A Risk Scoring System to Determine Recurrence in Early-Stage Type 1 Endometrial Cancer: A French Multicentre Study

Background

To develop a risk scoring system (RSS) to determine recurrence in women with early-stage type 1 endometrial cancer (EC).

Methods

Data of 396 women with early-stage type 1 EC who received primary surgical treatment between January 2001 and December 2012 were abstracted from multicentre database (training set). A risk model for predicting recurrence was developed and internally validated with the bootstrap technique. The RSS was externally validated using data from an independent population.

Results

Overall, the recurrence rate was 12.1 %. The median follow-up and initial time to recurrence were 34 (range 1–152) and 26 (range 1–151) months, respectively. Recurrence was associated with five variables: age ≥60 years, histological grade III, primary tumor diameter >2 cm, depth of myometrial invasion ≥50 %, and the positive lymphovascular space involvement status. These variables were included in the RSS and assigned scores. A total score of 6.5 points corresponded to the optimal threshold of the RSS. For women with a score <6.5 or ≥6.5, the recurrence rates were 8.4 % (30/357) and 48.7 % (19/39) in the training set, respectively. At this threshold, the diagnostic accuracy of the RSS was 87 %. Areas under the curve of the receiver-operating characteristics for predicting recurrence at internal and external validation were 0.74 [95 % confidence interval (CI) 0.71–0.77] and 0.82 (95 % CI 79–85), respectively.

Conclusions

This RSS identified two subsets of women with low and high risk of recurrence among women with early-stage type 1 EC. It could be helpful to better define indications for nodal staging and adjuvant therapy.     

Minimally invasive percutaneous plate osteosynthesis for ankle fractures: a prospective observational cohort study

Background

The gold standard for the surgical management of ankle fractures is through open reduction and internal fixation. The rate of wound problems has been reported to be as high as 18 %, especially in patients with poor vascular supply or in diabetics. Minimally invasive percutaneous plate osteosynthesis (MIPPO) has been described as a potential solution for these patients.

Patients and methods

This is a prospective observational cohort study. From October 2009 to February 2010, and following ethical approval of our research, adult patients admitted at our level I trauma center with a closed lateral malleolar displaced unstable fracture (Lauge-Hansen supination-external rotation) with or without a medial-sided injury and patients with an undisplaced fracture associated with medial clear space opening on external rotation stress radiographs were recruited and managed using MIPPO technique. All patients were followed up for a minimum of 12 months post-surgery (12–20 with a mean of 16.5 months). Trauma mechanism, comorbidities, classifications, trauma-surgery interval, image intensifier duration, surgery duration, complications, and function American Orthopaedic Foot and Ankle Society (AOFAS) were analyzed.

Results

Thirty-two patients were recruited of which 20 fulfilled the inclusion criteria (16 females, 4 males) and were available for follow-up. Ten fractures (50 %) were classified as 44-B1, 7 fractures (35 %) as 44-B2, and 3 fractures (15 %) as 44-B3 according to the Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association classification (100 % were supination-external rotation injuries). At 8 weeks post-surgery, all fractures had healed. The duration of surgery ranged between 15 and 73 min (average 32.8) from skin incision to closure. There were 2 complications (1 malunion and 1 skin necrosis requiring implant removal). At 12-month follow-up, AOFAS average was 88.3 (72–100 standard deviation of 6.8 points).

Conclusion

MIPPO technique proved to be a viable option for lateral malleolar fracture treatment with a low complication rate and high functional outcome at 1 year. It is particularly useful in patients with a high risk of wound complication.     

Effects of Δ9-tetrahydrocannabinol in individuals with a familial vulnerability to alcoholism

Background and aims

A family history (FH) of alcoholism accounts for approximately 50 % of the risk of developing alcohol problems. Several lines of preclinical evidence suggest that brain cannabinoid receptor (CB₁R) function may mediate the effects of alcohol and risk for developing alcoholism including the observations that reduced CB₁R function decreases alcohol-related behaviors and enhanced CB₁R function increases them. In this first human study, we probed CB₁R function in individuals vulnerable to alcoholism with the exogenous cannabinoid Δ⁹-tetrahydrocannabinol (Δ⁹-THC).

Design, setting, and participants

Healthy volunteers (n?=?30) participated in a three test day study during which they received 0.018 and 0.036 mg/kg of Δ⁹-THC, or placebo intravenously in a randomized, counterbalanced order under double-blind conditions.

Measurements

Primary outcome measures were subjective “high,” perceptual alterations, and memory impairment. Secondary outcome measures consisted of stimulatory and depressant subjective effects, attention, spatial memory, executive function, Δ⁹-THC and 11-hydroxy-THC blood levels, and other subjective effects. FH was calculated using the Family Pattern Density method and was used as a continuous variable.

Findings

Greater FH was correlated with greater “high” and perceptual alterations induced by Δ⁹-THC. This enhanced sensitivity with increasing FH was specific to Δ⁹-THC’s rewarding effects and persisted even when FH was calculated using an alternate method.

Conclusions

Enhanced sensitivity to the rewarding effects of Δ⁹-THC in high-FH volunteers suggests that alterations in CB₁R function might contribute to alcohol misuse vulnerability.     

Assessment of bronchial obstruction and its reversibility by shape indexes of the flow‐volume loop in asthmatic children

Asthma assessment by spirometry is challenging in children as forced expiratory volume in 1 s (FEV1) is frequently normal at baseline. Bronchodilator (BD) reversibility testing may reinforce asthma diagnosis but FEV1 sensitivity in children is controversial. Ventilation inhomogeneity, an early sign of airway obstruction, is described by the upward concavity of the descending limb of the forced expiratory flow‐volume loop (FVL), not detected by FEV1. The aim was to test the sensitivity and specificity of FVL shape indexes as β‐angle and forced expiratory flow at 50% of the forced vital capacity (FEF50)/peak expiratory flow (PEF) ratio, to identify asthmatics from healthy children in comparison to “usual” spirometric parameters. Seventy‐two school‐aged asthmatic children and 29 controls were prospectively included. Children performed forced spirometry at baseline and after BD inhalation. Parameters were expressed at baseline as z‐scores and BD reversibility as percentage of change reported to baseline value (Δ%). Receiver operating characteristic curves were generated and sensitivity and specificity at respective thresholds reported. Asthmatics presented significantly smaller zβ‐angle, zFEF50/PEF and zFEV1 (p ≤ .04) and higher BD reversibility, significant for Δ%FEF50/PEF (p = .02) with no difference for Δ%FEV1. zβ‐angle and zFEF50/PEF exhibited better sensitivity (0.58, respectively 0.60) than zFEV1 (0.50), and similar specificity (0.72). Δ%β‐angle showed higher sensitivity compared to Δ%FEV1 (0.72 vs. 0.42), but low specificity (0.52 vs. 0.86). Quantitative and qualitative assessment of FVL by adding shape indexes to spirometry interpretation may improve the ability to detect an airway obstruction, FEV1 reflecting more proximal while shape indexes peripheral bronchial obstruction.     

Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN-amplified neuroblastoma

MYCN-amplified neuroblastoma is a lethal subset of pediatric cancer. MYCN drives numerous effects in the cell, including metabolic changes that are critical for oncogenesis. The understanding that both compensatory pathways and intrinsic redundancy in cell systems exists implies that the use of combination therapies for effective and durable responses is necessary. Additionally, the most effective targeted therapies exploit an “Achilles’ heel” and are tailored to the genetics of the cancer under study. We performed an unbiased screen on select metabolic targeted therapy combinations and correlated sensitivity with over 20 subsets of cancer. We found that MYCN-amplified neuroblastoma is hypersensitive to the combination of an inhibitor of the lactate transporter MCT1, AZD3965, and complex I of the mitochondrion, phenformin. Our data demonstrate that MCT4 is highly correlated with resistance to the combination in the screen and lowly expressed in MYCN-amplified neuroblastoma. Low MCT4 combines with high expression of the MCT2 and MCT1 chaperone CD147 in MYCN-amplified neuroblastoma, altogether conferring sensitivity to the AZD3965 and phenformin combination. The result is simultaneous disruption of glycolysis and oxidative phosphorylation, resulting in dramatic disruption of adenosine triphosphate (ATP) production, endoplasmic reticulum stress, and cell death. In mouse models of MYCN-amplified neuroblastoma, the combination was tolerable at concentrations where it shrank tumors and did not increase white-blood-cell toxicity compared to single drugs. Therefore, we demonstrate that a metabolic combination screen can identify vulnerabilities in subsets of cancer and put forth a metabolic combination therapy tailored for MYCN-amplified neuroblastoma that demonstrates efficacy and tolerability in vivo.

Despite their relative rarity compared to blood cancers, solid-tumor pediatric cancers are now the leading cause of pediatric cancer-related deaths. Among the most deadly is high-risk neuroblastoma (NB): amplification of MYCN confers high risk and is the clear driver of NB in these cancers (1). As such, MYCN remains the most important drug target in NB and one of the most important in pediatric cancer. Unfortunately, direct chemical targeting of MYCN has not yet been successful, and despite advancements in anti-GD2 immunotherapy (2), alternate ways of targeting MYCN-amplified NB may be needed to successfully treat this cancer.One approach is to find tumor-specific vulnerabilities, which are exploitable pharmacologically. Many efforts, including ours (3), have exhaustively looked for kinase inhibitors with particular efficacy in MYCN-amplified NBs. However, the emerging picture is a lack of kinase inhibitor efficacy in MYCN-amplified NB. Other vulnerabilities may be classified under the broad category of drugs targeting epigenetic modifiers. For example, using a CRISPR/Cas9 screen, Stegmaier and colleagues demonstrated that MYCN-amplified NB may be susceptible to targeting the H3K27me methylase EZH2 (4); in a different study, they demonstrated the susceptibility of MYCN-amplified NB to the combination of BRD4 inhibitors with CDK7 inhibitors (5). In addition, Thiele and colleagues (6) demonstrated high-risk NBs were susceptible to inhibition of the lysine methyltransferase SETD8. As promising as these data are, it remains unknown whether tolerability and/or clinical activity in MYCN-amplified NB will occur and SETD8, BRD4, and CDK7 inhibitors so far are not in the pediatric clinic. Cell death inducers constitute a third category. To this point, we recently uncovered a susceptibility of MYCN-amplified NB to the BCL-2 inhibitor venetoclax (3), confirmed by others (7). There, MYCN-driven NOXA expression sensitizes cells to venetoclax (3). Venetoclax is now in early phase trials in pediatric patients including those with NB ({"type":"clinical-trial","attrs":{"text":"NCT03236857","term_id":"NCT03236857"}}NCT03236857). It remains to be seen whether or not it will elicit responses in NB patients as a single agent.A fourth distinct category of therapeutic strategies to indirectly target oncogenes is through metabolism targeting, involving the growing coterie of drugs targeting the pathways fulfilling the high-energy demands of cancer cells. A major energy currency in cells is adenosine triphosphate (ATP). The Warburg effect describes the propensity of cancer cells (and highly proliferating normal cells) to produce ATP in the presence of oxygen with the less efficient, extramitochondrial glycolysis, as opposed to the more efficient mitochondria-based oxidative phosphorylation occurring in most noncancerous cells (8). The mechanistic explanation of the Warburg effect and how it might benefit cancer cells has been revised dramatically over the years. It was originally proposed that mitochondria from cancer cells were defective and lacked oxidative phosphorylation capabilities (9); on the contrary, emerging data show that many cancers rely on oxidative phosphorylation to facilitate the generation of ATP (8, 10). Interestingly, while amplified MYCN directly regulates the expression of many of the key glycolytic enzymes and as such contributes to the Warburg effect (11, 12), a study utilizing a Seahorse respirator demonstrated that a MYCN-amplified NB cell line favored oxidative phosphorylation over glycolysis for the metabolic needs, while the reverse was true for a MYCN wild-type NB cell line (13). In an independent study, MYCN was associated with higher glycolytic flux and oxidative phosphorylation and conferred sensitivity to fatty acid oxidation disruption (12). Overall, since c-MYC, which shares ∼40% binding homology to DNA-binding sites throughout the genome with MYCN, has been extensively characterized as a metabolic master regulator (14, 15), it is likely there are other MYCN-driven metabolic processes that may represent significant drug targets.Monocarboxylate transporters (MCTs) consist of four members (MCT1–4) in mammalian cells. Among their most critical substrates are lactate and pyruvate; MCT1 and MCT4 are responsible for lactate export across the plasma membrane to the extracellular space (16). AZD3965 (17) (AstraZeneca) is the first in-class–specific MCT1/2 dual inhibitor and is currently in early phase trials for diverse cancers; however, other inhibitors from different companies have recently been developed as well (18). Of note, AZD3965 has demonstrated good tolerability in diverse patients (clinical trial number {"type":"clinical-trial","attrs":{"text":"NCT01791595","term_id":"NCT01791595"}}NCT01791595). Although rare (65 cases/100,000 person-years), lactic acidosis led to the market retrieval of phenformin in America (19), yet phenformin remains in use as a type II antidiabetic drug in Europe, functioning centrally as a mitochondrial complex I electron transport chain (ETC) inhibitor. Phenformin reduces both glycolytic intermediates and pyruvate, increases shunting of glucose-derived carbon (increasing total lactate production), and markedly reduces tricarboxylic acid cycle intermediates (20). Indeed, there has been a recent resurgence in interest in the use of phenformin to treat cancer. For example, in BRAF mutant melanoma, phenformin sensitized cells to BRAF inhibitor through cooperative suppression of the metabolic sensor pathway mTORC1 (21). These preclinical data have led to a clinical trial of phenformin in combination with BRAF inhibitor in BRAF mutant melanoma ({"type":"clinical-trial","attrs":{"text":"NCT03026517","term_id":"NCT03026517"}}NCT03026517). Overall, while targeting individual metabolic pathways has demonstrated some preclinical success in different cancer models, it is limited with significant redundancy in pathways to generate ATP and regenerate NAD+ (22). We therefore assessed potential combination therapies involving metabolic targeting drugs to identify a strategy for MYCN-amplified NB.     

A Dietary portfolio: Maximal reduction of low-density lipoprotein cholesterol with diet

Over the past two decades, cholesterol-lowering drugs have proven to be effective and have been found to significantly reduce the risk of coronary heart disease (CHD). However, diet and lifestyle factors are still recognized as the first line of intervention for CHD risk reduction by the National Cholesterol Education Program and the American Heart Association, which now advocate use of viscous fibers and plant sterols, and soy protein and nuts, respectively. In a series of metabolically controlled studies, we have combined these four cholesterol-lowering dietary components in the same diet (ie, a dietary portfolio of cholesterol-lowering foods) in an attempt to maximize low-density lipoprotein cholesterol reduction. We have found that the portfolio diet reduced low-density lipoprotein cholesterol by approximately 30% and produced clinically significant reductions in CHD risk. These reductions were the same as found with a starting dose of a first-generation statin drug.     

Novel Betacoronavirus in Dromedaries of the Middle East, 2013

In 2013, a novel betacoronavirus was identified in fecal samples from dromedaries in Dubai, United Arab Emirates. Antibodies against the recombinant nucleocapsid protein of the virus, which we named dromedary camel coronavirus (DcCoV) UAE-HKU23, were detected in 52% of 59 dromedary serum samples tested. In an analysis of 3 complete DcCoV UAE-HKU23 genomes, we identified the virus as a betacoronavirus in lineage A1. The DcCoV UAE-HKU23 genome has G+C contents; a general preference for G/C in the third position of codons; a cleavage site for spike protein; and a membrane protein of similar length to that of other betacoronavirus A1 members, to which DcCoV UAE-HKU23 is phylogenetically closely related. Along with this coronavirus, viruses of at least 8 other families have been found to infect camels. Because camels have a close association with humans, continuous surveillance should be conducted to understand the potential for virus emergence in camels and for virus transmission to humans.