Canadian guidelines on the management of colorectal peritoneal metastases.

Modern management of colorectal cancer (crc) with peritoneal metastasis (pm) is based on a combination of cytoreductive surgery (crs), systemic chemotherapy, and hyperthermic intraperitoneal chemotherapy (hipec). Although the role of hipec has recently been questioned with respect to results from the prodige 7 trial, the role and benefit of a complete crs were confirmed, as observed with a 41-month gain in median survival in that study, and 15% of patients remaining disease-free at 5 years. Still, crc with pm is associated with a poor prognosis, and good patient selection is essential. Many questions about the optimal management approach for such patients remain, but all patients with pm from crc should be referred to, or discussed with, a pm surgical oncologist, because cure is possible. The objective of the present guideline is to offer a practical approach to the management of pm from crc and to reflect on the new practice standards set by recent publications on the topic.

Tumour response 3 months after neoadjuvant single-fraction radiotherapy for low-risk breast cancer.

Introduction: Standard treatment for early-stage invasive breast cancer (bca) consists of breast-conserving surgery and several weeks of adjuvant radiotherapy (rt). Neoadjuvant single-fraction rt is a novel approach for early-stage bca. We sought to investigate the effect of delaying surgery after neoadjuvant rt with respect to the rate of pathologic response (pr). Methods: Women 65 years of age or older with a new diagnosis of stage i luminal A bca were eligible for inclusion. A single 20 Gy dose to the primary breast tumour was given, followed by breast-conserving surgery 3 months later. The primary endpoint was the pr rate assessed by microscopic evaluation using the Miller-Payne system. Results: To date, 10 patients have been successfully treated. Median age of the patients was 72 years (range: 65-84 years). In 8 patients, neoadjuvant rt resulted in a tumour pr with median residual cellularity of 3%. No immediate rt complications other than mild dermatitis were noted. Conclusions: This study demonstrates a method for delivering single-fraction rt that can lead to a high level of pr in most patients. Continued accrual to this study and subsequent trials are needed to determine the feasibility, safety, and role of this novel technique in the management of early-stage bca.

The current practice of cytoreductive surgery and HIPEC for colorectal peritoneal metastases: Results of a worldwide web-based survey of the Peritoneal Surface Oncology Group International (PSOGI).

BACKGROUND: At present, selected patients with resectable colorectal peritoneal metastases (CRC-PM) are increasingly treated with a combination therapy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of this study was to investigate the current worldwide practice. METHODS: HIPEC experts from 19 countries were invited through the Peritoneal Surface Oncology Group International (PSOGI) to complete an online survey concerning their personal expertise and current hospital and countrywide practice. RESULTS: It is estimated that currently more than 3800 patients with CRC-PM (synchronous and metachronous) are annually treated with CRS and HIPEC in 430 centers. Integration of CRS and HIPEC in national guidelines varies, resulting in large treatment disparities between countries. Amongst the experts, there was general agreement on issues related to indication, surgical technique and follow up but less on systemic chemotherapy or proactive strategies. CONCLUSION: This international survey demonstrates that CRS and HIPEC is now performed on a large scale for CRC-PM patients. Variation in treatment may result in heterogeneity in surgical and oncological outcomes, emphasising the necessity to reach consensus on several issues of this comprehensive procedure. Future initiatives directed at achieving an international consensus statement are needed.

Rationale for the administration of systemic 5-FU in combination with heated intraperitonal oxaliplatin.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin (OX) is the standard of care for selected patients with peritoneal carcinomatosis of colorectal origin. Because 5-FU is mandatory to improve efficacy of OX when used by systemic route, several teams now empirically combine intravenous (IV) 5-FU with HIPEC OX, but this practice has yet to be supported by preclinical data. Using a murine model, we studied the impact of IV 5-FU on peritoneal absorption of HIPEC OX. METHODS: Under general anesthesia, 24 Sprague-Dawley rats were submitted to 4 different doses of IV 5-FU (0, 100, 400 and 800 mg/m2) and a fixed dose of HIPEC OX (460 mg/m2) perfused at 40 °C during 25 min. At 25 min, samples in different compartments were harvested (peritoneum, portal vein and systemic blood) and the concentrations of 5-FU and OX were measured by high performance liquid chromatography. RESULTS: Peritoneal absorption of OX was significantly higher (17.0, 20.1, 34.9 and 38.1 nmol/g, p < 0.0001) with increasing doses of 5-FU (0, 100, 400 and 800 mg/m2, respectively). Peritoneal absorption of OX reached a plateau between 400 and 800 mg/m2 of IV 5-FU. CONCLUSION: IV 5-FU enhances peritoneal absorption of HIPEC OX. The most efficient dose of IV 5-FU to be used in combination with HIPEC OX seems to be 400 mg/m2.

Recovery of ammonia and phosphate minerals from swine wastewater using gas-permeable membranes.

Gas-permeable membrane technology is useful to recover ammonia (NH3) from liquid manures. In this study, phosphorus (P) recovery via MgCl2 precipitation was enhanced by combining it with NH3 recovery through gas-permeable membranes. Anaerobically digested swine wastewater containing approximately 2300 mg NH4+-N L-1 and 450 mg P L-1 was treated using submerged membranes plus low-rate aeration to recover the NH3 from within the liquid and MgCl2 to precipitate the P. The experiments included a first configuration where N and P were recovered sequentially and a second configuration with simultaneous recovery. The low-rate aeration reduced the natural carbonate, increased pH and accelerated NH3 uptake by the gas-permeable membrane system, which in turn benefited P recovery. Phosphorus removal efficiency was >90% and P recovery efficiency was about 100%. With higher NH3 capture, the recovered P contained higher P2O5 content (37-46%, >98% available), similar to the composition of the biomineral newberyite (MgHPO4·3H2O).

Enhancing recovery of ammonia from swine manure anaerobic digester effluent using gas-permeable membrane technology.

Gas-permeable membrane technology is useful to recover ammonia from manure. In this study, the technology was enhanced using aeration instead of alkali chemicals to increase pH and the ammonium (NH4(+)) recovery rate. Digested effluents from covered anaerobic swine lagoons containing 1465-2097 mg NH4(+)-N L(-1) were treated using submerged membranes (0.13 cm(2) cm(-3)), low-rate aeration (120 mL air L-manure(-1) min(-1)) and nitrification inhibitor (22 mg L(-1)) to prevent nitrification. The experiment included a control without aeration. The pH of the manure with aeration rose from 8.6 to 9.2 while the manure without aeration decreased from 8.6 to 8.1. With aeration, 97-99% of the NH4(+) was removed in about 5 days of operation with 96-98% recovery efficiency. In contrast, without aeration it took 25 days to treat the NH4(+). Therefore, the recovery of NH4(+) was five times faster with the low-rate aeration treatment. This enhancement could reduce costs by 70%.

Guidelines on the use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with peritoneal surface malignancy arising from colorectal or appendiceal neoplasms.

To meet the needs of patients, Canadian surgical and medical oncology leaders in the treatment of peritoneal surface malignancies (psms), together with patient representatives, formed the Canadian HIPEC Collaborative Group (chicg). The group is dedicated to standardizing and improving the treatment of psm in Canada so that access to treatment and, ultimately, the prognosis of Canadian patients with psm are improved. Patients with resectable psm arising from colorectal or appendiceal neoplasms should be reviewed by a multidisciplinary team including surgeons and medical oncologists with experience in treating patients with psm. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy should be offered to appropriately selected patients and performed at experienced centres. The aim of this publication is to present guidelines that we recommend be applied across the country for the treatment of psm.

Broadband, unpolarized repumping and clearout light sources for Sr(+) single-ion clocks.

Future transportable optical clocks require compact and reliable light sources. Here, broadband, unpolarized repumper and state clearout sources for Sr+ single-ion optical clocks are reported. These turn-key devices require no frequency stabilization or external modulators. They are fiber based, inexpensive, and compact. Key characteristics for clock operation are presented, including optical spectra, induced light shifts, and required extinction ratios. Tests with an operating single-ion standard show a clearout efficiency of 100%. Compared to a laser-based repumper, the achievable fluorescence rates for ion detection are a few tens of percent lower. The resulting ion kinetic temperature is 1-1.5 mK, near the Doppler limit of the ion system. Similar repumper light sources could be made for Ca+ (866 nm) and Ba+ (650 nm) using semiconductor gain media.

Treatment for calcium channel blocker poisoning: a systematic review.

CONTEXT: Calcium channel blocker poisoning is a common and sometimes life-threatening ingestion. OBJECTIVE: To evaluate the reported effects of treatments for calcium channel blocker poisoning. The primary outcomes of interest were mortality and hemodynamic parameters. The secondary outcomes included length of stay in hospital, length of stay in intensive care unit, duration of vasopressor use, functional outcomes, and serum calcium channel blocker concentrations. METHODS: Medline/Ovid, PubMed, EMBASE, Cochrane Library, TOXLINE, International pharmaceutical abstracts, Google Scholar, and the gray literature up to December 31, 2013 were searched without time restriction to identify all types of studies that examined effects of various treatments for calcium channel blocker poisoning for the outcomes of interest. The search strategy included the following Keywords: [calcium channel blockers OR calcium channel antagonist OR calcium channel blocking agent OR (amlodipine or bencyclane or bepridil or cinnarizine or felodipine or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or prenylamine or verapamil or diltiazem)] AND [overdose OR medication errors OR poisoning OR intoxication OR toxicity OR adverse effect]. Two reviewers independently selected studies and a group of reviewers abstracted all relevant data using a pilot-tested form. A second group analyzed the risk of bias and overall quality using the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) checklist and the Thomas tool for observational studies, the Institute of Health Economics tool for Quality of Case Series, the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines, and the modified NRCNA (National Research Council for the National Academies) list for animal studies. Qualitative synthesis was used to summarize the evidence. Of 15,577 citations identified in the initial search, 216 were selected for analysis, including 117 case reports. The kappa on the quality analysis tools was greater than 0.80 for all study types. RESULTS: The only observational study in humans examined high-dose insulin and extracorporeal life support. The risk of bias across studies was high for all interventions and moderate to high for extracorporeal life support. High-dose insulin. High-dose insulin (bolus of 1 unit/kg followed by an infusion of 0.5-2.0 units/kg/h) was associated with improved hemodynamic parameters and lower mortality, at the risks of hypoglycemia and hypokalemia (low quality of evidence). Extracorporeal life support. Extracorporeal life support was associated with improved survival in patients with severe shock or cardiac arrest at the cost of limb ischemia, thrombosis, and bleeding (low quality of evidence). Calcium, dopamine, and norepinephrine. These agents improved hemodynamic parameters and survival without documented severe side effects (very low quality of evidence). 4-Aminopyridine. Use of 4-aminopyridine was associated with improved hemodynamic parameters and survival in animal studies, at the risk of seizures. Lipid emulsion therapy. Lipid emulsion was associated with improved hemodynamic parameters and survival in animal models of intravenous verapamil poisoning, but not in models of oral verapamil poisoning. Other studies. Studies on decontamination, atropine, glucagon, pacemakers, levosimendan, and plasma exchange reported variable results, and the methodologies used limit their interpretation. No trial was documented in humans poisoned with calcium channel blockers for Bay K8644, CGP 28932, digoxin, cyclodextrin, liposomes, bicarbonate, carnitine, fructose 1,6-diphosphate, PK 11195, or triiodothyronine. Case reports were only found for charcoal hemoperfusion, dialysis, intra-aortic balloon pump, Impella device and methylene blue. CONCLUSIONS: The treatment for calcium channel blocker poisoning is supported by low-quality evidence drawn from a heterogeneous and heavily biased literature. High-dose insulin and extracorporeal life support were the interventions supported by the strongest evidence, although the evidence is of low quality.

Nonsyndromic tooth agenesis patterns and associated developmental dental anomalies: a literature review with radiographic illustrations.

Tooth agenesis is one of the most intriguing phenomena, because it is frequently associated with other oral anomalies, structural variations and malformations of other teeth, late eruption, transposition and crowding. The diagnosis can be quite challenging as radiographic examination is critical for the diagnosis but not always possible and the late developing teeth may be sometimes scored developmentally missing. Accurate diagnosis therefore requires radiographic, clinical, and dental cast examinations. It is an important clinical and public health problem. Patients with missing permanent teeth may suffer from a reduced chewing ability, inarticulate pronunciation, and an unfavorable aesthetic appearance. Clinically, early diagnosis of a dental anomaly can alert the clinician to the possible development of other associated dental anomalies in the same patient or family, and avoid the possible sequelae. Understanding of tooth agenesis patterns and their impact on diagnosis, prevention, and eventually therapeutics are becoming integral parts of comprehensive dental care. Dental examination with radiographic screening of hypodontia in early childhood should be emphasized as part of public oral health policy to allow early diagnosis and timely intervention.

Prolonged Therapy with Imatinib Mesylate before Surgery for Advanced Gastrointestinal Stromal Tumor Results of a Phase II Trial.

Purpose. Proven efficacy of imatinib mesylate in gastrointestinal stromal tumour (GIST) has led to its use in advanced disease and, more recently, in adjuvant and neoadjuvant settings. The purpose of this study was to evaluate the optimal neoadjuvant imatinib duration to reduce the morbidity of surgery and increase the possibility of resection completeness in advanced tumours. Patients and Method. Patients with advanced GIST were enrolled into a registered open-label multicenter trial and received imatinib daily for a maximum of 12 months, followed by en bloc resection. Data were prospectively collected regarding tumour assessment, response rate, surgical characteristics, recurrence, and survival. Results. Fourteen patients with advanced GIST were enrolled. According to RECIST criteria, 6 patients had partial response and 8 had stable disease. The overall tumour size reduction was 25% (0-62.5%), and there was no tumour progression. Eleven patients underwent tumour resection, and all had R0 resection. After a median followup of 48 months, 4-year OS and DFS were 100% and 64%, respectively. Conclusion. This prospective trial showed that one year of neoadjuvant imatinib in advanced GIST is safe and associated with high rate of complete microscopic resection. It is not associated with increased resistance, progression, or complication rates.

Electric quadrupole shift cancellation in single-ion optical frequency standards.

The electric quadrupole shift is presently the most significant source of uncertainty on the systematic shifts for several single-ion optical frequency standards. We present a simple method for cancelling this shift based on measurements of the Zeeman spectrum of the clock transition. This method is easy to implement and yields very high cancellation levels. A fractional uncertainty of 5 x 10(-18) for the canceled quadrupole shift is estimated for a measurement of the absolute frequency of the 5s (2)S(1/2)-4d (2)D(5/2) clock transition of 88Sr+.

Scalar interaction limits from the beta-nu correlation of trapped radioactive atoms.

We have set limits on contributions of scalar interactions to nuclear beta decay. A magneto-optical trap provides a localized source of atoms suspended in space, so the low-energy recoiling nuclei can freely escape and be detected in coincidence with the beta. This allows reconstruction of the neutrino momentum, and the measurement of the beta-nu correlation, in a more direct fashion than previously possible. The beta-nu correlation parameter of the 0(+)-->0(+) pure Fermi decay of (38)K(m) is a =0.9981+/-0.0030+0.0032 / -0.0037, consistent with the standard model prediction a =1.

Nutrient, neural and endocrine control of glucagon-like peptide secretion.

The intestinal glucagon-like peptides, GLP-1 and GLP-2, are important regulators of nutrient intake, digestion, absorption and metabolism. Extensive studies have shown that the co-secretion of GLP-1 and GLP-2 is regulated by a variety of dietary nutrient, neural and endocrine inputs. Furthermore, secretion of these peptides is altered in a number of pathological conditions, including type 2 diabetes and obesity. The purpose of this review is to discuss the regulation of GLP-1 and GLP-2 secretion in both health and disease.

Novel search for heavy nu mixing from the beta+ decay of 38mK confined in an atom trap.

A new technique, full neutrino momentum reconstruction, is used to set limits on the admixture of heavy neutrinos into the electron neutrino. We measure coincidences between nuclear recoils and positrons from the beta decay of trapped radioactive atoms and deduce the neutrino momentum. A search for peaks in the reconstructed recoil time-of-flight spectrum as a function of positron energy is performed. The admixture upper limits range from 4 x 10(-3) to 2 x 10(-2) and are the best direct limits for neutrinos (as opposed to antineutrinos) for the mass region of 0.7 to 3.5 MeV.

Structural organisation of the head-to-tail interface of a bacterial virus.

In tailed icosahedral bacteriophages the connection between the 5-fold symmetric environment of the portal vertex in the capsid and the 6-fold symmetric phage tail is formed by a complex interface structure. The current study provides the detailed analysis of the assembly and structural organisation of such an interface within a phage having a long tail. The region of the interface assembled as part of the viral capsid (connector) was purified from DNA-filled capsids of the Bacillus subtilis bacteriophage SPP1. It is composed of oligomers of gp6, the SPP1 portal protein, of gp15, and of gp16. The SPP1 connector structure is formed by a mushroom-like portal protein whose cap faces the interior of the viral capsid in intact virions, an annular structure below the stem of the mushroom, and a second narrower annulus that is in direct contact with the helical tail extremity. The layered arrangement correlates to the stacking of gp6, gp15, and gp16 on top of the tail. The gp16 ring is exposed to the virion outside. During SPP1 morphogenesis, gp6 participates in the procapsid assembly reaction, an early step in the assembly pathway, while gp15 and gp16 bind to the capsid portal vertex after viral chromosome encapsidation. gp16 is processed during or after tail attachment to the connector region. The portal protein gp6 has 12-fold cyclical symmetry in the connector structure, whereas assembly-naïve gp6 exhibits 13-fold symmetry. We propose that it is the interaction of gp6 with other viral morphogenetic proteins that drives its assembly into the 12-mer state.

A role for IL-1 alpha in inducing pathologic inflammation during bacterial infection.

Infection with pathogenic microbes often results in a significant inflammatory response. A cascade of proinflammatory cytokines including tumor necrosis factor alpha (TNF-alpha) and IL-1 initiates this response. Although there is a clear role for IL-1 during infection, little is known to distinguish the role of IL-1 alpha from that of IL-1 beta during this process. With the use of Yersinia enterocolitica as a model enteric pathogen, we have identified a specific role for IL-1 alpha in inducing pathologic inflammation during bacterial infection. Depletion of IL-1 alpha in mice infected with wild-type Y. enterocolitica results in significantly decreased intestinal inflammation. Furthermore, a bacterial mutant that does not induce IL-1 alpha expression but induces normal levels of IL-1 beta, TNF-alpha, and IFN-gamma, causes greatly reduced intestinal inflammation and is attenuated by LD(50) analysis in the C57BL/6 mouse model. These results demonstrate a distinct and unrecognized role for IL-1 alpha in inducing intestinal inflammation that cannot be compensated for by the endogenous levels of IL-1 beta, TNF-alpha, or IFN-gamma that are produced in response to Y. enterocolitica. Additionally, these results suggest that IL-1 alpha-induced inflammation is a major contributor to the pathology of yersiniosis.

Palladium and Raney nickel catalyzed methanolic cleavage of stable borane-amine complexes.

[figure: see text] Palladium and Raney nickel were found to catalyze the methanolysis of borane-amine adducts. Hence, strongly complexed amines can now be liberated by simple treatment with Pd/C or Raney Ni in methanol. The method is applicable to primary, secondary, tertiary, and aromatic amines, and the mildness of the reaction conditions allows preservation of otherwise labile functional groups.

Three-dimensional structure of the anaphase-promoting complex.

The anaphase-promoting complex (APC) is a cell cycle-regulated ubiquitin-protein ligase, composed of at least 11 subunits, that controls progression through mitosis and G1. Using cryo-electron microscopy and angular reconstitution, we have obtained a three-dimensional model of the human APC at a resolution of 24 A. The APC has a complex asymmetric structure 140 A x 140 A x 135 A in size, in which an outer protein wall surrounds a large inner cavity. We discuss the possibility that this cavity represents a reaction chamber in which ubiquitination reactions take place, analogous to the inner cavities formed by other protein machines such as the 26S proteasome and chaperone complexes. This cage hypothesis could help to explain the great subunit complexity of the APC.