Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142.

BACKGROUND: In the phase II multicohort CheckMate 142 study, nivolumab plus low-dose (1 mg/kg) ipilimumab provided robust and durable clinical benefit with a manageable safety profile in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) at 13.4- and 25.4-month median follow-up (Overman MJ, Lonardi S, Wong KYM et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36:773-779. Overman MJ, Lonardi S, Wong KYM, et al. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: long-term follow-up. J Clin Oncol. 2019;37:635). Here, we present results from the 4-year follow-up of these patients. PATIENTS AND METHODS: Patients received nivolumab (3 mg/kg) plus low-dose (1 mg/kg) ipilimumab every 3 weeks (four doses) followed by nivolumab (3 mg/kg) every 2 weeks until disease progression. Primary endpoint was investigator-assessed objective response rate (ORR; as per RECIST version 1.1). RESULTS: A total of 119 patients were treated; 76% had ≥2 prior lines of therapy. Median follow-up was 50.9 months (range 46.9-62.7 months). Median duration of therapy was 24.9 months [95% confidence interval (CI) 15.8-33.2 months]. Investigator-assessed ORR increased from 55% (95% CI 45% to 64%) at 13.4 months to 65% (95% CI 55% to 73%) at 50.9 months with a disease control rate of 81% (95% CI 72% to 87%). The complete response rate increased from 3% at 13.4 months to 13% at 50.9 months. Partial responses were observed in 52% of patients; 21% had stable disease, and 12% had progressive disease. Median time to response was 2.8 months (range 1.1-37.1 months), and median duration of response was not reached (range 1.4+ to 58.0+ months). At data cut-off, 37 (48%) patients had ongoing responses. Median progression-free survival was not reached [95% CI 38.4 months-not estimable (NE)], and median overall survival was not reached (95% CI NE). Grade 3-4 treatment-related adverse events (TRAEs) were observed in 32% of patients; 13% of patients had any-grade TRAEs leading to discontinuation. CONCLUSIONS: The results confirm long-term benefit of nivolumab plus low-dose ipilimumab for previously treated patients with MSI-H/dMMR mCRC. The safety profile was manageable with no new safety signals.

Immediate unilateral breast reconstruction and contralateral breast augmentation with bilateral free deep inferior epigastric perforator flaps.

A 42-year-old woman was referred for consideration of left-sided mastectomy and immediate reconstruction. She previously had a bilateral breast augmentation using silicone implants. She desired to maintain her breast size and natural appearance. Owing to the availability of sufficient abdominal tissue, the option of an immediate unilateral breast reconstruction and contralateral augmentation with a differentially split deep inferior epigastric perforator flaps was offered to the patient. The patient had a successful reconstructive and contralateral symmetrising procedure with an uneventful postoperative recovery. She was satisfied with her breast size, which was achieved without the use of implants. In selected patients the free deep inferior epigastric perforator flap provides an appropriate option for unilateral breast reconstruction and contralateral breast augmentation. It has numerous advantages including making use of available excess abdominal tissue and avoiding implant related complications.

Neonatal outcomes of preterm or very-low-birth-weight infants over a decade from Queen Mary Hospital, Hong Kong: comparison with the Vermont Oxford Network.

INTRODUCTION: There is a paucity of local data on neonatal outcomes of preterm/very-low-birth-weight infants in Hong Kong. This study aimed to evaluate the survival rate on discharge and morbidity of preterm/very-low-birth-weight infants (≤29+6 weeks and/or birth weight <1500 g) over a decade at Queen Mary Hospital in Hong Kong, so as to provide centre-specific data for prenatal counselling and to benchmark these results against the Vermont Oxford Network. METHODS: Standardised perinatal/neonatal data were collected for infants with gestational age of 23+0 to 29+6 weeks and/or birth weight of <1500 g who were born at Queen Mary Hospital between 1 January 2005 and 31 December 2014. These data were compared with all neonatal centres in the Vermont Oxford Network in 2013. The Chi squared test was used to compare the categorical Queen Mary Hospital data with that of Vermont Oxford Network. A two-tailed P value of <0.05 was considered statistically significant. RESULTS: The overall survival rate on discharge from Queen Mary Hospital for 449 infants was significantly higher than that of the Vermont Oxford Network (87% versus 80%; P=0.0006). The morbidity-free survival at Queen Mary Hospital (40%) was comparable with the Vermont Oxford Network (44%). At Queen Mary Hospital, 86% of infants had respiratory distress syndrome, 40% bronchopulmonary dysplasia, 44% patent ductus arteriosus, 7% severe intraventricular haemorrhage, 5% necrotising enterocolitis, 10% severe retinopathy of prematurity, 10% late-onset sepsis, and 84% growth failure on discharge. Rates of respiratory distress syndrome, intraventricular haemorrhage, necrotising enterocolitis, and severe retinopathy of prematurity were similar in the two populations. At Queen Mary Hospital, significantly more infants had bronchopulmonary dysplasia (P=0.011), patent ductus arteriosus (P=0.015), and growth failure (P=0.0001) compared with the Vermont Oxford Network. In contrast, rate of late-onset sepsis was significantly lower at Queen Mary Hospital than the Vermont Oxford Network (P=0.0002). CONCLUSIONS: Mortality rate and most of the morbidity rates of our centre compare favourably with international standards, but rates of bronchopulmonary dysplasia and growth failure are of concern. A regular benchmarking process is crucial to audit any change in clinical outcomes after implementation of a local quality improvement project.

MUC13 protects colorectal cancer cells from death by activating the NF-κB pathway and is a potential therapeutic target.

MUC13 is a transmembrane mucin glycoprotein that is over produced by many cancers, although its functions are not fully understood. Nuclear factor-κB (NF-κB) is a key transcription factor promoting cancer cell survival, but therapeutically targeting this pathway has proved difficult because NF-κB has pleiotropic functions. Here, we report that MUC13 prevents colorectal cancer cell death by promoting two distinct pathways of NF-kB activation, consequently upregulating BCL-XL. MUC13 promoted tumor necrosis factor (TNF)-induced NF-κB activation by interacting with TNFR1 and the E3 ligase, cIAP1, to increase ubiquitination of RIPK1. MUC13 also promoted genotoxin-induced NF-κB activation by increasing phosphorylation of ATM and SUMOylation of NF-κB essential modulator. Moreover, elevated expression of cytoplasmic MUC13 and NF-κB correlated with colorectal cancer progression and metastases. Our demonstration that MUC13 enhances NF-κB signaling in response to both TNF and DNA-damaging agents provides a new molecular target for specific inhibition of NF-κB activation. As proof of principle, silencing MUC13 sensitized colorectal cancer cells to killing by cytotoxic drugs and inflammatory signals and abolished chemotherapy-induced enrichment of CD133+ CD44+ cancer stem cells, slowed xenograft growth in mice, and synergized with 5-fluourouracil to induce tumor regression. Therefore, these data indicate that combining chemotherapy and MUC13 antagonism could improve the treatment of metastatic cancers.

Comparing the meanings of living with advanced breast cancer between women resilient to distress and women with persistent distress: a qualitative study.

BACKGROUND: Most women with advanced breast cancer (ABC) show little distress, but about one in ten show persistent distress over time. It remains unclear if meanings ascribed by patients to ABC differentiate these distress trajectories. STUDY AIMS: This qualitative study (a) compared illness meanings of ABC between women with persistent psychological distress and those with low/transient distress, and (b) examined how illness meanings might influence coping strategies. METHODS: The sample was drawn from a prior quantitative study exploring psychological distress trajectories following ABC diagnosis. Overall, 42 Cantonese- or Mandarin-speaking Chinese women diagnosed with locally advanced or metastatic ABC were recruited based on their distress trajectory status (low-stable, transient, or persistent distress). Interviews were recorded, transcribed, and analyzed following grounded theory approach using simultaneous analysis. RESULTS: Women with persistent distress viewed their diagnosis as another blow in life, the illness was global, permeating every aspect of their life. Maladaptive rumination and thought suppression were common responses to illness demands. These women had poor social support. A sense of demoralization stood out in their narratives. In contrast, women with transient/low-stable distress encapsulated the illness, with minimum impacts of their life. They did not evidence dysfunctional repetitive thoughts. Living in a supportive environment, they were able to accept and/or live in the present-moment. CONCLUSIONS: Rumination, thought suppression, social constraints, and pre-existing exposure to life stress may be potential risks for chronic distress in response to advanced breast cancer. Persistent and transient distress responses to cancer may have different underpinnings. Copyright © 2016 John Wiley & Sons, Ltd.

Apical lymph node dissection of the inferior mesenteric artery.

AIM: It is controversial whether a high or low ligation of the inferior mesenteric artery (IMA) is superior. The former allows an extended lymph node clearance whereas the latter preserves the distal vascular supply via the left colic artery (LCA). Apical lymph node dissection of the IMA (ALMA) harvests nodal tissue along the IMA proximal to the LCA whilst performing a low ligation. This anatomically replicates the oncological benefit of high ligation and the vascular preservation of low ligation. Our study evaluates the nodal yield of ALMA and the short-term outcome of this technique. METHOD: We retrospectively studied 19 patients with sigmoid or rectal cancer who underwent curative surgical resection with ALMA. All ALMAs were performed with a standard technique previously described (Kobayashi et al., Surg Endosc 2005, 20:563-9; Sekimoto et al. Surg Endosc 2010, 25:861-6) . The lymph node yield from the dissection (the ALMA specimen) was compared with the total lymph node yield. Data on the LCA anatomy, time required to perform ALMA, complications and postoperative recovery were evaluated. RESULTS: ALMA was successful in 18 patients. Median postoperative hospitalization was 5 (2-26) days without ALMA-related morbidity or mortality. The median lymph node yield was 20 (9-41) and a median of 14.3 (0-80)% were harvested with ALMA. Two patients not having neoadjuvant chemoradiotherapy had fewer than 12 lymph nodes, excluding nodes harvested from ALMA. The average time required for ALMA was 18 min. CONCLUSION: ALMA is a safe and feasible technique, allowing extended lymphadenectomy without sacrificing the LCA. In this small group of patients none were upstaged due to cancerous involvement of the proximal nodes.

Gluteal fold flap in perineal reconstruction for Crohn's disease-associated fistulae.

INTRODUCTION: Crohn's disease is increasing in incidence worldwide. It is associated with many complications including fistulae, which may require surgical intervention. Occasionally, formal perineal reconstruction is needed for extensive or definitive fistula surgery. Reconstruction for inflammatory disease presents unique challenges and often calls for innovative solutions. Gluteal fold flaps (GFFs), which have been widely used in vulvo-vaginal malignancy and anorectal cancer surgery, have not hitherto been reported for Crohn's disease-associated fistulae. CASE PRESENTATION: A 30-year-old female presented with a 5-year history of Crohn's-associated perianal and rectovaginal fistulae. She had a previous small bowel resection and ileostomy. A laparascopic pan-proctocolectomy was carried out followed by perineal reconstruction in a single stage procedure using a pedicled fasciocutaneous GFF. Seven months postoperatively, revisional surgery was carried out using the contralateral GFF due to two areas of persistent wound dehiscence. The outcome was complete resolution of the fistulae, stable wound closure and good cosmesis. DISCUSSION & CONCLUSION: This case demonstrates that it is practical to use the GFF for perineal reconstruction following excision of complex Crohn's-associated fistulae. The flap avoids the sequelae associated with sacrifice of regional muscle flaps and specifically circumvents the unavailability of the rectus abdominis flap in slim patients or those with in-situ ileostomies. It is easy and quick to raise and does not require an intra-operative change in the patient's position. The GFF ensured well vascularised skin cover, adequate flap volume with no loss of function and low donor site morbidity.

The evolution of psychological distress trajectories in women diagnosed with advanced breast cancer: a longitudinal study.

BACKGROUND: Anxiety and depression (distress) over the first year following the initial adjuvant therapy for advanced breast cancer (ABC) remain poorly documented in non-Caucasian populations. This study describes trajectories of distress and their determinants in Chinese women with ABC. METHODS: Of the 228 Chinese women newly diagnosed with ABC recruited from six oncology units, 192 completed an interview before their first course of chemotherapy (baseline) and follow-up interviews at 1.5, 3, 6, and 12 months thereafter. At baseline, participants were assessed for supportive care needs, psychological distress, physical symptom distress, optimism, and cancer-related rumination. At follow-up, participants completed the measure of psychological distress. Latent growth mixture modeling was used to identify trajectory patterns of distress. Multinominal logistic regression was used to identify predictors of trajectory patterns adjusted for demographic and medical characteristics. RESULTS: Four distinct trajectories of anxiety and depression were identified. Most women showed low-stable levels of anxiety (68%) and depression (68%), but one in 11 women were chronically anxious (9%) and depressed (9%). Optimism, negative cancer-related rumination, and physical symptom distress predicted both anxiety and depression trajectories. Psychological needs predicted anxiety trajectories. Women in the low-stable distress group reported high optimism, low psychological supportive care needs, low physical symptom distress, and low negative cancer-related rumination. CONCLUSION: Most women with ABC did not experience psychological distress over 12 months following diagnosis of ABC. Preventive interventions should focus on women at risk of high persistent distress and reducing rumination, providing emotional support, and managing physical symptoms.

Reconstruction of chest wall chondrosarcoma with an anterolateral thigh free flap: An illustration of decision-making in chest wall reconstruction.

INTRODUCTION: Chondrosarcomas are the most common primary chest wall malignancy. The mainstay of treatment is radical resection, which often requires chest wall reconstruction. This presents numerous challenges and more extensive defects mandate the use of microvascular free flaps. Selecting the most appropriate flap is important to the outcome of the surgery. PRESENTATION OF CASE: A 71-year-old male presented with a large chondrocarcoma of the chest wall. The planned resection excluded use of the ipsilateral and contralateral pectoralis major flap because of size and reach limitations. The latissimus dorsi flap was deemed inappropriate on logistical grounds as well as potential vascular compromise. The patient was too thin for reconstruction using an abdominal flap. Therefore, following radical tumour resection, the defect was reconstructed with a methyl methacrylate polypropylene mesh plate for chest wall stability and an anterolateral thigh free flap in a single-stage joint cardiothoracic and plastic surgical procedure. The flap was anastomosed to the contralateral internal mammary vessels as the ipsilateral mammary vessels had been resected. DISCUSSION: The outcome was complete resection of the tumour, no significant impact on ventilation and acceptable cosmesis. CONCLUSION: This case demonstrates the complex decision making process required in chest wall reconstruction and the versatility of the ALT free flap. The ALT free flap ensured adequate skin cover, subsequent bulk, provided an excellent operative position, produced little loss of donor site function, and provided an acceptable cosmetic result.

Molecular mechanisms underlying bile acid-stimulated glucagon-like peptide-1 secretion.

BACKGROUND AND PURPOSE: The glucagon-like peptides GLP-1 and GLP-2 are secreted from enteroendocrine L-cells following nutrient ingestion. Drugs that increase activity of the GLP-1 axis are highly successful therapies for type 2 diabetes, and boosting L-cell secretion is a potential strategy for future diabetes treatment. The aim of the present study was to further our understanding of the bile acid receptor GPBA (TGR5), an L-cell target currently under therapeutic exploration. EXPERIMENTAL APPROACH: GLUTag cells and mixed primary murine intestinal cultures were exposed to bile acids and a specific agonist, GPBAR-A. Secretion was measured using hormone assays and intracellular calcium and cAMP responses were monitored using real-time imaging techniques. KEY RESULTS: Bile acid-triggered GLP-1 secretion from GLUTag cells was GPBA-dependent, as demonstrated by its abolition following tgr5 siRNA transfection. Bile acids and GPBAR-A increased GLP-1 secretion from intestinal cultures, with evidence for synergy between the effects of glucose and GPBA activation. Elevation of cAMP was observed following GPBA activation in individual GLUTag cells. Direct calcium responses to GPBAR-A were small, but in the presence of the agonist, a subpopulation of cells that was previously poorly glucose-responsive exhibited robust glucose responses. In vivo, increased delivery of bile to more distal regions of the ileum augmented L-cell stimulation. CONCLUSIONS AND IMPLICATIONS: GPBA signalling in L-cells involves rapid elevation of cAMP, and enhanced calcium and secretory responses to glucose. Modulation of this receptor therapeutically may be an attractive strategy to enhance GLP-1 secretion and achieve better glycaemic control in diabetic patients.

Occupation and risk of non-Hodgkin's lymphoma in Singapore.

BACKGROUND: Some epidemiological studies have reported that teachers may be at increased risk of non-Hodgkin's lymphoma (NHL), but results are inconsistent. AIMS: To examine the possible association between occupation and risk of NHL in the Singapore population. METHODS: A hospital-based interviewer-administered case-control study was carried out in five major hospitals in Singapore between April 2004 and December 2008. A complete occupational history, which included all jobs lasting over 1 year since graduation from school, was obtained for each participant. The Singapore Standard Occupational Classification was used for coding all occupations recorded. RESULTS: Eight hundred and thirty controls and 465 NHL cases, comprising B-cell (n = 404, 87%) as well as T- and NK-cell (n = 61, 13%) neoplasms, were recruited. Having ever worked as a teacher was associated with a significantly higher risk of NHL (adjusted OR 2.04, 95% CI 1.12-3.72). Teachers who had taught for ≤10 years had a significantly higher risk of NHL (adjusted OR 2.44, 95% CI 1.11-5.34), but we did not observe an elevated risk for those who reported teaching for >10 years. Among the 31 teachers with NHL, 23% taught in upper secondary schools, with equal proportions (13%) teaching in primary and pre-primary schools, respectively. The remainder taught in other settings. CONCLUSIONS: Teachers come into frequent contact with children and may consequently have higher rates of exposure to common infectious agents. Therefore, the hypothesis of an infective aetiology of NHL may be supported by our findings.

Annexin-1-deficient mice exhibit spontaneous airway hyperresponsiveness and exacerbated allergen-specific antibody responses in a mouse model of asthma.

BACKGROUND: Glucocorticoids are the mainstream drugs used in the treatment and control of inflammatory diseases such as asthma. Annexin-1 (ANXA1) is an anti-inflammatory protein which has been described as an endogenous protein responsible for some anti-inflammatory glucocorticoid effects. Previous studies have identified its importance in other immune diseases such as rheumatoid arthritis and cystic fibrosis. ANXA1-deficient ((-/-)) mice are Th2 biased, and ANXA1 N-terminus peptide exhibits anti-inflammatory activity in a rat model of pulmonary inflammation. OBJECTIVE: ANXA1 protein is found in bronchoalveolar lavage fluid from asthmatics. However, the function of ANXA1 in the pathological development of allergy or asthma is unclear. Thus, in this study we intended to examine the effect of ANXA1 deficiency on allergen-specific antibody responses and airway responses to methacholine (Mch). METHODS: ANXA1(-/-) mice were sensitized with ovalbumin (OVA) and challenged with aerosolized OVA. Airway resistance, lung compliance and enhanced pause (PenH) were measured in naïve, sensitized and saline or allergen-challenged wild-type (WT) and ANXA1(-/-) mice. Total and allergen-specific antibodies were measured in the serum. RESULTS: We show that allergen-specific and total IgE, IgG2a and IgG2b levels were significantly higher in ANXA1(-/-) mice. Furthermore, naïve ANXA1(-/-) mice displayed higher airway hypersensitivity to inhaled Mch, and significant differences were also observed in allergen-sensitized and allergen-challenged ANXA1(-/-) mice compared with WT mice. CONCLUSIONS: In conclusion, ANXA1(-/-) mice possess multiple features characteristic to allergic asthma, such as airway hyperresponsiveness and enhanced antibody responses, suggesting that ANXA1 plays a critical regulatory role in the development of asthma. CLINICAL RELEVANCE: We postulate that ANXA1 is an important regulatory factor in the development of allergic disease and dysregulation of its expression can lead to pathological changes which may affect disease progression.

Validation of the Chinese version of the short-form Supportive Care Needs Survey Questionnaire (SCNS-SF34-C).

BACKGROUND: There is no instrument available in Chinese for assessing psychosocial needs. This study aimed to assess the validity and reliability of the Chinese version of the Supportive Care Needs Survey short form (SCNS-SF34-C) in Chinese women with breast cancer (BC). METHODS: The Chinese version of the 34-item SCNS-SF34-C, a self-report measure for assessing psychosocial unmet needs, was administered to 348 Chinese women with BC at the outpatient oncology unit. Exploratory factor analysis (EFA) tested the factor structure. The internal consistency, convergent, divergent, and discriminant validity of the identified factor structure were assessed. RESULTS: In contrast to the five-factor structure identified in the original 34-item SCNS-SF34, our EFA produced a 33-item solution accounting for 54% of score variance comprising four-factors: (1) Health system, information, and patient support, (2) Psychological needs, (3) Physical and daily living, and (4) Sexuality needs. Separate dimensions for Health system and information, and the Patient care and support domains were not supported. Cronbach alphas ranged from 0.75 to 0.92. Correlations of psychological and physical symptom distress measures indicated acceptable convergent validity. No correlation with optimism and positive affect measures indicated divergent validity. Discriminant validity was demonstrated by effective differentiation between clinically distinct patient groups (no active treatment versus active treatment; advanced BC versus localized BC). DISCUSSION: The Chinese version of the Supportive Care Needs Survey has suitable factor structure and psychometric properties for use in assessing psychosocial needs among Chinese women with BC. Further validation is needed for other cancer types.

Smoking cessation and lung cancer risk in an Asian population: findings from the Singapore Chinese Health Study.

BACKGROUND: Smoking cessation is an important strategy for reducing the harmful effects of tobacco, particularly in the prevention of lung cancer; however, prospective data on the impact of smoking cessation on lung cancer risk in Asian populations are limited. METHODS: We studied a population-based cohort of Chinese men and women aged 45-74 years--participants of the Singapore Chinese Health Study. Information on smoking, lifestyle and dietary habits was collected at the time of recruitment in 1993-1998; and smoking status was assessed again at a second interview in 1999-2004 (mean interval 5.8 years). Participants were followed up to 31 December 2007, and incident cases of lung cancer were ascertained by linkage with population-wide registries. RESULTS: Among 45,900 participants, there were 463 incident cases of lung cancer. Relative to current smokers, those who quit smoking subsequent to baseline assessment had a 28% decrease in the risk of lung cancer (adjusted hazard ratio (HR) 0.72; 95% CI (95% confidence interval): 0.53-0.98). The risk was less than half in ex-smokers who had quit before the first interview and maintained their status (HR 0.42; 95% CI: 0.32-0.56). CONCLUSIONS: Reduction in lung cancer incidence with smoking cessation in Asian populations is substantial and can be observed within a few years after quitting.

Epigenetic inactivation of the miR-34a in hematological malignancies.

miR-34a is a transcriptional target of p53 and implicated in carcinogenesis. We studied the role of miR-34a methylation in a panel of hematological malignancies including acute leukemia [acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)], chronic leukemia [chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML)], multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). The methylation status of miR-34a promoter was studied in 12 cell lines and 188 diagnostic samples by methylation-specific polymerase chain reaction. miR-34a promoter was unmethylated in normal controls but methylated in 75% lymphoma and 37% myeloma cell lines. Hypomethylating treatment led to re-expression of pri-miR-34a transcript in lymphoma cells with homozygous miR-34a methylation. In primary samples at diagnosis, miR-34a methylation was detected in 4% CLL, 5.5% MM samples and 18.8% of NHL at diagnosis but none of ALL, AML and CML (P = 0.011). In MM patients with paired samples, miR-34a methylation status remained unchanged at progression. Amongst lymphoid malignancies, miR-34a was preferentially methylated in NHL (P = 0.018), in particular natural killer (NK)/T-cell lymphoma. In conclusion, amongst hematological malignancies, miR-34a methylation is preferentially hypermethylated in NHL, in particular NK/T-cell lymphoma, in a tumor-specific manner, therefore the role of miR-34a in lymphomagenesis warrants further study.