of the HKBCS, the Cancer Expert Working Group on Cancer Prevention and Screening (CEWG) has reviewed and updated its BC screening recommendations. Existing recommendations were preserved for women at high risk and slightly changed for women at moderate risk. The following major updates have been made concerning recommendations for other women in the general population: Women aged 44 to 69 with certain combinations of personalised risk factors (including presence of history of BC among first-degree relative, a prior diagnosis of benign breast disease, nulliparity and late age of first live birth, early age of menarche, high body mass index and physical inactivity) putting them at increased risk of BC are recommended to consider mammography screening every 2 years. They should discuss with their doctors on the potential benefits and harms before undergoing mammography screening. A risk assessment tool for local women (eg, one developed by HKU) is recommended to be used for estimating the risk of developing BC with regard to the personalised risk factors described above.

Thioproline Serves as an Efficient Antioxidant Protecting Human Cells from Oxidative Stress and Improves Cell Viability.

Oxidative stress is associated with the pathophysiology of many degenerative human diseases, including Alzheimer's disease, atherosclerosis, Parkinson's disease, and cancers. We discovered in our previous study that thioproline (SPro), a proline analogue, is generated in oxidant-exposed cells. With the prior observation that SPro served as an efficient nitrile trapping agent, we tested in this study the hypothesis that this oxidative stress generated cysteine-formaldehyde adduct, SPro, may serve as an antioxidant protecting cells from oxidative stress. Interestingly, results showed that HeLa cells cultured in SPro-supplemented culture media are more tolerant of oxidative stress, indicated by a dosage-dependent increase in cell viability. Investigation of the molecular mechanism of the observed increase in cell tolerance to oxidative stress revealed SPro acting as an effective antioxidant by sacrificial oxidation. Results also showed that SPro had been incorporated into cellular proteins and induced changes in protein expression profiles of treated cells. Despite being yet to determine the participation of individual factors to the observed increase of cell tolerance to oxidative stress, this study sheds light on the potential use of SPro as a dietary supplement for protecting humans from oxidative stress-associated degenerative human diseases.

Proteomics Study of DNA-Protein Crosslinks in Methylmethanesulfonate and Fe2+-EDTA-Exposed Human Cells.

The formation of covalently bound DNA-protein crosslinks (DPCs) is linked to the pathophysiology of cancers and many other degenerative diseases. Knowledge of the proteins that were frequently involved in forming DPCs will improve our understanding of the etiological mechanism of diseases and facilitate the establishment of preventive measures and treatment methods. By using SDS-PAGE and nano-LC coupled Orbitrap LC-MS/MS analyses, we identified, for the first time, that the major DNA-cross-linked proteins in HeLa cells exposed to a methylating agent (methylmethanesulfonate) or hydroxyl free radicals are transcription-associated proteins. In particular, histone H2B3B and poly(rC) binding protein 2 were identified as the most frequent DPC-forming proteins.

Liquid chromatography-tandem mass spectrometry analysis of aristolochic acids in soil samples collected from Serbia: Link to Balkan endemic nephropathy.

RATIONALE: Over the past six decades, residents of farming villages in multiple countries of the Balkan peninsula have been suffering from a unique type of chronic renal disease, Balkan endemic nephropathy (BEN). It was speculated that environmental pollution by aristolochic acids (AAs) produced naturally by Aristolochia clematitis L., a weed that grows in the area, was causing the disease. However, the human exposure pathway to this class of phytotoxin remains obscure. Knowledge of the sink and stability of AAs in the environment would assist in the formulation of policy reducing exposure risk. METHODS: Using our newly developed liquid chromatography/tandem mass spectrometry method of high sensitivity and selectivity, we analysed over 130 soil samples collected from cultivation fields in southern Serbia for the presence of AAs. The environmental stability of AAs was also investigated by incubating soil samples spiked with AAs at various temperatures. RESULTS: The analysis detected AA-I in over two-fifths of the tested samples at sub-µg/kg to µg/kg levels, with higher concentrations observed in more acidic farmland soil. Furthermore, analysis of soil samples incubated at various temperatures revealed half-lives of over 2 months, indicating that AAs are relatively resistant to degradation. CONCLUSIONS: Cultivation soil in southern Serbia is being extensively contaminated with AAs released from the decomposition of A. clematitis weeds. Since AAs are resistant to degradation, it is possible that AAs could have been taken up by root absorption and transported to the edible part of food crops. Prolonged exposure to AA-contaminated food grown from polluted soil could be one of the main aetiological mechanisms of BEN observed in the area.

A prospective evaluation of the outcome of submucosal ligation of fistula tract.

AIM: Fistula-in-ano (FIA) is an anomalous passage between perianal skin and the anal canal or the rectum that presents many management difficulties. Ligation of intersphincteric fistula tract (LIFT) was introduced as a cost-effective sphincter-saving procedure with a reported success rate of 94.4%. Unfortunately, this procedure is technically challenging, and recently submucosal ligation of fistula tract (SLOFT), a simplification of LIFT, was proposed. Our aim was to assess the SLOFT technique over a longer follow-up period to determine its effectiveness. METHOD: A prospective observational study was performed in 47 patients with FIA treated by SLOFT from September 2017 to February 2019. RESULTS: There were 47 patients, of whom 33(70.2%) were men. The median age was 39 years (range 30-50 years). All the patients had primary FIA of cryptoglandular origin. The patients were followed up for 1 year and were postoperatively assessed at 2, 4, 12 and 24 weeks and 1 year. The median body mass index was 27.3 kg/m2 (range 24.3-29.4 kg/m2 ) and the median duration of surgery was 15 min (range 13-20 min). Most (83.0%) of the fistulas were trans-sphincteric. The success rates at the end of 24 weeks and 1 year were 87.2% and 80.9%, respectively. No postoperative incontinence was recorded. CONCLUSION: In our series the success rate of SLOFT was 80.9%. There were no sphincter-related complications. Repeat SLOFT was feasible for cases of recurrence. Therefore, SLOFT should be considered an alternative sphincter-saving procedure to LIFT for the management of FIA.

Quantitation of N6-Formyl-lysine Adduct Following Aristolochic Acid Exposure in Cells and Rat Tissues by Liquid Chromatography-Tandem Mass Spectrometry Coupled with Stable Isotope-Dilution Method.

N6-Formyl-lysine (FLys) is an abundant and lasting protein adduct formed when formaldehyde generated by nitrosative/oxidative stress and inflammation reacts with lysine residues. It is believed that the post-translational N6-formylation of lysine is associated with a variety of pathological processes and human diseases. Thus, FLys may serve well as a dosimetric biomarker for exposure to formaldehyde and other oxidative stress-inducing toxicants. However, since current methods for FLys determination are tedious and time-consuming, we developed and validated an aqueous normal phase liquid chromatography-tandem mass spectrometry (LC-MS/MS) coupled with isotope-dilution method for the rigorous quantification of FLys with enhanced sensitivity and selectivity. After validating the accuracy and precision of the method with a synthetic peptide containing FLys, the method was applied to quantitate the concentration-dependent formation of FLys in cells exposed to formaldehyde and Fe2+-EDTA, an OH radical-mediated oxidant. The study reveals formaldehyde and Fe2+-EDTA produced FLys at a frequency of 20.2 and 4.1 per 104 lysine per mM, respectively, after correcting for losses during protein digestion steps. The study was further extended to quantitate the concentration-dependent formation of FLys in aristolochic acid I (AA-I) exposed Escherichia coli cells and rat tissues. This study demonstrates for the first time that AA-I exposure induces time- and dose-dependent formation of FLys in cellular proteins. Furthermore, results show AA-I exposure leads to organotropic N6-formylation of lysine, with elevated levels of FLys detectable in the kidney, which is the one of the tumor targeting organs of AAs. Previous studies have also revealed AA exposure induced renal interstitial fibrosis in both laboratory rodents and humans, by a yet to be determined molecular mechanism. These data shed light on the potential caustative role of N6-formylation in the pathophysiology of AA nephrotoxicity and carcinogenicity.

Systemic therapies for recurrent or metastatic nasopharyngeal carcinoma: a systematic review.

BACKGROUND: The majority of published studies in recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) are single-arm trials. Reliable modelling of progression-free survival (PFS) and overall survival (OS) outcomes, therefore, is difficult. This study aim to analyse existent literature to estimate the relative efficacy of available systemic regimens in RM-NPC, as well as provide estimates of aggregate OS and PFS. METHODS: We conducted a systematic search of MEDLINE, EMBASE and the Cochrane Library to March 2015. Clinical trials (in English only) investigating cytotoxic and molecularly targeted agents in adult patients with RM-NPC were included. All relevant studies were assessed for quality using Downs and Blacks (DB) checklist (maximum quality score of 27). Aggregate data analysis and Student's t-test were performed for all identified studies (model A). For studies that published analysable Kaplan-Meier curves, survival data were extracted and marginal proportional hazards models were constructed (model B). RESULTS: A total of 56 studies were identified and included in model A, 26 of which had analysable Kaplan-Meier curves and were included in model B. The 26 studies in model B had significantly higher mean DB scores than the remaining 30 (17.3 vs 13.7, P=0.002). For patients receiving first line chemotherapy, the estimated median OS was 15.7 months by model A (95% CI, 12.3-19.1), and 19.3 months by model B (95% CI, 17.6-21.1). For patients undergoing second line or higher therapies (2nd+), the estimated median OS was 11.5 months by model A (95% CI 10.1-12.9), and 12.5 months by model B (95% CI 11.9-13.4). PFS estimates for patients undergoing first-line chemotherapy by model A was 7.6 months (95% CI, 6.2-9.0), and 8.0 months by model B (95% CI, 7.6-8.8). For patients undergoing therapy in the 2nd+ setting, the estimated PFS by model A was 5.4 months (95% CI, 3.8-7.0), and 5.2 months by model B (95% CI, 4.7-5.6). CONCLUSIONS: We present the first aggregate estimates of OS and PFS for RM-NPC patients receiving first and second-line or higher treatment settings, which could inform the design of future clinical trials in this disease setting.

A systematic review and network meta-analysis of post-imatinib therapy in advanced gastrointestinal stromal tumour.

BACKGROUND: The standard first-line systemic therapy for advanced gastrointestinal stromal tumour (gist) is imatinib. However, most gists develop imatinib resistance, highlighting the need for new agents in the imatinib-refractory setting. Currently, no randomized studies have directly compared the available post-first-line treatments. METHODS: In a systematic review, the medline, embase, and central databases, and American Society of Clinical Oncology abstracts to July 2014 were searched to identify randomized controlled trials that included gist patients treated with post-first-line therapies. Hazard ratios (hrs) for progression-free (pfs) and overall survival (os) were extracted. Direct pairwise meta-analyses and indirect comparisons using the Butcher method were performed. RESULTS: Four studies were identified for the systematic review. One study showed that sunitinib in the second-line setting (vs. placebo) was associated with improved pfs, but not improved os. Three studies examined the third-line setting (imatinib resumption vs. placebo, regorafenib vs. placebo, nilotinib vs. best supportive care). In the third-line settings, the two placebo-controlled and the non-placebo-controlled trials showed significant heterogeneity (I2 = 98%). Indirect comparisons of imatinib resumption and regorafenib suggested that the hr for pfs was 0.59 (95% confidence interval: 0.31 to 1.12; p = 0.10), trending in favour of regorafenib. Indirect comparisons found that toxicities were higher in the regorafenib group, with a risk difference of 27.8% for any-grade toxicities and 19.5% for grades 3 and 4 toxicities. CONCLUSIONS: Because a head-to-head study of imatinib resumption compared with regorafenib is unlikely ever to be conducted, our study suggests that, in terms of pfs, regorafenib might be the preferred treatment. However, given the increased toxicity observed with regorafenib, clinicians should interpret that evidence with caution at an individual patient level.

Systemic therapy in the curative treatment of head-and-neck squamous cell cancer: Cancer Care Ontario clinical practice guideline.

OBJECTIVE: The aim of the present work was to make recommendations about the use of systemically administered drugs in combination or in sequence with radiation (rt) or surgery, or both, for cure or organ preservation, or both, in patients with locally advanced nonmetastatic (stages iii-ivb) squamous cell carcinoma of the head and neck (lascchn). METHODS: The Meta-analysis of Chemotherapy in Head and Neck Cancer (mach-nc) reports have, de facto, guided practice since 2000, and so we searched the literature for systematic reviews published from January 2000 to February 2015 in reference to five research questions. A search was also conducted up to February 2015 for randomized trials (rcts) not included in the meta-analyses. Recommendations were constructed using the Cancer Care Ontario Program in Evidence-Based Care practice guidelines development cycle. RESULTS: In addition to updated mach-nc reports, five additional meta-analyses and thirty rcts were identified. Five recommendations for lascchn treatment were generated based on those data. Concurrent chemoradiation (ccrt) is recommended to maximize the chance of cure in patients less than 71 years of age when rt is used as definitive treatment. The same recommendation also applies to patients with resected lascchn considered to be at high risk for locoregional recurrence. For lascchn patients who are candidates for organ preservation strategies and would otherwise require total laryngectomy, either ccrt or induction chemotherapy, followed by rt or surgery based on tumour response is recommended. The addition of cetuximab to intensified rt (concomitant boost or hyperfractionated schedule) is an alternative to ccrt. Routine use of induction chemotherapy to improve overall survival is not recommended. CONCLUSIONS: We were able to use high-level evidence from patients receiving rt as definitive or postoperative treatment to generate recommendations for the use of systemic therapy in the treatment of lascchn. A limitation is a lack of stratification for human papillomavirus-related cancers of the oropharynx. One rct provided evidence for the use of cetuximab as an alternative to chemotherapy in the definitive rt setting. Concurrent chemoradiation provides one strategy for larynx preservation, but the best strategy is unclear. Use of induction chemotherapy does not improve overall survival, and its use should be limited to patients requiring immediate tumour downsizing before local therapy.

Impact of the pan-Canadian Oncology Drug Review on provincial concordance with respect to cancer drug funding decisions and time to funding.

BACKGROUND: The pan-Canadian Oncology Drug Review (pcodr) was implemented in 2011 to address uneven drug coverage and lack of transparency with respect to the various provincial cancer drug review processes in Canada. We evaluated the impact of the pcodr on provincial decision concordance and time from Notice of Compliance (noc) to drug funding. METHODS: In a retrospective review, Health Canada's Drug Product Database was used to identify new indications for cancer drugs between January 2003 and May 2014, and provincial formulary listings for drug-funding dates and decisions between 1 January 2003 and 31 December 2014 were retrieved. Multiple linear models and quantile regressions were used to evaluate changes in time to decision-making before and after the implementation of the pcodr. Agreement of decisions between provinces was evaluated using kappa statistics. RESULTS: Data were available from 9 provinces (all Canadian provinces except Quebec), identifying 88 indications that represented 51 unique cancer drugs. Two provinces lacked available data for all 88 indications at the time of data collection. Interprovincial concordance in drug funding decisions significantly increased after the pcodr's implementation (Brennan-Prediger coefficient: 0.54 pre-pcodr vs. 0.78 post-pcodr; p = 0.002). Nationwide, the median number of days from Health Canada's noc date to the date of funding significantly declined (to 393 days from 522 days, p < 0.001). Exploratory analyses excluding provinces with incomplete data did not change the results. CONCLUSIONS: After the implementation of the pcodr, greater concordance in cancer drug funding decisions between provinces and decreased time to funding decisions were observed.

Interpreting febrile neutropenia rates from randomized, controlled trials for consideration of primary prophylaxis in the real world: a systematic review and meta-analysis.

BACKGROUND: Guidelines recommend primary prophylaxis (PP) with granulocyte-colony-stimulating factors (G-CSF) for patients above a febrile neutropenia (FN) risk threshold of 20%. Practitioners often use FN rates of regimens based on data from randomized, controlled trials (RCTs), which are often comprised of highly selected patients. Patients in the community setting may be at higher risk of FN. MATERIALS AND METHODS: A systematic literature search was conducted for full-length articles reporting FN rates for breast cancer-related chemotherapies between January 1996 and February 2014. A regimen was included if there was at least one RCT and one observational study. Meta-regression was used to model the odds of FN. RESULTS: 130 studies involving 29 regimens and 50 069 patients were identified. Sixty-five observational study (n = 7812) and 110 RCT (n = 42 257) cohorts were included. The unadjusted FN rate was 11.7% in observational and 7.9% in RCT cohorts. The univariable odds ratio (OR) for FN in the observational study compared with RCT cohorts was 1.58 [95% confidence interval (CI) 1.09-2.28; P = 0.017]. The FN rates remained significantly higher in the observational study compared with RCT cohorts (OR = 1.74; 95% CI 1.15-2.62; P = 0.012) after adjusting for age, chemotherapy intent, and regimen; this meant that a 13% (95% CI 8.7% to 17.9%) FN rate in RCT would translate into 20% FN rate in observational study. CONCLUSIONS: FN rates in the observational studies are significantly higher than suggested by RCTs. Guidelines should clarify how FN rates from RCTs should be applied in clinical practice. Large population-based studies are needed to confirm FN rates in the real world.

Identification of Protein Thiazolidination as a Novel Molecular Signature for Oxidative Stress and Formaldehyde Exposure.

Chemical modifications of proteins have been well-documented to play important roles in normal cell physiology such as cell signaling and protein functions. They have also been demonstrated to be one of the milestones in the pathophysiology of many human diseases such as cancer, age-related pathology, and neurodegenerative disorders. Here, we report the initial identification of a novel protein modification, cysteine thiazolidination, through reaction with endogenous and exogenous formaldehyde with cysteine residues in proteins. Using an isotope-dilution liquid chromatography-tandem mass spectrometric (LC-MS3) method, we initiated the study by quantitating thioproline in formaldehyde-treated Escherichia coli (E. coli) protein. The study was then extended to quantitate thioproline in protein obtained from formaldehyde- and oxidant-exposed E. coli. Furthermore, N6-formyllysine, a well-defined formylation product between formaldehyde and lysine, was exploited in a comparative study to evaluate the relative reactivity and amount of cysteine thiazolidination in the reaction of formaldehyde with proteins. It is anticipated that cysteine thiazolidination may serve as a novel biomarker for oxidative stress and formaldehyde exposure.