Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2- breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2.

BACKGROUND: Acquired ESR1 mutations in estrogen receptor-positive (ER+) metastatic breast cancer (mBC) drive treatment resistance and tumor progression; new treatment strategies are needed. Lasofoxifene, a next-generation, oral, endocrine therapy and tissue-specific ER antagonist, provided preclinical antitumor activity, alone or combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in ESR1-mutated mBC. PATIENTS AND METHODS: In the open-label, phase II, ELAINE 2 trial (NCT04432454), women with ESR1-mutated, ER+/human epidermal growth factor receptor 2-negative (HER2-) mBC who progressed on prior therapies (including CDK4/6i) received lasofoxifene 5 mg/day and abemaciclib 150 mg b.i.d until disease progression/toxicity. The primary endpoint was safety/tolerability. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), and objective response rate (ORR). RESULTS: Twenty-nine women (median age 60 years) participated; all but one were previously treated with a CDK4/6i (median duration 2 years). The lasofoxifene-abemaciclib combination was well tolerated with primarily grade 1/2 treatment-emergent adverse events (TEAEs), most commonly diarrhea, nausea, fatigue, and vomiting. One patient (with no prior CDK4/6i) discontinued treatment due to grade 2 diarrhea. No deaths occurred during the study. Median PFS was 56.0 weeks [95% confidence interval (CI) 31.9 weeks-not estimable; ∼13 months]; PFS rates at 6, 12, and 18 months were 76.1%, 56.1%, and 38.8%, respectively. CBR at 24 weeks was 65.5% (95% CI 47.3% to 80.1%). In 18 patients with measurable lesions, ORR was 55.6% (95% CI 33.7% to 75.4%). ESR1-mutant circulating tumor DNA (ctDNA) allele fraction decreased from baseline to week 4 in 21/26 (80.8%) patients. CONCLUSIONS: Lasofoxifene plus abemaciclib had an acceptable safety profile, was well tolerated, and exhibited meaningful antitumor activity in women with ESR1-mutated, ER+/HER2- mBC after disease progression on prior CDK4/6i. Observed decreases in ESR1-mutant ctDNA with lasofoxifene concordant with clinical response suggest target engagement. If the ELAINE 2 findings are confirmed in the initiated, phase III, ELAINE 3 trial, these data could be practice-changing and help address a critical unmet need.

A review of cinnabar (HgS) and/or realgar (As4S4)-containing traditional medicines.

ETHNOPHARMOCOLOGICAL RELEVANCE: Herbo-metallic preparations have a long history in the treatment of diseases, and are still used today for refractory diseases, as adjuncts to standard therapy, or for economic reasons in developing countries. AIM OF THE REVIEW: This review uses cinnabar (HgS) and realgar (As4S4) as mineral examples to discuss their occurrence, therapeutic use, pharmacology, toxicity in traditional medicine mixtures, and research perspectives. MATERIALS AND METHODS: A literature search on cinnabar and realgar from PubMed, Chinese pharmacopeia, Google and other sources was carried out. Traditional medicines containing both cinnabar and realgar (An-Gong-Niu-Huang Wan, Hua-Feng-Dan); mainly cinnabar (Zhu-Sha-An-Shen Wan; Zuotai and Dangzuo), and mainly realgar (Huang-Dai Pian; Liu-Shen Wan; Niu-Huang-Jie-Du) are discussed. RESULTS: Both cinnabar and realgar used in traditional medicines are subjected to special preparation procedures to remove impurities. Metals in these traditional medicines are in the sulfide forms which are different from environmental mercurials (HgCl2, MeHg) or arsenicals (NaAsO2, NaH2AsO4). Cinnabar and/or realgar are seldom used alone, but rather as mixtures with herbs and/or animal products in traditional medicines. Advanced technologies are now used to characterize these preparations. The bioaccessibility, absorption, distribution, metabolism and elimination of these herbo-metallic preparations are different from environmental metals. The rationale of including metals in traditional remedies and their interactions with drugs need to be justified. At higher therapeutic doses, balance of the benefits and risks is critical. Surveillance of patients using these herbo-metallic preparations is desired. CONCLUSION: Chemical forms of mercury and arsenic are a major determinant of their disposition, efficacy and toxicity, and the use of total Hg and As alone for risk assessment of metals in traditional medicines is insufficient.

Retrospective review of Surgical Availability and Readiness in 8 African countries.

OBJECTIVES: The purpose of this study was to assess surgical availability and readiness in 8 African countries using the WHO's Service Availability and Readiness Assessment (SARA) tool. SETTING: We analysed data for surgical services, including basic and comprehensive surgery, comprehensive obstetric care, blood transfusion, and infection prevention, obtained from the WHO's SARA surveys in Sierra Leone, Uganda, Mauritania, Benin, Zambia, Burkina Faso, Democratic Republic of Congo and Togo. PRIMARY AND SECONDARY OUTCOME MEASURES: Among the facilities that were expected to offer surgical services (N=3492), there were wide disparities between the countries in the number of facilities per 100 000 population that reported offering basic surgery (1.0-12.1), comprehensive surgery (0.1-0.8), comprehensive obstetric care (0.1-0.8) and blood transfusion (0.1-0.8). Only 0.1-0.3 facilities per 100 000 population had all three bellwether procedures available, namely laparotomy, open fracture management and caesarean section. In all the countries, the facilities that reported offering surgical services generally had a shortage of the necessary items for offering the services and this varied greatly between the countries, with the facilities having on average 27-53% of the items necessary for offering basic surgery, 56-83% for comprehensive surgery, 49-72% for comprehensive obstetric care and 54-80% for blood transfusion. Furthermore, few facilities had all the necessary items present. However, facilities that reported offering surgical services had on average most of the necessary items for the prevention of infection. CONCLUSIONS: There are important gaps in the surgical services in the 8 African countries surveyed. Efforts are therefore urgently needed to address deficiencies in the availability and readiness to deliver surgical services in these nations, and this will require commitment from multiple stakeholders. SARA may be used to monitor availability and readiness at regular intervals, which will enable stakeholders to evaluate progress and identify gaps and areas for improvement.

Human pregnane X receptor compromises the function of p53 and promotes malignant transformation.

The pregnane X receptor (PXR) is well established as a nuclear receptor that has a central role in xenobiotic metabolism and disposition. However, emerging evidence suggests that PXR is also a regulator of apoptosis, promoting a malignant phenotype both in vitro and in vivo. The tumor suppressor p53 can be activated in the presence of DNA damage and induce cell cycle arrest to allow for DNA repair or, ultimately, apoptosis to suppress tumor formation. We previously identified p53 as a novel PXR-associated protein by using a mass spectrometric approach. In the current study, we identified a novel inhibitory effect of PXR on p53, revealing an anti-apoptotic function of PXR in colon carcinogenesis. PXR expression reduced p53 transactivation and the expression of its downstream target genes involved in cell cycle arrest and apoptosis by decreasing p53 recruitment to the promoter regions of these genes. Consistent with the inhibitory effect of PXR on p53, elevated PXR levels decreased doxorubicin- or nutlin-3a-mediated toxicity and promoted malignant transformation in colon cancer cells. Our findings show for the first time that PXR expression modulates p53 target gene promoter binding and contributes to the downregulation of p53 function in human colon cancer cells. These results define the functional significance of PXR expression in modulating p53-mediated mechanisms of tumor suppression.

Basal and copper-induced expression of metallothionein isoform 1,2 and 3 genes in epithelial cancer cells: The role of tumor suppressor p53.

Metallothioneins (MTs) are a ubiquitous low-molecular weight, cysteine rich proteins with a high affinity for metal ions. The expression and induction of MTs have been associated with protection against DNA damage, oxidative stress, and apoptosis. Our past research had shown that p53 is an important factor in metal regulation of MTs. The present study was undertaken to explore further the interrelationship between p53 and MTs. We investigated whether silencing of p53 could affect expression pattern of basal and copper induced metallothioneins. The silencing of wild-type p53 (wt-p53) in epithelial breast cancer MCF7 cells affected the basal level of MT-2A RNA, whereas the levels of MT-1A and MT-1X RNA remained largely unchanged. The expression of MT-3 was undetectable in MCF7 with either functional or silenced p53. MCF7 cells with silenced wt-p53 failed to upregulate MT-2A in response to copper and showed a reduced sensitivity toward copper induced cell apoptotic death. Similarly in MCF7-E6 and MDA-MB-231 cells, the presence of inactive/mutated p53 halted MT-1A and MT-2A gene expression in response to copper. Constitutive expression of MT-3 RNA was detectable in the presence of mutated p53 (mtp53). Transient transfection of MDA-MB-231 cells with wt-p53 enabled copper induced upregulation of both MT-1A and MT-2A but not basal level of MT-2A, MT-1E, MT-1X and MT-3. Inactivation of p53 in HepG2 cells amplified the basal expression of studied MT isoforms, including MT-3, as well as copper-induced mRNA expression of MTs except MT-1H and MT-3. Presented data demonstrate a direct relation between p53 and MT-1A and MT-2A and they also indicate that wt-p53 might be a negative regulator of MT-3 in epithelial cancer cells.

Placental involvement by non-Hodgkin lymphoma in a Crohn disease patient on long-term thiopurine therapy.

We report the first published case of aggressive diffuse large B-cell (non-Hodgkin) lymphoma in a 35-year-old pregnant woman who had Crohn disease and was taking long-term thiopurine therapy: the patient developed placental insufficiency, and there was intrauterine fetal death.

Deficiencies in the availability of essential musculoskeletal surgical services at 883 health facilities in 24 low- and lower-middle-income countries.

BACKGROUND: The sequelae of acute musculoskeletal conditions, especially injuries and infections, are responsible for significant disability in low- and middle-income countries. This study characterizes the availability of selected musculoskeletal surgical services at different tiers of the health system in a convenience sample of 883 health facilities from 24 low- and lower-middle-income countries. METHODS: Selected data points from the World Health Organization's (WHO) tool of situational analysis of surgical availability were extracted from the WHO's database in December, 2013. These included infrastructure, physical resources and supplies, interventions, and human resources. For a descriptive analysis, facilities were divided into two groups based on number of beds (<100, 100-300, and >300) and level of facility (primary referral, secondary/tertiary, and Private/NGO/Mission). Statistical comparison was made between public and Private/NGO/Mission facilities based on number of beds (≤100, 100-300, and >300) using a Chi-Square analysis, with statistical significance at p < 0.05. FINDINGS: Significant deficiencies were noted in infrastructure, physical resources and supplies, and human resources for the provision of essential orthopedic surgical services at all tiers of the health system. Availability was significantly lower in public versus Private/NGO/Mission facilities for nearly all categories in facilities with ≤100 beds, and in a subset of measures in facilities with between 100 and 300 beds. INTERPRETATION: Deficiencies in the availability of orthopedic surgical services were observed at all levels of health facility and were most pronounced at facilities with ≤100 beds in the public sector. Strengthening the delivery of essential surgical services, including orthopedics, at the primary referral level must be prioritized if we are to reduce the burden of death and disability from a variety of emergent health conditions. FUNDING: There were no sources of funding.

Two rare cases of Epstein-Barr virus-associated lymphoproliferative disorders in inflammatory bowel disease patients on thiopurines and other immunosuppressive medications.

The setting of chronic immunosuppression in inflammatory bowel disease (IBD) may promote the proliferation of Epstein-Barr virus-positive neoplastic clones. We report two rare cases of Epstein-Barr virus-associated lymphoproliferative disorder in IBD patients: one resembled lymphomatoid granulomatosis, and the other was a lymphoma resembling Hodgkin lymphoma. There are currently no guidelines for the prevention of lymphoproliferative disorder in IBD patients on immunosuppressive therapy.

Emergency and surgery services of primary hospitals in the United Republic of Tanzania.

OBJECTIVE: The primary objective was to evaluate the capacity of first-referral health facilities in Tanzania to perform basic surgical procedures. The intent was to assist in planning strategies for universal access to life-saving and disability-preventing surgical services. DESIGN: Cross-sectional survey. SETTING: First-referral health facilities in the United Republic of Tanzania. PARTICIPANTS: 48 health facilities. MEASURES: The WHO Tool for Situational Analysis to Assess Emergency and Essential Surgical Care was employed to capture a health facility's capacity to perform basic surgical (including obstetrics and trauma) and anaesthesia interventions by investigating four categories of data: infrastructure, human resources, interventions available and equipment. The tool queried the availability of eight types of care providers, 35 surgical interventions and 67 items of equipment. RESULTS: The 48 facilities surveyed served 18.6 million residents (46% of the population). Supplies for basic airway management were inconsistently available. Only 42% had consistent access to oxygen, and only six functioning pulse oximeters were located in all facilities surveyed. 37.5% of facilities reported both consistent running water and electricity. While very basic interventions (suturing, wound debridement, incision and drainage) were provided in nearly all facilities, more advanced life-saving procedures including chest tube thoracostomy (30/48), open fracture management (29/48) and caesarean section delivery (32/48) were not consistently available. CONCLUSIONS: Based on the results in this WHO country survey, significant gaps exist in the capacity for emergency and essential surgical services in Tanzania including deficits in human resources, essential equipment and infrastructure. The information in this survey will provide a foundation for evidence-based decisions in country-level policy regarding the allocation of resources and provision of emergency and essential surgical services.

Outcomes of Endovascular Coiling in Patients with Intracranial Aneurysms Presenting with Poor Clinical and SAH Grade.

Although the treatment of intracranial aneurysms has made significant advances, prediction of outcomes in poor grades has always been difficult. We present our findings of patients in poor clinical and SAH grade treated with endovascular coiling. We aimed to evaluate the clinical outcomes in patients presenting with poorer neurological and SAH grades treated by endovascular techniques. Of 190 patients who presented with SAH over a period of nine years, 34 were of poorer clinical grade (Hunt & Hess Grades 4 and 5), of whom 30 presented with H&H grade 4 and four with grade 5. 44.1% of the 34 patients belonged to Fischer grade 4. We assessed the technical success and final outcomes based on the Glasgow outcome scale. Of the 30 patients with grade 4, 81.4% had a good outcome. Two out of four patients with grade 5 had a poor outcome. 82.5% of the patients with Fischer grade 4 had a good outcome. None of the poor outcomes were procedure-related. Endovascular treatment with its higher rates of technical success, lower complication rates and better outcomes should be recommended as the treatment of choice in patients with intracranial aneurysms even in patients with poorer clinical and SAH grades.

Oxygen is an essential medicine: a call for international action.

Hypoxaemia is commonly associated with mortality in developing countries, yet feasible and cost-effective ways to address hypoxaemia receive little or no attention in current global health strategies. Oxygen treatment has been used in medicine for almost 100 years, but in developing countries most seriously ill newborns, children and adults do not have access to oxygen or the simple test that can detect hypoxaemia. Improving access to oxygen and pulse oximetry has demonstrated a reduction in mortality from childhood pneumonia by up to 35% in high-burden child pneumonia settings. The cost-effectiveness of an oxygen systems strategy compares favourably with other higher profile child survival interventions, such as new vaccines. In addition to its use in treating acute respiratory illness, oxygen treatment is required for the optimal management of many other conditions in adults and children, and is essential for safe surgery, anaesthesia and obstetric care. Oxygen concentrators provide the most consistent and least expensive source of oxygen in health facilities where power supplies are reliable. Oxygen concentrators are sustainable in developing country settings if a systematic approach involving nurses, doctors, technicians and administrators is adopted. Improving oxygen systems is an entry point for improving the quality of care. For these broad reasons, and for its vital importance in reducing deaths due to lung disease in 2010: Year of the Lung, oxygen deserves a higher priority on the global health agenda.

An unusual case of coil migration. A case report.

Migration of endovascular coils from aneurysms has been reported in the past. However, we report a case where the entire coil mass migrated out of the aneurysm into the anterior cerebral artery with associated doubling of aneurysm diameter in the intervening two weeks period post-coiling.

Wnt pathway aberrations including autocrine Wnt activation occur at high frequency in human non-small-cell lung carcinoma.

Lung cancer is the most common cause of cancer mortality worldwide. Non-small-cell lung carcinomas (NSCLCs), which represent around 80% of lung tumors, exhibit poor prognosis and are usually refractory to conventional chemotherapy. Elucidating the molecular and cellular mechanisms that are dysregulated in NSCLCs may lead to new possibilities for targeted therapy or enhanced efficacy of current therapies. Here we demonstrate Wnt pathway activation in around 50% of human NSCLC cell lines and primary tumors, through different mechanisms, including autocrine Wnt pathway activation involving upregulation of specific Wnt ligands. Downregulation of activated Wnt signaling inhibited NSCLC proliferation and induced a more differentiated phenotype. Together, our findings establish importance of activated Wnt signaling in human NSCLCs and offer the possibility of targeting upregulated Wnt signaling as a new therapeutic modality for this disease.

Expression of functional metallothionein isoforms in papillary thyroid cancer.

Metallothionein (MT) isoforms have not been studied in papillary thyroid cancer. We examined how the functional MT1 and MT2 isoforms were expressed in papillary thyroid cancer (KAT5) cells. We demonstrated that KAT5 cells expressed eight functional MT1 and MT2 isoforms induced by cadmium. Elevated calcium and activated ERK1/2 predated MT expression. The inhibition of either calcium or ERK1/2 significantly blocked the isoform expression. The induction of these isoforms accompanied an increased progression of cell cycle from G0/G1 to G2-M. The alternation in cell cycle disappeared when the expression of MT isoforms was blocked by calcium inhibitor or ERK1/2 inhibitor. Collectively, KAT5 cells express eight functional MT1 and MT2 isoforms in a pathway controlled by calcium and ERK1/2. The elevation of the MT isoforms contributes to the decreased G0/G1 but increased G2-M phase. These results reveal a novel pathway for the expression of the functional MT in papillary thyroid cancer.

Polymorphisms in metallothionein-1 and -2 genes associated with the risk of type 2 diabetes mellitus and its complications.

Metallothionein (MT) as a potent antioxidant can affect energy metabolism. The present study was undertaken to investigate the association between MT gene polymorphism and type 2 diabetes mellitus. Using the PCR-based restriction fragment length polymorphism method, seven single nucleotide polymorphisms (SNPs) in MT genes (rs8052394 and rs11076161 in MT1A gene, rs8052334, rs964372, and rs7191779 in MT1B gene, rs708274 in MT1E gene, and rs10636 in MT2A gene) were detected in 851 Chinese people of Han descent (397 diabetes and 454 controls). Several serum measurements were also examined randomly for 43 diabetic patients and 41 controls. The frequency distributions of the G allele in SNP rs8052394 of MT1A gene were significantly associated with the incidence of type 2 diabetes. There was no difference between patients and controls for the rest of six SNPs. Serum levels of interleukin-6 and tumor necrosis factor-alpha were higher, and serum superoxide dismutase activity was significantly lower in the diabetic group than those in the control group. For diabetic patients, serum superoxide dismutase activity was significantly lower in GG or GA carriers than those of AA carriers of rs8052394 SNP. Increased serum levels in diabetic patients were positively associated with rs964372 SNP, and type 2 diabetes with neuropathy was positively associated with rs10636 and rs11076161. These results suggest that multiple SNPs in MT genes are associated with diabetes and its clinical symptoms. Furthermore, MT1A gene in rs8052394 SNP is most likely the predisposition gene locus for diabetes or changes of serum superoxide dismutase activity.

The World Health Organization and anaesthesia.

The World Health Organization has been involved in a wide range of global healthcare initiatives for many years. Recently an initiative 'Safe Surgery Saves Lives' has been launched to improve the safety of surgery throughout the world. Safe anaesthesia is a key component to achieving this aim.

Metal complexes of dietary flavonoids: evaluation of radical scavenger properties and protective activity against oxidative stress in vivo.

Interaction of certain flavonoids with transition metals increases their water solubility and leads to the formation of flavonoid-metal complexes, which may act as superoxide dismutase mimics with high scavenger potencies toward superoxide. Effect of serum albumin on stability of flavonoid-metal complexes was studied and complex of rutin with iron (II) was found to be the most stable. The ability of flavonoid metal complexes to catalyze homolytic cleavage of hydrogen peroxide was also studied and rutin iron (II) complex was found to be relatively poor Fenton catalyst. The potential therapeutic benefits of this new antioxidant agent were studied using experimental model of pathological states associated with oxidative stress in vivo. Acute hepatic injury in MT-I/MT-II null transgenic mice induced by injections of thioacetamide was used for this purpose. It was found that pretreatment with rutin- iron complex protected against thioacetamide induced hepatotoxicity as observed by a significant reduction in the elevated levels of serum enzymes and partial normalization of GSH/GSSG ratio, glutathione peroxidase II and glutathione reductase activity in mice liver. The results demonstrate that flavonoid-metal complexes possess effective free radical scavenger ability and have potent therapeutic benefits for the treatment of oxidative stress-related diseases and dysfunction.

P53 mediated regulation of metallothionein transcription in breast cancer cells.

Recent studies have shown that only breast cancer epithelial cells with intact p53 can induce metallothionein (MT) synthesis after exposure to metals. In this study, the potential role of p53 on regulation of MT was investigated. Results demonstrate that zinc and copper increased metal response elements (MREs) activity and MTF-1 expression in p53 positive MN1 and parental MCF7 cells. However, inactivation of p53 by treatment with pifithrin-alpha or the presence of inactive p53 inhibited MRE-dependent reporter gene expression in response to metals. MTF-1 levels remained unchanged after treatment with zinc in cells with nonfunctional p53. The introduction of wild-type p53 in MDD2 cells, containing nonfunctional p53, enhanced the ability of zinc to increase MRE-dependent reporter gene expression. The cellular level of p21Cip1/WAF1 was increased in MDD2 cells after p53 transfection, confirming the presence of active p53. The treatment of MN1 and parental MCF7 with trichostatin A led to a sixfold increase in the MRE activity in response to zinc. On the contrary, MRE activity remained unaltered in MDD2 cells with inactive p53. The above results demonstrate that activation of p53 is an important factor in metal regulation of MT.