Association between early postoperative nutritional supplement utilisation and length of stay in malnourished hip fracture patients.

BACKGROUND: Malnutrition in older hip fracture patients is associated with increased complication rates and mortality. As postoperative nutrition delivery is essential to surgical recovery, postoperative nutritional supplements including oral nutritional supplements or tube feeding formulas can improve postoperative outcomes in malnourished hip/femur fracture patients. The association between early postoperative nutritional supplements utilisation and hospital length of stay was assessed in malnourished hip/femur fracture patients. METHODS: This is a retrospective cohort study of malnourished hip/femur fracture patients undergoing surgery from 2008 to 2018. Patients were identified through International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) codes and nutritional supplement utilisation via hospital charge codes. The primary outcome was hospital length of stay. Secondary outcomes included infectious complications, hospital mortality, ICU admission, and costs. Propensity matching (1:1) and univariable analysis were performed. RESULTS: Overall, 160 151 hip/femur fracture surgeries were identified with a coded-malnutrition prevalence of 8.7%. Early postoperative nutritional supplementation (by hospital day 1) occurred in 1.9% of all patients and only 4.9% of malnourished patients. Propensity score matching demonstrated early nutritional supplements were associated with significantly shorter length of stay (5.8 [6.6] days vs 7.6 [5.8] days; P<0.001) without increasing hospital costs. No association was observed between early nutritional supplementation and secondary outcomes. CONCLUSION: Malnutrition is underdiagnosed in hip/femur fracture patients, and nutritional supplementation is underutilised. Early nutritional supplementation was associated with a significantly shorter hospital stay without an increase in costs. Nutritional supplementation in malnourished hip/femur fracture patients could serve as a key target for perioperative quality improvement.

Postoperative Utilization of Oral Nutrition Supplements in Surgical Patients in US Hospitals.

BACKGROUND: Postoperative nutrition delivery is essential to surgical recovery; unfortunately, postoperative dietary intake is often poor. Recent surgical guidelines recommend use of oral nutritional supplements (ONS) to improve nutrition delivery. Our aim was to examine prevalence of coded ONS use over time and coded malnutrition rates in postoperative patients. METHODS: The Premier Healthcare Database (PHD) was queried for postoperative patients found to have charges for ONS between 2008-2014. ONS use identified via charge codes. Descriptive statistics utilized to examine prevalence of malnutrition and ONS utilization. Multilevel, multivariable logistic regression models were fit to examine factors associated with ONS use. RESULTS: A total of 2,823,532 surgical encounters were identified in PHD in 172 hospitals utilizing ONS charge codes. ONS-receiving patients were 72% Caucasian, 65% Medicare patients with mean age of 66 ± 16.5 years. Compared with patients not receiving ONS, ONS patients had higher van Walraven severity scores (7.3 ± 7.8 vs 2.3 ± 5.6, P < .001) with greater comorbidities. Overall coded malnutrition prevalence was 4.3%. Coded malnutrition diagnosis increased from 4.4% to 5.2% during study period. Only 15% of malnourished patients received ONS. Individual hospital practice explained much of variation in early postoperative ONS use. CONCLUSION: In this large surgical population, inpatient ONS use is most common in older, Caucasian, Medicare patients with high comorbidity burden. Despite increased malnutrition during study period, observed ONS prescription rate did not increase. Our data indicate current ONS utilization in surgical patients, even coded with malnutrition, is limited and is a critical perioperative quality improvement opportunity.

Impact of early postoperative oral nutritional supplement utilization on clinical outcomes in colorectal surgery.

BACKGROUND: Small randomized trials of early postoperative oral nutritional supplementation (ONS) suggest various health benefits following colorectal surgery (CRS). However, real-world evidence of the impact of early ONS on clinical outcomes in CRS is lacking. METHODS: Using a nationwide administrative-financial database (Premier Healthcare Database), we examined the association between early ONS use and postoperative clinical outcomes in patients undergoing elective open or laparoscopic CRS between 2008 and 2014. Early ONS was defined as the presence of charges for ONS before postoperative day (POD) 3. The primary outcome was composite infectious complications. Key secondary efficacy (intensive care unit (ICU) admission and gastrointestinal complications) and falsification (blood transfusion and myocardial infarction) outcomes were also examined. Propensity score matching was used to assemble patient groups that were comparable at baseline, and differences in outcomes were examined. RESULTS: Overall, patients receiving early ONS were older with greater comorbidities and more likely to be Medicare beneficiaries with malnutrition. In a well-matched sample of early ONS recipients (n = 267) versus non-recipients (n = 534), infectious complications were significantly lower in early ONS recipients (6.7% vs. 11.8%, P < 0.03). Early ONS use was also associated with significantly reduced rates of pneumonia (P < 0.04), ICU admissions (P < 0.04), and gastrointestinal complications (P < 0.05). There were no significant differences in falsification outcomes. CONCLUSIONS: Although early postoperative ONS after CRS was more likely to be utilized in elderly patients with greater comorbidities, the use of early ONS was associated with reduced infectious complications, pneumonia, ICU admission, and gastrointestinal complications. This propensity score-matched study using real-world data suggests that clinical outcomes are improved with early ONS use, a simple and inexpensive intervention in CRS patients.

Tutorial: Development and Implementation of a Multidisciplinary Preoperative Nutrition Optimization Clinic.

Although much is known about surgical risk, little evidence exists regarding how best to proactively address preoperative risk factors to improve surgical outcomes. Preoperative malnutrition is a widely prevalent and modifiable risk factor in patients undergoing surgery. Malnutrition prior to surgery portends significantly higher postoperative mortality, morbidity, length of stay, readmission rates, and hospital costs. Unfortunately, perioperative malnutrition is poorly screened for and remains largely unrecognized and undertreated-a true "silent epidemic" in surgical care. To better address this silent epidemic of surgical nutrition risk, here we describe the rationalization, development, and implementation of a multidisciplinary, registered dietitian-driven, preoperative nutrition optimization clinic program designed to improve perioperative outcomes and reduce cost. Implementation of this novel Perioperative Enhancement Team (POET) Nutrition Clinic required a collaboration among many disciplines, as well as an identified need for multidimensional scheduling template development, data tracking systems, dashboard development, and integration of electronic health records. A structured malnutrition risk score (Perioperative Nutrition Screen score) was developed and is being validated. A structured malnutrition pathway was developed and is under study. Finally, the POET Nutrition Clinic has established a novel role for a perioperative registered dietitian as the integral point person to deliver perioperative nutrition care. We hope this structured model of perioperative nutrition assessment and optimization will allow for wide implementation and generalizability in other centers worldwide to improve recognition and treatment of perioperative nutrition risk.

Perioperative Nutrition Care of Orthopedic Surgery Patient.

Despite evidence that malnutrition is associated with significant complications in orthopedic surgery1, unrecognized malnutrition continues to be a "silent epidemic", effecting up to 50% of hospitalized patients. Specifically, pre-surgical malnutrition is associated with increased risk for surgical site infections, increased length of hospital stay, and increased health care costs in patients following total joint arthroplasty. Serologic markers (i.e. serum albumin and total lymphocyte count), anthropometric measurements, (i.e. calf muscle circumference and triceps skin fold) and assessment and screening tools (i.e. The Rainey-MacDonald Nutritional Index, the Mini Nutrition Assessment Short Form, the Malnutrition Universal Screening Tool and the Nutrition Risk Screening 2002) have all been used to aid in the diagnosis of malnutrition in orthopedic patients, yet there is no universal gold standard for screening or assessing nutritional risk and no accepted guideline for perioperative nutritional optimization in this patient population. Recently, the Perioperative Nutrition Screen (PONS) was introduced2 as an easy and efficient way to preoperatively identify and risk stratify patients for malnutrition in order to guide perioperative nutrition optimization. Given malnutrition is associated with increased risk of surgical site infections and increased length of hospital stay, adequate assessment of perioperative risk for malnutrition and preoperative nutrition optimization, including structured weight loss in the obese population, consumption of high protein oral nutritional supplements, immunonutrition oral supplements and adequate glucose control, may improve perioperative outcomes. The presence of a Registered Dietician (RD) should be a standard of care in all pre-operative clinics to improve nutrition care and surgical outcomes.

Focused cardiac ultrasound in preoperative assessment: the perioperative provider's new stethoscope?

Focused cardiac ultrasound (FoCUS)-a simplified, qualitative version of echocardiography-is a well-established tool in the armamentarium of critical care and emergency medicine. This review explores the extent to which FoCUS could also be used to enhance the preoperative physical examination to better utilise resources and identify those who would benefit most from detailed echocardiography prior to surgery. Among the range of pathologies that FoCUS can screen for, the conditions it provides the most utility in the preoperative setting are left ventricular systolic dysfunction (LVSD) and, in certain circumstances, significant aortic stenosis (AS). Thus, FoCUS could help answer two common preoperative diagnostic questions. First, in a patient with high cardiovascular risk who subjectively reports a good functional status, is there evidence of LVSD? Second, does an asymptomatic patient with a systolic murmur have significant aortic stenosis? Importantly, many cardiac pathologies of relevance to perioperative care fall outside the scope of FoCUS, including regional wall motion abnormalities, diastolic dysfunction, left ventricular outflow obstruction, and pulmonary hypertension. Current evidence suggests that after structured training in FoCUS and performance of 20-30 supervised examinations, clinicians can achieve competence in basic cardiac ultrasound image acquisition. However, it is not known precisely how many training exams are necessary to achieve competence in FoCUS image interpretation. Given the short history of FoCUS use in preoperative evaluation, further research is needed to determine what additional questions FoCUS is suited to answer in the pre-operative setting.

Trypanosoma brucei Secreted Aromatic Ketoacids Activate the Nrf2/HO-1 Pathway and Suppress Pro-inflammatory Responses in Primary Murine Glia and Macrophages.

African trypanosomes, such as Trypanosoma brucei (T. brucei), are protozoan parasites of the mammalian vasculature and central nervous system that are best known for causing fatal human sleeping sickness. As exclusively extracellular parasites, trypanosomes are subject to constant challenge from host immune defenses but they have developed very effective strategies to evade and modulate these responses to maintain an infection while simultaneously prolonging host survival. Here we investigate host parasite interactions, especially within the CNS context, which are not well-understood. We demonstrate that T. brucei strongly upregulates the stress response protein, Heme Oxygenase 1 (HO-1), in primary murine glia and macrophages in vitro. Furthermore, using a novel AHADHinT. brucei cell line, we demonstrate that specific aromatic ketoacids secreted by bloodstream forms of T. brucei are potent drivers of HO-1 expression and are capable of inhibiting pro-IL1ß induction in both glia and macrophages. Additionally, we found that these ketoacids significantly reduced IL-6 and TNFα production by glia, but not macrophages. Finally, we present data to support Nrf2 activation as the mechanism of action by which these ketoacids upregulate HO-1 expression and mediate their anti-inflammatory activity. This study therefore reports a novel immune evasion mechanism, whereby T. brucei secretes amino-acid derived metabolites for the purpose of suppressing both the host CNS and peripheral immune response, potentially via induction of the Nrf2/HO-1 pathway.

Pharmacological interventions for chronic pain in children: an overview of systematic reviews.

We know little about the safety or efficacy of pharmacological medicines for children and adolescents with chronic pain, despite their common use. Our aim was to conduct an overview review of systematic reviews of pharmacological interventions that purport to reduce pain in children with chronic noncancer pain (CNCP) or chronic cancer-related pain (CCRP). We searched the Cochrane Database of Systematic Reviews, Medline, EMBASE, and DARE for systematic reviews from inception to March 2018. We conducted reference and citation searches of included reviews. We included children (0-18 years of age) with CNCP or CCRP. We extracted the review characteristics and primary outcomes of ≥30% participant-reported pain relief and patient global impression of change. We sifted 704 abstracts and included 23 systematic reviews investigating children with CNCP or CCRP. Seven of those 23 reviews included 6 trials that involved children with CNCP. There were no randomised controlled trials in reviews relating to reducing pain in CCRP. We were unable to combine data in a meta-analysis. Overall, the quality of evidence was very low, and we have very little confidence in the effect estimates. The state of evidence of randomized controlled trials in this field is poor; we have no evidence from randomised controlled trials for pharmacological interventions in children with cancer-related pain, yet cannot deny individual children access to potential pain relief. Prospero ID: CRD42018086900.

The malnourished surgery patient: a silent epidemic in perioperative outcomes?

PURPOSE OF REVIEW: As many as two of every three major surgery patients are malnourished preoperatively - a diagnosis rarely made and treated even less frequently. Unfortunately, perioperative malnutrition is perhaps the least often identified surgical risk factor and is among the most treatable to improve outcomes. RECENT FINDINGS: Two important perioperative nutrition guidelines were published recently. Both emphasize nutrition assessment as an essential component of preoperative screening. The recently published perioperative nutrition screen (PONS) readily identifies patients at malnutrition risk, allowing for preoperative nutritional optimization. The use of computerized tomography scan and ultrasound lean body mass (LBM) evaluation to identify sarcopenia associated with surgical risk and guide nutrition intervention is garnering further support. Preoperative nutrition optimization in malnourished patients, use of immunonutrition in all major surgery, avoidance of preoperative fasting, inclusion of postoperative high-protein nutritional supplements, and early postoperative oral intake have all recently been shown to improve outcomes and should be utilized. SUMMARY: The recent publication of new surgical nutrition guidelines, the PONS score, and use of LBM assessments will allow better identification and earlier intervention on perioperative malnutrition. It is essential that in the future no patient undergoes elective surgery without nutrition screening and nutrition intervention when malnutrition risk is identified.

Gas exchange characteristics of giant cacti species varying in stem morphology and life history strategy.

PREMISE OF THE STUDY: Giant cacti species possess long cylindrical stems that store massive amounts of water and other resources to draw on for photosynthesis, growth, and reproduction during hot and dry conditions. Across all giant cacti taxa, stem photosynthetic surface area to volume ratio (S:V) varies by several fold. This broad morphological diversity leads to the hypothesis that giant cacti function along a predictable resource use continuum from a "safe" strategy reflected in low S:V, low relative growth rates (RGR), and low net assimilation rates (Anet ) to a high-risk strategy that is reflected in high S:V, RGR, and Anet . METHODS: To test this hypothesis, whole-plant gas exchange, chlorophyll fluorescence, and whole-spine-tissue carbon isotope ratios (δ13 C) were measured in four giant cacti species varying in stem morphology and RGR. Measurements were conducted on five well-watered, potted plants per species. KEY RESULTS: Under conditions of mild diel temperatures and low atmospheric vapor pressure deficit, Anet , transpiration (E), and stomatal conductance (Gs ) were significantly higher, and water-use efficiency (Anet : Gs ) was lower in fast-growing, multi-stemmed species compared to the slower growing, single-stemmed species. However, under warmer, less optimal conditions, gas exchange converged between stem types, and neither δ13 C nor chlorophyll fluorescence varied among species. CONCLUSIONS: The results add to a growing body of evidence that succulent-stemmed plants function along a similar economic spectrum as leaf-bearing plants such that functional traits including stem RGR, longevity, morphology, and gas exchange are correlated across species with varying life-history strategies.

Antitumor Activity of MEDI3726 (ADCT-401), a Pyrrolobenzodiazepine Antibody-Drug Conjugate Targeting PSMA, in Preclinical Models of Prostate Cancer.

Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase that is highly expressed in nearly all prostate cancers with the highest expression in metastatic castration-resistant prostate cancer (mCRPC). The prevalence of increased surface expression and constitutive internalization of PSMA make it an attractive target for an antibody-drug conjugate (ADC) approach to treating patients with mCRPC. MEDI3726 (previously known as ADCT-401) is an ADC consisting of an engineered version of the anti-PSMA antibody J591 site specifically conjugated to the pyrrolobenzodiazepine (PBD) dimer tesirine. MEDI3726 specifically binds the extracellular domain of PSMA and, once internalized, releases the PBD dimer to crosslink DNA and trigger cell death. In vitro, MEDI3726 demonstrated potent and specific cytotoxicity in a panel of PSMA-positive prostate cancer cell lines, consistent with internalization and DNA interstrand crosslinking. In vivo, MEDI3726 showed robust antitumor activity against the LNCaP and the castration-resistant CWR22Rv1 prostate cancer cell line xenografts. MEDI3726 also demonstrated durable antitumor activity in the PSMA-positive human prostate cancer patient-derived xenograft (PDX) LuCaP models. This activity correlated with increased phosphorylated Histone H2AX in tumor xenografts treated with MEDI3726. MEDI3726 is being evaluated in a phase I clinical trial as a treatment for patients with metastatic castrate-resistant prostate cancer (NCT02991911). Mol Cancer Ther; 17(10); 2176-86. ©2018 AACR.

Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine.

Synthetic pyrrolobenzodiazepine (PBD) dimers, where two PBD monomers are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether, are highly efficient DNA minor groove cross-linking agents with potent cytotoxicity. PBD dimer SG3199 is the released warhead component of the antibody-drug conjugate (ADC) payload tesirine (SG3249), currently being evaluated in several ADC clinical trials. SG3199 was potently cytotoxic against a panel of human solid tumour and haematological cancer cell lines with a mean GI50 of 151.5 pM. Cells defective in DNA repair protein ERCC1 or homologous recombination repair showed increased sensitivity to SG3199 and the drug was only moderately susceptible to multidrug resistance mechanisms. SG3199 was highly efficient at producing DNA interstrand cross-links in naked linear plasmid DNA and dose-dependent cross-linking was observed in cells. Cross-links formed rapidly in cells and persisted over 36 hours. Following intravenous (iv) administration to rats SG3199 showed a very rapid clearance with a half life as short as 8 minutes. These combined properties of cytotoxic potency, rapid formation and persistence of DNA interstrand cross-links and very short half-life contribute to the emerging success of SG3199 as a warhead in clinical stage ADCs.

ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies.

Human CD19 antigen is a 95-kDa type I membrane glycoprotein in the immunoglobulin superfamily whose expression is limited to the various stages of B-cell development and differentiation and is maintained in the majority of B-cell malignancies, including leukemias and non-Hodgkin lymphomas of B-cell origin. Coupled with its differential and favorable expression profile, CD19 has rapid internalization kinetics and is not shed into the circulation, making it an ideal target for the development of antibody-drug conjugates (ADCs) to treat B-cell malignancies. ADCT-402 (loncastuximab tesirine) is a novel CD19-targeted ADC delivering SG3199, a highly cytotoxic DNA minor groove interstrand crosslinking pyrrolobenzodiazepine (PDB) dimer warhead. It showed potent and highly targeted in vitro cytotoxicity in CD19-expressing human cell lines. ADCT-402 was specifically bound, internalized, and trafficked to lysosomes in CD19-expressing cells and, following release of the PBD warhead, resulted in formation of DNA crosslinks that persisted for 36 hours. Bystander killing of CD19- cells by ADCT-402 was also observed. In vivo, single doses of ADCT-402 resulted in highly potent, dose-dependent antitumor activity in several subcutaneous and disseminated human tumor models with marked superiority to comparator ADCs delivering tubulin inhibitors. Dose-dependent DNA crosslinks and γ-H2AX DNA damage response were measured in tumors by 24 hours after single dose administration, whereas matched peripheral blood mononuclear cells showed no evidence of DNA damage. Pharmacokinetic analysis in rat and cynomolgus monkey showed excellent stability and tolerability of ADCT-402 in vivo. Together, these impressive data were used to support the clinical testing of this novel ADC in patients with CD19-expressing B-cell malignancies.

Paracetamol (acetaminophen) for chronic non-cancer pain in children and adolescents.

BACKGROUND: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past, pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as important.We designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol as priority areas) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents.As the leading cause of morbidity in children and adolescents in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (lasting three months or longer) can arise in the paediatric population in a variety of pathophysiological classifications: nociceptive, neuropathic, idiopathic, visceral, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, and other unknown reasons.Paracetamol (acetaminophen) is one of the most widely used analgesics in both adults and children. The recommended dosage in the UK, Europe, Australia, and the USA for children and adolescents is generally 10 to 15 mg/kg every four to six hours, with specific age ranges from 60 mg (6 to 12 months old) up to 500 to 1000 mg (over 12 years old). Paracetamol is the only recommended analgesic for children under 3 months of age. Paracetamol has been proven to be safe in appropriate and controlled dosages, however potential adverse effects of paracetamol if overdosed or overused in children include liver and kidney failure. OBJECTIVES: To assess the analgesic efficacy and adverse events of paracetamol (acetaminophen) used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries. SELECTION CRITERIA: Randomised controlled trials, with or without blinding, of any dose and any route, treating chronic non-cancer pain in children and adolescents, comparing paracetamol with placebo or an active comparator. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and numbers needed to treat, using standard methods where data were available. We assessed GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table. MAIN RESULTS: No studies were eligible for inclusion in this review. We rated the quality of the evidence as very low. We downgraded the quality of evidence by three levels due to the lack of data reported for any outcome. AUTHORS' CONCLUSIONS: There was no evidence from randomised controlled trials to support or refute the use of paracetamol (acetaminophen) to treat chronic non-cancer pain in children and adolescents. We are unable to comment about efficacy or harm from the use of paracetamol to treat chronic non-cancer pain in children and adolescents.We know from adult randomised controlled trials that paracetamol, can be effective, in certain doses, and in certain pain conditions (not always chronic).This means that no conclusions could be made about efficacy or harm in the use of paracetamol (acetaminophen) to treat chronic non-cancer pain in children and adolescents.

Synthesis and in vitro evaluation of SG3227, a pyrrolobenzodiazepine dimer antibody-drug conjugate payload based on sibiromycin.

A novel pyrrolobenzodiazepine dimer payload, SG3227, was rationally designed based on the naturally occurring antitumour compound sibiromycin. SG3227 was synthesized from a dimeric core in an efficient fashion. An unexpected room temperature Diels-Alder reaction occurred during the final step of the synthesis and was circumvented by use of an iodoacetamide conjugation moiety in place of a maleimide. The payload was successfully conjugated to trastuzumab and the resulting ADC exhibited potent activity against a HER2-expressing human cancer cell line in vitro.

Design and Synthesis of Tesirine, a Clinical Antibody-Drug Conjugate Pyrrolobenzodiazepine Dimer Payload.

Pyrrolobenzodiazepine dimers are an emerging class of warhead in the field of antibody-drug conjugates (ADCs). Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics. One of the reactive imines was capped with a cathepsin B-cleavable valine-alanine linker. A robust synthetic route was developed to allow the production of tesirine on clinical scale, employing a flexible, convergent strategy. Tesirine was evaluated in vitro both in stochastic and engineered ADC constructs and was confirmed as a potent and versatile payload. The conjugation of tesirine to anti-DLL3 rovalpituzumab has resulted in rovalpituzumab-tesirine (Rova-T), currently under evaluation for the treatment of small cell lung cancer.

ADCT-301, a Pyrrolobenzodiazepine (PBD) Dimer-Containing Antibody-Drug Conjugate (ADC) Targeting CD25-Expressing Hematological Malignancies.

Despite the many advances in the treatment of hematologic malignancies over the past decade, outcomes in refractory lymphomas remain poor. One potential strategy in this patient population is the specific targeting of IL2R-α (CD25), which is overexpressed on many lymphoma and leukemic cells, using antibody-drug conjugates (ADC). ADCT-301 is an ADC composed of human IgG1 HuMax-TAC against CD25, stochastically conjugated through a dipeptide cleavable linker to a pyrrolobenzodiazepine (PBD) dimer warhead with a drug-antibody ratio (DAR) of 2.3. ADCT-301 binds human CD25 with picomolar affinity. ADCT-301 has highly potent and selective cytotoxicity against a panel of CD25-expressing human lymphoma cell lines. Once internalized, the released warhead binds in the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links. A strong correlation between loss of viability and DNA cross-link formation is demonstrated. DNA damage persists, resulting in phosphorylation of histone H2AX, cell-cycle arrest in G2-M, and apoptosis. Bystander killing of CD25-negative cells by ADCT-301 is also observed. In vivo, a single dose of ADCT-301 results in dose-dependent and targeted antitumor activity against both subcutaneous and disseminated CD25-positive lymphoma models. In xenografts of Karpas 299, which expressed both CD25 and CD30, marked superiority over brentuximab vedotin (Adcetris) is observed. Dose-dependent increases in DNA cross-linking, γ-H2AX, and PBD payload staining were observed in tumors in vivo indicating a role as relevant pharmacodynamic assays. Together, these data support the clinical testing of this novel ADC in patients with CD25-expressing tumors. Mol Cancer Ther; 15(11); 2709-21. ©2016 AACR.

Genetically Encoded Azide Containing Amino Acid in Mammalian Cells Enables Site-Specific Antibody-Drug Conjugates Using Click Cycloaddition Chemistry.

Antibody-drug conjugates (ADC) have emerged as potent antitumor drugs that provide increased efficacy, specificity, and tolerability over chemotherapy for the treatment of cancer. ADCs generated by targeting cysteines and lysines on the antibody have shown efficacy, but these products are heterogeneous, and instability may limit their dosing. Here, a novel technology is described that enables site-specific conjugation of toxins to antibodies using chemistry to produce homogeneous, potent, and highly stable conjugates. We have developed a cell-based mammalian expression system capable of site-specific integration of a non-natural amino acid containing an azide moiety. The azide group enables click cycloaddition chemistry that generates a stable heterocyclic triazole linkage. Antibodies to Her2/neu were expressed to contain N6-((2-azidoethoxy)carbonyl)-l-lysine at four different positions. Each site allowed over 95% conjugation efficacy with the toxins auristatin F or a pyrrolobenzodiazepine (PBD) dimer to generate ADCs with a drug to antibody ratio of >1.9. The ADCs were potent and specific in in vitro cytotoxicity assays. An anti Her2/neu conjugate demonstrated stability in vivo and a PBD containing ADC showed potent efficacy in a mouse tumor xenograph model. This technology was extended to generate fully functional ADCs with four toxins per antibody. The high stability of the azide-alkyne linkage, combined with the site-specific nature of the expression system, provides a means for the generation of ADCs with optimized pharmacokinetic, biological, and biophysical properties.

Photosynthesis of temperate Eucalyptus globulus trees outside their native range has limited adjustment to elevated CO2 and climate warming.

Eucalyptus species are grown widely outside of their native ranges in plantations on all vegetated continents of the world. We predicted that such a plantation species would show high potential for acclimation of photosynthetic traits across a wide range of growth conditions, including elevated [CO2] and climate warming. To test this prediction, we planted temperate Eucalyptus globulus Labill. seedlings in climate-controlled chambers in the field located >700 km closer to the equator than the nearest natural occurrence of this species. Trees were grown in a complete factorial combination of elevated CO2 concentration (eC; ambient [CO2] +240 ppm) and air warming treatments (eT; ambient +3 °C) for 15 months until they reached ca. 10 m height. There was little acclimation of photosynthetic capacity to eC and hence the CO2-induced photosynthetic enhancement was large (ca. 50%) in this treatment during summer. The warming treatment significantly increased rates of both carboxylation capacity (V(cmax)) and electron transport (Jmax) (measured at a common temperature of 25 °C) during winter, but decreased them significantly by 20-30% in summer. The photosynthetic CO2 compensation point in the absence of dark respiration (Γ*) was relatively less sensitive to temperature in this temperate eucalypt species than for warm-season tobacco. The temperature optima for photosynthesis and Jmax significantly changed by about 6 °C between winter and summer, but without further adjustment from early to late summer. These results suggest that there is an upper limit for the photosynthetic capacity of E. globulus ssp. globulus outside its native range to acclimate to growth temperatures above 25 °C. Limitations to temperature acclimation of photosynthesis in summer may be one factor that defines climate zones where E. globulus plantation productivity can be sustained under anticipated global environmental change.

Antibody-drug conjugates - a perfect synergy.

INTRODUCTION: There is a great unmet need for effective new treatments in cancer, which continues to be a major cause of death. Antibody-drug conjugates (ADCs) are emerging, after a long gestation, as a class of biopharmaceuticals with the potential to address this need by directing highly potent cytotoxic drugs to their point of action. There is increasing interest in ADCs by major pharmaceutical companies and a growing pipeline of candidates for clinical use. This review summarises progress with development of this new class of drugs. AREAS COVERED: The authors describe separately the antibody and drug elements of ADCs and then examine the technology and consequences of linkage. The work is presented in the light of recent developments in the design, using clinical examples where possible. EXPERT OPINION: Since their emergence as independent drugs, antibodies and chemotherapy are being brought together in effective synergy. The conjunction is timely: many of the technical challenges in preparing antibodies have been addressed; potent new drugs are available and linker technology is advancing apace. ADCs however are not just a sum of their individual parts. The current challenge is in understanding the holistic nature of this exciting class of drugs that promise a new avenue for cancer treatment. Target selection, the interaction of ADC with tumour and off-tumour targets and the internalisation of ADCs, are critical to the effective maturation of ADC technology. Ongoing recent developments in attachment sites and linker chemistry can provide fine-tuning of drug loading, elements of ADC PK and off-target ADC toxicity.