Initial experience of TAS-102 chemotherapy in Australian patients with Chemo-refractory metastatic colorectal cancer.

For patients with refractory metastatic colorectal cancer (mCRC) treatment with Trifluridine/Tipiracil, also known as TAS-102, improves overall survival. This study aims to investigate the efficacy and safety of TAS-102 in a real-world population from Victoria, Australia. A retrospective analysis of prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was undertaken. The characteristics and outcomes of patients receiving TAS-102 were assessed and compared to those enrolled in the registration study (RECOURSE). Across 13 sites, 107 patients were treated with TAS-102. The median age was 60 years (range: 31-83), compared to 63 for RECOURSE. Comparing registry TAS-102-treated and RECOURSE patients, 75% vs 100% were ECOG performance status 0-1, 74% vs 79% had initiated treatment more than 18 months from diagnosis of metastatic disease and 36% vs 49% were RAS wild-type. Median time on treatment was 10.4 weeks (range: 1.7-32). Median progression-free survival (PFS) was 3.3 months compared to 2 months in RECOURSE, while median overall survival was the same at 7.1 months. Two patients (2.3%) had febrile neutropenia and there were no treatment-related deaths, where TAS-102 dose at treatment initiation was at clinician discretion.TRACC registry patients treated with TAS-102 were younger than those from the RECOURSE trial, with similar overall survival observed. Less strict application of RECIST criteria and less frequent imaging may have contributed to an apparently longer PFS.

Metabolic response of rectal cancer assessed by 18-FDG PET following chemoradiotherapy is prognostic for patient outcome.

BACKGROUND: Complete pathological response has proven prognostic benefits in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Sequential 18-FDG PET may be an early surrogate for pathological response to chemoradiotherapy. OBJECTIVES: The aim of this study was to identify whether metabolic response measured by FDG PET following chemoradiotherapy is prognostic for tumor recurrence and survival following neoadjuvant therapy and surgical treatment for primary rectal cancer. METHODS: Patients with primary rectal cancer treated by long-course neoadjuvant chemoradiotherapy followed by surgery had FDG PET performed before and 4 weeks after treatment, before surgical resection was performed. Retrospective chart review was undertaken for patient demographics, tumor staging, recurrence rates, and survival. RESULTS: : Between 2000 and 2007, 78 patients were identified (53 male, 25 female; median age, 64 y). After chemoradiotherapy, 37 patients (47%) had a complete metabolic response, 26 (33%) had a partial metabolic response, and 14 (18%) had no metabolic response as assessed by FDG PET (1 patient had missing data). However, only 4 patients (5%) had a complete pathological response. The median postoperative follow-up period was 3.1 years during which 14 patients (19%) had a recurrence: 2 local, 9 distant, and 3 with both local and distant. The estimated percentage without recurrence was 77% at 5 years (95% CI 66%-89%). There was an inverse relationship between FDG PET metabolic response and the incidence of recurrence within 3 years (P = .04). Kaplan-Meier analysis of FDG PET metabolic response and overall survival demonstrated a significant difference in survival among patients in the 3 arms: complete, partial, and no metabolic response (P = .04); the patients with complete metabolic response had the best prognosis. CONCLUSION: Complete or partial metabolic response on PET following neoadjuvant chemoradiotherapy and surgery predicts a lower local recurrence rate and improved survival compared with patients with no metabolic response. Metabolic response may be used to stratify prognosis in patients with rectal cancer.

How good are newly qualified doctors at digital rectal examination?

AIM: Digital rectal examination (DRE) is an essential skill which all newly qualified doctors should have. There is evidence in the literature that junior doctors lack this important examination technique. The aim of our study was to determine, with the help of a questionnaire, the abilities of foundation year 1 (FY1) doctors to perform DRE. METHOD: A questionnaire was developed and sent to newly qualified FY1 doctors qualified in two universities (Nottingham and Sheffield) within the first 4 weeks of starting as a FY1 doctor. RESULTS: Ninety (75%) out of 120 questionnaires were completed. Most FY1 doctors had very little experience in performing DRE on a patient, and 68 (76%) had performed less than 10 procedures prior to qualification. Very few of these doctors had their clinical findings on DRE checked by a senior doctor (n = 7, 8%). Comparing DRE with other forms of examination, newly qualified doctors were most confident at groin hernia examination followed by testicular examination. They were least confident with vaginal examination and DRE (ANOVA P = 0.0082). CONCLUSION: Digital rectal examination is frequently performed by the most inexperienced doctor and may not be verified by a more senior colleague. More training and supervision of junior doctors are required both prior to qualification and during the early stages of their medical career.

Fibrin glue for the treatment of fistulae in ano--a method worth sticking to?

OBJECTIVE: The current evidence for fibrin glue as a treatment for anal fistulae is mixed. This study reviews the experience of fibrin glue as a treatment for anal fistulae in a single tertiary referral centre and attempts to identify factors related to failure of therapy and the length of follow-up required. METHOD: Patients with fistulae in ano that were treated with fibrin glue between February 2004 and August 2008 were analysed. All procedures were performed by two colorectal consultants based at the Queens Medical Centre, Nottingham. All patients were followed-up to assess the outcome of this treatment. RESULTS: Forty patients (21 male, 19 female) with a mean age of 46.5 years were studied. The mean duration of symptoms prior to presentation was 39 months (range 4-240 months). Presenting symptoms included perianal discharge (72.5%), perianal abscess (57.5%), pain (12.5%), PR bleeding (7.5%), itching (5%) and urgency (2.5%). Patients had a minimum of two follow-up appointments and the median follow-up period was 5.2 months (range 1-16 months). Following MRI and operative assessment, 28 (70%) of the 40 fistulae were considered complex (high trans-sphincteric, extra-sphincteric, pouch-vaginal). Patients who had inflammatory bowel disease were classified as simple tracts but all failed to heal (three patients). Twenty of the complex fistulae failed to heal. Three patients who had repeat application of glue for their complex fistulae failed to heal on follow-up. Of the remaining 12 patients who had simple fistulae in ano, five (41.7%) healed completely. There were no complications such as abscess, related to treatment. All patients who were asymptomatic at 3 months did not develop any further recurrence. CONCLUSION: Fibrin glue is a simple treatment strategy, preserves sphincter function with minimal adverse side effects. It should therefore be considered as possible first line treatment in simple fistulae but it is less likely to be successful in complex or those fistulae associated with inflammatory bowel disease. Repeat gluing is unlikely to be successful. Fistulae that have failed to heal by 3 months will need further treatment.

Intraoperative radiotherapy and colorectal cancer.

Intraoperative radiotherapy (IORT) is a highly specialized component of multidisciplinary management of advanced and recurrent colorectal cancer. The aim of this review was to assess its role and effectiveness in the management of colorectal cancer. A literature search was performed using Medline, Embase, Ovid and Cochrane to identify English language studies which have used IORT in the multidisciplinary management of primary and recurrent colon and rectal cancers. Improved survival and local control in patients with involved surgical margins treated with IORT have been shown in many studies, but these results have been mainly from retrospective studies. There is associated morbidity from IORT. IORT does have a role in the management of colorectal cancer. Further research needs to be performed to optimize the application of this therapy.

Colonic tattooing in laparoscopic surgery - making the mark?

OBJECTIVE: Laparoscopic surgery for colorectal cancer is now widespread. Small lesions in the colon can be difficult to palpate and with lack of tactile sensation, it is essential to accurately localize them preoperatively. This is a review article on current methods of tattooing including the use of different agents and associated complications. Aim To review current techniques in preoperative tumour localization and methods used for colonic tattooing including agents used, dosage and potential complications. METHOD: A literature search (Medline and Pubmed) was performed with manual cross referencing of all articles related to colonic tattooing. RESULTS: Methods for localizing colonic tumours for laparoscopic resection include preoperative barium enema examination, CT colonography and intraoperative colonoscopy. The most effective method is, however, by tattooing with India ink performed endoscopically before surgery. CONCLUSION: India ink is a reliable method of marking tumour location within the colon as prelude to laparoscopic resection. Surgeons must, however, be aware of potential complications associated with this technique.

Community nurses' practices in managing perianal abscesses.

A survey of community nurses identified that a wide range of dressings, and in some cases unethical practices, are being used for this simple postoperative condition. Communication between hospital, community staff and patients was poor.

Surgical treatment of in-growing toenails performed by senior house officers: are they good enough?

BACKGROUND: Although the surgical treatment of in-growing toenails is a common procedure, the success of ingrown toenail surgery is extremely variable and recurrences frequently impair the quality of lift of those who have this condition. In most hospitals this procedure is commonly performed by junior surgical trainees who may have little experience. AIM: We proposed to find out if the success of this procedure is operator-dependent by comparing the results of standard of toenail surgery performed by basic surgical trainees (BSTs) in our hospitals with already published data. METHODS: A retrospective analysis of nail bed ablation surgery performed by BSTs under local anaesthesia over a 15-month period in a district general hospital was conducted. RESULTS: 106 phenol ablations and 46 germinal matrix excisions were prformed. Symptomatic recurrence rates 12 months following the procedure were 5.7% for phenol ablation and 4.3% for germinal matrix excisions. CONCLUSION: Our results are comparable to published data, and we conclude that toenail ablation surgery can be just as successfully performed by junior surgeons after relatively little training in the procedure.

Effect of diabetes on the cutaneous microcirculation of the feet in patients with intermittent claudication.

AIMS: To evaluate endothelial-dependent and - independent cutaneous vasodilator responses in the feet of patients with peripheral arterial disease (PAD) with or without Type 2 diabetes. METHODS: Cutaneous microvascular responses in the dorsum of both lower limbs were measured in the supine position using Laser Doppler Fluximetry combined with iontophoretic administration of endothelial-dependent (acetylcholine, Ach) and -independent (sodium nitroprusside, SNP) vasodilators in diabetic (n = 19) and non diabetic (n = 17) patients with PAD (presenting as unilateral calf intermittent claudication (IC). RESULTS: In patients with diabetes and IC, endothelial-dependent vasodilation was significantly impaired in the symptomatic limb [74 (57,105) vs 68 (24,81) PU, Z =-2.79, p = 0.005] compared to the asymptomatic limb. Patients without diabetes showed no impairment of vasodilation. Resting ankle-brachial pressure index did not identify the presence of abnormalities in microvascular function. CONCLUSIONS: The combination of diabetes and PAD is associated with a reduction in endothelial-dependent cutaneous vasodilation in the feet without an associated reduction in endothelial independent vasodilation.

Synthesis of N-(3,6-dihydro-1(2H)-pyridinyl)benzamides with hyperglycemic-hypoglycemic activity.

A group of N-(3,6-dihydro-1(2H)-pyridinyl)benzamides 7 were synthesized to determine the effect that the position and physicochemical properties of substituents attached to the heterocyclic ring have on blood glucose levels. 5-Methyl-N-(3,6-dihydro-1(2H)-pyridinyl)benzamide 7b was the most active hyperglycemic agent, elevating blood glucose 124% and 116% at 2 and 4 h, respectively, after a 100 mg/kg po dose. The most active hypoglycemic agent was the 4-acetyl analogue 7o, which was about 50% as active as chlorpropamide, lowering blood glucose 19% at 4 h after a 100 mg/kg po dose. A correlation between blood glucose levels and the partition coefficient P was not observed.

Synthesis of N-[[(substituted-phenyl)carbonyl]amino]-1,2,3,6-tetrahydropyridines with analgesic and hyperglycemic activity.

A group of N-[(phenylcarbonyl)amino]1-2,3,6-tetrahydropyridines, 5, were synthesized to determine the effect that changes in aromatic substitution on the phenyl ring have on analgesic, hyperglycemic, and antiinflammatory activities. All of the N-[(phenylcarbonyl)amino]-1,2,3,6-tetrahydropyridines 5 exhibited potent analgesic activity, relative to morphine, irrespective of the position and physicochemical properties of the aromatic substituent. Pretreatment with naloxone did not alter the analgesic activity of the 4-fluorophenyl derivative 5P. N-[[(2-Fluorophenyl)-carbonyl]amino]-1,2,3,6-tetrahydropyridine (5n) was one of the most active hyperglycemic agents, elevating blood glucose 213 and 127% at 2 and 4 h after a 100 mg/kg po dose. Incorporation of aromatic substituents into the 3 and 4 positions of 1 abolished antiinflammatory activity.

Synthesis of N-(carbonylamino)-1,2,3,6-tetrahydropyridines with analgesic, antiinflammatory, and hyperglycemic activity.

A group of N-(carbonylamino)-1,2,3,6-tetrahydropyridines was synthesized to investigate the effects that changes in functionality at the carbonyl group have on analgesic, antiinflammatory, and hyperglycemic activities. One of the most active analgesic compounds was N-[(ethoxycarbonyl)amino]-1,2,3,6-tetrahydropyridine (5o), which was comparable to that of morphine. Pretreatment with naloxone did not alter the activity of 5o or 5q. N-[(2-Furanylcarbonyl)amino]-1,2,3,6-tetrahydropyridine (5q) was the most potent hyperglycemic agent, elevating blood glucose 181% at 2 and 4 h after a 100 mg/kg po dose.

Coordinated expression of Hoxa2, Hoxd1 and Pax6 in the developing diencephalon.

Coordinated expression of Hoxa2, Hoxd1 and Pax6 proteins were found to coincide with the three developmental stages of the diencephalon, as described for the mouse brain. In the first stage (embryonic day (E) 10-12) Hoxa2, Hoxd1 and Pax6 (an early marker gene of the diencephalon) were expressed as early as E10.5 in prosomeres (p), p2 and p3. All three proteins continue to exhibit overlapping domains of expression at E12.5-13 (beginning of the second stage) when the primitive dense cell layer begins to differentiate into the internal germinal, external germinal and mantle layers. Towards the end of the second stage (E15), Pax6 expression was down-regulated whereas Hoxa2 and Hoxd1 continued to exhibit overlapping domains of expression for both protein and mRNA. Hoxd1 expression decreased significantly in the third stage of diencephalic development (E16-postnatal) such that only Hoxa2 expression persisted in the diencephalon of newborn mice. The temporal and spatial expression of these three proteins imply that coordinated waves of Hoxa2, Hoxd1 and Pax6 expression may be required to provide positional information for the specification of the diencephalon.

Rapid analysis of beta-phenylethylamine in tissues and body fluids utilizing pentafluorobenzoylation followed by electron-capture gas chromatography.

A rapid, sensitive gas chromatographic procedure for analysis of beta-phenylethylamine is reported. The procedure involves extraction with a liquid ion-pairing compound, back-extraction with HCl, basification and reaction with pentafluorobenzoyl chloride under aqueous conditions. The pentafluorobenzoyl derivative of beta-phenylethylamine is then separated and analyzed on a gas chromatograph equipped with a capillary column and an electron-capture detector. The procedure produces a derivative which has good chromatographic properties and a high degree of stability. The method has been applied to analysis of beta-phenylethylamine in a variety of tissues and body fluids.

Effects of the antidepressant phenelzine on brain levels of gamma-aminobutyric acid (GABA).

Time- and dose-response studies were carried out on the effects of the monoamine oxidase-inhibiting antidepressant and antipanic drug phenelzine on GABA levels in rat whole brain. At a dose of 15 mg/kg i.p., phenelzine significantly elevated GABA levels at all time intervals studied (1, 2, 4, 8, 16, and 24 h). A further investigation indicated that this was a dose-dependent effect. The possible importance of GABA in the etiology and pharmacotherapy of depression and panic disorder is discussed.

Criteria to determine food allergen priority.

The emergent health issue of food allergens presents an important challenge to the food industry. More than 170 foods have been reported in the scientific literature as causing allergic reactions. Clearly, it would be impossible to deal with the presence of trace amounts of all these in the context of food labeling. If the decision to classify major allergens is based solely on the knowledge and experience of allergists and food scientists in the field, without scientifically defined criteria, it is likely to lead to a proliferation of lists. Such practices may lead to an unnecessary elimination of foods containing important nutrients. This paper defines food allergy, food intolerance, and food anaphylaxis and identifies criteria for classifying food allergens associated with frequent allergic reactions. A practical list of food allergens that may result in potentially life-threatening allergic reactions is provided. A mechanism-based (i.e., immunoglobulin E mediated), acute life-threatening anaphylaxis that is standardized and measurable and reflects the severity of health risk is proposed as the principal inclusion criterion for food allergen labeling. Where available, prevalence in the population and threshold levels of allergens should be used as an additional guide to identify possible future labeling needs.

Biological fate of fumonisin B1 in food-producing animals.

The presence of mycotoxins in grains and feedstuffs causes not only animal health problems, but also a valid concern about the transmission of potentially toxic residues into animal-derived products intended for human consumption. In a series of studies at Agriculture and Agri-Food Canada, we investigated the biological fate of fumonisin B1 (FB1) in several food-producing animals (grower pigs, laying hens, dairy cattle), as well as monitored various parameters for evidence of toxicity in these species. In several experiments involving either single-dose protocols (iv, po) or longer-term feeding trials, the pharmacokinetic profiles of FB1 (purity > 95%) in these species were determined, including tissue accumulation and transmission of residues. Toxicological (and economical) implications such as performance (feed consumption, growth), productivity, and carcass quality were also measured when appropriate.

Survey of total tetrahydrophthalimide in baby foods using both enzyme-linked immunosorbent assay and gas chromatography/mass spectrometry: a comparative study.

An enzyme-linked immunosorbent assay (ELISA) method was compared with a gas chromatographic/mass spectrometric (GC/MS) method for determining the concentration (in parts per million) of the combination of captan and its degradation product tetrahydrophthalimide (THPI) in 13 fruit samples and in a survey of baby foods. Ninety baby foods (49 fruits, 28 juices, and 13 vegetables) from 2 different suppliers were sampled. All captan in the samples was converted to THPI before each analysis. None of the samples contained a concentration of combined captan and THPI that violated the maximum residue limit of 5.0 ppm. Eight samples of baby food tested positive for THPI at levels ranging from 0.019-0.041 ppm by the GC/MS method, whereas 20 samples tested positive in the ELISA assay. All samples that tested positive with the GC/MS method also tested positive with the ELISA method. Thirteen percent of the baby food samples tested false positive with the ELISA method. The ELISA assay also gave higher values than the GC/MS method. The ELISA method can be effectively used as a primary screening tool to select samples testing positive for THPI. The concentration of THPI in these samples can then be verified using the GC/MS method.

Enzyme immunoassay for determination of peanut proteins in food products.

Food allergy presents a problem for many parts of society, including sensitive subjects, schools, health authorities, and the food industry. Once food allergy is diagnosed, dietary avoidance is the principle method of management. Because trace levels of peanuts can elicit an adverse to fatal reaction, unintentional exposure to the offending allergens may have devastating consequences to sensitive individuals. However, determination of trace amounts of unintentional peanut contamination in our food supply is very difficult. Recently, we developed polyclonal antibodies specific to peanut proteins that do not cross-react with 22 legumes, tree nuts, or other common snack ingredients. An antiserum containing the polyclonal antibodies was used to develop a sensitive enzyme-linked immunosorbent assay (ELISA) for determination of peanut proteins in snack foods. This study reports the first successful ELISA test to detect trace amounts of peanut allergens in a variety of foods. The concentration of peanut protein that inhibited 50% of antibody-antigen binding (IC50) was 12 ng/mL, the linear range was 1-63 ng/mL, and the detection limit was 400 ng/g (ppb) for the various foods tested. Recoveries ranged from 68 to 90%, with coefficients of variation of 2-22%, depending on the commodity. Using this new procedure, allergy-related complaint samples from various food groups were analyzed, and undeclared peanut proteins were identified in some products.