An innovative model of delivering cancer care in the community: the experience of a tertiary cancer centre in Singapore.

BACKGROUND: Cancer care has evolved rapidly, increasing the demand on healthcare resources. While many non-oral cancer treatments are administered in the hospital, not all necessitate complex medical care. Treatments that can be administered subcutaneously, intramuscularly, or as short intravenous infusions with a low risk of extravasation can be safely administered in the community. PATIENTS AND METHODS: Since 2017, the National University Cancer Institute, Singapore (NCIS) has operated a program called NCIS on-the-go (NOTG) comprising a network of community cancer treatment clinics located within 20 km of the hospital. NOTG provides 17 low-risk treatments and nursing services run by oncology-trained nurses without on-site physicians. Patients who receive their first dose of cancer treatment uneventfully in the cancer centre can opt-in to receive subsequent doses at any NOTG clinic. RESULTS: Treatment at NOTG has become more mainstream over the years, with its workload increasing by over sevenfold since 2017, and is now responsible for ∼10% of the total main cancer centre workload. The program is sustainable and financially viable to operate. A survey of 155 patients revealed a 96.8% user satisfaction rate, with the majority reporting tangible savings in travelling time, waiting time, and travelling costs. The diversion of low-risk treatments to NOTG has indirectly increased capacity and reduced waiting times at the main cancer centre for patients requiring complex cancer treatments, resulting in a win-win situation. CONCLUSIONS: NOTG represents an innovative model of care to deliver low-risk cancer treatments safely in the community and can be easily replicated in other countries.

Therapeutic applications of germline testing for cancer predisposition genes in Asia in the real world.

BACKGROUND: Germline genetic testing is traditionally carried out in patients suspected with hereditary cancer syndrome for enhanced cancer surveillance and/or preventive strategies, but is increasingly carried out for therapeutic indications. MATERIALS AND METHODS: We conducted a retrospective review of patients who underwent germline genetic testing at our centre to determine the prevalence of actionable pathogenic germline variants (PGV) and their clinical utility. RESULTS: From 2000 to 2022, 1154 cancer patients underwent germline testing, with the majority (945/1154) tested with multi-gene panels. Four hundred and eleven (35.6%) patients harboured a PGV and 334 (81%) were clinically actionable. BRCA1/2 accounted for 62.3% of actionable mutations, followed by mismatch repair (18%), and other homologous recombination repair (HRR) genes (19.7%). One hundred and fifty-two germline-positive patients have advanced cancers, and 79 received germline-directed therapies (poly ADP ribose polymerase inhibitors = 75; immunotherapy = 4). Median duration of immunotherapy and poly ADP ribose polymerase were 20.5 months (range 5-40 months) and 8 months (range 1-76 months), respectively. Among BRCA/HRR mutation carriers who received platinum-based chemotherapy, pathological complete response rate in the neoadjuvant setting was 53% (n = 17 breast cancers) and objective response rate was >80% in the advanced setting (n = 71). CONCLUSIONS: One-third of cancer patients tested carried a PGV and ∼80% were clinically actionable. Three-quarters of germline-positive advanced cancer patients received germline-directed therapies in the real world, underscoring the practical utility of germline testing to guide cancer therapeutics.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with early breast cancer.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with early breast cancer were updated and published online in 2023, and adapted, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with early breast cancer. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with breast cancer representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), co-ordinated by ESMO and KSMO. The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with early breast cancer across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling, as well as the age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer (MBC) was published in 2021. A special, hybrid guidelines meeting was convened by ESMO and the Korean Society of Medical Oncology (KSMO) in collaboration with nine other Asian national oncology societies in May 2022 in order to adapt the ESMO 2021 guidelines to take into account the differences associated with the treatment of MBC in Asia. These guidelines represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with MBC representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). The voting was based on the best available scientific evidence and was independent of drug access or practice restrictions in the different Asian countries. The latter were discussed when appropriate. The aim of these guidelines is to provide guidance for the harmonisation of the management of patients with MBC across the different regions of Asia, drawing from data provided by global and Asian trials whilst at the same time integrating the differences in genetics, demographics and scientific evidence, together with restricted access to certain therapeutic strategies.

Use of local anesthesia for inguinal hernia repair has decreased over time in the VA system.

PURPOSE: In 2003, randomized trials demonstrated potentially improved outcomes when local instead of general anesthesia is used for inguinal hernia repair. Our study aimed to evaluate how the use of local anesthesia for this procedure changed over time following the publication of the trials' level 1 evidence. METHODS: We used the 1998-2018 Veterans Affairs Surgical Quality Improvement Program database to identify adults who underwent open, unilateral inguinal hernia repair under local or general anesthesia. Our primary outcome was the percentage of cases performed under local anesthesia. We used a time-series design to examine the trend and rate of change of the use of local anesthesia. RESULTS: We included 97,437 veterans, of which 22,333 (22.9%) had hernia surgery under local anesthesia. The median age of veterans receiving local anesthesia remained stable at 64-67 years over time. The use of local anesthesia decreased steadily, from 38.2% at the beginning year to 15.1% in the final year (P < 0.0001). The publication of results from randomized trials (in 2003) did not appear to increase the overall use or change the rate of decline in the use of local anesthesia. Overall, we found that the use of local anesthesia decreased by about 1.5% per year. CONCLUSION: The utilization of local anesthesia for inguinal hernia repair in the VA has steadily declined over the last 20 + years, despite data showing equivalence or superiority to general anesthesia. Future studies should explore barriers to the use of local anesthesia for hernia repair.

Reproductive factors and breast arterial calcification: a systematic review and meta-analysis.

BACKGROUND: Breast arterial calcification (BAC) is a common incidental finding on screening mammography. Recent evidence suggests that BAC is associated with cardiovascular disease (CVD). We systematically reviewed the associations between BAC and reproductive factors (menopausal status, hormone replacement therapy [HRT] use, oral contraceptive [OC] use and parity). METHODS: MEDLINE and EMBASE databases, references of relevant papers and Web of Science were searched up to February 2020 for English-language studies that evaluated these associations. Study quality were determined and a random effects model was used to assess these associations. RESULTS: Nineteen observational studies (n = 47,249; three cohort studies, seven case-control studies, nine cross-sectional studies) were included. BAC was associated with menopause (nine studies; n = 15,870; odds ratio [OR] 2.67; 95% confidence interval [CI] 1.50-4.77) and parity (seven studies; n = 27,728; OR 2.50; 95% CI 1.68-3.71) and inversely with HRT use (10 studies; n = 33,156; OR 0.57; 95% CI 0.40-0.80). No association was found with OC use. Eleven studies were considered good in quality. Marked heterogeneity existed across all analyses. CONCLUSIONS: BAC is associated with HRT use, menopause and parity. However, careful interpretation is required as marked heterogeneity existed across all analyses. Traditional cardiovascular risk factors may need to be taken into account in future investigations of associations between BAC and reproductive factors. PROSPERO: CRD42020141644.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with early breast cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS.

In view of the planned new edition of the most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of primary breast cancer published in 2015, it was decided at the ESMO Asia Meeting in November 2018, by both the ESMO and the Korean Society of Medical Oncology (KSMO), to convene a special face-to-face guidelines meeting in 2019 in Seoul. The aim was to adapt the latest ESMO 2019 guidelines to take into account the ethnic and geographical differences associated with the treatment of early breast cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with early breast cancer representing the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO) Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices, and the drug availability and reimbursement situations, in the individual participating Asian countries.

Diagnostic value of electrocardiogram in cardiac tamponade.

INTRODUCTION: We aim to study the diagnostic value of electrocardiogram (ECG) in cardiac tamponade. METHODS: This study was a single centre, retrospective casecontrol study. We recruited 42 patients diagnosed with cardiac tamponade of various aetiologies confirmed by transthoracic echocardiography and 100 controls between January 2011 and December 2015. The ECG criteria of cardiac tamponade we adopted was as follows: 1) Low QRS voltage in a) the limb leads alone, b) in the precordial leads alone or, c) in all leads, 2) PR segment depression, 3) Electrical alternans, and 4) Sinus tachycardia. RESULTS: Malignancy was the most common causes of cardiac tamponade, the two groups were of similar proportion of gender and ethnicity. We calculated the sensitivity (SN), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV) of each ECG criteria. Among the ECG abnormalities, we noted the SN of 'low voltage in all chest leads' (69%), 'low voltage in all limb leads' (67%) and 'sinus tachycardia' (69%) were higher as compared to 'PR depression' (12%) and 'electrical alternan' (5%). On the other hand, 'low voltage in all chest leads' (98%), 'low voltage in all leads' (99%), 'PR depression' (100%) and 'electrical alternans' (100%) has highest SP. CONCLUSION: Our study reaffirmed the findings of previous studies that electrocardiography cannot be used as a screening tool for diagnosing cardiac tamponade due to its low sensitivity. However, with clinical correlation, electrocardiography is a valuable adjuvant test to 'rule in' cardiac tamponade because of its high specificity.

Comparison between the effects of deep and moderate neuromuscular blockade during transurethral resection of bladder tumor on endoscopic surgical condition and recovery profile: a prospective, randomized, and controlled trial.

PURPOSE: To compare between deep neuromuscular blockade (NMB) and moderate NMB with respect to endoscopic surgical conditions and recovery profiles in patients with general anesthesia for transurethral resection of bladder (TURB). METHODS: 108 patients undergoing elective TURB were randomized into two groups: the moderate NMB (n = 54) or deep NMB (n = 54) group. After the operation, NMB was reversed with 2 mg/kg sugammadex at a train-of-four (TOF) count of 1 or 2 (moderate NMB group) or with 4 mg/kg sugammadex at post-tetanic count (PTC) of 2 (deep NMB group). Surgeons, who were blinded to the study design, rated the endoscopic surgical condition on a 5-point scale (1 = extremely poor, 2 = poor, 3 = acceptable, 4 = good, 5 = optimal) immediately following the operation. Recovery profiles, including postoperative residual curarization (PORC), respiratory complication, and recovery time, were recorded. RESULTS: No difference was observed between the two groups regarding patients and anesthesia characteristics. There were statistically significant differences in endoscopic surgical conditions between the two groups (P < 0.001). Thirty-eight patients in the deep NMB group (74%) showed optimal surgical conditions, whereas 16 patients in the moderate NMB group (30%) showed optimal endoscopic surgical conditions. No PORC and respiratory complications occurred in both groups, and no difference was found between the two groups in terms of recovery profiles, including recovery time and other adverse events. CONCLUSIONS: Deep NMB and reversal with sugammadex improved the endoscopic surgical condition without complications compared with moderate NMB and reversal with sugammadex in patients undergoing TURB.

Real-world evidence of improved healthcare utilization in patients with schizophrenia or schizoaffective disorder after early treatment of paliperidone palmitate once-monthly treatment in Hong Kong.

BACKGROUND: Very few data are available to demonstrate the economic benefit of early paliperidone palmitate once-monthly long-acting injectable (PP1M) treatment in patients with schizophrenia or schizoaffective disorder. METHODS AND MATERIALS: This study has retrospectively compared the healthcare utilization and associated costs of pre- and post-PPIM treatment in 413 patients with schizophrenia or schizoaffective disorder recruited from three major public hospitals providing psychiatric services in Hong Kong. Patients were categorized into early treatment (≤3 years since diagnosis) and chronic (>3 years) groups, and also whether they were receiving polypharmacy (POP). RESULTS: It was found that patients who were started on early therapy with no POP had the most favourable outcomes. Overall results of the entire cohort, including both early and late treatments, indicate that there was a slight increase in annual in-patient days (IP) per patient and outpatient visit (OP) by 3.18 and 1.87, respectively, and a decrease in emergency room visit (ER) of 0.9 (p < 0.05). For non-polypharmacy (NP) patients receiving early PP1M therapy, there was a significant decrease in IP and ER of 21.56 (p < 0.05) and 1.15 (p < 0.05), respectively, but an increase in OP of 1.88 (p < 0.05). For patients with POP, there was an all-across increase in IP and all-across decrease in OP and ER. In monetary terms, a NP patient receiving early therapy may have an overall saving of HKD40,878 (USD5,241, 1USD = 7.8HKD) per year compared to HKD6,224 (USD798) in patients where therapy was given after 3 years. For patients with POP, there was an all-across increase in overall spending despite reductions in OP and ER. CONCLUSIONS: From the 413 patients studied, potential annual savings is higher by early administration of PPIM in patients with NP. Analysis using multivariate linear regression based on generalized estimating equations and sensitivity analysis using a linear mixed model supported the findings.

[3D augmented reality visualization for navigated osteosynthesis of pelvic fractures]. / "3D-augmented-reality"-Visualisierung für die navigierte Osteosynthese von Beckenfrakturen.

BACKGROUND: Despite great advances in the development of hardware and software components, surgical navigation systems have only seen limited use in current clinical settings due to their reported complexity, difficulty of integration into clinical workflows and questionable advantages over traditional imaging modalities. OBJECTIVES: Development of augmented reality (AR) visualization for surgical navigation without the need for infrared (IR) tracking markers and comparison of the navigation system to conventional imaging. MATERIAL AND METHODS: Novel navigation system combining a cone beam computed tomography (CBCT) capable C­arm with a red-green-blue depth (RGBD) camera. Testing of the device by Kirschner wire (K-wire) placement in phantoms and evaluation of the necessary operating time, number of fluoroscopic images and overall radiation dose were compared to conventional x­ray imaging. RESULTS: We found a significant reduction of the required time, number of fluoroscopic images and overall radiation dose in 3D AR navigation in comparison to x­ray imaging. CONCLUSION: Our AR navigation using RGBD cameras offers a flexible and intuitive visualization of the operating field for the navigated osteosynthesis without IR tracking markers, enabling surgeons to complete operations quicker and with a lower radiation exposure to the patient and surgical staff.

Risk of death from cardiovascular disease following breast cancer in Southeast Asia: a prospective cohort study.

Breast cancer incidence and survival is high in Southeast Asia. As such, many women diagnosed with breast cancer are at risk of dying of other causes. Given the increased risk of cardiotoxicity induced by breast cancer treatments, it is important to identify patients at high risk of cardiovascular disease (CVD) mortality. The aim of this study was to investigate if this risk varies by age and ethnicity. Patient details were obtained from 5,868 Chinese, Malay, and Indian women diagnosed with in situ or non-metastasized invasive breast cancer at the National University Hospital of Singapore and KK Women's and Children's Hospital in Singapore. Death causes were obtained from the National Registry of Births and Deaths. Flexible parametric survival models estimated CVD mortality rates and hazard ratios. During a median follow-up of six years, 1,010 deaths occurred of which 6.8% were due to CVD. CVD mortality rates of older women peaked within the first year following diagnosis and increased over time since diagnosis. Indian had more than double the risk of CVD mortality than Chinese, independent of age at diagnosis and stage. Taking ethnicity and age into account may promote CVD risk stratification and management in (Southeast Asian) women with breast cancer.

Cancer risk from polycyclic aromatic compounds in fine particulate matter generated from household coal combustion in Xuanwei, China.

Polycyclic aromatic hydrocarbons (PAHs) and their polar derivatives (oxygenated PAHs: OPAHs and azaarenes: AZAs) were characterized in fine particulates (PM2.5) emitted from indoor coal combustion. Samples were collected in Xuanwei (Yunnan Province), a region in China with a high rate of lung cancer. A sample from the community with the highest mortality contained the highest total concentration of PAHs, OPAHs and AZAs and posed the highest excess cancer risk from a lifetime of inhaling fine particulates. Positive correlations between total carbonyl-OPAHs, total AZAs and total PAHs implied that the emissions were dependent on similar factors, regardless of sample location and type. The calculated cancer risk ranged from 5.23-10.7 × 10-3, which is higher than the national average. The risk in each sample was ∼1-2 orders of magnitude higher than that deemed high risk, suggesting that the safety of these households is in jeopardy. The lack of potency equivalency factors for the PAH derivatives could possibly have underestimated the overall cancer risk.

Occurrence of gastro-intestinal parasites among small ruminants in Malaysia: highlighting Dicrocoelium infection in goats.

The aim of the present study was to determine the gastro-intestinal (GI) parasitic infections among small ruminants (i.e., goats, sheep, deer) in Malaysia through formalin-ether concentration technique. Overall, 70.9% or 302 out of 426 small ruminants (79.4% or 251/316 goats; 87.5% or 35/40 sheep; 22.9% or 16/70 deer) were infected with at least one species of GI parasites. Overall, ten types of GI parasites [Helminth: strongyle (57.7%), Moniezia spp. (5.4%), Paramphistomum spp. (4.5%), Strongyloides spp. (4.2%), Dicrocoelium spp. (2.3%), Trichuris spp. (2.3%); Protozoa: Eimeria spp. (23.7%), Entamoeba spp. (18.8%), Giardia spp. (1.9%), Cryptosporidium spp. (0.2%)] were detected in this study. Among the studied animals, goats harboured the highest diversity of GI parasites (ten types), followed by sheep (six types) and deer (two types). Polyparasitism was observed in goats (43.7% or 138 of 316) and sheep (15.0% or 6 of 40). Cumulatively, a total of 32 combinations of coinfections (Helminth+Helminth: 8 combinations; Helminth+Protozoa: 20 combinations; Protozoa+Protozoa: 4 combinations) between detected parasites with up to quintuple infections were reported. Among these parasites, "strongyle + Eimeria spp." and "Moniezia spp. + strongyle" were the commonest infections in goats (13.5% or 34 of 251) and sheep (5.7% or 2 of 6), respectively. This study is a comprehensive documentation on multiple GI parasitisms among small ruminant in Malaysia, and the findings are crucial for effective farm management, especially for the formulation of parasitic control and elimination strategies.

An epithelial marker promoter induction screen identifies histone deacetylase inhibitors to restore epithelial differentiation and abolishes anchorage independence growth in cancers.

Epithelial-mesenchymal transition (EMT), a crucial mechanism in development, mediates aggressiveness during carcinoma progression and therapeutic refractoriness. The reversibility of EMT makes it an attractive strategy in designing novel therapeutic approaches. Therefore, drug discovery pipelines for EMT reversal are in need to discover emerging classes of compounds. Here, we outline a pre-clinical drug screening platform for EMT reversal that consists of three phases of drug discovery and validation. From the Phase 1 epithelial marker promoter induction (EpI) screen on a library consisting of compounds being approved by Food and Drug Administration (FDA), Vorinostat (SAHA), a histone deacetylase inhibitor (HDACi), is identified to exert EMT reversal effects by restoring the expression of an epithelial marker, E-cadherin. An expanded screen on 41 HDACi further identifies 28 compounds, such as class I-specific HDACi Mocetinosat, Entinostat and CI994, to restore E-cadherin and ErbB3 expressions in ovarian, pancreatic and bladder carcinoma cells. Mocetinostat is the most potent HDACi to restore epithelial differentiation with the lowest concentration required for 50% induction of epithelial promoter activity (EpIC-50).The HDACi exerts paradoxical effects on EMT transcriptional factors such as SNAI and ZEB family and the effects are context-dependent in epithelial- and mesenchymal-like cells. In vitro functional studies further show that HDACi induced significant increase in anoikis and decrease in spheroid formation in ovarian and bladder carcinoma cells with mesenchymal features. This study demonstrates a robust drug screening pipeline for the discovery of compounds capable of restoring epithelial differentiation that lead to significant functional lethality.

Activation of salt-inducible kinase 2 promotes the viability of peritoneal mesothelial cells exposed to stress of peritoneal dialysis.

Maintaining mesothelial cell viability is critical to long-term successful peritoneal dialysis (PD) treatment. To clarify the viability mechanism of peritoneal mesothelial cells under PD solutions exposure, we examined the mechanisms of cellular response to this stress conditions. Here we report that the proteasome activity is inhibited when treated with PD solutions. Proteasome inhibition-mediated activation of salt-inducible kinase 2 (SIK2), an endoplasmic reticulum-resident protein, is important for mesothelial cell viability. SIK2 is mobilized to promote autophagy and protect the cells from apoptosis under PD solution or MG132 treatment. Immunofluorescence staining showed that SIK2 is colocalized with LC3B in the autophagosomes of mesothelial cells treated with PD solution or derived from patients undergoing PD treatment. SIK2 activation is likely via a two-step mechanism, upstream kinases relieving the autoinhibitory conformation of SIK2 molecule followed by autophosphorylation of Thr175 and activation of kinase activity. These results suggest that activation of SIK2 is required for the cell viability when proteasome activity is inhibited by PD solutions. Maintaining or boosting the activity of SIK2 may promote peritoneal mesothelial cell viability and evolve as a potential therapeutic target for maintaining or restoring peritoneal membrane integrity in PD therapy.

Single-port versus conventional three-port laparoscopic totally extraperitoneal inguinal hernia repair: a randomized controlled trial.

BACKGROUND: Single-port laparoscopic surgery (SPLS) has been introduced for totally extraperitoneal (TEP) inguinal hernia repair. Clinically, however, the benefits of single-port TEP (SP TEP) are unclear. This study aimed to compare short-term surgical outcomes between SP TEP and conventional laparoscopic TEP(CL TEP) inguinal hernia repair. METHODS: Between January 2013 and February 2015, 99 men with primary unilateral inguinal hernia were randomized to the single-port or conventional 3-port TEP procedures. The primary end point was postoperative pain. Secondary end points were complications, postoperative hospital stay, days to return to daily normal activities, cosmesis, and quality of life (QOL). RESULTS: We randomized 50 patients to SP TEP and 49 to CL TEP repair. The SP TEP group patients had significantly lower pain scores (visual analog scale) 7 days postoperation (p = 0.017). However, there were no significant differences between the two groups in postoperative pain scores 24 h (p = 0.44) and 4 weeks (p = 0.677) after operation and analgesic requirements on the operation day (p = 0.303) and 7 days after the operation (p = 0.204). Operation time, postoperative hospital stay, and complications were comparable between the two groups. The days to return to daily normal activities, QOL, and cosmetic satisfaction were not different between the two groups. CONCLUSION: The outcomes of SP TEP hernia repair for operation time and morbidities were comparable to CL TEP, and postoperative pain was lower at 7 days than in CL TEP hernia repair. The SP TEP technique can be recommended as an alternative treatment for inguinal hernia repair in experienced hands.

Essential role of insulin-like growth factor 2 in resistance to histone deacetylase inhibitors.

Histone deacetylase (HDAC) inhibitors (HDIs) are promising anticancer therapies and have been clinically used for the treatment of hematological malignancy. However, their efficacy in solid tumors is marginal and drug resistance hampers their further clinical utility. To develop novel strategies for the HDI-based anticancer therapeutics in non-small cell lung cancer (NSCLC), in the present study, we investigated the mechanisms underlying resistance to HDI treatment in NSCLC cells. We show the STAT3-mediated IGF2/IGF-1R signaling cascade as a key modulator for both acquired and primary HDI resistance. The treatment with HDI upregulated IGF2 transcription in NSCLC cells carrying intrinsic or acquired drug resistance via direct binding of STAT3 in IGF2 P3 and P4 promoters. Acetylated STAT3 emerged upon HDAC inhibition was protected from the proteasome-mediated degradation of STAT3 and functioned as a direct transcription factor for IGF2 expression. Genomic or pharmacological strategies targeting STAT3 diminished the HDI-induced IGF2 mRNA expression and overcame the resistance to HDI treatment in HDI-resistant NSCLC- or patient-derived tumor xenograft models. These findings provide new insights into the role of acetylated STAT3-mediated activation of IGF2 transcription in HDI resistance, suggesting IGF2 or STAT3 as novel targets to overcome HDI resistance in NSCLC.

Effect of intravitreal dexamethasone implant on retinal and choroidal thickness in refractory diabetic macular oedema after multiple anti-VEGF injections.

AimsTo investigate the effect of intravitreal dexamethasone implant (IVD) on central foveal thickness (CFT), choroidal thickness (CT) and its correlation with visual acuity in eyes with refractory diabetic macular oedema (DMO).MethodsThis was a retrospective interventional case-series. Thirty-five eyes of 35 patients were treated with a single injection of IVD because of refractory DMO with CFT over 300 µm, and persistent intraretinal and subretinal fluid despite of multiple intravitreal bevacizumab injections. Patients were followed-up for 6 months for the evaluation of CFT and subfoveal CT by spectral-domain optical coherence tomography.ResultsAll eyes (mean age: 59.4±12.35 years; 18 males, 17 females) had been previously treated with multiple bevacizumab injections and showed persistent DMO (mean number of injections 4.08±2.98) The preoperative logMAR BCVA was 0.49±0.24, which gradually improved to 0.46±0.32 at 6 months (P=0.652) and 26% gained two or more lines of Snellen visual acuity. At baseline, the mean CFT was 526.29±123.48 µm, which significantly improved to 316.15±100.09 µm at 3 months (P<0.001). However, CFT deteriorated to 457.07±136.53 µm at 6 months (P=0.051). Similarly, the mean preoperative subfoveal CT was 288.91±36.47 µm and it decreased to 266.85±30.93 µm at 3 months (P<0.01), but increased to 278.63±32.55 µm at 6 months (P=0.137). The reduction of CFT from baseline showed significant correlation with that of subfoveal CT at 3 months (P=0.041) and at 6 months (P=0.008).ConclusionsIn DMO refractory to multiple bevacizumab injections, IVD significantly reduced CFT and subfoveal CT, with BCVA improvement in one-fourth of the patients. The reduction of CFT showed significant correlation with reduction of subfoveal CT.