[Prevention and treatment of endometrial cancer].

Endometrial cancer is rising in incidence, especially in young women. This rise in incidence has implications for both primary prevention and screening in high-risk population. In the past several years, our understanding of the integration of clinically related genomic and pathologic data optimized the management of endometrial cancer. The updated 2023 FIGO staging includes the histological and molecular classification to better reflect the improved understanding of the heterogenous nature of endometrial carcinoma. Standard primary treatment is quite essential, however, selection of patients for adjuvant radiation or chemotherapy remains in controversy. Molecular characterization of endometrial cancer is becoming critical in directing treatment for advanced and recurrent disease, and the addition of immunotherapy to frontline chemotherapy is becoming the standard of care. More attention should be given to increase awareness of survivorship issues and improve patient quality-of-life.

Analysis of the Safety and Pregnancy Outcomes of Fertility-sparing Surgery in Ovarian Malignant Sex Cord-stromal Tumours: A Multicentre Retrospective Study.

AIMS: To assess the difference in survival between fertility-sparing surgery (FSS) and radical surgery and explore pregnancy outcomes after FSS in stage I malignant sex cord-stromal tumours (MSCSTs). MATERIALS AND METHODS: We carried out a multicentre retrospective cohort study on patients who were diagnosed with MSCSTs and the tumour was confined to one ovary. The patients were divided into FSS and radical surgery groups. Inverse probability of treatment weighting (IPTW) was used to balance variables between the two groups. Kaplan-Meier analysis was used to compare the difference in disease-free survival (DFS). Univariate and multivariate Cox regression analysis was used to find risk factors of DFS. Univariate logistic regression analysis was used to assess risk factors of pregnancy. RESULTS: In total, 107 patients were included, of whom 54 (50.5%) women underwent FSS and 53 (49.5%) received radical surgery. After IPTW, a pseudo-population of 208 was determined and all of the covariates were well balanced. After a median follow-up time of 50 months (range 7-156 months), 10 patients experienced recurrence and two died. There was no significant difference in DFS between the two groups, both in unweighted (P = 0.969) or weighted cohorts (P = 0.792). In the weighted cohort, stage IC (P = 0.014), tumour diameter >8 cm (P = 0.003), incomplete staging surgery (P = 0.003) and no adjuvant chemotherapy (P < 0.001) were the four high-risk factors associated with a shorter DFS. Among 14 patients who had pregnancy desire, 11 (78.6%) women conceived successfully; the live birth rate was 76.9%. In univariate analysis, only adjuvant chemotherapy (P = 0.009) was associated with infertility. CONCLUSIONS: On the premise of complete staging surgery, FSS is safe and feasible in early stage MSCSTs with satisfactory reproductive outcomes.

[Lithocholic acid decreases mRNA stability of nuclear receptor PPARα by upregulating miR-21 expression in hepatoma HepG2 cells].

OBJECTIVE: To investigate the regulatory effects of lithocholic acid (LCA) on nuclear receptor peroxisome proliferatoractivated receptor-alpha (PPARα) mRNA stability at the post-transcriptional level. METHODS: PPARα 3'UTR luciferase reporter gene vectors were constructed and transfected into HepG2 cells to observe the changes in cellular luciferase activity in response to LCA treatments. Bioinformatic prediction and miRNA PCR array technique were used to identify the differentially expressed miRNAs induced by LCA and their potential binding sites on the 3'UTR. The binding sites (Mut1, Mut2 and Mut1+Mut2) were mutated to compare the changes in cellular luciferase activity following LCA treatment. Western blotting and RTqPCR were used to detect the activated signaling pathway and the expression levels of its downstream transcription factors in LCA-treated cells. The changes in PPARα protein expression level were detected in the cells following overexpression of the transcription factors. RESULTS: Treatment with 100 µmol/L LCA significantly reduced luciferase activity of PPARα 3'UTR1 and 3'UTR2 in HepG2 cells by more than 50% (P<0.01) and induced significant upregulation of miR-21 and miR-22, especially the former (by 2.35 folds, P<0.05). Two predicted miR-21-binding sites in the 3'UTR1 were mutated to construct Mut1, Mut2 and Mut1+Mut2 reporter gene vectors. LCA treatment down-regulated 3'UTR1 luciferase activity by 51%, while Mut1, Mut2, and Mut1+Mut2 were down-regulated by 37%, 39%, and 13%, respectively. LCA caused ERK1/2 phosphorylation and activation of the ERK1/2 signaling pathway, and treatment with 100 µmol/L LCA upregulated the expression of transcription factor early growth response 1 (EGR1) by 5.83 folds (P<0.01). Transient overexpression of EGR1 significantly decreased cellular PPARα protein levels (P<0.05). CONCLUSION: LCA reduces PPARα mRNA stability and thus decreases PPARα mRNA and protein expressions in hepatocytes by activating the ERK1/2 signaling pathway and upregulating EGR1 and miR-21, which targets 3'UTR regulatory region of PPARα mRNA.

Niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using an individualized starting dose (NORA): a randomized, double-blind, placebo-controlled phase III trial☆.

BACKGROUND: This study evaluated maintenance treatment with niraparib, a potent inhibitor of poly(ADP-ribose) polymerase 1/2, in patients with platinum-sensitive recurrent ovarian cancer. PATIENTS AND METHODS: In this phase III, double-blind, placebo-controlled study conducted at 30 centers in China, adults with platinum-sensitive recurrent ovarian cancer who had responded to their most recent platinum-containing chemotherapy were randomized 2 : 1 to receive oral niraparib (300 mg/day) or matched placebo until disease progression or unacceptable toxicity (NCT03705156). Following a protocol amendment, patients with a bodyweight <77 kg or a platelet count <150 × 103/µl received 200 mg/day, and all other patients 300 mg/day, as an individualized starting dose (ISD). Randomization was carried out by an interactive web response system and stratified by BRCA mutation, time to recurrence following penultimate chemotherapy, and response to most recent chemotherapy. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review. RESULTS: Between 26 September 2017 and 2 February 2019, 265 patients were randomized to receive niraparib (n = 177) or placebo (n = 88); 249 patients received an ISD (300 mg, n = 14; 200 mg, n = 235) as per protocol. In the intention-to-treat population, median PFS was significantly longer for patients receiving niraparib versus placebo: 18.3 [95% confidence interval (CI), 10.9-not evaluable] versus 5.4 (95% CI, 3.7-5.7) months [hazard ratio (HR) = 0.32; 95% CI, 0.23-0.45; P < 0.0001], and a similar PFS benefit was observed in patients receiving an ISD, regardless of BRCA mutation status. Grade ≥3 treatment-emergent adverse events occurred in 50.8% and 19.3% of patients who received niraparib and placebo, respectively; the most common events were neutrophil count decreased (20.3% versus 8.0%) and anemia (14.7% versus 2.3%). CONCLUSIONS: Niraparib maintenance treatment reduced the risk of disease progression or death by 68% and prolonged PFS compared to placebo in patients with platinum-sensitive recurrent ovarian cancer. Individualized niraparib dosing is effective and safe and should be considered standard practice in this setting.

Cystatin C alleviates H2O2-induced H9c2 cell injury.

OBJECTIVE: At present, the incidence of acute myocardial infarction is increasing year by year, and it has become one of the diseases with the highest mortality rate in humans. Myocardial ischemia-reperfusion injury (MIRI) is a major problem in the treatment of myocardial infarction, but clinically there is no effective way to treat MIRI. This study used Cystatin C (Cys C) to treat cardiomyocytes and rats to investigate the effect of Cys C on MIRI. MATERIALS AND METHODS: We used H2O2 to induce rat cardiomyocytes (H9c2 cells) injury and stimulated the cells with Cys C. Cell counting kit 8 (CCK8) assay was used to determine the optimal concentration of H2O2 and Cys C to stimulate H9c2 cells. We determined the effects of Cys C on oxidative stress and apoptosis levels in H9c2 cells by measuring the activity of dehydrogenase (LDH), superoxide dismutase (SOD) and malondialdehyde (MDA), and the expression of apoptosis-related molecules (caspase3/8/9, Bax and Bcl-2). Changes in the activity of the NF-κB signaling pathway in H9c2 cells were also detected. In addition, we made rat MIRI models by ligating the coronary arteries and used Cys C to treat rats to verify the effect of Cys C on MIRI. RESULTS: According to the results of the CCK8 assay, 1000 µM of H2O2 and 15 µM of Cys C were used to stimulate H9c2 cells. Cys C alleviated H2O2-induced H9c2 cell injury, manifested as a decrease in LDH and MDA activity and an increase in SOD activity. Cys C also reduced the apoptosis level in H9c2 cells. The activity of NF-κB signaling pathway in injured H9c2 cells was increased, and stimulation of Cys C could inhibit the NF-κB signaling pathway in H9c2 cells. The application of Cys C in MIRI rats also verified its therapeutic effect on MIRI. CONCLUSIONS: Cys C reduced the oxidative stress and apoptosis levels of cardiomyocytes by inhibiting the activity of NF-κB signaling pathway in cardiomyocytes, thereby reducing cardiomyocyte injury and treating MIRI.

[Effects of Prrx2 gene silencing on the proliferation of breast cancer and its molecular mechanisms].

Objective: The aim of this study was to investigate the effects of silencing Paired related homoeobox 2 (Prrx2) expression on the proliferation of breast cancer and its molecular mechanisms. Methods: Short hairpin RNA knockdown of Prrx2 was used to examine cellular effects of Prrx2. The level of Prrx2 was verified by Western blot. MTT assay was used to analyze the proliferation of breast cancer cells in vitro. To investigate the effect of Prrx2 depletion on tumor growth in vivo, a nude mouse xenograft model was performed. Results: The expression of Prrx2 decreased 91.2% in MDA-MB-231 cells and 88.7% in MCF-7 cells after transfection with interfering vectors (P<0.05). MTT assay showed that the proliferation of cells in silenced Prrx2 expression group was significantly inhibited compared with the control group (P<0.05). Nude mice transplanted tumors showed that the growth of transplanted tumors was slow after silencing Prrx2 expression, and the weight of the tumors of silenced Prrx2 expression group were smaller than those of the control group ((160.2±26.3)mg vs (365.4±19.7)mg, P<0.05). Western blot showed that silencing Prrx2 expression inhibited the expression of ß-catenin in breast cancer cell nucleus and down-regulated the activity of Wnt/ß-catenin signaling pathway. Conclusions: Silencing Prrx2 expression can effectively inhibit the proliferation and growth of breast cancer, suggesting that Prrx2 may become a new target for the treatment of breast cancer.

MiR-9-5p could promote angiogenesis and radiosensitivity in cervical cancer by targeting SOCS5.

OBJECTIVE: The aim of this study was to investigate the molecular mechanism of miRNA-9-5p in cervical cancer. PATIENTS AND METHODS: The expression level of microRNA-9-5p (miR-9-5p) in cervical cancer (CC) tissues and cell lines was examined by quantitative Real Time-Polymerase Chain Reaction. Cells were transfected with Lipofectamine 3000. Cell proliferation was measured by Cell Counting Kit-8 (CCK-8). Invasion assays were performed in 24-well transwell chambers system with 8 µm pores. Cell invasion was evaluated by transwell assay. Western blot was used to detect the changes of epithelial-mesenchymal transition (EMT) and SOCS5. The effects of miR-9-5p on tubule formation were examined under different doses of γ radiation. Immunohistochemistry assay was used to analyze the protein expression of SOCS5. Fluorescence microscopy analysis was used to measure autophagosomes after cells treated with γ irradiation. RESULTS: From the Cancer Genome Atlas (TCGA) database, the expression of miR-9-5p was significantly higher in cervical cancer patients than in the negative ones, and it was verified in 22 paired of lymph node-positive patient tissues and negative. The overexpression of miR-9-5p promoted proliferation and invasion of cervical cancer cells in vitro and primary tumor growth in vivo. MiR-9-5p reduced the tubule generation after the radiation dose of 4Gy. Besides, we identified SOCS5 as the target of miR-9-5p, and the overexpression of SOCS5 could inhibit miR-9-5p mimics from promoting tubule formation. CONCLUSIONS: MiR-9-5p could promote proliferation and invasion of CC cells in vitro and in vivo. MiR-9-5p could affect angiogenesis and radiosensitivity of CC cells by targeting SOCS5.

Cloning, overexpression, purification, and modeling of a lectin (Rhinocelectin) with antiproliferative activity from Tiger Milk Mushroom, Lignosus rhinocerus.

A lectin gene from the Tiger Milk Mushroom Lignosus rhinocerus TM02® was successfully cloned and expressed via vector pET28a in Escherichia coli BL21(DE3). The recombinant lectin, Rhinocelectin, with a predicted molecular mass of 22.8 kDa, was overexpressed in water-soluble form without signal peptide and purified via native affinity chromatography Ni-NTA agarose. Blast protein analysis indicated the lectin to be homologous to jacalin-related plant lectin. In its native form, Rhinocelectin exists as a homo-tetramer predicted with four chains of identical proteins consisting of 11 beta-sheet structures with only one alpha-helix structure. The antiproliferative activity of the Rhinocelectin against human cancer cell lines was concentration dependent and selective. The IC50 values against triple negative breast cancer cell lines MDA-MB-231 and breast cancer MCF-7 are 36.52 ± 13.55 µg mL-1 and 53.11 ± 22.30 µg mL-1 , respectively. Rhinocelectin is only mildly cytotoxic against the corresponding human nontumorigenic breast cell line 184B5 with IC50 value at 142.19 ± 36.34 µg mL-1 . The IC50 against human lung cancer cell line A549 cells is 46.14 ± 7.42 µg mL-1 while against nontumorigenic lung cell line NL20 is 41.33 ± 7.43 µg mL-1 . The standard anticancer drug, Doxorubicin exhibited IC50 values mostly below 1 µg mL-1 for the cell lines tested. Flow cytometry analysis showed the treated breast cancer cells were arrested at G0/G1 phase and apoptosis induced. Rhinocelectin agglutinated rat and rabbit erythrocytes at a minimal concentration of 3.125 µg mL-1 and 6.250 µg mL-1 , respectively.

Left atrial appendage mass.

Left atrial (LA) masses are known to be associated with peripheral embolization. Accurate identification of etiology is crucial because treatment strategies may differ. We present the case of a young woman, who was initially diagnosed with a LA thrombus and anticoagulated. The diagnosis was revised to a primary cardiac tumor after review of the echocardiographic findings. Surgical excision revealed an atrial myxoma in an unusual location.

Rapid rise in the incidence and clinical characteristics of pediatric inflammatory bowel disease in a South-East Asian cohort in Singapore, 1994-2015.

OBJECTIVES: Epidemiological studies on pediatric-onset inflammatory bowel disease (PIBD) are scarce in South-East Asia (SEA). This study aimed to evaluate the incidence trend and clinical characteristics of PIBD in a SEA cohort in Singapore over 22 years (1994-2015). METHODS: Case records of PIBD ≤18 years from the only two tertiary pediatric hospitals in Singapore were reviewed. The mean annual incidence (MAI) of PIBD was calculated based on Singapore's age-specific population data. RESULTS: Overall MAI of PIBD was 1.26 per 100 000 (95% confidence interval [CI] 0.56-1.96). During the first decade (1994-2004) MAI was 0.23 per 100 000 (95% CI 0.08-0.39); this rose almost 10-fold to 2.28 per 100 000 (95% CI 1.15-3.41) during the second decade (2005-2015). Linear regression analysis showed significant increase in MAI over the 22-year period (r = 0.826, P < 0001). Of the 228 patients, 61.0% had Crohn's disease (CD), 30.3% ulcerative colitis and 8.7% IBD-unclassified, with a mdian age at diagnosis of 10.47 years and a male predominance (58.3%); 37.7% of them aged <10 years at diagnosis and 17.5% were very early-onset IBD. In CD, 27.3% had stricturing and/or penetrating disease and 21.6% were with perianal disease. Indians had a disproportionately high representation while positive family history was rare (1.3%). CONCLUSIONS: Although PIBD is uncommon in Singapore, its incidence has risen dramatically over recent decades. A younger age of disease onset and higher proportions of perianal and stricturing/penetrating diseases suggest more aggressive disease than in Western data.

Identification of mitochondrial hormone receptors in avian muscle cells.

The major objective of this study was to assess the expression of mitochondrial hormone receptors for progesterone (PR), estrogen (ER), glucocorticoid (GR), thyroid (TR), and insulin (IR) in avian muscle cells (quail muscle 7, QM7) and in breast muscle of quail and broilers. Visualization of receptor location in QM7 cells was accomplished by immunofluorescence. QM7 cells were stained with Mito Tracker Deep Red CMX, fixed in methanol, immune stained with anti-PR, -GR, -TR, -IR, and -ER primary antibodies overnight at 4°C, and visualized with Alexa Fluor 488-conjugated secondary antibody. After staining the nucleus with 4',6-diamidino-2-phenylindole, images were obtained by immunofluorescence microscopy. Merged images revealed the presence of all 5 hormone receptors on mitochondria in QM7 cells. Western blot analysis identified; (a) the ß-isoform of the PR, (b) the α-isoform of GR, (c) the α-receptor of TR, (d) the ß-subunit of IR, and (e) the α-isoform of the ER on mitochondria isolated from broiler breast muscle. Similar results were obtained in quail breast muscle mitochondria with the exception that the α-isoform of the GR was not detected. To our knowledge, this is the first report of hormone receptors (PR, TR, GR, IR, and ER) on mitochondria in avian cells. We hypothesize that these receptors could play important roles in regulating mitochondrial function in avian muscle cells.

KrasG12D-LOH promotes malignant biological behavior and energy metabolism of pancreatic ductal adenocarcinoma cells through the mTOR signaling pathway.

Oncogenic Kras with loss of heterozygosity (LOH) is frequently detected in various tumours. However, the exact function and mechanism by which KrasG12D-LOH operates remain unclear. Therefore, the current study investigated the effect of KrasG12D-LOH on the malignant phenotype of pancreatic ductal adenocarcinoma (PDAC) cells. Our investigation revealed that KrasG12D-LOH is associated with increased proliferation, invasion and reduced apoptosis in PDAC cells. The results also exhibited enhanced glycolytic phenotype of KrasG12D-LOH PDAC cells. Hyperactive mTOR plays a significant role in the initiation and maintenance of tumors. To investigate the correlation between KrasG12D-LOH and mTOR, the mTOR signaling pathway was detected by western blot analysis. We found that KrasG12D-LOH up-regulated Akt, AMPK, REDD1 and mTOR in PDAC cells. In summary, our results demonstrated that KrasG12D-LOH promotes oncogenic Kras-induced PDAC by regulating energy metabolism and mTOR signaling pathway. These data may provide novel therapeutic perspectives for PDAC.

[DNA methylation modification of BRMS1 in triple-negative breast cancer and its correlation with tumor metastasis].

Objective: To investigate the effect of methylation status of breast cancer metastasis suppressor gene 1 (BRMS1) on the expression of breast cancer and the biological behavior of cancer cells in triple-negative breast cancer (TNBC). Methods: The expression of BRMS1 in TNBC tissues and corresponding non-malignant tissues and its relationship with clinicopathological parameters were detected by immunohistochemistry. The mRNA and protein expression of BRMS1 in normal breast epithelial cells and TNBC cells were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The methylation specific polymerase chain reaction (MSP) was used to detect the methylation status of BRMS1 in each cell. These cells were treated with demethylated preparations (5-Aza-dC) to re-activate BRMS1 expression. Using tumor cell invasion assay to detect influence of BRMS1 demethylation on the invasion capacity of cancer cells. The data were statistically analyzed. Results: The positive expression rate of BRMS1 protein in TNBC tissues was significantly lower than that in corresponding non-malignant tissues (χ(2)= 6.635, P<0.05). The mRNA expression level of BRMS1 in patients with lymph node metastasis was significantly lower than those with no lymph node metastasis (P=0.018). The down-regulation of BRMS1 expression was related to the methylation of DNA promoter, which was statistically significant (χ(2)=14.68, P<0.05). The mRNA and protein expression of BRMS1 was also correlated with tumor size and TNM staging (P=0.000-0.003). After using 5-Aza-dC, the number of cells with invasive capacity was significantly lower than those of the control group (t=3.262-10.72, P<0.05). Conclusions: The decrease of BRMS1 expression in TNBC cells is related to the methylation of DNA. Demethylation can inhibit the invasion of breast cancer cells.

Enhanced expression of proteins involved in energy production and transfer in breast muscle of pedigree male broilers exhibiting high feed efficiency.

In cells with fluctuating energy demand (e.g., skeletal muscle), a transfer system of proteins across the inner and outer mitochondrial membranes links mitochondrial oxidative phosphorylation to cytosolic phosphorylated creatine (PCr) that serves as a phosphate reservoir for rapid repletion of cytosolic adenosine triphosphate (ATP). Crucial proteins of this energy transfer system include several creatine kinase (CK) isoforms found in the cytosol and mitochondria. In a recent proteomic study (Kong et al., 2016), several components of this system were up-regulated in high feed efficiency (FE) compared to low FE breast muscle; notably adenine nucleotide translocase (ANT), voltage dependent activated channel (VDAC), the brain isoform of creatine kinase (CK-B), and several proteins of the electron transport chain. Reexamination of the original proteomic dataset revealed that the expression of two mitochondrial CK isoforms (CKMT1A and CKMT2) had been detected but were not recognized by the bioinformatics program used by Kong et al. (2016a). The CKMT1A isoform was up-regulated (7.8-fold, P = 0.05) in the high FE phenotype but there was no difference in CKMT2 expression (1.1-fold, P = 0.59). From these findings, we hypothesize that enhanced expression of the energy production and transfer system in breast muscle of the high FE pedigree broiler male could be fundamentally important in the phenotypic expression of feed efficiency.

A systems approach identifies time-dependent associations of multimorbidities with pancreatic cancer risk.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed in late adulthood; therefore, many patients suffer or have suffered from other diseases. Identifying disease patterns associated with PDAC risk may enable a better characterization of high-risk patients. METHODS: Multimorbidity patterns (MPs) were assessed from 17 self-reported conditions using hierarchical clustering, principal component, and factor analyses in 1705 PDAC cases and 1084 controls from a European population. Their association with PDAC was evaluated using adjusted logistic regression models. Time since diagnosis of morbidities to PDAC diagnosis/recruitment was stratified into recent (<3 years) and long term (≥3 years). The MPs and PDAC genetic networks were explored with DisGeNET bioinformatics-tool which focuses on gene-diseases associations available in curated databases. RESULTS: Three MPs were observed: gastric (heartburn, acid regurgitation, Helicobacter pylori infection, and ulcer), metabolic syndrome (obesity, type-2 diabetes, hypercholesterolemia, and hypertension), and atopic (nasal allergies, skin allergies, and asthma). Strong associations with PDAC were observed for ≥2 recently diagnosed gastric conditions [odds ratio (OR), 6.13; 95% confidence interval CI 3.01-12.5)] and for ≥3 recently diagnosed metabolic syndrome conditions (OR, 1.61; 95% CI 1.11-2.35). Atopic conditions were negatively associated with PDAC (high adherence score OR for tertile III, 0.45; 95% CI, 0.36-0.55). Combining type-2 diabetes with gastric MP resulted in higher PDAC risk for recent (OR, 7.89; 95% CI 3.9-16.1) and long-term diagnosed conditions (OR, 1.86; 95% CI 1.29-2.67). A common genetic basis between MPs and PDAC was observed in the bioinformatics analysis. CONCLUSIONS: Specific multimorbidities aggregate and associate with PDAC in a time-dependent manner. A better characterization of a high-risk population for PDAC may help in the early diagnosis of this cancer. The common genetic basis between MP and PDAC points to a mechanistic link between these conditions.

In vivo functional dissection of a context-dependent role for Hif1α in pancreatic tumorigenesis.

Hypoxia-inducible factor 1α (Hif1α) is a key regulator of cellular adaptation and survival under hypoxic conditions. In pancreatic ductal adenocarcinoma (PDAC), it has been recently shown that genetic ablation of Hif1α accelerates tumour development by promoting tumour-supportive inflammation in mice, questioning its role as the key downstream target of many oncogenic signals of PDAC. Likely, Hif1α has a context-dependent role in pancreatic tumorigenesis. To further analyse this, murine PDAC cell lines with reduced Hif1α expression were generated using shRNA transfection. Cells were transplanted into wild-type mice through orthotopic or portal vein injection in order to test the in vivo function of Hif1α in two major tumour-associated biological scenarios: primary tumour growth and remote colonization/metastasis. Although Hif1α protects PDAC cells from stress-induced cell deaths in both scenarios-in line with the general function Hif1α-its depletion leads to different oncogenic consequences. Hif1α depletion results in rapid tumour growth with marked hypoxia-induced cell death, which potentially leads to a persistent tumour-sustaining inflammatory response. However, it simultaneously reduces tumour colonization and hepatic metastases by increasing the susceptibility to anoikis induced by anchorage-independent conditions. Taken together, the role of Hif1α in pancreatic tumorigenesis is context-dependent. Clinical trials of Hif1α inhibitors need to take this into account, targeting the appropriate scenario, for example palliative vs adjuvant therapy.

Suprascapular neuropathy in massive rotator cuff tears with severe fatty degeneration in the infraspinatus muscle.

AIMS: Our aim was to describe the atypical pattern of increased fatty degeneration in the infraspinatus muscle compared with the supraspinatus in patients with a massive rotator cuff tear. We also wished to describe the nerve conduction and electromyography findings in these patients. PATIENTS AND METHODS: A cohort of patients undergoing surgery for a massive rotator cuff tear was identified and their clinical records obtained. Their MRI images were reviewed to ascertain the degree of retraction of the torn infraspinatus and supraspinatus muscles, and the degree of fatty degeneration in both muscles was recorded. Nerve conduction studies were also performed in those patients who showed more degeneration in the infraspinatus than in the supraspinatus. RESULTS: Out of a total of 396 patients who underwent surgery for a massive rotator cuff tear between 2006 and 2015, 35 who had more severe fatty degeneration in the infraspinatus than in the supraspinatus were identified. There were 13 men and 22 women. Their mean age was 67.2 years (56 to 81). A total of 20 (57%) had grade 4 fatty degeneration as classified by Fuchs et al, in the infraspinatus. Patte grade 3 muscle retraction was seen in 25 patients (71%). In all, eight patients (23%) had abnormal nerve conduction studies. The mean retraction of the infraspinatus was 3.6 cm (2.1 to 4.8) in patients with more severe fatty degeneration in the infraspinatus, versus 3.0 cm (1.7 to 5.5) in those with more severe degeneration in the supraspinatus (p = 0.003). The retraction ratios were 0.98 (0.61 to 1.57) and 0.77 (0.38 to 1.92), respectively (p < 0.001). CONCLUSION: Fatty degeneration affecting the infraspinatus more than the supraspinatus may be, in the context of a massive rotator cuff tear, due to entrapment of the suprascapular nerve at the spinoglenoid notch. Cite this article: Bone Joint J 2016;98-B:1505-9.

Activity and safety of radiotherapy with anti-PD-1 drug therapy in patients with metastatic melanoma.

The anti-PD-1 antibodies nivolumab and pembrolizumab are active in metastatic melanoma; however, there is limited data on combining anti-PD-1 antibody and radiotherapy (RT). We sought to review clinical outcomes of patients receiving RT and anti-PD-1 therapy. All patients receiving anti-PD-1 antibody and RT for metastatic melanoma were identified. RT and systemic treatment, clinical outcome, and toxicity data were collected. Fifty-three patients were included; 35 patients received extracranial RT and/or intracranial stereotactic radiosurgery (SRS) and 21 received whole brain radiotherapy (WBRT) (three of whom also received SRS/extracranial RT). Patients treated with extracranial RT or SRS received treatment either sequentially (RT then anti-PD-1, n = 11), concurrently (n = 16), or concurrent "salvage" treatment to lesions progressing on anti-PD-1 therapy (n = 15). There was no excessive anti-PD-1 or RT toxicity observed in patients receiving extracranial RT. Of six patients receiving SRS, one patient developed grade 3 radiation necrosis. In 21 patients receiving WBRT, one patient developed Stevens-Johnson syndrome, one patient developed acute neurocognitive decline, and one patient developed significant cerebral edema in the setting of disease. Response in irradiated extracranial/intracranial SRS lesions was 44% for sequential treatment and 64% for concurrent treatment (p=0.448). Likewise there was no significant difference between sequential or concurrent treatment in lesional response of non-irradiated lesions. For progressing lesions subsequently irradiated, response rate was 45%. RT and anti-PD-1 antibodies can be safely combined, with no detectable excess toxicity in extracranial sites. WBRT and anti-PD-1 therapy is well tolerated, although there are rare toxicities and the role of either anti-PD-1 or WBRT in the etiology of these is uncertain.