Spatial transcriptomics reveals discrete tumour microenvironments and autocrine loops within ovarian cancer subclones.

High-grade serous ovarian carcinoma (HGSOC) is genetically unstable and characterised by the presence of subclones with distinct genotypes. Intratumoural heterogeneity is linked to recurrence, chemotherapy resistance, and poor prognosis. Here, we use spatial transcriptomics to identify HGSOC subclones and study their association with infiltrating cell populations. Visium spatial transcriptomics reveals multiple tumour subclones with different copy number alterations present within individual tumour sections. These subclones differentially express various ligands and receptors and are predicted to differentially associate with different stromal and immune cell populations. In one sample, CosMx single molecule imaging reveals subclones differentially associating with immune cell populations, fibroblasts, and endothelial cells. Cell-to-cell communication analysis identifies subclone-specific signalling to stromal and immune cells and multiple subclone-specific autocrine loops. Our study highlights the high degree of subclonal heterogeneity in HGSOC and suggests that subclone-specific ligand and receptor expression patterns likely modulate how HGSOC cells interact with their local microenvironment.

Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes.

PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

TRACEBACK: Testing of Historical Tubo-Ovarian Cancer Patients for Hereditary Risk Genes as a Cancer Prevention Strategy in Family Members.

PURPOSE: Tubo-ovarian cancer (TOC) is a sentinel cancer for BRCA1 and BRCA2 pathogenic variants (PVs). Identification of a PV in the first member of a family at increased genetic risk (the proband) provides opportunities for cancer prevention in other at-risk family members. Although Australian testing rates are now high, PVs in patients with TOC whose diagnosis predated revised testing guidelines might have been missed. We assessed the feasibility of detecting PVs in this population to enable genetic risk reduction in relatives. PATIENTS AND METHODS: In this pilot study, deceased probands were ascertained from research cohort studies, identification by a relative, and gynecologic oncology clinics. DNA was extracted from archival tissue or stored blood for panel sequencing of 10 risk-associated genes. Testing of deceased probands ascertained through clinic records was performed with a consent waiver. RESULTS: We identified 85 PVs in 84 of 787 (11%) probands. Familial contacts of 39 of 60 (65%) deceased probands with an identified recipient (60 of 84; 71%) have received a written notification of results, with follow-up verbal contact made in 85% (33 of 39). A minority of families (n = 4) were already aware of the PV. For many (29 of 33; 88%), the genetic result provided new information and referral to a genetic service was accepted in most cases (66%; 19 of 29). Those who declined referral (4 of 29) were all male next of kin whose family member had died more than 10 years before. CONCLUSION: We overcame ethical and logistic challenges to demonstrate that retrospective genetic testing to identify PVs in previously untested deceased probands with TOC is feasible. Understanding reasons for a family member's decision to accept or decline a referral will be important for guiding future TRACEBACK projects.

Lynch syndrome associated endometrial carcinomas in Western Australia: an analysis of universal screening by mismatch repair protein immunohistochemistry.

BACKGROUND: In 2016 universal screening with mismatch repair protein immunohistochemistry in all newly diagnosed endometrial carcinomas was introduced in Western Australia. OBJECTIVE: To compare the prevalence of Lynch syndrome associated endometrial carcinomas between 2016 and 2019 with a historical control (2015). Additionally, to compare the number of cases appropriately referred for genetic assessment. METHODS: A cross-sectional study of cases presented at the Western Australia gynecologic oncology tumor board was carried out. The primary outcome was the prevalence of Lynch syndrome associated endometrial carcinomas. A secondary outcome was the number of cases appropriately referred for genetic assessment. The following variables were extracted: date of birth; age at diagnosis; vital status; tumor mismatch repair protein expression status (retained or lost) and if lost, the specific mismatch repair protein deficiency; patients who were referred to a genetic clinic; and family history, if recorded. Data were collected from the clinical databases of the Familial Cancer Program at Genetic Services of Western Australia and WOMEN Center, to determine whether patients were appropriately referred for genetic evaluation and to ascertain the results of genetic testing. RESULTS: Between 2016 and 2019, there were 1040 new endometrial carcinomas. Tumors of 883 (85%) patients underwent mismatch repair protein immunohistochemistry compared with 117 of 199 patients (59%) in 2015 (χ2 73.14, p<0.001). Of 883 tumors tested, 242 (27%) showed loss of mismatch repair protein expression. In 2015, 30 (26%) tumors of 117 tested showed loss of mismatch repair protein expression. During the 4 years of universal screening, 13 (1.5%) of 883 patients screened were diagnosed with Lynch syndrome compared with 2 (1.7%) of 117 in 2015 (Fisher's exact test 0.04, p=0.69). In 2015, 11 (37%) of 30 patients with loss of mismatch repair protein expression were not referred for genetic assessment compared with 36 (17%) of 209 patients in the universal screening group (χ2 6.28, p=0.02). No cases of Lynch syndrome were diagnosed in patients aged over 70 years. CONCLUSIONS: Universal immunohistochemical screening did not increase the proportion of Lynch syndrome associated endometrial carcinomas identified, although the study was underpowered to detect small differences. There was an improvement in appropriate referrals for genetic assessment.

Postoperative use of slow-release opioids: The impact of the Australian and New Zealand College of Anaesthetists/Faculty of Pain Medicine position statement on clinical practice.

Dose titration with immediate-release opioids is currently recommended for acute pain. The Australian and New Zealand College of Anaesthetists and the Faculty of Pain Medicine released a statement in March 2018 supporting their use in the treatment of opioid-naïve patients; however, the impact of this statement on clinical practice is currently unknown. This retrospective cohort study was conducted to compare opioid prescribing patterns before and after the release of the recommendations. Data were collected on 184 patients (2017, n = 78; 2018, n = 106) admitted to the Prince of Wales Hospital in November 2017 and 2018, which consisted of demographic data, opioid prescriptions and discharge opioid information. The main outcome is the number of prescriptions of slow-release opioids in 2017 versus 2018 after the recommendations were published. Confounding factors were accounted for using logistic and multiple regression as appropriate. There was a 29% decrease in slow-release opioid prescriptions during hospitalisation (n = 31, 40% versus n = 12, 11%; P < 0.001) and 17% decrease at discharge (n = 20, 26% versus n = 9, 9%; P = 0.02) post-publication. After adjusting for confounders, the odds of slow-release opioids being prescribed postoperatively and at discharge reduced by 86% and 88%, respectively (postoperative period: odds ratio 0.14, P < 0.05; discharge: odds ratio 0.12, P < 0.05). In addition, orthopaedic patients were more likely to receive slow-release opioids, consistent with existing literature. As the use of slow-release opioids has been associated with increased harm and protracted opioid use compared to immediate-release opioids, it is hoped that wider dissemination of these recommendations and a change in prescribing practice can be a step towards overcoming the opioid crisis.

Excisional treatment comparison for in situ endocervical adenocarcinoma (EXCISE): A phase 2 pilot randomized controlled trial to compare histopathological margin status, specimen size and fragmentation after loop electrosurgical excision procedure and cold knife cone biopsy.

OBJECTIVE: Adenocarcinoma in situ (AIS) of the cervix is a precursor to cervical adenocarcinoma. When AIS is detected by cervical screening an excision biopsy is mandatory to exclude invasion. We aimed to compare margins status, specimen size and fragmentation after loop electrosurgical excision procedure (LEEP) and 'cold knife cone biopsy' (CKC). METHODS: The EXCISE Trial was an investigator-initiated, multicenter, open-label, parallel-group, phase 2, randomized study. Patients were enrolled at seven hospitals in Australia and New Zealand. We randomly assigned women aged ≥18 to ≤45 years with screen detected AIS to LEEP or CKC. Co-primary endpoints were margin status, specimen size and fragmentation. Analysis was by intention-to-treat. RESULTS: Between August 2, 2017 and September 6, 2019, 40 patients were randomly assigned 2:1 to LEEP or CKC. Margin status was evaluable in 36 cases. The proportion of patients with involved margins did not differ between groups. 25 of 26 LEEP and all 14 CKC biopsies were excised as single specimens (p = 1·00). There were no differences in specimen dimensions. Patients in the CKC group had more post-operative complications (64.3% compared to 15.4% for LEEP p = ·00). There were no differences in grade three complications (p = ·65). CONCLUSIONS: LEEP was not associated with a greater likelihood of positive margins, specimen fragmentation or smaller excision compared to CKC when performed according to a standardized protocol. However, the study was not powered to establish non-inferiority of LEEP and a definitive phase 3 trial to compare margin status and rates of treatment failure after LEEP and CKC is warranted.

A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases.

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.

Peritumoral granulomatous reaction in endometrial carcinoma: association with DNA mismatch repair protein deficiency, particularly loss of PMS2 expression.

AIMS: The observation of peritumoral granulomatous reactions (PGRs) in two endometrial carcinomas (ECs) with a PMS2-deficient/MLH1-intact expression pattern led us to investigate whether PGRs in EC were specifically associated with DNA mismatch repair (MMR) protein deficiency, particularly PMS2 loss. METHODS AND RESULTS: Hysterectomy specimens from 22 MMR protein-intact and 54 MMR protein-deficient ECs were reviewed with specific attention to the presence of a PGR and a tumour-associated lymphoid reaction [including tumour-infiltrating lymphocytes (TILs) and stromal lymphoid infiltrates]. The MMR protein-deficient ECs included 22 cases with combined MLH1/PMS2 loss, 11 with combined MSH2/MSH6 loss, 11 with isolated MSH6 loss, and 10 with PMS2 loss but intact MLH1 staining (including the two 'index' cases). Overall, PGRs were identified in seven of 54 (13%) MMR protein-deficient ECs, five of which showed a PMS2-deficient/MLH1-intact immunophenotype; three of these patients had germline PMS2 mutations and one additional patient had a germline MSH6 mutation. None of the MMR protein-intact tumours showed a PGR. Although five of the seven PGR-positive ECs had a high-grade histological component, six were stage I. Most ECs with PGRs also showed TILs and stromal lymphoid reactions, similarly to MMR protein-deficient ECs in general. CONCLUSIONS: MMR protein-deficient ECs, particularly those with PMS2 loss, occasionally show PGRs in addition to stromal lymphoid infiltrates and TILs. Therefore, PGRs could be considered to constitute a histological prompt for consideration of Lynch syndrome. The potential prognostic significance of PGRs in EC requires further study.

Prognostic Role of Histological Tumor Regression in Patients Receiving Neoadjuvant Chemotherapy for High-Grade Serous Tubo-ovarian Carcinoma.

OBJECTIVE: Our objective was to validate the prognostic role of the chemotherapy response score (CRS), which has been proposed for measuring tumor response to neoadjuvant chemotherapy in patients with high-grade serous tubo-ovarian carcinoma, in predicting progression-free survival (PFS) and overall survival (OS). METHODS: A retrospective cohort study was conducted of patients with advanced high-grade serous tubo-ovarian carcinoma diagnosed between January 1, 2010, and December 31, 2014, and treated with neoadjuvant chemotherapy. Treatment-related tumor regression was determined according to the 3-tier CRS, and results were compared with standard clinicopathological variables. Survival analysis was performed using Cox proportional hazards models and the log-rank test. RESULTS: Seventy-one patients were eligible for analysis. Median OS was 25.5 months. Fifty-eight patients (82%) had disease recurrence and 32 (45%) had died at study census. Of the 71 patients, 19, 29, and 23 patients had a CRS of 1, 2, and 3, respectively. On univariate analysis, the CRS significantly predicted PFS (hazard ratio [HR], 3.77; 95% confidence interval [CI], 1.83-7.78; P = 0.000) and OS (HR, 2.81; 95% CI, 1.16-6.79; P = 0.022). In a multivariate model, the CRS was significantly associated with PFS (HR, 2.81; 95% CI, 1.16-6.79; P = 0.022) but not with OS (HR, 2.39; 95% CI, 0.47-3.08; P = 0.079). Patients with CRS of 1 and 2 combined were twice as likely to progress during the study period compared with patients with a CRS of 3 (HR, 2.0; 95% CI, 1.06-3.78; P = 0.032; median PFS, 16 vs 26 months). No significant association was observed for OS (CRS 1/2 vs 3; HR, 1.57; 95% CI, 0.68-3.65; P = 0.291). CONCLUSIONS: In this study, the CRS showed independent prognostic significance for PFS but not for OS.

Predicting obstructive sleep apnea using the STOP-Bang questionnaire in the general population.

OBJECTIVE: The STOP-Bang questionnaire was developed as a quick and simple screening tool for obstructive sleep apnea (OSA) in preoperative clinics. We aimed to evaluate the validity of the STOP-Bang questionnaire to predict moderate-to-severe and severe OSA in the general population. METHODS: A sample of 242 subjects selected from a population-based cohort in Singapore completed home-based sleep testing with a type 3 monitor. Subjects were asked to complete the STOP questionnaire while body mass index (BMI), age, neck circumference, and sex were recorded. A score of ≥3 on the questionnaire indicated high risk of OSA. RESULTS: A total of 68 subjects (28.1%) and 26 subjects (10.7%) had an apnea-hypopnea index (AHI) of ≥15 and ≥30 events per hour, respectively. Of the subjects, 89 (36.8%) were classified as high risk based on the questionnaire. The sensitivity of a STOP-Bang score of ≥3 was 66.2% to detect AHI ≥15 and 69.2% to detect AHI ≥30. The specificities were 74.7% and 67.1%, respectively. The negative predictive values were 85% for moderate-to-severe OSA and 94.8% for severe OSA. The corresponding positive predictive values were 50.6% and 20.2%, respectively. Using BMI cutoffs of 30 and 27.5 for Asians compared to the original cutoff of 35 did not improve the questionnaire performance significantly. CONCLUSION: The STOP-Bang questionnaire can be used as a screening tool in the general population in view of its moderate sensitivity and high negative predictive value for subjects with moderate-to-severe and severe OSA. The cutoff of BMI >35 can be used in Asians, as lower BMI cutoffs did not improve questionnaire performance.

SF1 immunohistochemistry is useful in differentiating uterine tumours resembling sex cord-stromal tumours from potential histological mimics.

The aim of this study was to perform an immunohistochemical comparison of uterine tumour resembling ovarian sex cord-stromal tumour (UTROSCT) and other uterine lesions with sex cord-like (SCL) differentiation. Six UTROSCTs and 10 potential histological mimics with focal SCL elements were examined, the latter comprising three endometrial stromal nodules, three low-grade endometrial stromal sarcomas, three Müllerian adenosarcomas, and one case of adenomyosis. All cases were stained immunohistochemically for SF1, FOXL2, calretinin and inhibin, and for the less specific markers smooth muscle actin, desmin, CD10, CD56, CD99, cytokeratin, oestrogen receptor and progesterone receptor. Three, four, six and three UTROSCT expressed SF1, FOXL2, calretinin and inhibin, respectively. However, calretinin staining was focal (≤50% cells positive) in five of the cases. Three potential histological mimics demonstrated calretinin, FOXL2 and/or inhibin staining but none was SF1 positive. Most cases in both groups expressed the less specific immunomarkers. SF1 and FOXL2 immunoreactivity in UTROSCT further supports the concept that these tumours demonstrate genuine sex cord-stromal differentiation. While calretinin was the most sensitive UTROSCT marker, staining was usually focal and expression was also seen in two of 10 potential histological mimics. SF1 staining was 100% specific for UTROSCT in this series but this finding should be confirmed in larger studies.

Morcellation of occult uterine malignancies: an Australian single institution retrospective study.

INTRODUCTION: Morcellation for tissue extraction during laparoscopic hysterectomy or myomectomy has recently been questioned because of the potential to spread occult uterine cancers. The Australian Therapeutic Goods Administration (TGA) issued a safety advisory in August 2014, estimating the risk of occult malignancy in the Australian population to be one in 1000 or lower, based on estimates from overseas studies in the absence of any local data. AIMS: The aim of this study was to determine the incidence of occult uterine malignancies in morcellated surgical specimens at St John of God Hospital in Perth, Western Australia. MATERIALS AND METHODS: All women who had a hysterectomy or myomectomy with morcellation of the surgical specimen for presumed benign uterine fibroids at our institution from 01 November 2009 to 12 March 2015 were identified and stratified into benign disease, uncertain malignant potential and malignant. RESULTS: Seven hundred and thirty-four women were included, and three malignancies were identified: two cases with leiomyosarcoma (LMS) and another with an endometrioid endometrial adenocarcinoma (EAC). One case of serous tubal in situ carcinoma (STIC) and two cases of benign metastasising leiomyoma/leiomyomatosis were also identified. The overall risk of malignancy in a morcellated surgical specimen was 0.41% (three in 734). The risk of morcellating an incidental uterine malignancy was 0.27% for LMS and 0.14% for EAC. All three incidental malignancies were diagnosed in premenopausal women. CONCLUSIONS: The risk of unintended morcellation of uterine malignancy in our study is higher than that estimated by the Australian TGA and highlights the urgent need for further studies in Australia.

Diffuse Malignant Peritoneal Mesothelioma Presenting with Psammomatous Calcification on a Cervical Smear.

BACKGROUND: Psammoma bodies in cervical smears are rare but may be associated with benign and malignant diseases of the female genital tract. CASE: A 52-year-old nulliparous woman presented with a 2-month history of intermittent vaginal spotting and post-coital bleeding. A cervical smear showed an inconclusive high-grade glandular lesion with psammomatous calcification. Previous cervical smears had been normal. This smear contained papillary tissue fragments, occasional spheres of gland-like cells and frequent psammoma bodies. The patient underwent a laparoscopic hysterectomy, bilateral salpingo-oophorectomy and omentectomy. The surface of the omentum and both ovaries contained psammoma bodies with groups of cells identical to those in the cervical smear. Within the omentum, there were invasive malignant epithelioid cells positive for CK7, CK5/6, calretinin, D2-40, WT-1, CK5/6, p16 and EMA. Desmin and PAX-8 immunostains were negative. There was also evidence of BRCA1-associated protein 1 (BAP1) dysfunction compatible with diffuse malignant peritoneal mesothelioma (DMPM). CONCLUSION: We describe the first reported case of DMPM presenting with an abnormal cervical smear, a rare but important differential diagnosis to consider in abnormal cervical smears showing psammomatous calcification.

Overcoming the barriers to diagnosis of Morquio A syndrome.

BACKGROUND: Morquio A syndrome is an autosomal recessive lysosomal storage disease often resulting in life-threatening complications. Early recognition and proficient diagnosis is imperative to facilitate prompt treatment and prevention of clinical complications. METHODS: Experts in Asia Pacific reviewed medical records focusing on presenting signs and symptoms leading to a diagnosis of Morquio A syndrome. RESULTS: Eighteen patients (77% female) had a mean (median; min, max) age of 77.1 (42.0; 0.0, 540.0) months at symptom onset, 78.9 (42.0; 4.5, 540.0) months at presentation and 113.8 (60.0; 7.0, 540.0) months at diagnosis. Orthopedic surgeons and pediatricians were most frequently consulted pre-diagnosis while clinical geneticists/metabolic specialists most frequently made the diagnosis. Delayed diagnoses were due to atypical symptoms for 5 patients (28%), while 4 patients (22%) experienced each of subtle symptoms, symptoms commonly associated with other diseases, or false-negative urine glycosaminoglycan analysis. Two patients (11%) each experienced overgrowth within the first year of life. Two patients with Morquio A syndrome (11%) were diagnosed with craniosynostosis and 1 (6%) for each of Legg-Calvé-Perthes disease, Leri-Weill syndrome, and pseudoachondroplasia. Early radiographic features of Morquio A syndrome led to more efficient diagnosis. CONCLUSIONS: Increased awareness of clinical symptomology overlapping with Morquio A syndrome is essential. Clinicians encountering patients with certain skeletal dysplasia should consider Morquio A syndrome in their differential diagnosis. Atypical or subtle symptoms should not eliminate Morquio A syndrome from the differential diagnosis, especially for patients who may have non-classical phenotype of Morquio A syndrome.

Deletion of bone-marrow-derived receptor for AGEs (RAGE) improves renal function in an experimental mouse model of diabetes.

AIMS/HYPOTHESIS: The AGEs and the receptor for AGEs (RAGE) are known contributors to diabetic complications. RAGE also has a physiological role in innate and adaptive immunity and is expressed on immune cells. The aim of this study was to determine whether deletion of RAGE from bone-marrow-derived cells influences the pathogenesis of experimental diabetic nephropathy. METHODS: Groups (n = 8/group) of lethally irradiated 8 week old wild-type (WT) mice were reconstituted with bone marrow from WT (WT → WT) or RAGE-deficient (RG) mice (RG → WT). Diabetes was induced using multiple low doses of streptozotocin after 8 weeks of bone marrow reconstitution and mice were followed for a further 24 weeks. RESULTS: Compared with diabetic WT mice reconstituted with WT bone marrow, diabetic WT mice reconstituted with RG bone marrow had lower urinary albumin excretion and podocyte loss, more normal creatinine clearance and less tubulo-interstitial injury and fibrosis. However, glomerular collagen IV deposition, glomerulosclerosis and cortical levels of TGF-ß were not different among diabetic mouse groups. The renal tubulo-interstitium of diabetic RG → WT mice also contained fewer infiltrating CD68(+) macrophages that were activated. Diabetic RG → WT mice had lower renal cortical concentrations of CC chemokine ligand 2 (CCL2), macrophage inhibitory factor (MIF) and IL-6 than diabetic WT → WT mice. Renal cortical RAGE ligands S100 calgranulin (S100A)8/9 and AGEs, but not high mobility box protein B-1 (HMGB-1) were also decreased in diabetic RG → WT compared with diabetic WT → WT mice. In vitro, bone-marrow-derived macrophages from WT but not RG mice stimulated collagen IV production in cultured proximal tubule cells. CONCLUSIONS/INTERPRETATION: These studies suggest that RAGE expression on haemopoietically derived immune cells contributes to the functional changes seen in diabetic nephropathy by promoting macrophage infiltration and renal tubulo-interstitial damage.

Prognostic implication of obstructive sleep apnea diagnosed by post-discharge sleep study in patients presenting with acute coronary syndrome.

OBJECTIVE: We aimed to determine the prognostic implications of obstructive sleep apnea (OSA) diagnosed during the recovery phase of acute coronary syndrome (ACS). METHODS: Patients presenting with ACS and treated with percutaneous coronary intervention were recruited prospectively for a home-based sleep study within 30 days of hospital discharge. Major adverse cardiac and cerebrovascular events (MACCEs) assessed included cardiac death, myocardial infarction, stroke, unplanned revascularization, and hospitalization for heart failure. RESULTS: Of the 85 patients recruited, 68 successfully completed the study. The median time from percutaneous coronary intervention to sleep study was 14 days (interquartile range: 7.5-27 days). OSA was diagnosed in 24 patients (35.3%) (apnea-hypopnea index > or =15). A drug-eluting stent was implanted into the target lesion in 45 patients (66.2%). None of the study patients had received treatment for OSA. At 24-month follow-up, the MACCE incidence was 34.9% in the OSA group and 5.1% in the non-OSA group (P=0.008, log-rank test). After adjusting for the possible confounding effect of age, gender, coronary intervention indications, hypertension, smoking, and body mass index, OSA remained an independent predictor of MACCEs (adjusted hazard ratio, 6.95; 95% confidence interval, 1.17-41.4; P=0.033). CONCLUSION: OSA diagnosed in patients treated with percutaneous coronary intervention for ACS by post-discharge sleep studies conducted 2 weeks after percutaneous coronary intervention was independently associated with MACCEs at 24-month follow-up.

Impact of a palliative care initiative on end-of-life care in the general wards: a before-and-after study.

BACKGROUND: Data on deaths in the general wards of our hospital in 2007 revealed infrequent discussions on end-of-life care and excessive burdensome interventions. AIM: A physician order form to withhold inappropriate life-sustaining interventions was initiated in 2009. The use of the form was facilitated by staff educational sessions and a palliative care consult service. This study aims to evaluate the impact of these interventions in 2010. DESIGN: Retrospective medical chart review with comparisons was made for the following: baseline patient characteristics, orders concerning life-sustaining therapies, treatment provided in last 24 h of life, and discussion of specific life-sustaining therapies with patients and families. SETTINGS/PARTICIPANTS: This study included all adult patients who died in our hospital's general wards in 2007 (N = 683) versus 2010 (N = 714). RESULTS: There was an increase in orders to withhold life-sustaining therapies, such as cardiopulmonary resuscitation (66.2%-80.0%). There was a decrease in burdensome interventions such as antibiotics (44.9%-24.9%) and a small increase in palliative treatments such as analgesia (29.1%-36.7%). There were more discussions on the role of cardiopulmonary resuscitation with conversant patients (4.6%-10.2%) and families (56.5%-79.8%) (p-value all < 0.05). On multivariate analysis, the physician order form independently predicted orders to withhold cardiopulmonary resuscitation. CONCLUSIONS: A multifaceted intervention of a physician order form, educational sessions, and palliative care consult service led to an improvement in documentation of end-of-life discussions and was associated with an increase in such discussions and less burdensome treatments. There were small improvements in the proportion of palliative treatments administered.