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Abnormal growth of airway smooth muscle cells is one of the key features in asthmatic airway remodeling, which is associated with asthma severity. The mechanisms underlying inappropriate airway smooth muscle cell growth in asthma remain largely unknown. Myocd has been reported to act as a key transcriptional coactivator in promoting airway-specific smooth muscle development in fetal lungs. Whether Myocd controls airway smooth muscle remodeling in asthma has not been investigated. Mice with lung mesenchyme-specific deletion of Myocd after lung development were generated, and a chronic asthma model was established by sensitizing and challenging the mice with ovalbumin for a prolonged period. Comparison of the asthmatic pathology between the Myocd knockout mice and the wild-type controls revealed that abrogation of Myocd mitigated airway smooth muscle cell hypertrophy and hyperplasia, accompanied by reduced peri-airway inflammation, decreased fibrillar collagen deposition on airway walls, and attenuation of abnormal mucin production in airway epithelial cells. Our study indicates that Myocd is a key transcriptional coactivator involved in asthma airway remodeling. Inhibition of Myocd in asthmatic airways may be an effective approach to breaking the vicious cycle of asthmatic progression, providing a novel strategy in treating severe and persistent asthma. © 2022 The Authors. The Journal of Pathology published by John WileySons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Background: In addition to inhibiting cell cycle progression, CDK4/6 inhibitors have been found to modulate anti-cancer immune response (Goel S, et al. Nature. 2017;548:471-475). Data from preclinical studies suggested multiple mechanisms—involving changes in both cancer cells and immune cells—by which CDK4/6 inhibition can enhance anti-cancer immunity. These mechanisms include increased antigen presentation, interferon response triggering, and regulatory T-cell suppression. Clinical correlates to preclinical observations have so far been obtained using paired biopsies from neoadjuvant breast cancer trials (Johnston S, et al. J Clin Oncol. 2019;37:178-189; Hurvitz S, et al. Clin Cancer Res. 2020; ;26:566-80). Here, we describe a gene expression analysis of paired pre- and on-treatment biopsies from CLEE011A2115C and CLEE011X2107, two phase I clinical trials evaluating ribociclib in combination with ET in the metastatic breast cancer (MBC) setting. Methods: The nCounter PanCancer IO 360 Panel (NanoString) was used to quantify expression of 770 genes in 7 pairs of tumor samples (baseline vs. cycle 1 day 15) from two phase I trials in the MBC setting (5 patients from CLEE011A2115C and 2 from CLEE011X2107). All patients were treated with ribociclib and an ET. Pairwise differential gene expression analysis of individual genes and previously published immune-related gene signatures was conducted (Bedognetti D, et al. Curr Opin Oncol. 2015;27:433-444). Results: Many genes that were markedly suppressed with treatment (eg, MKI67, MYC, CDK2, CCNB1, TYMS, and DNMT1) were related to proliferation, DNA replication, and G1/S transition of the cell cycle, as expected. Interestingly, expression of numerous genes involved in immune response was increased. These were mostly interferon-regulated genes; particularly, a gene signature indicative of a T cell-inflamed tumor microenvironment (Ayers M, et al. J Clin Invest. 2017;127:2930-2940) was upregulated. Immune-related genes tended to preferentially increase with treatment in patients who later experienced a clinical response. Since bulk RNA from tumor biopsies was analyzed, we could not distinguish whether the observed expression changes reflected increased infiltration by immune cells or an endogenous interferon response in cancer cells. The latter could be triggered by DNMT1 suppression (as previously described), which then promotes T cell-mediated immunity by increasing antigen presentation and chemokine production in cancer cells. Conclusions: This analysis was conducted with a small sample size and is considered hypothesis generating; further investigation is needed. Cell cycle and proliferation markers showed robust suppression by ribociclib-based treatment regimens, as expected. Conversely, a notable increase in immune-related genes was detected that tended to occur preferentially in patients who later experienced more favorable clinical outcomes. Both changes occurred early (cycle 1 day 15). To our knowledge, this is the first clinical biomarker report of immune activation mediated by CDK4/6 inhibition in MBC. Citation Format: Dejan Juric, Chong Ma, Ralph Tiedt, Yoon-Sim Yap, Joanne Chiu, Pamela Munster, Roohi Ismail-Khan, Laura Garcia-Estevez, Ingrid A. Mayer, Carlos Becerra, Nadia Solovieff, Agnes Lteif, Faye Su, Yen-Shen Lu. Upregulation of immune response biomarkers by ribociclib plus endocrine therapy (ET) in paired tumor samples from phase I studies [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-18.

Introduction. We investigated the safety and efficacy of a pegylated arginase (PEG-BCT-100) in combination with chemotherapy (oxaliplatin and capecitabine) [PACOX] in advanced HCC patients. Methods. This was a single centre phase 1 trial to assess the safety and tolerability of PACOX. All the enrolled subjects received treatment in 3-weekly cycles: intravenous PEG-BCT-100 2.7 mg/kg on days 1, 8 and 15 of each cycle; oral capecitabine 1000 mg/m2 twice daily on day 1–14 of each cycle and intravenous oxaliplatin on day 1. Three dose levels of oxaliplatin (85 mg/m2, 100 mg/m2 or 130 mg/m2) were studied to define the maximum tolerated dose (MTD). Adverse events (AEs), efficacy by RECIST v1.1, time to progression (TTP), progression-free survival (PFS) and overall survival (OS) were studied. Results. Seventeen patients were enrolled at 3 dose levels of oxaliplatin: 85 mg/m2 (8 patients), 100 mg/m2 (3 patients), and 130 mg/m2 (6 patients). The median age was 55 years; all had had locoregional chemotherapy or targeted therapy such as sorafenib, but no systemic chemotherapy. The most common AEs were nausea (82%), injection site reaction (76%), palmar-plantar erythrodysesthesia (59%), oral mucositis (53%) and vomiting (53%). There was no dose-limiting toxicity (DLT). Median duration on study was 8 weeks overall. In 14 evaluable cases, one achieved partial response (PR), 4 had stable disease (SD); disease control rate was 36%; most responses were observed in the 130 mg/m2 cohort with 1 PR and 2 SDs. Median TTP and PFS were both 7.0 weeks. Overall median OS was 10.7 months; the median OS was not reached at 19.4 months of follow-up in the 130 mg/m2 cohort. Conclusion. The PACOX regimen demonstrated good anti-cancer activity and survival advantage in advanced pre-treated HCC with favourable safety profile. It warrants further phase II/III studies.

Concurrent anthracycline and taxane is an effective and efficient way to deliver neoadjuvant chemotherapy for HER2-negative breast cancers. Data on efficacy and tolerance to 6 cycles of concurrent docetaxel, epirubicin, and cyclophosphamide (TEC) is limited. All patients with HER2-negative breast cancers who received neoadjuvant TEC from January 2013 to December 2019 were reviewed. A total of 71 patients [57 luminal B disease; 14 triple negative breast cancer (TNBC)] received neoadjuvant TEC with prophylactic granulocyte colony-stimulating factor (G-CSF). The pathological complete response (pCR) rate was 26.3% and 28.6% for luminal B and TNBC, respectively. With median follow-up of 48.9 months, 3 years disease-free survival was 85.9%, and 3 years overall survival was 89.6%. Non-hematological toxicities were common but the majority was grade 1 or 2. The most common grade 3 or 4 toxicity were hematological, including neutropenia (26.8%) and anemia (15.5%). There was no cardiotoxicity observed. Half of the patients had at least one dose reduction but all patients completed the planned 6 cycles and had breast surgery done. Six cycles of TEC with prophylactic G-CSF is an effective and tolerable neoadjuvant regime for HER2-negative breast cancers. Hematological toxicities were the most common toxicities. Although many patients required dose reduction, all patients completed treatment and there was no observed cardiotoxicity.

Treatment of hepatocellular carcinoma (HCC) recurrences following liver transplant (LT) is challenging. Most clinical trials of systemic therapies for advanced HCC excluded patients with any history of organ transplant. We aimed to assess the outcomes in using various systemic therapies in patients with post-LT recurrence. Consecutive patients with HCC and recurrences following LT at a large tertiary centre from 2005 to 2018 were reviewed. Overall survival (OS), response rates and adverse events (AEs) were analysed. Forty-three consecutive patients with a recurrence of HCC following LT were identified from 2005 to 2018. Median OS from diagnosis of recurrence was 17 months (CI 11.3, 22.7). Early recurrence within 12 months of transplant was associated with a significantly worse median survival of 10 months (CI 8.5, 11.4) compared to 26 months (CI 18.8, 33.2) when recurrences occurred after 12 months from transplant (p

The TGF-β signaling pathway plays a pivotal role in controlling organogenesis during fetal development. Although the role of TGF-β signaling in promoting lung alveolar epithelial growth has been determined, mesenchymal TGF-β signaling in regulating lung development has not been studied in vivo due to a lack of genetic tools for specifically manipulating gene expression in lung mesenchymal cells. Therefore, the integral roles of TGF-β signaling in regulating lung development and congenital lung diseases are not completely understood. Using a Tbx4 lung enhancer-driven Tet-On inducible Cre transgenic mouse system, we have developed a mouse model in which lung mesenchyme-specific deletion of TGF-β receptor 2 gene ( Tgfbr2) is achieved. Reduced airway branching accompanied by defective airway smooth muscle growth and later peripheral cystic lesions occurred when lung mesenchymal Tgfbr2 was deleted from embryonic day 13.5 to 15.5, resulting in postnatal death due to respiratory insufficiency. Although cell proliferation in both lung epithelium and mesenchyme was reduced, epithelial differentiation was not significantly affected. Tgfbr2 downstream Smad-independent ERK1/2 may mediate these mesenchymal effects of TGF-β signaling through the GSK3β-β-catenin-Wnt canonical pathway in fetal mouse lung. Our study suggests that Tgfbr2-mediated TGF-β signaling in prenatal lung mesenchyme is essential for lung development and maturation, and defective TGF-β signaling in lung mesenchyme may be related to abnormal airway branching morphogenesis and congenital airway cystic lesions.

Purpose BioPATH is a non-interventional study evaluating the relationship of molecular biomarkers (PTEN deletion/downregulation, PIK3CA mutation, truncated HER2 receptor [p95HER2], and tumor HER2 mRNA levels) to treatment responses in Asian patients with HER2+ advanced breast cancer treated with lapatinib and other HER2-targeted agents. Materials and methods Female Asian HER2+ breast cancer patients (n=154) who were candidates for lapatinib-based treatment following metastasis and having an available primary tumor biopsy specimen were included. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, overall survival on lapatinib, correlation between biomarker status and PFS for any previous trastuzumab-based treatment, and conversion/conservation rates of the biomarker status between tissue samples collected at primary diagnosis and at recurrence/metastasis. Potential relationships between tumor mRNA levels of HER2 and response to lapatinib-based therapy were also explored. Results p95HER2, PTEN deletion/downregulation, and PIK3CA mutation did not demonstrate any significant co-occurrence pattern and were not predictive of clinical outcomes on either lapatinib-based treatment or any previous trastuzumab-based therapy in the metastatic setting. Proportions of tumors positive for p95HER2 expression, PIK3CA mutation, and PTEN deletion/down-regulation at primary diagnosis were 32%, 31.2%, and 56.2%, respectively. Despite limited availability of paired samples, biomarker status patterns were conserved in most samples. HER2 mRNA levels were not predictive of PFS on lapatinib. Conclusion The prevalence of p95HER2 expression, PIK3CA mutation, and PTEN deletion/downregulation at primary diagnosis were similar to previous reports. Importantly, no difference was observed in clinical outcome based on the status of these biomarkers, consistent with reports from other studies.

Introduction: We investigated the safety and efficacy of PEG-BCT-100 in combination with oxaliplatin and capecitabine (PACOX) in advanced HCC patients.Methods: This was a single centre phase 1 trial to assess the safety and tolerability of PACOX. All the enrolled subjects received treatment in 3-weekly cycles: IV PEG-BCT-100 2.7 mg/kg on day 1, 8 and 15 of each cycle; oral capecitabine 1000 mg/m2 twice daily on day 1-14 of each cycle and IV oxaliplatin on day 1. Three dose levels of oxaliplatin (85 mg/m2, 100 mg/m2 or 130 mg/m2) were studied to define the maximum tolerated dose (MTD). Adverse events (AEs), efficacy by RECIST v1.1, time to progression (TTP), progression-free survival (PFS) and overall survival (OS) were studied.Results: Seventeen patients were enrolled at 3 doses of oxaliplatin: 85 mg/m2 (8 patients), 100 mg/m2 (3 patients), and 130 mg/m2 (6 patients). The median age was 55 years; all had local-regional chemotherapy or target therapy such as sorafenib, but no systemic chemotherapy. Most common AEs were nausea (82%), injection site reaction (76%), palmar-plantar erythrodysesthesia (59%), oral mucositis (53%) and vomiting (53%). There was no dose-limiting toxicity (DLT). Median duration on study was 8 weeks overall. In 14 evaluable cases, one achieved partial response (PR), 4 had stable disease (SD); disease control rate was 36% (5/14); most responses were observed in the 130 mg/m2 cohort with 1 PR and 2 SDs (3/6 or 50%). The median TTP, PFS were both 7.0 weeks. Overall median OS was 10.7 months; the median OS was not reached at 19.4 months of follow-up in the third cohort.Conclusion: The PACOX regimen demonstrated good anti-cancer activity and survival advantage in advanced pre-treated HCC with favourable safety profile. It warrants further phase II/III studies.

Background Subcutaneous (SC) trastuzumab is similar to intravenous trastuzumab in terms of pharmacokinetics, efficacy and tolerability. The use of dual anti-HER2 agents trastuzumab and pertuzumab has become the new standard for node-positive HER2-positive breast cancers at adjuvant setting, but the safety and tolerability of combining SC trastuzumab and intravenous pertuzumab is not well studied. Methods This was a prospective single-arm pilot study with locally advanced HER2-positive breast cancer who received adjuvant SC trastuzumab and intravenous pertuzumab after standard anti-HER2 treatment with chemotherapy. Primary outcomes included adverse events (AEs), severe AEs and cardiac AEs. Secondary outcome was invasive disease-free survival (iDFS). Results With a median follow-up of 21.7 months, 20 patients were enrolled. One patient (5%) developed asymptomatic drop in left ventricular ejection fraction from 69% to 53%. Two patients (10%) developed grade 1 injection site reaction related to SC trastuzumab. There were no grade 2 or above AEs. All AEs were transient. No new AEs were observed. The 1-year iDFS was 90% (95% CI 0.656 to 0.974) Conclusions Combination of SC trastuzumab and intravenous pertuzumab for HER2-positive breast cancer is a safe and well-tolerated option in adjuvant setting.

Simple Summary The vascular endothelial growth factor and c-MET pathways are strongly implicated in hepatocellular carcinoma (HCC). Cabozantinib inhibits both pathways and has been approved in sorafenib-exposed advanced HCC (aHCC). We aimed to evaluate the real-life pattern of use, efficacy, and safety of cabozantinib in aHCC patients in a territory-wide study. In single-agent cabozantinib patients (n = 27), we found that 3.7% had a response, 44.4% had disease control, and the median overall survival (OS) was 8.28 months. Around 74.1% of patients had adverse events (AEs). We also did an exploratory analysis of patients who received cabozantinib as an add-on to immune-checkpoint inhibitors (ICIs) after progression on ICIs. Out of 15 such patients, 6.7% had a response and the median OS was 15.1 months, with 73.3% of patients having AEs. Overall, cabozantinib had good efficacy, survival, and safety in aHCC patients in a real-life setting. Abstract (1) Background: Cabozantinib is approved in sorafenib-exposed advanced hepatocellular carcinoma (aHCC). We evaluated the real-life pattern of use, efficacy, and tolerability of cabozantinib in aHCC. (2) Methods: This territory-wide study included consecutive aHCC patients who received cabozantinib between February 2018 and September 2020 in Hong Kong. The objective response rate (ORR), disease control rate (DCR), overall survival (OS), and adverse events (AE) were assessed. (3) Results: Overall, 42 patients were included. Approximately 83.3% had Child-Pugh A cirrhosis. About 64.3% received cabozantinib as a single agent, and the remaining 35.7% received cabozantinib as an add-on to immune checkpoint inhibitors (ICIs). For single-agent patients, the median follow-up was 6.7 months. The ORR was 3.7%, DCR was 44.4%, and the median OS was 8.28 months. About 74.1% of patients experienced any AEs with 7.4% having grade ≥3 AEs. Among patients who received prior ICIs (n = 16), the ORR was 6.3%, and the median OS was 8.28 months. An exploratory analysis of patients who received cabozantinib as an add-on to ICIs showed an ORR of 6.7% and a median OS of 15.1 months, with 73.3% having any AE and 13.3% having grade ≥3 AEs. (4) Conclusions: Cabozantinib had good anti-tumor activity, survival benefits, and acceptable tolerability in real-life aHCC patients.

The systemic treatment of advanced, unresectable hepatocellular carcinoma (HCC) has undergone an evolution in recent years. In March 2020, a combination of nivolumab and ipilimumab was approved by the FDA for treatment of patients with advanced HCC who received prior sorafenib. This was based on the results of the phase I/II CheckMate-040 cohort 4 trials, which showed a promising overall response rate and encouraging overall survival with a manageable safety profile.This article reviews the pharmacology, efficacy and safety of nivolumab-ipilimumab in advanced HCC with prior sorafenib. Other existing systemic treatment options for advanced HCC will be described and compared to nivolumab-ipilimumab. Impact of different dose regimes, ongoing research and future developments of nivolumab-ipilimumab will be discussed. We focus on the analysis from the aforementioned CheckMate-040 cohort 4 registration trial.The approval of nivolumab-ipilimumab in the second-line treatment of advanced HCC by the FDA is an important development for treatment of advanced HCC. However, further investigations are needed to optimize dosing regimens and explore the use of nivolumab-ipilimumab in other combinations and settings.

Aim: To evaluate the efficacy and safety of neratinib as extended adjuvant therapy in patients from Asia based on exploratory analyses of the Phase III ExteNET trial. Patients & methods: A total of 2840 women with early stage HER2-positive breast cancer were randomly assigned to neratinib 240 mg/day or placebo for 1 year after trastuzumab-based adjuvant therapy. Results: A total of 341 patients were from Asia (neratinib, n = 165; placebo, n = 176). 2-year invasive disease-free survival rates were 92.8 and 90.8% with neratinib and placebo, respectively (HR: 0.70; 95% CI: 0.31–1.55), and 5-year rates were 91.9 and 87.2%, respectively (HR: 0.57; 95% CI: 0.27–1.13). Diarrhea was the most common adverse event with neratinib. Conclusion: Extended adjuvant therapy with neratinib reduces disease recurrences in Asian women with HER2-positive breast cancer. Trial registration: Clinicaltrials.gov NCT00878709.

Background Expression of LAG-3, an inhibitory immunoreceptor, has been linked to reduced T-cell proliferation and cytokine production. LAG525 is a humanized IgG4 anti-LAG-3 antibody which inhibits LAG-3 binding to MHC class II. Spartalizumab is a humanized IgG4 anti-PD-1 mAb which inhibits PD-1 binding with its ligands PD-L1 and PD-L2. Preclinical data have shown promising antitumor activity when blocking LAG-3 and PD-1. Methods The Phase II part of the first-in-human study (NCT02460224) explored LAG525 + spartalizumab in patients with advanced/metastatic non-small cell lung cancer (NSCLC), cutaneous and non-cutaneous melanoma, renal cell carcinoma (RCC), mesothelioma, or triple-negative breast cancer (TNBC). The dose/schedule of LAG525 and spartalizumab was 400 mg IV Q3W and 300 mg IV Q3W, respectively. Half of patients with TNBC naive to anti-PD-1/PD-L1 received LAG525 at 600 mg IV Q4W and spartalizumab at 400 mg IV Q4W. The primary endpoint was overall response rate (ORR) using RECIST v1.1. Results As of June 1, 2020, 235 patients were enrolled in the Phase II part of the study, including patients with NSCLC (n=42), melanoma (n=42), RCC (n=38), mesothelioma (n=57), or TNBC (n=56). In total, 142 patients were naive to, and 93 patients were pretreated with, PD-1/PD-L1 inhibitors. Overall, 232 patients (99%) discontinued treatment, 76% due to progressive disease.ORR and disease control rate by indication and prior anti-PD-1/PD-L1 treatment are summarized below (table 1). Best overall response was 3 (1.3%) CR, 23 (9.8%) PR, 84 (35.7%) SD, 95 (40.4%) PD, and 30 (12.8%) unknown. For patients naive to anti-PD-1/PD-L1, median progression free survival (mPFS) in months (90% CI) was 3.9 (1.7–5.6) for NSCLC, 2.2 (1.6–5.6) for melanoma, 4.4 (2.1–11.1) for RCC, 5.5 (3.5–6.4) for mesothelioma, and 1.9 (1.6–2.6) for TNBC. For patients pretreated with anti-PD-1/PD-L1, mPFS in months (90% CI) was 3.5 (1.9–4.9) for NSCLC, 1.9 (1.8–3.7) for melanoma, 3.0 (1.6–3.9) for RCC, 3.4 (1.8–3.8) for mesothelioma, and 1.7 (1.3–3.4) for TNBC. Adverse events of any grade, regardless of cause, were reported in 233 (99%) patients; the most common (occurring in >20%) were nausea (25%), fatigue (23%), and dyspnea (21%). Conclusions LAG525 + spartalizumab exhibited antitumor activity across different indications, including patients with melanoma, RCC, and mesothelioma who had been pretreated with PD-1/-L1 inhibitors, suggesting that this combination may salvage prior PD-1/-L1 resistance. The combination was well tolerated, and no new safety signals were observed. Biomarker analysis is ongoing. Trial Registration NCT02460224 Ethics Approval This study was approved by an independent ethics committee or institutional review board at each site.

The ongoing, Phase Ib MONALEESASIA study is evaluating the efficacy and safety of ribociclib plus endocrine therapy in Asian patients with hormone receptor‐positive, human epidermal growth factor receptor 2‐negative advanced breast cancer. Eligible patients from Japan, Hong Kong, and Singapore were enrolled in this 2‐phase study consisting of a dose‐escalation phase to determine the maximum‐tolerated dose and the recommended Phase II dose of ribociclib plus letrozole, and a dose‐expansion phase to evaluate safety and tolerability of ribociclib plus letrozole, fulvestrant, or tamoxifen. An exploratory biomarker analysis evaluating expression of target genes was also conducted. In the dose‐escalation phase, the maximum‐tolerated/recommended Phase II doses of ribociclib were lower in Japanese patients (300 mg) than in Asian non‐Japanese patients (600 mg). Ribociclib plus endocrine therapy at the recommended Phase II dose had a manageable safety profile, with neutropenia and elevated liver transaminases being the most common adverse events leading to dose modifications or discontinuations, and it demonstrated evidence of clinical activity in both Japanese and Asian non‐Japanese patients. Preliminary efficacy in Asian populations is similar to that observed in White populations studied in previous ribociclib (MONALEESA) trials. Biomarker analysis demonstrated suppression of pharmacodynamic biomarker gene expression, indicating inhibition of target genes by ribociclib combined with endocrine therapy. Results from the ongoing study support the use of ribociclib in combination with letrozole in Asian non‐Japanese patients at the same dose (600 mg) as White patients. In Japanese patients, a lower dose of ribociclib (300 mg) should be considered. Clinicaltrials.gov: NCT02333370., The recommended Phase II dose of ribociclib, a CDK4/6 inhibitor, when given with endocrine therapy, was determined in Asian patients with HR+, HER2– advanced breast cancer. The recommended dose was established to be lower in Japanese patients, but similar in Asian non‐Japanese patients, compared with White patients. Importantly, the combination therapies presented a manageable safety profile and demonstrated evidence of clinical activity in both Asian populations, supporting the use of ribociclib in the treatment of these patients.

Compared to standard component therapy, fresh whole blood (FWB) offers potential benefits to neonates undergoing cardiopulmonary bypass (CPB) in the context of open cardiac surgery: decreased blood loss and subsequent risk of volume overload, improved coagulation status, higher platelet counts during and following CPB, circumvention of limited vascular access, and significantly reduced donor exposures. Obtaining FWB, however, entails 2–5 days of preparation, which often precludes its availability for neonates requiring CPB in the immediate newborn period. Using a multidisciplinary approach and molecular ABO/RHD genotyping on amniotic fluid, we developed a protocol to allow procurement of FWB for timed delivery followed by open cardiac surgery. Eligible subjects include patients undergoing genetic amniocentesis following the diagnosis of a fetal cardiac anomaly likely to require open surgical repair in the initial days after birth. This protocol has been successfully implemented following prenatal diagnosis of severe fetal cardiac anomalies. Taking advantage of the prenatal time period and the ability to perform fetal blood typing prenatally using molecular genotyping makes possible a new paradigm for the availability of FWB for CPB to improve perioperative, short-term, and long-term outcomes in a population comprised of some of the smallest and sickest patients who will undergo CPB.

Palbociclib is a first-in-class inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) that inhibits cell proliferation and DNA synthesis by preventing cell-cycle progression from G1 to S phase (1). In cell line models of ER-positive breast cancer, estrogen activates CDK4/6 via cyclin D1, resulting in hyperphosphorylation of retinoblastoma (Rb) gene product, which leads to entry of the cell cycle (2). Endocrine resistance has been shown to be depends on cyclin D1 and CDK4/6 in vitro. Based on the impressive progression-free survival (PFS) found in the phase 2 study PALOMA-1 (3), palbociclib was granted accelerated approval in 2015 by the Food and Drug Administration (FDA) for treatment of estrogen-receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC).

Purpose of the study To evaluate the benefits and tolerability of regorafenib in the real-world setting, we performed a multicentre analysis in Hong Kong. Study design Individual patient data were retrieved from three leading oncology centres in Hong Kong for analyses. All patients with metastatic colorectal cancer (mCRC) treated with regorafenib after failure of all standard systemic options were included. Results From July 2013 to December 2015, 45 consecutive patients treated with regorafenib for mCRC were analysed. The median age was 63. Twenty patients were started at 160 mg, while the other 25 patients were started at a lower dose. The median progression-free survival was 15.6 weeks (95% CI 13.1 to 18.1 weeks) and the median overall survival was 30.4 weeks (95% CI 16.6 to 44.3 weeks). Among the 31 evaluable patients, only 1 patient (3.2%) achieved partial response and another 10 patients (32.3%) had stable disease. The commonest grade 3 non-haematological adverse event (AE) was hand–foot skin reaction (26.7%) and the commonest grade 3 or 4 haematological AE was anaemia (8.9%). Notably, patients who were started on a lower dose of regorafenib had significantly lower risk of grade 3 treatment-emergent AEs. Overall, 78.3% of the patients had dose reduction during the first and second cycles. Patients older than 65 years were more likely to experience cycle suspension and require dose reduction. Conclusions Our study confirmed the efficacy and tolerability of regorafenib in the real-world setting. It also suggested that individualised dosing of regorafenib in patients with mCRC might result in better clinical outcomes.

BackgroundProgrammed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICIs) is a standard therapy in advanced hepatocellular carcinoma (HCC) nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in patients with advanced HCC with progression on prior ICIs.MethodsPatients with advanced HCC with documented tumor progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analyzed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed.ResultsTwenty-five patients were included. The median age was 62 (range: 51–83). About 68% were of Child-Pugh (CP) Grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range: 2.76–30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% CI: 1.61 to 4.31). Median OS was 10.9 months (95% CI: 3.99 to 17.8) and the 1 year, 2 year and 3 year survival rates were 42.4%, 32.3% and 21.6%, respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) Grade 1 or 2. CP and ALBI Grades were significantly associated with OS (p=0.006 and pConclusionsIpilimumab and nivolumab/pembrolizumab can achieve durable antitumor activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.

We aimed to compare the efficacy and tolerability of SECOX regimen with sorafenib alone as first-line treatment of advanced HCC in a multicenter, open-label and randomized setting. Patients not suitable for surgery or loco-regional therapies and no prior systemic therapy for advanced HCC were recruited in 3 centres. Eligible patients were randomly assigned to receive either SECOX (sorafenib 400 mg BD continuously, oxaliplatin 85 mg/m2 on D1, and capecitabine 1700 mg/m2 on D1-7 q2w) or sorafenib alone in 1:1 ratio. Primary endpoint was time-to-progression (TTP). Secondary endpoints were tolerability, ORR, OS and PFS. 46 patients (pts) were randomized and treated, of whom 22 were in the SECOX arm. Median age was 64 years and majority were male (72%). 40 pts (87%) were HBV carrier, and 42 pts (91%) had Child-Pugh A liver function. 30 pts (65%) had received prior non-systemic treatment for HCC. Median duration of follow-up was 7.8 months (mos) (range 0.3-25.8). At the time of analysis, 1 pt in the SECOX arm is still receiving treatment. Median TTP was 3.2 mos (95% CI 1.7-5.8) for SECOX vs 2.8 mos (95% CI 1.8-4.0) for sorafenib. The hazard ratio (HR) for TTP was 0.91 (95% CI 0.5-1.7; p = 0.77; predetermined futility boundary HR ≥ 0.86). Median OS was 7.1 mos (95% CI 3.0-15.3) for SECOX vs 12.5 mos (95% CI 7.2-15.4) for sorafenib (p = 0.29). Median PFS was 3.1 mos (95% CI 1.6-5.8) for SECOX vs 2.7 mos (95% CI 1.8-4.0) for sorafenib. 2 pts (9%) and no pts achieved PR in the SECOX and sorafenib arms, respectively. The clinical benefit rate (CR+PR+SD) was 36% for the SECOX arm and 21% for the sorafenib arm (p = 0.50). Incidence of treatment-related AEs (trAEs) was common in both SECOX and sorafenib arms (64% and 71% respectively, p = 0.75). The most common grade 3-4 trAE was ALP increase (14%) for SECOX and hand-foot skin reaction (25%) for sorafenib. Conclusions: The addition of capecitabine and oxaliplatin to sorafenib did not result in significant improvement in TTP.

Background Over the last 10 years, there has been a major treatment revolution for early human epidermal growth factor receptor 2 (HER2)–positive breast cancer. We aimed to explore the outcome of different neoadjuvant chemotherapy in a tertiary breast cancer centre with early HER2-positive breast cancer as well as factors associated with pathological complete response (pCR) and recurrence-free survival (RFS). The pattern of recurrence was also studied. Methods This retrospective study analysed the outcome of neoadjuvant chemotherapy during the period 2005 to 2016 in a tertiary referral centre in Hong Kong. Patients were divided into three groups according to the neoadjuvant chemotherapy they received: chemotherapy only (Chemo), chemotherapy plus trastuzumab (Chemo-H) and chemotherapy plus double anti-HER2 therapy (Chemo-DH). Results There were 226 cases analysed during the study period. The rate of pCR was 5%, 26% and 60% in Chemo, Chemo-H and Chemo-DH groups, respectively (Chemo vs pooled Chemo-H/DH: p50 years) and hormone receptor negativity were associated with more pCR. pCR was associated with better RFS. Among those with recurrence, the proportion of patients with brain as the only site of recurrence increased remarkably with more efficacious anti-HER2 treatment (0% in Chemo, 8% in Chemo-H, 67% in Chemo-DH). Conclusion pCR remains an important predictive factor for improved RFS. In the era of dual anti-HER2 neoadjuvant therapy, brain-only recurrence poses a challenge to disease surveillance and treatment.

Treatment of urothelial cancer (UC) has seen limited advances over the last three decades. As new agents become available, a critical look at trial design across the spectrum of UC is needed. Early UC trials should aim to stratify patients by risk level, defined by molecular features to reduce the heterogeneity and improve interpretation of trial results. For muscle invasive UC, the practice of neoadjuvant chemotherapy should be encouraged, especially as complete pathological response could be used as a surrogate end-point measure on trials and has the potential for garnering expedited drug approval. The neoadjuvant setting also provides a unique opportunity for evaluating biomarkers and targeted therapy given the availability of tumor tissue. For advanced disease, more emphasis should be placed on studies for patients who are cisplatin-ineligible or have poorer performance status, which represents many UC patients. Bladder-sparing therapy, incorporating agents targeting the HER2 or PI3K/AKT/mTOR ...

Molecular aberrations in KRAS, NRAS, BRAF, and PIK3CA have been well-described in advanced colorectal cancer. The incidences of other mutations are less known. We report results of molecular profiling of advanced colorectal cancer in an academic cancer center.Patients with advanced colorectal were enrolled in an institution-wide molecular profiling program. Profiling was performed on formalin-fixed paraffin embedded archival tissues using a customized MassArray panel (23 genes, 279 mutations) or the Illumina MiSeq TruSeq Cancer Panel (48 genes, 212 amplicons, ≥ 500× coverage) in a Clinical Laboratory Improvement Amendments-certified laboratory. PTEN was determined by immunohistochemistry.From March 2012 to April 2014, 245 patients were enrolled. At least one mutation was found in 54% (97/178) and 91% (61/67) of patients using MassArray or MiSeq platforms, respectively (P .01). Of all patients, KRAS G12/13 mutation was identified in 39%, and non-G12/13 KRAS, BRAF, or NRAS mutations were present in 9%, 6%, and 4%, respectively. Other common mutations included TP53 (68.7%), APC (41.8%), and PIK3CA (13.5%). Co-mutation with KRAS, NRAS, or BRAF was found in 75% of patients with PIK3CA mutation. Of 106 patients with known PTEN immunohistochemistry status, 16% were negative. A higher average number of mutations were observed in right versus left colorectal cancer (P .01), with 13 of 14 BRAF mutations located in right colon cancer.Mutations are common in advanced colorectal cancer. Right colon cancers harbor more genetic aberrations than left colon or rectal cancers. These aberrations may contribute to differential outcomes to anti-epidermal growth factor receptor therapy among patients with right colon, left colon, or rectal cancers.

Background: MONALEESASIA (NCT02333370) is an ongoing Phase Ib study in which Asian patients (pts) with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) ABC are treated with ribociclib (a cyclin-dependent kinase 4/6 inhibitor) and either letrozole (all pts), fulvestrant, or tamoxifen (Japanese pts). Tumor biomarker analysis in MONALEESASIA using NanoString technology for gene expression was presented previously (Yap YS, et al. ESMO Asia 2018 [Abstract 400]). Here we report additional biomarker analysis of baseline ctDNA. Methods: Plasma samples were collected at baseline and end of treatment; ctDNA was extracted and used to generate next-generation sequencing libraries. The DNA libraries were then enriched for a specific 2.9 Mb of the human genome containing ≈550 oncogenes and tumor suppressor genes. Captured libraries were then combined in equimolar pools and sequenced, targeting ≥70 million sequencing reads per sample to ensure that unique coverage of the genes was >1000× or approached the maximal complexity of the library. Results: ctDNA was analyzed in baseline plasma samples collected from 77 pts (49 Japanese and 28 non-Japanese). Similar gene alteration frequencies were observed in Japanese and non-Japanese pts except for ESR1 alterations, which were more common in Japanese pts (Table). TP53 alterations were more common in pts with progressive disease, and the frequencies of TP53, ESR1, and FAT1 were slightly lower in pre- vs postmenopausal pts; however, these differences were not statistically significant. Response rates by genetic alteration are shown in the table. Conclusion: There appeared to be a trend toward a higher likelihood of alterations in TP53 and PIK3CA in pts with poorer responses, although the sample size was small. These data are hypothesis generating, and additional analysis is ongoing. Gene AlterationsPIK3CATP53CCND1FAT1ESR1FGFR1CDH1Frequency, n (%)Japanesen=4917 (35)11 (22)5 (10)3 (6)7 (14)5 (10)4 (8)Non-Japanesen=288 (29)7 (25)3 (11)5 (18)02 (7)0Best Overall Response, n of Patients with Alteration (% Response Type)PRn=359 (26)6 (17)5 (14)3 (9)2 (6)4 (11)0SDn=299 (31)7 (24)1 (3)3 (10)3 (10)03 (10)NCRNPDn=63 (50)1 (17)002 (33)1 (17)1 (17)PDn=74 (57)4 (57)2 (29)2 (29)02 (29)0CCND1, cyclin D1; CDH1, cadherin 1; ESR1, estrogen receptor 1; FAT1, FAT atypical cadherin 1; FGFR1, fibroblast growth factor receptor 1; NCRNPD, not complete response nor progressive disease; PD, progressive disease; PIK3CA, phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit α; PR, partial response; SD, stable disease; TP53, tumor protein p53. Citation Format: Yoon-Sim Yap, Faye Su, Nadia Solovieff, Yoshinori Ito, Norikaza Masuda, Takashi Ishikawa, Tomoyuki Aruga, Seung Jin Kim, Wei He, Mihaela Gazdoiu, Joanne Chiu. Baseline circulating tumor DNA (ctDNA) analysis in Asian women with HR+/HER2- advanced breast cancer (ABC) receiving ribociclib + endocrine therapy in the Phase Ib MONALEESASIA trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT143.

Prenatal detection (PND) has benefits for hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA), but socioeconomic and geographic barriers are unknown. We evaluated the association between socioeconomic position, public insurance, race/ethnic group, and distance from

e15630 Background: We aimed to compare the efficacy and tolerability of SECOX regimen with sorafenib alone as first-line treatment of advanced hepatocellular cancer (HCC) in a multicenter, open-label and randomized setting. Methods: Patients not suitable for surgery or various loco-regional therapies and no prior systemic therapy for advanced HCC were recruited in 3 centres. Eligible patients were randomly assigned to receive either SECOX (sorafenib 400 mg BD continuously, oxaliplatin 85 mg/m2 on D1, and capecitabine 1700 mg/m2 on D1-7 q2w) or sorafenib alone continuously in 1:1 ratio. Primary endpoint was time-to-progression (TTP). Secondary endpoints were tolerability, overall tumor response rate, overall survival (OS) and progression-free survival (PFS). Results: Forty-six patients were randomized and treated, of whom 22 were in the SECOX arm. Median age was 64 years and majority of the patients were male (72%). 40 patients (87%) were hepatitis B carrier, and 42 patients (91%) had Child-Pugh A liver function. Thirty patients (65%) had received prior non-systemic treatment for HCC. Median duration of follow-up was 7.8 months (mos) (range 0.3-25.8). At the time of analysis,one patient in the SECOX arm is still receiving treatment. Median TTP was 3.2 mos (95% CI 1.7-5.8) for SECOX vs 2.8 mos (95% CI 1.8-4.0) for sorafenib. The hazard ratio (HR) for TTP was 0.91 (95% CI 0.5-1.7; p = 0.77; predetermined futility boundary HR ≥ 0.86). Median OS was 7.1 mos (95% CI 3.0-15.3) for SECOX vs 12.5 mos (95% CI 7.2-15.4) for sorafenib (p = 0.29). Median PFS was 3.1 mos (95% CI 1.6-5.8) for SECOX vs 2.7 mos (95% CI 1.8-4.0) for sorafenib. 2 patients (9%) and no patients achieved partial response in the SECOX and sorafenib arms, respectively. The clinical benefit rate (CR+PR+SD) was 36% for the SECOX arm and 21% for the sorafenib arm (p = 0.50). Incidence of treatment-related adverse events (trAEs) was common in both SECOX and sorafenib arms (64% and 71% respectively, p = 0.75). The most common grade 3-4 trAE was ALP increase (14%) for SECOX and hand-foot skin reaction (25%) for sorafenib. Conclusions: The addition of capecitabine and oxaliplatin to sorafenib did not result in significant improvement in TTP. Clinical trial information: NCT02716766.

BACKGROUND: This study explored the efficacy, tolerability, and survival benefits of using sorafenib in patients with Child-Pugh class B (CPB) cirrhosis. METHODS: Patients with advanced hepatocellular carcinoma who were treated with sorafenib at Queen Mary Hospital, Hong Kong, China, were analyzed retrospectively. Treatment outcomes were analyzed according to their respective Child-Pugh status. Patients with CPB disease were further divided into CPB7 (those with a score of 7) and CPB8-9 (a score of 8 or 9) subgroups. RESULTS: The baseline demographic parameters were comparable between 108 patients with Child-Pugh class A (CPA) disease and 64 CPB patients. Both clinical benefit rate (21.3% vs 32.4% vs 14.8%; P = .23) and progression-free survival (median: 3.2 months vs 3.2 months vs 2.3 months; P = .26) were similar among CPA, CPB7, and CPB8-9 groups, respectively. The overall survival was different among these groups (P = .002) and showed a trend toward worse outcome in CPB patients: the median was 6.1, 5.4, and 2.7 months among CPA, CPB7, and CPB8-9 patients, respectively. The commonest grade 3/4 adverse events were hand-foot syndrome (13.5%), diarrhea (9.9%), and rash (7.0%). Grade 3/4 leukopenia, thrombocytopenia, and anemia occurred in 2.9%, 5.3%, and 8.8% of the patients, respectively. Overall, the 3 groups of patients experienced similar incidence of most of these adverse events. Nonetheless, CPB patients experienced more anemia (P = .01), gastrointestinal bleeding (P = .02), and hepatic encephalopathy (P = .02). CONCLUSIONS: CPA and CPB patients tolerated sorafenib similarly and derived similar clinical and progression-free survival benefit. Among CPB patients, most benefits were observed in patients with a score of 7. Nevertheless, CPB patients were more susceptible to developing cirrhotic complications, and thus more vigilant surveillance is needed. Cancer 2012. © 2012 American Cancer Society.

Development of systemic treatment for advanced pancreatic cancer (APC) has been challenging. After fluorouracil, gemcitabine (GEM) became the treatment of choice based on its benefit of symptom relief. Many cytotoxic agents have been combined with GEM in search of regimens with improved survival benefit. However, there were only marginal benefits in people with good performance status. Recently, the combination regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) was found to achieve unprecedented survival benefit and has become the preferred option for patients with good clinical conditions. On the other hand, many biological agents have been combined with GEM, but only erlotinib was found to derive statistically significant survival advantage. However, the effect was too small to be appreciated clinically. The effort in development of targeted therapy in APC continues. This paper summarized key findings in the development of chemotherapy and targeted therapy for APC patients and discussed future directions in management.

Background. With the aging population, hepatocellular carcinoma (HCC) in the elderly represents a significant health burden. We aimed to evaluate and compare the efficacy and tolerability of single-agent sorafenib in treating elderly patients with advanced HCC versus the younger population. Methods. We retrospectively analyzed a consecutive cohort of advanced HCC patients with Child-Pugh A or B liver function and an Eastern Cooperative Oncology Group performance status score of 0-2 treated with sorafenib. The patients were categorized into older (age ≥70 years) and younger (age, link_to_OA_fulltext

Human epidermal growth factor receptor (HER)-2 + breast cancer is a distinct molecular and clinical entity, the prognosis of which is improved by trastuzumab. However, primary resistance to Trastuzumab is observed in >50% of patients with HER-2 + advanced breast cancer, and the majority of patients who initially respond to treatment eventually develop disease progression. To facilitate crosstrial comparisons and the understanding of resistance mechanisms, we propose a unifying definition of trastuzumab resistance as progression at first radiological reassessment at 8-12 weeks or within 3 months after first-line trastuzumab in the metastatic setting or new recurrences diagnosed during or within 12 months after adjuvant trastuzumab. In contrast, we define trastuzumab-refractory breast cancer as disease progression after two or more lines of Trastuzumab-containing regimens that initially achieved disease response or stabilization at first radiological assessment. We review mechanisms of trastuzumab resistance mediated by p95HER-2 overexpression, phosphoinositide 3-kinase pathway activation, and signaling pathway activation driven by HER-3, epidermal growth factor receptor, and insulin-like growth factor 1 receptor. We distinguish in vitro from in vivo evidence, highlighting that most data describing trastuzumab resistance are derived from preclinical studies or small retrospective patient cohorts, and discuss targeted therapeutic approaches to overcome resistance. Prospective analysis through clinical trials with robust tissue collection procedures, prior to and following acquisition of resistance, integrated with next-generation tumor genome sequencing technologies, is identified as a priority area for development. The identification of predictive biomarkers is of paramount importance to optimize health economic costs and enhance stratification of anti-HER-2 targeted therapies. © AlphaMed Press., link_to_OA_fulltext

Primary breast invasive ductal carcinoma coexisting with ductal carcinoma in situ (IDC-DCIS) is characterized by lower proliferation rate and metastatic propensity than size-matched pure IDC. IDC-DCIS is also more often ER-positive, PR-positive and/or HER2-positive. This analysis aims to clarify whether the presence of coexisting DCIS in IDC affects tumor aggressiveness in various biological subtypes of breast cancer, respectively. Tumor data obtained from 1,355 consecutive female patients undergoing upfront surgery for primary breast cancer were analyzed retrospectively; 196 patients with pure DCIS were excluded. Based on evidence that immunohistochemistry (IHC) provides a reasonable approximation of molecular phenotypes, the tumor samples were divided into 4 groups: (1) luminal A (ER and/or PR-positive, HER2-negative, Ki67 ≤ 12), (2) luminal B (ER and/or PR-positive, HER2-negative, Ki67 > 12), (3) HER2 (HER2-positive) and (4) basal-like (triple-negative) disease. Ki67 expression and nodal involvement of IDC with or without DCIS in these groups were compared. The number of patients with luminal A, luminal B, HER2 and basal-like breast cancer were 396, 265, 258 and 117, respectively. Ki-67 was lower in IDC-DCIS than in size-adjusted pure IDC of both luminal A and luminal B subtypes (P = 0.15 and

524Background: The optimal duration of adjuvant therapy with targeted agents remains a question of ongoing relevance in oncology. ExteNET, an international, randomized, placebo-controlled phase III...

Cancer patients often seek complementary or alternative medicines to supplement or replace treatments prescribed by licensed medical practitioners. Traditional Chinese/herbal medicine (TCM) is a popular complementary intervention among cancer patients of Asian ethnicity, many of whom take it during their conventional treatment. Few of these patients inform their doctors, however, creating a risk of unexpected sequelae arising from either pharmacologic toxicity, unsuitable dosing, interactions with anti-cancer drugs or other medications, adulteration, or idiosyncratic reactions. If unrecognized, these problems may be misattributed to conventional treatment toxicity or disease progression, and remedial action may be inappropriate or delayed. The purpose of this review is to help oncologists recognize the common presentations of TCM-related problems in cancer patients—such as abnormal liver function tests, unexpectedly severe myelosuppression, hemostatic defects, renal functional impairment, or suspected drug interactions—and to teach strategies by which these problems can be anticipated, prevented, or managed. Through sensitive understanding of the reasons favoring TCM usage, oncologists can gain the trust and respect of their TCM-using patients while ensuring the safety and efficacy of conventional anticancer treatments.

Background Adenomatous polyposis coli (Apc) is a tumor suppressor that inhibits Wnt/Ctnnb1. Mutations of Apc will not only lead to familial adenomatous polyposis with associated epithelial lesions, but will also cause aggressive fibromatosis in mesenchymal cells. However, the roles of Apc in regulating mesenchymal cell biology and organogenesis during development are unknown. Results We have specifically deleted the Apc gene in lung mesenchymal cells during early lung development in mice. Loss of Apc function resulted in immediate mesenchymal cell hyperproliferation through abnormal activation of Wnt/Ctnnb1, followed by a subsequent inhibition of cell proliferation due to cell cycle arrest at G0/G1, which was caused by a mechanism independent of Wnt/Ctnnb1. Meanwhile, abrogation of Apc also disrupted lung mesenchymal cell differentiation, including decreased airway and vascular smooth muscle cells, the presence of Sox9-positive mesenchymal cells in the peripheral lung, and excessive versican production. Moreover, lung epithelial branching morphogenesis was drastically inhibited due to disrupted Bmp4-Fgf10 morphogen production and regulation in surrounding lung mesenchyme. Lastly, lung mesenchyme-specific Apc conditional knockout also resulted in altered lung vasculogenesis and disrupted pulmonary vascular continuity through a paracrine mechanism, leading to massive pulmonary hemorrhage and lethality at mid-gestation when the pulmonary circulation should have started. Conclusions Our study suggests that Apc in lung mesenchyme plays central roles in coordinating the proper development of several quite different cellular compartments including lung epithelial branching and pulmonary vascular circulation during lung organogenesis. Electronic supplementary material The online version of this article (doi:10.1186/s12915-015-0153-1) contains supplementary material, which is available to authorized users.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in most Asian countries due to the high prevalence of hepatitis B viral infection.1 Surgical resection and liver transplantation are regarded as the main curative treatments for HCC. Many patients, however, are not eligible for resection due to locally advanced tumour, underlying liver cirrhosis with suboptimal liver reserve or metastatic disease on presentation.1 Puppala et al 2 concisely summarise the modern image-guided therapy options for patients with advanced HCC, such as radiofrequency ablation (RFA), microwave ablation, percutaneous ethanol ablation (PEI), cryoablation, transarterial chemoembolisation (TACE) and yttrium-90 radioembolisation. However, most of these treatments are palliative in nature and the overall survival of HCC patients with locally advanced disease remains poor. The outcomes of these image-guided therapies depend on accurate tumour staging, the position of the tumour in the liver, as well as the expertise and available facilities of the individual treatment centres. Accurate staging and selection of HCC patients for image-guided therapy is crucial for treatment success. The staging of HCC differs significantly from that of other tumour types as the underlying liver disease has …

e15049 Background: Advanced colorectal cancer (CRC) refractory to oxaliplatin, irinotecan, and fluoropyrimidines is associated with poor prognosis. The triplet combination of 5-fluorouracil, oxaliplatin, and irinotecan has shown efficacy and tolerability in treatment-naive disease. We investigated the efficacy and tolerability of salvage capecitabine, oxaliplatin and irinotecan (Xeloxiri) in patients who progressed on standard chemotherapy. Methods: This prospective phase 2 study with a primary endpoint of overall response rate (ORR) recruited patients with advanced CRC that have progressed on standard chemotherapy containing fluoropyrimidines, oxaliplatin, and irinotecan either as monotherapy or doublets. Prior use of anti-VEGF, and anti-EGFR agents were allowed. Patients received capecitabine 1250mg/m2 twice daily on day 1-7, oxaliplatin 85mg/m2 and irinotecan 165mg/m2 on day 1 every 2 weeks until disease progression or intolerable toxicity. Secondary endpoints were progression free survival (PFS) and overall survival (OS). Results: Between July 2011 and May 2016, we recruited 32 patients. Median age was 57 and the median number of treatment cycles was 6. 16 patients (50%) were K-RAS wild-type (WT), of which 6 were also N-RAS WT. The ORR was 25% and the clinical benefit rate was 56%. 87.5% of patient received targeted therapy prior to study entry. 34% of patients had > 3 previous lines of therapy. Median PFS and OS were 5.0 months (95% CI 3.2 - 7.1) and 10.4 months (95% CI 7.2 - 11.4) respectively. K-RAS mutation status, number of lines of previous therapy, and site of primary tumour were not predictive of ORR, PFS or OS on univariate testing. Treatment-related adverse events (AEs) occurred in all patients, with the majority being hematological. Dose reductions occurred in 87.5% of patients. 59% required dose delays, and 56% received granulocyte-colony stimulating factor. Grade 3/4 AEs included neutropenia (34%), anemia (16%), thrombocytopenia (12.5%), febrile neutropenia (9%), diarrhea (6%), and anorexia (3%). Conclusions: Xeloxiri is efficacious and safe in patients with chemo-refractory CRC and is a promising treatment strategy as salvage. Clinical trial information: in progress.