Impact of Lactate Dehydrogenase and Hemoglobin Levels on Clinical Outcomes in Patients With Paroxysmal Nocturnal Hemoglobinuria: Results From the National Korean PNH Registry.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder caused by uncontrolled terminal complement activation, which leads to intravascular hemolysis (IVH), thromboembolism (TE), renal failure, and premature mortality. METHODS: We performed a secondary analysis of data collected from patients enrolled in the Korean National PNH Registry to assess the relative importance of risk factors, specifically lactate dehydrogenase (LDH) and hemoglobin (Hb), in predicting the incidence of TE, impaired renal function, and death in complement inhibitor-naïve patients with PNH. RESULTS: Multivariate regression modeling indicated that LDH ≥ 1.5 × upper limit of normal (ULN), male sex, and pain were associated with increased risk of TE (P = 0.016, 0.045, and 0.033, respectively), hemoglobinuria and pain were associated with an increased risk of impaired renal function (P = 0.034 and 0.022, respectively), and TE was associated with an increased incidence of death (P < 0.001). Hb < 8 g/dL was not a predictor of TE, impaired renal function, or death in multivariate regression analyses. Standardized mortality ratio analysis indicated that LDH ≥ 1.5 × ULN (P < 0.001), Hb < 8 g/dL (P < 0.001), and Hb ≥ 8 g/dL (P = 0.004) were all risk factors for death; in contrast, patients with LDH < 1.5 × ULN had similar mortality to the general population. CONCLUSION: In complement inhibitor-naïve patients with PNH, LDH ≥ 1.5 × ULN was a significant predictor of TE, and TE was a significant predictor of death. Hb was not a significant predictor of TE, impaired renal function, or death. Therefore, controlling IVH will improve clinical outcomes for patients with PNH.

Single-cyst transcriptome analysis of Drosophila male germline stem cell lineage.

The Drosophila male germline stem cell (GSC) lineage provides a great model to understand stem cell maintenance, proliferation, differentiation and dedifferentiation. Here, we use the Drosophila GSC lineage to systematically analyze the transcriptome of discrete but continuously differentiating germline cysts. We first isolated single cysts at each recognizable stage from wild-type testes, which were subsequently applied for RNA-seq analyses. Our data delineate a high-resolution transcriptome atlas in the entire male GSC lineage: the most dramatic switch occurs from early to late spermatocyte, followed by the change from the mitotic spermatogonia to early meiotic spermatocyte. By contrast, the transit-amplifying spermatogonia cysts display similar transcriptomes, suggesting common molecular features among these stages, which may underlie their similar behavior during both differentiation and dedifferentiation processes. Finally, distinct differentiating germ cell cyst samples do not exhibit obvious dosage compensation of X-chromosomal genes, even considering the paucity of X-chromosomal gene expression during meiosis, which is different from somatic cells. Together, our single cyst-resolution, genome-wide transcriptional profile analyses provide an unprecedented resource to understand many questions in both germ cell biology and stem cell biology fields.

Amivantamab compared with real-world therapies in patients with advanced non-small cell lung cancer EGFR Exon 20 insertion mutations after platinum-based chemotherapy.

BACKGROUND: In the single-arm CHRYSALIS trial, advanced non-small cell lung cancer patients harboring epidermal growth factor receptor (EGFR) exon 20 insertion (Exon 20ins) showed durable responses to amivantamab, an EGFR-MET bispecific antibody targeting tumors with EGFR Exon 20ins. This study compared the effectiveness of amivantamab to real-world systemic anti-cancer therapies in Japan. PATIENTS AND METHODS: External control patients were selected by applying CHRYSALIS eligibility to Japanese patients from LC-SCRUM-Asia. External control patients were included for every qualifying line of therapy after platinum-based chemotherapy. Propensity score weighting was applied to external control patients to adjust for differences in baseline characteristics. Outcomes were compared between external control patients, and all and Asian-only CHRYSALIS patients using weighted Cox proportional hazards regression models for progression-free survival (PFS), time to next therapy (TTNT), and overall survival (OS), and generalized estimating equations with repeated measurements for overall response rate (ORR). RESULTS: One hundred fifteen CHRYSALIS and 94 external control patients were identified. Compared to external control patients, amivantamab-treated patients had significantly longer OS (median OS 19.88 vs 14.09 months, HR [95% CI] 0.59 [0.40-0.88]), PFS (median PFS 6.74 vs 4.73 months, HR 0.59 [0.45-0.78]), TTNT (median TTNT 12.16 vs 5.09 months, HR 0.39 [0.29-0.53]), and significantly higher ORR (41.7% vs 14.1%). Analyses of amivantamab-treated Asian patients (n = 61) showed similar clinical benefits. CONCLUSION: In the absence of clinical evidence from randomized clinical trials, this study reflects the benefit of amivantamab after platinum-based chemotherapy for advanced non-small cell lung cancer patients harboring EGFR Exon 20ins, compared to current real-world therapies.

Phase I study of selinexor in combination with dexamethasone, ifosfamide, carboplatin, etoposide chemotherapy in patients with relapsed or refractory peripheral T-cell or natural-killer/T-cell lymphoma

Selinexor is a selective inhibitor of nuclear export with anti-cancer properties. We performed a phase I study to determine the safety and maximum tolerated dose (MTD) of selinexor when combined with high-dose dexamethasone, ifosfamide, carboplatin and etoposide (DICE) in relapsed/refractory (R/R) T-cell lymphoma (TCL) and natural-killer/T-cell lymphoma (NKTL). Patients with R/R TCL and NKTL were treated with standard dose ICE, dexamethasone 20mg on days 3 to 7, and escalating doses of oral selinexor on days 3, 5 and 7 in a 3+3 design. Dose level (DL) 1, 2 and 3 were 40, 60 and 80mg respectively. Eleven patients with a median age of 60 were enrolled; 6 at DL1 and 5 at DL2. Patients had received a median of 2 (range 1-4) prior lines of treatment and 7 had primary refractory disease at study entry. Patients received a median of 3 cycles (range 1-6) of selinexor-DICE. The most common grade (G) 1/2 toxicities included nausea (64%), fatigue (55%), and anorexia (45%) and the most common G 3/4 toxicities included thrombocytopenia (82%), anemia (82%), neutropenia (73%), and hyponatremia (73%). Two patients developed doselimiting toxicities at DL2 and one at DL1. Five patients discontinued treatment for reasons other than disease progression or lack of response. Of the 10 evaluable patients, the overall and complete response rates were 91% and 82% respectively. The MTD of selinexor was 40mg when combined with DICE. The combination showed promising CR rates in patients with R/R TCL and NKTL but was poorly tolerated.

An intronic FTO variant rs16952570 confers protection against thiopurine-induced myelotoxicities in multiethnic Asian IBD patients.

Thiopurines are used in the treatment of inflammatory bowel disease (IBD) but remain clinically challenging to manage due to wide interpatient variability in clinical outcomes and adverse events. Apart from genetic variants in thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) genes, polymorphisms in FTO alpha-ketoglutarate dependent dioxygenase (FTO) were found predictive of thiopurine-induced leukopenia, albeit with conflicting results. To clarify the role of FTO variants in a multiethnic Asian IBD cohort, we recruited 149 patients on thiopurine-based therapy and genotyped two FTO variants p.Ala134Thr (rs79206939) and rs16952570 T > C using Sanger sequencing. FTO p.Ala134Thr (rs79206939) was non-polymorphic and absent whereas intronic rs16952570 T > C was equally prevalent in Chinese (22%) and Indians (18%) and higher in Malays (28%). Higher nadir white blood cell (WBC) and absolute neutrophil count (ANC) levels were observed in patients harboring FTO rs16952570 CC genotypes compared with TT carriers at 4, 8, and 12 weeks after start of thiopurine therapy (P < 0.05). A similar trend was observed in patients carrying the previously well-characterized NUDT15 rs116855232 wild-type CC genotypes. Further in silico analysis suggests that FTO variants linked to rs16952570, particularly rs74018601, may play a regulatory role in altering the FTO expression. The findings from this study indicate a novel protective association with the FTO variant rs16952570 CC genotype and hematological parameters.

CRISPR-Knockout Screen Identifies Dmap1 as a Regulator of Chemically Induced Reprogramming and Differentiation of Cardiac Progenitors.

Direct in vivo reprogramming of cardiac fibroblasts into myocytes is an attractive therapeutic intervention in resolving myogenic deterioration. Current transgene-dependent approaches can restore cardiac function, but dependence on retroviral delivery and persistent retention of transgenic sequences are significant therapeutic hurdles. Chemical reprogramming has been established as a legitimate method to generate functional cell types, including those of the cardiac lineage. Here, we have extended this approach to generate progenitor cells that can differentiate into endothelial cells and cardiomyocytes using a single inhibitor protocol. Depletion of terminally differentiated cells and enrichment for proliferative cells result in a second expandable progenitor population that can robustly give rise to myofibroblasts and smooth muscle. Deployment of a genome-wide knockout screen with clustered regularly interspaced short palindromic repeats-guide RNA library to identify novel mediators that regulate the reprogramming revealed the involvement of DNA methyltransferase 1-associated protein 1 (Dmap1). Loss of Dmap1 reduced promoter methylation, increased the expression of Nkx2-5, and enhanced the retention of self-renewal, although further differentiation is inhibited because of the sustained expression of Cdh1. Our results hence establish Dmap1 as a modulator of cardiac reprogramming and myocytic induction. Stem Cells 2019;37:958-972.

Supporting the patients with advanced cancer and their family caregivers: what are their palliative care needs?

BACKGROUND: The impact and consequences of cancer on the patients and their family caregivers (FCs) are closely intertwined. Caregivers' burdens can be increased due to the patients' unmet needs and unresolved problems. Additionally, the caregivers' unmet needs may adversely affect their own well-being and the patients' health outcomes. This study aims to determine the palliative care needs and the factors associated with these needs in patients with advanced solid cancer and their FCs. METHODS: In a cross-sectional survey, 599 patients with advanced solid tumours and 599 FCs were recruited from the largest ambulatory cancer centre and the inpatient ward of the largest hospital in Singapore. Determinants of patients' and FCs' needs were assessed by the Comprehensive Needs Assessment Tool (CNAT) and CNAT-C respectively. Clinical characteristics of patients were obtained from medical records. RESULTS: The FCs (median age 51 years) were younger than the patients (median age 62 years), and were mostly female (62.6%) whereas the gender distribution of patients was quite balanced (49.2% male and 50.8% female). Both patients and FCs had "information" and "practical support" in their top three domains of palliative care needs. The second highest domain of needs was "psychological problems" (16.4 ± 21.5) in patients and "health-care staff" (23.4 ± 26.5) in FCs. The item that had the highest need score in "information" domain for both patients and FCs was "financial support for patients, either from government and/ or private organizations". Under clinical setting, the inpatients (19.2 ± 16.4) and their FCs (26.0 ± 19.0) tend to have higher needs than the outpatients (10.5 ± 12.1) and their FCs (14.7 ± 14.3). In terms of palliative care, higher total CNAT score was observed in both patients (16.6 ± 12.9 versus 13.3 ± 15.2) and their FCs (25.1 ± 18.6 versus 17.7 ± 16.7) who received palliative care. In terms of patients' KPS scores, patients with lower KPS scores tend to have higher needs. CONCLUSION: Overall, the findings confirm that patients with advanced cancer and their FCs have many palliative care needs irrespective of their clinical settings. Initiatives and interventions for the development of a comprehensive support system for both patients with advanced cancer and their FCs are warranted and can be derived from these findings.

Randomised prospective phase II trial in multiple brain metastases comparing outcomes between hippocampal avoidance whole brain radiotherapy with or without simultaneous integrated boost: HA-SIB-WBRT study protocol.

BACKGROUND: Recent evidence supports hippocampal avoidance with whole brain radiotherapy (HA-WBRT) as the recommended treatment option in patients with good prognosis and multiple brain metastases as this results in better neurocognitive preservation compared to whole brain radiotherapy. However, there is often poor tumour control with this technique due to the low doses given. Stereotactic Radiosurgery (SRS), a form of focused radiotherapy which is given to patients who have a limited number of brain metastases, delivers a higher radiation dose to the metastases resulting in better target lesion control. With improvements in radiation technology, advanced dose-painting techniques now allow a simultaneous integrated boost (SIB) dose to lesions whilst minimising doses to the hippocampus to potentially improve brain tumour control and preserve cognitive outcomes. This technique is abbreviated to HA-SIB-WBRT or HA-WBRT+SIB. METHODS: We hypothesise that the SIB in HA-SIB-WBRT (experimental arm) will result in better tumour control compared to HA-WBRT (control arm). This may also lead to better intracranial disease control as well as functional and survival outcomes. We aim to conduct a prospective randomised phase II trial in patients who have good performance status, multiple brain metastases (4-25 lesions) and a reasonable life expectancy (> 6 months). These patients will be stratified according to the number of brain metastases and randomised between the 2 arms. We aim for a recruitment of 100 patients from a single centre over a period of 2 years. Our primary endpoint is target lesion control. These patients will be followed up over the following year and data on imaging, toxicity, quality of life, activities of daily living and cognitive measurements will be collected at set time points. The results will then be compared across the 2 arms and analysed. DISCUSSION: Patients with brain metastases are living longer. Maintaining functional independence and intracranial disease control is thus increasingly important. Improving radiotherapy treatment techniques could provide better control and survival outcomes whilst maintaining quality of life, cognition and functional capacity. This trial will assess the benefits and possible toxicities of giving a SIB to HA-WBRT. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04452084 . Date of registration 30th June 2020.

Measurement Structure of the Pittsburgh Sleep Quality Index and Its Association with Health Functioning in Patients with Coronary Heart Disease.

Research on the underlying structure of sleep measures in patients with coronary heart disease (CHD) is lacking. Existing research on sleep and health outcomes primarily focused on only one dimension of sleep (e.g., sleep duration), leaving other aspects unexamined. To address this gap, this study examined the measurement structure of Pittsburgh Sleep Quality Index (PSQI) and its associations with health-related quality of life among CHD patients. Participants were 167 CHD patients from a cardiac wellness program. Confirmatory factor analysis revealed that the two-factor structure with sleep efficiency and perceived sleep quality best fitted the data. Concurrent validity analyses with structural equation modeling showed that, when considered simultaneously, perceived sleep quality, but not sleep efficiency, was significantly associated with emotional, physical, and social quality of life. Findings demonstrated that the PSQI consists of two moderately correlated factors that are differentially associated with separate health domains in cardiac patients.

Patterns of relapse after neoadjuvant chemotherapy in breast cancer: implications for surveillance in clinical practice.

PURPOSE: This study aimed to identify patterns of relapse after neoadjuvant chemotherapy (NAC) for breast cancer to refine follow-up recommendations. METHODS: Retrospective analysis on 523 breast cancer patients treated with NAC at two public hospitals in Singapore between 2000 and 2014. RESULTS: Majority of patients (71.9%) had locally advanced disease. Median follow-up was 55 months. 5-year recurrence rate was significantly higher in triple negative breast cancer (TNBC) than non-TNBC subtypes (38.4% vs. 29.5%; p = 0.042); 85% of recurrences involved distant sites. Among TNBC and HR (hormone receptor)-/HER2+ subtypes, 97.0% and 95.0% of relapses occurred within 3 years from diagnosis respectively while 10.6% of relapses among HR+ subgroup occurred beyond 5 years. Recurrence risk in high-grade tumours decreased with time. Stage III at diagnosis (hazard ratio = 2.94; p < 0.001), grade 3 tumours (hazard ratio = 2.87; p = 0.018), not achieving pathologic complete response (pCR) (hazard ratio = 8.77; p = 0.003) and not receiving adjuvant radiotherapy (hazard ratio = 3.19; p < 0.001) were independent predictors of inferior recurrence-free survival. Serum CA 15-3 was raised in 49% of patients upon relapse; it correlated with inferior post-relapse survival (median 11 months vs. 22 months; p = 0.019). CONCLUSIONS: While more intensive follow-up during the first 3 years may be required for patients who do not achieve pCR, especially those with TNBC and HR-/HER2+ tumours, the benefit from blood tests such as CA 15-3 appears limited, and the benefit from intensification of surveillance remains to be addressed in prospective studies on high-risk patients.

Breast cancer in women with neurofibromatosis type 1 (NF1): a comprehensive case series with molecular insights into its aggressive phenotype.

PURPOSE: The purpose of the study was to improve the understanding of NF1-associated breast cancer, given the increased risk of breast cancer in this tumour predisposition syndrome and the limited data. METHODS: We identified 18 women with NF1 and breast cancer at our institution. Clinical and pathologic characteristics of NF1-associated breast cancers were compared with 7132 breast cancers in patients without NF1 from our institutional database. Next generation sequencing was performed on DNA from blood and breast cancer specimens available. Blood specimens negative for NF1 mutation were subjected to multiplex ligation-dependent probe amplification (MLPA) to identify complete/partial deletions or duplications. Expression of neurofibromin in the NF1-associated breast cancers was evaluated using immunohistochemistry. RESULTS: There was a higher frequency of grade 3 (83.3% vs 45.4%, p = 0.005), oestrogen receptor (ER) negative (66.7% vs 26.3%, p < 0.001) and human epidermal growth factor receptor 2 (HER2)-positive (66.7% vs 23.4%, p < 0.001) tumours among NF1 patients compared to non-NF1 breast cancers. Overall survival was inferior in NF1 patients in multivariable analysis (hazard ratio 2.25, 95% CI 1.11-4.60; p = 0.025). Apart from germline NF1 mutations (11/16; 69%), somatic mutations in TP53 (8/10; 80%), second-hit NF1 (2/10; 20%), KMT2C (4/10; 40%), KMT2D (2/10; 20%), and PIK3CA (2/10; 20%) were observed. Immunohistochemical expression of neurofibromin was seen in the nuclei and/or cytoplasm of all specimens, but without any consistent pattern in the intensity or extent. CONCLUSIONS: This comprehensive series of NF1-associated breast cancers suggests that their aggressive features are related to germline NF1 mutations in cooperation with somatic mutations in TP53, KMT2C and other genes.

Correction to: Influence of afatinib dose on outcomes of advanced EGFR-mutant NSCLC patients with brain metastases.

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Influence of afatinib dose on outcomes of advanced EGFR-mutant NSCLC patients with brain metastases.

BACKGROUND: Afatinib is an oral irreversible epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) indicated in first-line treatment of advanced EGFR-mutant (EGFRm+) non-small cell lung cancer (NSCLC). Dose dependent side effects can limit drug exposure, which may impact on extracranial and central nervous system (CNS) disease control. METHODS: We performed a retrospective study of 125 patients diagnosed with advanced EGFRm+ NSCLC treated with first-line afatinib at a tertiary Asian cancer center, exploring clinicopathological factors that may influence survival outcomes. Median progression free survival (PFS) was estimated using the Kaplan-Meier method. Comparison of PFS between subgroups of patients was done using log-rank tests and Cox proportional hazards models. RESULTS: Out of 125 patients, 62 (49.6%) started on 40 mg once daily (OD) afatinib, 61 (48.8%) on 30 mg OD and 1 (0.8%) on 20 mg OD. After median follow-up of 13.8 months from afatinib initiation, the observed response rate was 70.4% and median PFS 11.9 months (95% CI 10.3-19.3). 42 (33.6%) patients had baseline brain metastases (BM) and PFS of those who started on 40 mg OD (n = 17) vs. 30 mg OD (n = 25) was 13.3 months vs. 5.3 months (HR 0.39, 95% CI 0.15-0.99). BM+ patients who started on 40 mg had similar PFS to patients with no BM (13.3 months vs. 15.0 months; HR 0.79, 95% CI 0.34-1.80). CONCLUSION: In patients with advanced EGFRm+ NSCLC with BM+, initiating patients on afatinib 40 mg OD was associated with improved PFS compared to 30 mg OD, underscoring the potential importance of dose intensity in control of CNS disease.

2015 Epidemic of Severe Streptococcus agalactiae Sequence Type 283 Infections in Singapore Associated With the Consumption of Raw Freshwater Fish: A Detailed Analysis of Clinical, Epidemiological, and Bacterial Sequencing Data.

BACKGROUND: Streptococcus agalactiae (group B Streptococcus [GBS]) has not been described as a foodborne pathogen. However, in 2015, a large outbreak of severe invasive sequence type (ST) 283 GBS infections in adults epidemiologically linked to the consumption of raw freshwater fish occurred in Singapore. We attempted to determine the scale of the outbreak, define the clinical spectrum of disease, and link the outbreak to contaminated fish. METHODS: Time-series analysis was performed on microbiology laboratory data. Food handlers and fishmongers were screened for enteric carriage of GBS. A retrospective cohort study was conducted to assess differences in demographic and clinical characteristics of patients with invasive ST283 and non-ST283 infections. Whole-genome sequencing was performed on human and fish ST283 isolates from Singapore, Thailand, and Hong Kong. RESULTS: The outbreak was estimated to have started in late January 2015. Within the study cohort of 408 patients, ST283 accounted for 35.8% of cases. Patients with ST283 infection were younger and had fewer comorbidities but were more likely to develop meningoencephalitis, septic arthritis, and spinal infection. Of 82 food handlers and fishmongers screened, none carried ST283. Culture of 43 fish samples yielded 13 ST283-positive samples. Phylogenomic analysis of 161 ST283 isolates from humans and fish revealed they formed a tight clade distinguished by 93 single-nucleotide polymorphisms. CONCLUSIONS: ST283 is a zoonotic GBS clone associated with farmed freshwater fish, capable of causing severe disease in humans. It caused a large foodborne outbreak in Singapore and poses both a regional and potentially more widespread threat.

MicroRNAs downregulate Bag of marbles to ensure proper terminal differentiation in the Drosophila male germline.

In many adult stem cell lineages, the continuous production of functional differentiated cells depends on the maintenance of progenitor cells in an undifferentiated and proliferative state, as well as the subsequent commitment to proper terminal differentiation. In the Drosophila male germline stem cell (GSC) lineage, a key differentiation factor, Bag of marbles (Bam), is required for the transition from proliferative spermatogonia to differentiating spermatocytes. We show that bam mRNA, but not Bam, is present in spermatocytes, suggesting that bam is regulated post-transcriptionally. Consistent with this, repression of Bam accumulation is achieved by microRNAs via the bam 3'UTR. When the bam 3'UTR was substituted with the 3'UTR of a constitutively expressed α-Tubulin, Bam became stabilized in spermatocytes. Moreover, such a persistent expression of Bam in spermatocytes was recapitulated by specifically mutating the putative miR-275/miR-306 recognition site at the bam 3'UTR. In addition, overexpression of miR-275 or miR-306 in spermatogonial cells resulted in a delay of the proliferation-to-differentiation transition and resembled the bam loss-of-function phenotype, suggesting that these microRNAs are sufficient to downregulate Bam. Finally, the failure of Bam downregulation in spermatocytes affected spermatid terminal differentiation and resulted in increased male sterility. Our results demonstrate that microRNAs control the stem cell differentiation pathway through regulating Bam, the downregulation of which is crucial for proper spermatid terminal differentiation.

Prospective Quality of Life Study for Colorectal Cancer Patients with Peritoneal Carcinomatosis Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is becoming accepted treatment for peritoneal carcinomatosis (PC) from colorectal cancer. Quality of life (QoL) for patients after surgery is still a concern amongst physicians despite studies that show that QoL recovers after surgery. We conducted a prospective QoL study on patients undergoing CRS and HIPEC and attempt to identify factors that affect the QoL. METHODS: Patients who underwent CRS and HIPEC for PC from colorectal cancer from March 2012 to January 2015 were included. The European Organization for the Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30) and the colorectal module (QLQ-CR29) were administered prior to surgery and thereafter at 3, 6, and 12 months. RESULTS: Twenty-three patients underwent 25 procedures. Median disease-free survival was 12.9 months [95 % confidence interval (CI) 2.5-19.3]. Physical and role functioning scores decreased at 3 months but returned to baseline at 6 months. There were significant increases in emotional and social functioning scores at 6-12 months and improvements in all symptoms scales at 6-12 months, especially the fatigue and appetite scores. A higher PCI score, longer duration of surgery, the presence of a stoma, and recurrence within 3 months were associated with a poorer QoL. CONCLUSIONS: QoL after CRS and HIPEC improved or returned to baseline in all categories by 6-12 months after surgery. Patient selection is important not only for improved survival but also for improved QoL.

Unresectability during open surgical exploration in planned cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are the treatment of choice for selected patients with peritoneal metastasis. Despite a stringent selection process, some patients were found to be unresectable only at surgery, which leads to disappointment and poor utilisation of limited infrastructural resources. This study aims to determine the pre-operative factors associated with unresectability in planned CRS and HIPEC. METHODS: Retrospective analysis of 172 consecutive patients eligible for CRS and HIPEC at the National Cancer Centre Singapore from April 2004 to May 2014 was performed. Pre-operative factors (clinical presentation, disease factors, and investigation findings) between the unresectable (13%) and the successful groups (87%) were compared. RESULTS: Patient demographics between the two cohorts were comparable. In terms of clinical presentation, the unresectable group was more likely to present with bloating (p = .00), altered bowel habits (p = .04), abdominal distension (p = .00), palpable abdominal masses (p = .00) and palpable pouch of Douglas nodules (p = .00). Differences were also noted in disease factors with the unresectable group having more high-grade tumours (p = .01), inadequate initial resections (p = .01), progression through chemotherapy (p = .00) and shorter median disease-free intervals (p = .03). In addition, investigations in the unresectable group revealed more patients with elevated tumour markers (p = .01), thrombocytosis (p = .00) and computed tomography findings of ascites (p = .00), omental thickening (p = .00), lymphadenopathy (p = .02) and small bowel disease (p = .00). CONCLUSIONS: Significant factors associated with unresectability that were identified in our study could potentially create a new treatment algorithm and refine current selection process to exclude patients at risk of unresectability in planned CRS and HIPEC.

Influenza-associated hospitalizations, Singapore, 2004-2008 and 2010-2012.

Studies of influenza-associated hospitalizations in tropical settings are lacking. To increase understanding of the effect of influenza in Singapore, we estimated the age-specific influenza-associated hospitalizations for pneumonia and influenza during 2004-2008 and 2010-2012. The rate of hospitalization was 28.3/100,000 person-years during 2004-2008 and 29.6/100,000 person-years during 2010-2012. The age-specific influenza-associated hospitalization rates followed a J-shaped pattern: rates in persons >75 years of age and in children <6 months of age were >47 times and >26 times higher, respectively, than those for persons 25-44 years of age. Across all ages during these 2 study periods, ≈12% of the hospitalizations for pneumonia and influenza were attributable to influenza. The rates and proportions of hospitalizations for influenza, particularly among the very young and the elderly, are considerable in Singapore and highlight the importance of vaccination in protecting populations at risk.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in Asian patients: 100 consecutive patients in a single institution.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been shown to improve survival in selected patients with peritoneal carcinomatosis. We review our institutional experience with the procedure and evaluate the overall survival (OS) and disease-free survival (DFS) rates in 100 consecutive patients. METHODS: Data were prospectively collected from 100 consecutive patients with peritoneal carcinomatosis treated by CRS and HIPEC at the National Cancer Centre Singapore between April 2001 and May 2012. Our primary end points were OS and DFS. RESULTS: Of the 100 patients, 84 were of Chinese ethnicity, 3 were Malay, 6 were Indian, and 7 were of other ethnicities. Primary tumors were ovarian cancer (n=39), colorectal cancer (n=28), primary peritoneal (n=6), appendiceal cancer (n=20), and mesothelioma (n=7). Median follow-up duration was 21 months. At 5 years, the DFS was 26.3% and OS was 50.9%. Factors influencing OS and DFS were cytoreductive score, primary cancer, and disease-free interval of more than 12 months on univariate analysis. The only factors that remained significant for prognosis after multivariate analysis were primary cancer and cytoreductive score. Thirty-day morbidity was 56%, and there were no 30-day mortalities. CONCLUSIONS: CRS and HIPEC can be safely carried out in Asian patients with peritoneal carcinomatosis from ovarian, colorectal, appendiceal, mesothelioma, and primary peritoneal origins. Overall, the ovarian, appendiceal, mesothelioma, and primary peritoneal cancer patients tended to do better than the colorectal patients, but careful patient selection ensuring that optimal cytoreduction can be achieved is essential for the success of this procedure.

Incidence and outcomes of delayed presentation and surgery in peritoneal surface malignancies.

Background: Peritoneal surface malignancies (PSM) present insidiously and often pose diagnostic challenges. There is a paucity of literature quantifying the frequency and extent of therapeutic delays in PSM and its impact on oncological outcomes. Methods: A review of a prospectively maintained registry of PSM patients undergoing Cytoreductive Surgery and Hyperthermic Intra-peritoneal Chemotherapy (CRS-HIPEC) was conducted. Causes for treatment delays were identified. We evaluate the impact of delayed presentation and treatment delays on oncological outcomes using Cox proportional hazards models. Results: 319 patients underwent CRS-HIPEC over a 6-years duration. 58 patients were eventually included in this study. Mean duration between symptom onset and CRS-HIPEC was 186.0 ± 37.1 days (range 18-1494 days) and mean duration of between patient-reported symptom onset and initial presentation was 56.7 ± 16.8 days. Delayed presentation (> 60 days between symptom onset and presentation) was seen in 20.7% (n=12) of patients and 50.0% (n=29) experienced a significant treatment delay of > 90 days between 1st presentation and CRS-HIPEC. Common causes for treatment delays were healthcare provider-related i.e. delayed or inappropriate referrals (43.1%) and delayed presentation to care (31.0%). Delayed presentation was a significantly associated with poorer disease free survival (DFS) (HR 4.67, 95% CI 1.11-19.69, p=0.036). Conclusion: Delayed presentation and treatment delays are common and may have an impact on oncological outcomes. There is an urgent need to improve patient education and streamline healthcare delivery processes in the management of PSM.